Rehabilitation Evidence

Spinal Cord Injury is a complex condition affecting many different areas of health (click on your area of interest to the left).

Members of the SCIRE Team have reviewed and rated the scientific research on SCI rehabilitation to make quality information more available and ultimately improve the health of people living with SCI.

In using SCIRE:

Aging

Mortenson WB, Sakakibara BM, Miller WC, Willms R, Hitzig SL, Eng JJ (2014). Aging Following Spinal Cord Injury. In Eng JJ, Teasell RW, Miller WC, Wolfe DL, Townson AF, Hsieh JTC, Connolly SJ, Noonan VK, Loh E, McIntyre A, editors. Spinal Cord Injury Rehabilitation Evidence. Version 5.0. Vancouver: p 1- 91. 


Abbreviations

25(OH)-D        hydroxyvitamin D

AB                   able-bodied

AIS                  ASIA Impairment Scale

AN                   anemia

BCM                body cell mass

BEE                 basal energy expenditure

BMC                bone mineral content

BMD                bone mineral density

BMI                  body mass index

CAC                coronary artery calcium

CHD                coronary heart disease

CRP                C-reactive proteins

CTT                 colorectal transit time

CSA                 cross-sectional area

DBP                 diastolic blood pressure

DPA                 dual photon absorptiometry

DXA / DEXA    dual-energy X-ray absorptiometry

ECM                extra-cellular mass

ECW                extra-cellular water

FBG                 fasting blood glucose

FEV1               forced expiratory volume in 1 second

FFM                 fat-free mass

FIM                  functional independence measure

FM                   fat mass

FVC                 forced vital capacity

GITT                gastrointestinal transit time

HA                   hypoalbuminemia

HDL                 high density lipoprotein

hGH                 human growth hormone

IGF-1               insulin-like growth factor 1

LBM                 lean body mass

LDL                 low density lipoprotein

LH                   luteinizing hormone

MRI                 magnetic resonance imaging

MSK                musculoskeletal

OGTT              oral glucose tolerance test

PH                   plasma homocysteine

PL                    plasma leptin

pQCT              peripheral quantitative computed tomography

PSA                 prostate specific antigen

PTH                 parathyroid hormone

REE                 resting energy expenditure

SBP                 systolic blood pressure

SDB                 sleep disordered breathing

sEMG              surface electromyography

SHBG              sex hormone binding globulin

SmC                somatomedin C

SMR                standardized mortality ratio

SRP                 self reported health

T3                    triiodothyronine

T4                    thyroxin

TBK                 total body potassium

TBM                total bone mass

TBW                total body water

TC                   total cholesterol

TG                   triglycerides

US                   ultrasound

UTI                  urinary tract infection

QoL                 quality of life

YPI                  years post-injury

Introduction

Life expectancy following spinal cord injury (SCI) has increased steadily in the past few decades, and is approaching that of the able-bodied population (Geisler et al. 1983; Whiteneck et al. 1992; Hartkopp et al. 1997; McColl et al. 1997; Frankel et al. 1998; DeVivo et al. 1999; Yeo et al. 1998; Krause et al. 2004). Due to advances in emergency, acute, and rehabilitation treatments, persons with SCI are now living many decades post-injury. There are increasing numbers of persons with long-term SCI who are over 55 years of age (Adkins 2001).

Initially, SCI was considered a relatively stable condition, and persons with SCI were thought to be able to maintain the same functional level for most of their lives (Trieschmann 1987). However, this static view of aging with SCI has been replaced by one that acknowledges that aging is a multi-dimensional and complex process of physical, psychological, and social change (Aldwin & Gilmer 2004).

McColl and colleagues (2002) described five changes that persons with SCI undergo as they age: 1) the effects of living with SCI long-term (e.g. shoulder pain, chronic bladder infections); 2) secondary health conditions of the original lesion (e.g. post-traumatic syringomyelia); 3) pathological processes unrelated to the SCI (e.g. cardiovascular disease); 4) degenerative changes associated with aging (e.g. joint problems); and 5) environmental factors (e.g., societal, cultural) that may potentially complicate the experience of aging with a SCI.  All of these factors have the potential to compromise a person with SCI’s ability to sustain independence and ability to participate in their communities at later stages in life. 

Chronological Age, Years Post-Injury, and Age at Injury

One problem with research on aging after SCI is that the relationship between age at injury, current chronological age, and years post-injury (YPI) are all linearly dependent. This limits the ability to assess the influence of all three factors at the same time statistically (Adkins 2001). Hence, investigators are limited to examine only three possible combinations of factors, which include: 1) current age and YPI; 2) current age and age at injury; and 3) age at injury and YPI.  Furthermore, historical changes in the treatment and rehabilitation of SCI, increases the complexity of the assessment of aging effects associated with this condition (Adkins 2004). 

Despite these issues, the field continues to strive to attribute changes in health and wellbeing to these aging variables.  Thompson and Yakura (2001) comment that, “developing an understanding of the effect of advancing age versus longer durations of injury on the incidence and type of changes can help in the prediction of when people with SCI might be susceptible to changes in function” (p. 73).  This information can inform the creation of better health promotion strategies to mitigate declines in health and wellbeing since even slight changes in functioning after SCI can adversely affect a person’s level of independence.

Spinal Cord Injury: A Model of Premature Aging?

SCI has been described as a model of premature aging (Bauman & Spungen 1994).  According to this theory, premature aging of certain body systems may occur because additional stresses, resulting from SCI, can exceed the capacity of those body systems to repair themselves (e.g., cardiovascular, musculoskeletal) (Charlifue & Lammertse 2002). Although the aging process occurs at varying rates and at different ages for each individual (Charlifue 1993), it is generally accepted that bodily functions reach a maximum capacity prior to or during early adulthood, and then begin a gradual decline. This decline is thought to commence at approximately 25 years of age when the developmental process plateaus and biological capacity has peaked (Capoor & Stein 2005).  A classic study published in Science (Strehler & Mildvan 1960) used mathematical models to show that physiological function declines at a consistent rate of 0.5-1.3% per year beyond age 30.  This physical peak can be measured by examining the functioning of individual organ systems. For example, we can assess cardiovascular capacity by how well the heart can pump blood.  Similarly, we can assess the individual’s maximum functional capacities (e.g. how much weight an individual can lift).  Hence, the average person at age 70 has approximately 50% of his/her capacity remaining in each organ system, which does not necessarily impact negatively on health or functioning since all organ systems have an ‘excess reserve’ (i.e., more cells, structure and supportive tissue than is required to meet daily life needs; Adkins 2004).

When reserve capacity declines below 40% of original functioning, there is greater chance of becoming injured, and/or more susceptible to infection or disease (Kemp & Thompson 2002).  With the occurrence of a SCI, physiological and functional changes potentially accelerate bodily declines for a period of time, after which the effect of aging is thought to proceed at a normal rate (Adkins 2004).

Age of injury may have important consequences on different aspects of health.  Because there are increasing numbers of seniors incurring a SCI due to falls, a bi-modal age-of-onset distribution exists, with the prevalence of SCI peaking among individuals who are 30 and 60 years of age (Pickett et al. 2006).  As a result, researchers have been able to investigate and compare age-related outcomes after SCI.  For example, there are a number of studies showing that persons who incur a SCI at later ages have poorer functional outcomes than those injured at younger ages (DeVivo et al. 1990; Alander et al. 1994; Alander et al. 1997; Scivoletto et al. 2004), although in some instances, the impact of SCI may be minimized in older persons. 

Within a reserve capacity model of biological aging that is disrupted by SCI, Adkins (2004) theorizes that the impact of injury “decreases the further out on the age continuum the injury occurs” (p. 5).  However, if the injury occurs far enough along the continuum, then even a minimal change in rate will lower reserve capacity below 40% soon after injury since capacity is already low.   Further, adults with older ages of SCI-onset may have other pre-existing or vulnerabilities to co-morbidities that affect outcomes compared to younger adults (Furlan et al. 2009). 

Given the increasing mean age of SCI onset, along with increased life expectancy, it may be possible to identify changes to systems that are 1) attributed to the SCI, 2) related to chronological age and the aging process, and 3) caused as a result of their interaction.  Adkins (2004), however, suggests that it may be prudent to establish age of onset exclusion criteria when studying biological aging with SCI.  In addition, completeness and neurological level of SCI must also be taken into account since a person with a complete lesion may experience aging in a different manner than someone with an incomplete lesion (Charlifue 1993).

Aging and Quality of Life                                       

Although some biological changes are unavoidable with aging, other aspects are more malleable. Unlike physical aging, it may be that these aspects of a person’s life may actually improve, and may be more amenable to intervention to either delay, modify or eliminate their potential negative impact (Charlifue & Lammertse 2002). There are a multitude of factors that must be considered when evaluating how people age with SCI, including personality traits, economic factors, environmental barriers and facilitators, cultural issues, and social networks (intimate and remote) (Charlifue & Lammertse 2002). Given the complex interaction among these factors, it is not surprising that several studies report contradictory findings, with life satisfaction and community integration decreasing with age, but increasing with years post-injury (YPI; i.e. Eisenberg & Saltz 1991; Krause & Crewe 1991; McColl & Rosenthal 1994; Pentland et al. 1995; Westgren & Levi 1998; Dowler et al. 2001; Tonack et al. 2008).  To ensure that people with SCI are not only living long, but that they are also living well, it is important to identify factors that lead to higher levels of quality of life that would be amenable to intervention.

Chapter Purpose

The chapter summarizes some key issues in the SCI aging literature, and evaluates the level of evidence provided by selected studies on aging with SCI.  The selected research for evaluation includes longitudinal studies (duration of at least 2 years or more), case-control and cross-sectional comparative studies that focus on analyses relevant to aging. As longitudinal studies inherently include at least a baseline and follow-up evaluation, these studies were graded with a level of evidence of 4 (at least equivalent to pre-post studies).  Prospective longitudinal studies that also included a control group (e.g., able-bodied group) were graded with a level of evidence of 2 as they are considered cohort studies where one group is exposed to a particular condition (in this case, a spinal cord injury). Longitudinal studies that included historical controls (from chart review or database) were graded with a level of evidence of 3. Comparative studies utilizing both individuals with SCI and able-bodied controls at one point in time were graded with a level of evidence of 5.  Studies involving mixed populations in which < 50% of the subjects had a SCI were excluded as were articles not in English. As well, studies with small sample sizes (less than 5 SCI participants) and/or with limited age ranges (i.e., only persons in their twenties and/or early thirties, etc.) were excluded.

Although the use of longitudinal designs is preferred, comparison studies with age-matched able-bodied (AB) controls is a useful approach for studying aging after SCI because it provides some awareness of the factors associated with the typical aging process (Charlifue 1993), while helping to illuminate whether changes are due to YPI rather than current age per se. After sustaining a SCI, age and YPI increase at the same pace, and so using age-matched AB controls allows us to determine the effects that might have occurred without SCI and those that occurred with SCI (Adkins 2004). This approach may offer some insight on whether changes after SCI are unique and/or accelerated in persons with SCI or if they are typical of the aging process.

The issues related to aging are described as mortality and life expectancy (see Table 1), physiological aging, which includes health status and physical functioning (see Table 2), the cardiovascular and endocrine systems (see Table 3), immune system (see Table 4), musculoskeletal system (see Table 5), respiratory system (see Table 6), nervous system (see Table 7), skin and subcutaneous tissues (see Table 8), the genitourinary and gastrointestinal systems (see Table 9), secondary health complications (see Table 10 & 11), functional independence (see Table 12 & 13), and quality of life and community reintegration (see Table 14 & 15).

Mortality and Life Expectancy

Survival rates for individuals with SCI have made steady improvements over the past five decades. Prior to World War II life expectancy for individuals with SCI was quite poor (Geisler et al. 1983). Leading causes of death were those resulting from renal failure and infection (Lammertse 2001).  Since the introduction of antibiotics, improved emergency transportation, advances in long-term health interventions, and the availability of preventative care at specialized treatment centres, mortality rates have been steadily decreasing and the causes of death have begun to mirror those of the general population (Whiteneck et al. 1992; DeVivo et al. 1999). However, life expectancy is still diminished compared to the general population (Whiteneck et al. 1992; Hartkopp et al. 1997; McColl et al. 1997; Frankel et al. 1998; DeVivo et al. 1999; Yeo et al. 2000; Krause et al. 2004). 

Causes of death among individuals with SCI and those in the general population appear to be similar. In 2011, the two leading causes of death in high- and middle-income countries for the general population were ischemic heart disease and stroke (WHO 2011).  Other common causes were tracheal bronchus and lung cancers, chronic obstructive pulmonary disease, lower respiratory infections, and Alzheimer’s disease and other dementias (WHO 2011). Similarly, two leading causes of death in the SCI population are respiratory complications and heart disease (Hartkopp et al.1997; Frankel et al.1998; DeVivo et al. 1999; Soden et al. 2000; Zeilig et al. 2000; Garshick et al. 2005).  Additionally, the latest report from the National Spinal Cord Injury Database (NSCIDB) indicates the main causes of death in persons with SCI in the United States are pneumonia and septicemia (NSCISC 2013).  The high rates of cardiovascular disease in the SCI population may be partly due to physiological and functional changes following injury (Dearwater et al. 1986; Yekutiel et al. 1989; Bauman et al. 1992a, b; Gupta 2006). Interestingly, cancer is a growing cause of death in persons with SCI (DeVivo et al. 1999; Zeilig et al. 2000; Imai et al. 2004).

In general, it appears that as individuals with SCI age, cause of death becomes similar to age matched controls (Capoor & Stein 2005).  Some deaths, however, may occur prematurely (e.g., from cardiovascular disease; Yekutiel et al. 1995), and there are some notable differences in mortality patterns between the SCI and the general populations.

In this section, 5 longitudinal studies and 1 cross-sectional study (see Table 1) on mortality and life expectancy among individuals with spinal cord injury are reviewed.

Table 1:  Mortality and Life-Expectancy

Discussion

Rabadi et al. (2013) reported a 10-year survival rate of 87% from time of injury and a mean age of injury of 39. Pickelsimer and colleagues (2010) reported a 10-year survival rate of 84.5% from time of injury with a mean age of injury of 41 and excuded those that died in the first 89 days.  

Although Samsa et al. (1993) found that injury level was not a significant predictor for mortality, they noted a near significant effect (p=0.06) for complete cervical injuries compared to all other injuries. Similarly, in an 11-year longitudinal study, Cao et al. (2013) reported the likelihood of death in individuals with injuries at the C1-4 levels to be 1.6 times greater than for individuals with injuries at other levels. Several studies have found no association between impairment and mortality (e.g. Liang et al. 2001; Imai et al. 2004; Garshick et al. 2005), whereas other studies have highlighted the importance of impairment as a prognostic factor (Whiteneck et al. 1992; McColl et al. 1997; Coll et al. 1998; DeVivo et al. 1999; Soden et al. 2000; Yeo et al. 2000; Strauss et al. 2006).  Samsa and colleagues (1993) found age of onset to be a significant predictor of long-term survival, which is consistent with other longitudinal studies that did not meet our inclusion criteria (Whiteneck et al. 1992; Frankel et al. 1998).  Rabadi et al. (2013) reported age of onset to be the only predictor of mortality.

With regards to causes of mortality, Samsa et al. (1993) found that diseases of the genitourinary system (i.e. renal failure, septicemia) disproportionately accounted for death in their SCI sample, but the patterns of death began to approach that of the general population by 20 years post-injury.  For instance, the rates of circulatory disease and neoplasms steadily increased across time points.  Interestingly, the causes of death due to injury and poisoning, and external conditions were the highest at 3-months to 5 years post-SCI, and steadily decreased across time points.  In a 12-year longitudinal study of 147 veterans with SCI, Rabadi et al. (2013) reported infection, cardiovascular, and cancer to be the three primary causes of death.  Although not discussed, causes of death may have also included suicides.  Regardless, the findings of lower levels of evidence highlighting the high rates of suicide as a cause of death (i.e. Imai et al. 2004) reinforces the need to provide psychosocial services to help minimize the occurrence of suicide in persons with SCI.  

An acknowledged limitation of the study by Samsa et al. (1993) is the reliance on secondary data sources for case identification, control selection, and mortality assessment.  The study was also only on male veterans and did not include women or persons who did not survive acute SCI (i.e. less than 3 months post-SCI).Causes of death were not reported by Pickelsimer et al. (2010) or by Savic et al. (2010).

Conclusion

There is level 4 evidence that the 10 year survival rate post injury is 84-87% (Rabadi et al. 2013; Pickelsimer et al. 2010).

There is Level 4 evidence (Frisbie 2010) that the mortality rate post-SCI over a 10-year period may be 15.5% to 25.8%, and level 4 evidence (Cao et al. 2013) that the mortality rate is higher for individuals with SCI than the general population.

There is Level 4 evidence (Cao et al. 2013) that mortality may be higher for persons with SCIs at the C1-4 level than other spinal cord levels.

There is Level 4 (Frisbie 2010) to Level 5 evidence (Samsa et al. 1993) that the causes of death post-SCI are beginning to approximate those of the general population.

There is Level 4 and 5 evidence (Samsa et al. 1993; Cao et al. 2013) that life expectancy for males with SCI is lower than the general male population.

There is level 4 evidence (Rabadi et al. 2013) that older age at time of injury is a predictor of SCI-related mortality.

  • Life expectancy for males with SCI is likely lower than the general male population.

    Persons injured at a younger age will likely have a longer life expectancy than persons injured at an older age.

    Causes of death post-SCI may be similar to those of the general population.

Physiological Aging

Aging is a highly complex phenomenon that can be examined at the genetic, cellular, organ-system, and psychosocial levels (Aldwin & Gilmer 2004).  Although there are some conflicting evidence on which systems decline, for the most part, persons aging with SCI exhibit decreases in health status and physical functioning over time (see Table 2), which could serve as markers of premature aging. 

In this section, 1 systematic review (see Table 2) on physiological aging after SCI is reviewed.

Table 2: Systematic Review on Physiological Aging

Discussion

In this systematic review (Hitzig et al. 2011), the hypothesis that SCI represents a model for premature aging is supported by level 5 evidence for the cardiovascular and endocrine systems, level 2, 4 and 5 evidence for the musculoskeletal system, and limited level 5 evidence for the immune system. Only a few level 4 and 5 studies for the respiratory system were found. Evidence on the genitourinary system, gastrointestinal system, and for skin and subcutaneous tissues provide level 4 and 5 evidence that premature aging may not be occurring in these systems.

  • SCI may represent a partial model for premature aging.

    There is stronger evidence that the endocrine and musculoskeletal systems are prematurely aging.

    There is limited evidence that the respiratory, skin and subcutaneous tissues, genitourinary, and gastrointestinal systems are prematurely aging.

    There is weak and limited evidence that the immune and nervous system are prematurely aging.

The following sections review each body system individually, including the cardiovascular and endocrine systems (see Table 3), immune system (see Table 4), musculoskeletal system (see Table 5), respiratory system (see Table 6), nervous system (see Table 7), skin and subcutaneous tissues (see Table 8), and the genitourinary and gastrointestinal systems (see Table 9).

Cardiovascular and Endocrine Systems

Similar to the general population, cardiovascular disease has become one of the leading causes of death in the SCI population (DeVivo et al. 1989; DeVivo et al. 1993; Frankel et al. 1998).  There are multiple risk factors for its premature development due to physiological and functional changes following SCI (Bauman et al. 1994; Bauman & Spungen 2001a; Bauman & Spungen, 2001b).  For instance, many age-associated disorders such as carbohydrate intolerance, insulin resistance (Duckworth et al. 1980; Duckworth et al. 1983; Bauman et al. 1992a; Karlsson 1999) and lipid abnormalities (LaPorte et al. 1983; Brenes et al. 1986; Bauman et al. 1992b; Bauman & Spungen 2001a) are known to occur prematurely in persons with SCI.  Some have hypothesized that a marked decrease in physical activity (Myers et al. 2007), along with injury-related changes in metabolic function lead to an increased risk and premature development of cardiovascular disease (Bravo et al. 2004) and diabetes mellitus (Bauman et al.1992a). 

Related to the metabolic changes noted above, there is a high prevalence of muscle weakness in persons with SCI attributed to a loss of lean body mass (Thompson & Yakura 2001) that is possibly linked to reduced activity, and abnormally low levels of endogenous anabolic hormones (i.e., human growth hormone and testosterone; Bauman et al. 1994).  In the general population, age-related declines in the endocrine systems also lead to decreases in lean muscle mass and an increase in fat (Tenover 1999).  However, these declines have been shown to be greater in persons with SCI (Bauman & Spungen 2001b).  Similarly, noted changes in insulin resistance are thought to account for the high rates of diabetes mellitus in persons with SCI (Yekutiel et al. 1989).  This in turn leads to an increased risk for cardiovascular disease since the development of diabetes impairs the circulatory system (Halter 1999).  As such, it may be that alterations in body composition, which occur early following SCI, contribute to premature development of these disorders as compared to the AB population (Bauman et al. 1994).  With some of the literature below, young adults with SCI are compared to young adults without SCI. Thus, aging effects due to SCI may be a factor when changes in the cardiovascular and endocrine systems occur in these young adults with SCI that would be typically expected to occur in older adults (e.g. characteristics associated heart disease such as poor lipid profiles, elevated glucose, high BMI).  However, it is not always possible to disentangle mechanisms involving premature aging versus direct effects on the organs from the SCI itself.

In this section, 3 longitudinal studies and 26 cross-sectional studies (see Table 3) on cardiovascular and endocrine systems after SCI are reviewed.

Table 3: Cardiovascular and Endocrine Systems

Discussion

Cardiovascular System

In this section, the evidence reviewed appears to support the notion that the cardiovascular system is prematurely aging.  With regard to risk factors for cardiovascular disease, Bauman and colleagues (2001a) found that regardless of age or sex, persons with SCI had significantly higher levels of plasma homocysteine than able bodied (AB) controls, and that older persons with SCI (>50 years) had higher levels than younger persons with SCI.  Plasma homocysteine is thought to promote coagulation and to decrease the resistance of the endothelium to thrombosis (Malinow 1994), and is a clear independent marker for the prediction of vascular disease (Clarke et al. 1991; Stampfer et al. 1992).  The findings regarding lipid profiles also support an increased risk for the development of cardiovascular disease.  Several studies (Demirel et al. 2001; Zlotolow et al. 1992; Bauman & Spungen 1994; Bauman et al. 1995; Bauman et al. 1999; Liang et al. 2007; Wang et al. 2007) found that serum high-density lipoprotein cholesterol (HDL-c) are depressed in persons with SCI compared to AB controls, which is associated with an increased risk for developing coronary heart disease (Goldbour & Medalie 1979; Castelli 1984). 

An important factor influencing these variables might be lifestyle.  For instance, one longitudinal study (Shiba et al. 2010) on athletes with SCI (N = 7) found that physical capacity was maintained over a span of two decades.  The results of this study, however, are limited to individuals participating in strenuous sport activities, a sample that is not representative of the general SCI population (Maki et al. 1995). Although no blood pressure changes were noted, the sample did have a significantly higher BMI from baseline to 20-year follow-up.  Unfortunately, data on lipid profiles were not collected in this study.  Further work on the role of diet and physical activity is needed to help clarify their impact on aging with SCI.

One study provides evidence that C-reactive protein levels were higher in men with SCI (N = 62) compared to AB controls (N = 29), which could also account for the decreases in total cholesterol, low-density lipoprotein and high-density lipoprotein.  At the same time, increases in C-reactive protein levels may also partly explain why persons with SCI are nonetheless at increased risk for accelerated atherogenesis (Wang et al. 2007).  A risk factor for vascular disease in both symptomatic (Budoff et al. 2005) and asymptomatic (Raggi 2000) populations is coronary artery calcification (CAC), which is a component of atherosclerotic plaque.  Orakzai and colleagues (2007) found significantly higher levels of CAC in persons with SCI (N = 82) compared to AB controls (N = 273), and that the risk was higher for males and for persons with tetraplegia.

Sustaining a SCI also affects blood pressure by altering the sympathetic activity to blood vessels.  There is evidence that men with tetraplegia (Yamamoto et al. 1999) and paraplegia (Petrofsky & Laymon 2002) have increased blood pressure responses during exercise compared to AB controls.  As well, Petrofsky and Laymon (2002) found that their group with paraplegia had a larger change in blood pressure both at rest and during exercise and was more associated with aging than for the controls.  Disturbingly, static exercise has been found to cause tachycardia in AB controls, but not in persons with SCI (Petrofsky & Laymon 2002; Orakzai et al. 2007) when paralyzed muscles were engaged.  Several studies highlight that irregular blood pressure responses post-SCI have significant implications for cardiovascular health (Bluvshtein et al. 2011; Groothuis et al. 2010a; Groothuis et al. 2010b; La Fountaine et al. 2010; Yasar et al. 2010). Overall, these findings are indicative of altered autonomic control, but not necessarily of aging.  Further work is needed to determine the long-term implications for cardiovascular health.

Decreases in physical activity may contribute to the development of cardiovascular disease, which may be reflected in body composition changes following SCI.  Two longitudinal studies from the same author (de Groot et al. 2010; 2013) found that body mass index (BMI) increases over time in individuals with SCI. In the de Groot et al. (2010) study of 184 individuals, BMI was observed to significantly increase the year after discharge from in-patient rehabilitation.  In the de Groot et al. (2013) study of 130 individuals, BMI was observed to increase from discharge to a 5-year follow up. Individuals in this study, however, showed no change in their lipid profie over the 5 years of observation.  Similar BMI findings have been reported by Crane and colleagues (Crane et al. 2011). However, studies comparing BMI between individuals with SCI and AB individuals have demonstrated mixed results.  One study (Spungen et al. 2000) found greater BMI levels in persons with SCI compared to AB controls, whereas other studies found the opposite (Bauman et al. 1999; Bauman et al. 2004; Wang et al. 2007), or no differences at all (Zlotolow et al. 1992; Jones et al. 2003; Bauman et al. 1996). 

Given these contradictory findings, BMI may not be an appropriate measure for SCI since studies that also examined lean and fat mass tissue (Bauman et al. 1996; Bauman et al. 1999; Spungen et al. 2000; Bauman et al. 2004; Jones et al. 2004) found that persons with SCI had significantly higher levels of fat mass tissue and lower levels of lean tissue than AB controls.  These differences in lean and fat mass tissue appear to be attributable to YPI, and not age.  For instance, Spungen et al. (2000) found lower lean mass and higher fat mass in persons with SCI who were matched with their AB monozygotic twin, which was directly related to YPI.  As well, Bauman and colleagues (2004) concluded from their monozygotic SCI twin study that reductions in lean muscle tissue lead to reduced energy expenditure, which appeared to be related – albeit not significantly – to YPI.  These findings are congruent with SCI-only cross-sectional studies examining body composition (Cardus & McTaggart 1985; Shizgal et al. 1986; Rossier et al. 1991).

The findings from a cross sectional study (Hosier et al. 2012) comparing cardiometabolic risk profiles in pre and post-menopausal women reported that post-menopausal women with SCI have higher triglycerides, total cholesterol, and low density lipoprotein than pre-menopausal women. No differences were observed in BMI or glycemic indices. The authors suggest that post-menopaual women with SCI have risk profiles that are similar to those observed in women without SCI, characterized by increases in triglycerides, total cholesterol, and low density lipoprotein, despite favorable BMIs and glycemic indices.

Endocrine System

Metabolic changes after SCI may also be associated with changes in body composition, and may increase the risk of developing diabetes mellitus.  Tsitouras and colleagues (1995) posited that impaired hGH secretion may be partially responsible for SCI- and aging-associated lean body and muscle mass depletion.  Several identified studies (Shetty et al. 1993; Bauman et al. 1994; Tsitouras et al. 1995) provide evidence that serum IGF-I levels are lower in persons with SCI compared to age-matched controls, and that this depletion is associated with impaired hGH.  Bauman et al. (1994) found that the average IGF-I was significantly lower in younger individuals with SCI than that in younger AB controls, but not in those greater than 45 years of age.  As such, this pattern of IGF-I levels in younger males with SCI appears to be similar to those of elderly AB individuals (Bauman et al. 1994). 

Related to this, Bauman and Spungen (1994) found that persons with SCI had a higher mean glucose and insulin levels, and lower mean fasting plasma glucose levels than the AB control group.  This intolerance was found to be present in two-thirds of their group with tetraplegia, and in half their group with paraplegia.  Further, 22% of the persons with SCI met the diagnostic criteria for having diabetes mellitus, whereas only 6% of the AB controls were found to be diabtetic.  Since these adverse clinical features occurred at younger ages in their SCI sample, Bauman and Spungen (1994) interpreted their findings as being a model of premature aging.  The findings of Jones and colleagues (2004), and LaVela and colleagues (2006) appear to support this hypothesis as they both found higher rates of metabolic syndrome and diabetes in their SCI samples compared to the AB population. Conversely, Liang et al. (2007) found that males with SCI (N = 185) were not at higher risk for metabolic syndrome compared to AB controls (N = 185).  This discrepancy may be due to some of the study’s limitations (i.e. reliance on self-report height and weight to calculate BMI) and because they used a standard, rather than a modified, criteria for the syndrome which is not appropriate for persons with SCI. 

The predisposition to diabetes and lipid abnormalities is thought to be largely a consequence of extreme inactivity, and the constellation of metabolic changes (i.e. human growth hormone deficiency, testosterone deficiency) appears to be occurring prematurely in persons with SCI (Bauman & Spungen 1994). As well, several studies have shown evidence of thyroid impairment after SCI compared to the AB population (Wang et al. 1992; Huang et al. 1993; Cheville & Kirshblum 1995).All of these findings suggest that persons with SCI may be frequently physiologically comprised, and more susceptible to minor pathologic insults.  Along with associated changes in body composition, an increased risk for the development of cardiovascular disease, diabetes mellitus, and infection is higher following SCI (Bauman & Spungen 2001b).

Conclusion

There is Level 5 evidence from one cross-sectional study (Bauman & Spungen 2001a) that plasma homocysteine levels are higher in persons with SCI compared to the AB population, with the greatest discrepancy in older adults with SCI (> 50 years).

There is Level 5 evidence from nine cross-sectional studies (Zlotolow et al. 1992; Huang et al. 1993; Bauman & Spungen 1994; Bauman et al. 1996; Huang et al. 1998; Bauman et al. 1999; Demirel et al. 2001; Liang et al. 2007; Wang et al. 2007) that lipid profiles are altered after SCI which may contribute to the development of cardiovascular disease. 

There is Level 4 evidence (Shiba et al. 2010) that physical capacity can be maintained long-term in male athletes with SCI.

There is Level 4 evidence from one longitudinal study (de Groot et al. 2013) that lipid profiles in adults with SCI remain stable during the 5 years after inpatient rehabilitation.

There is Level 4 evidence (Apstein & George 1998) that total cholesterol (TC), total glycerides (TG), and low-density lipoproteins (LDL) increased while LDL/high-density lipoproteins (HDL) ratios decreased for males with tetraplegia and paraplegia from the acute phase until 1 YPI.  All lipid profiles were significantly depressed compared to controls.

There is Level 4 evidence (Apstein & George 1998) that persons with tetraplegia had low HDL and elevated LDL/HDL ratios, which places them at an increased risk for coronary artery disease.    

There is Level 5 evidence (Wang et al. 2007) that C-reactive protein levels are higher in males with SCI, which could also account for the decreases in TC, LDL, and HDL.  Elevated C-reactive protein levels may also partly explain why persons with SCI are at increased risk for accelerated atherogenesis.  

There is Level 5 evidence (Orakzai et al. 2007) that persons with SCI have greater atherosclerotic burden compared to an AB reference population.

There is Level 5 evidence from two studies that men with complete paraplegia (Petrofsky & Laymon 2002) and with complete Tetraplgia (Yamamoto et al. 1999) have an abnormal (absent) heart rate response to isometric exercise.

There is Level 5 evidence that men with complete tetraplegia demonstrate increased blood pressure (Yamamoto et al. 1999) response to isometric contraction.

There is Level 5 evidence (Wang et al. 1992: 63 men; Tsitouras et al. 1995; Shetty et al. 1993) that there is lower secretion of testosterone and human growth hormone levels in men with SCI compared to AB controls.

There is Level 5 evidence from two studies (Tsitouras et al. 1995; Bauman et al. 1994) that serum IGF-I levels are impaired in persons with SCI compared to the AB population, which may be a sign of premature aging.

There is Level 5 evidence from three studies (Bauman & Spungen 1994; Jones et al. 2004; Liang et al. 2007) that glucose tolerance is impaired after SCI, which may lead to an increased risk for premature diabetes mellitus.

There is Level 5 evidence (LaVela et al. 2006) that diabetes mellitus occurs prematurely in male veterans with SCI compared to AB individuals in the general population, but not veteran controls.

There is Level 5 evidence (Lewis et al. 2010) that men with SCI have slower plasma-free cortisol responses than AB controls.

There is Level 4 evidence from three longitudinal studies (de Groot et al. 2010 & 2013; Crane et al. 2011) that BMI increases significantly over time in persons with SCI.

Seven studies (Nuhlicek et al. 1988; Bauman et al. 1996; Bauman et al. 1999; Spungen et al. 2000; Jones et al. 2003; Jones et al. 2004; Emmons et al. 2011) provide Level 5 evidence that persons with SCI are likely to have higher levels of fat mass, and that age-related declines of lean tissue in males with SCI may occur at a significantly faster rate than the AB population.

There is Level 5 evidence from one monozygotic twin study (Bauman et al. 2004) that basal and resting energy expenditures are lower in males with SCI compared to their AB twin.

There is Level 5 evidence from one cross-sectional study (Hosier et al. 2012) that post-menopaual women with SCI have cardiometabolic risk profiles that are similar to those observed in women without SCI.

  • Greater levels of arthersclerotic burden, higher levels of C-reactive protein levels and abnormal lipid profiles compared to the able-bodied population increases the risk for the development of cardiovascular disease in persons with SCI.

    Men with complete SCI have abnormal heart rate and blood pressure responses to isometric exercise compared to able-bodied controls, which are indicative of altered autonomic control, but this may not represent premature aging.

    Impaired secretion of both testosterone and human growth hormone in men with SCI may be due to SCI, and not from advancing age per se.

    Serum IGF-I levels may be impaired compared to the able-bodied population, which may be a sign of premature aging.

    Glucose tolerance and slower plasma-free cortisol responsesmay be impaired in persons with SCI, which may lead to an increased risk for premature diabetes mellitus.

    Persons with SCI are at higher risk for the development of cardiovascular disease and diabetes mellitus than the able-bodied population.

    Persons with SCI may have higher levels of fat mass than the able-bodied population. Although BMI increases over time in people with SCI, an active lifestyle may help to preserve physical capacity.

    Age-related declines of lean tissue in males with SCI may occur at a significantly faster rate than the able-bodied population.

    Age of onset may not influence hematologic abnormalities at the acute phase post-SCI (within first week post-injury).

Immune System

Although the immune system is affected by a number of factors, including nutritional status, stress, exercise, neuroendocrine change, and disease, there is consensus that immune functioning undergoes some age-related declines (Miller 1996; Burns & Leventhal 2000; Rabin 2000). There is limited evidence on the effects of SCI on the immune system with aging, but several studies (i.e., Lyons 1987; Nash 1994; Kliesch et al. 1996; Campagnolo et al. 1999; Cruse et al. 2000) suggest deficits in immune functioning.  Hence, there is greater likelihood of immune impairment in the aging SCI population compared to the non-disabled population (Charlifue & Lammertse 2002).

In this section, 1 longitudinal study and 4 cross-sectional studies (see Table 4) on the immune system after SCI are reviewed.

Table 4: Immune System

Discussion

One study provides level 4 evidence (Frisbie 2010) that persons with SCI have a high prevalence of anemia and hypoalbuminemia which might serve as markers for infection. Additionally, two studies provide level 5 evidence that this system is compromised at the acute and chronic stages of SCI compared with AB controls. Persons with acute and chronic SCI who have complete injuries (N = 5) demonstrated altered immune function compared to AB controls (Campagnolo et al. 1994).  As well, Campagnolo et al. (1999) compared persons with SCI (N = 18) to AB controls (N = 18), and found that persons with SCI have higher levels of cortisol and dehydroepiandrosterone sulfate (DS), but comparable levels of dehydroepiandrosterone, adrenocorticotropin, and prolactin.  Additionally, they found that DS and dehydroepiandrosterone were higher in persons with tetraplegia compared to controls, but no differences were found between persons with paraplegia and controls.  Campagnolo et al. (1999) concluded that immune functioning is altered after SCI, but may be mediated by level of injury.  Thus, persons with tetraplegia may have a greater degree of alteration to the immune system compared to persons with paraplegia.  Unfortunately, the sample sizes in both studies were quite small.

Further research related to the immune system is required given that older age of SCI-onset leads to poorer outcomes (Prusmack et al. 2006), and SCI of long duration results in increased infection (Whiteneck et al. 1992).  Because persons with SCI are treated with antiobiotics throughout their lives, there are a number of important questions regarding the long-term effects on the immune system (Adkins 2004).

Conclusion

There is Level 4 evidence that persons with SCI have a prevalence of anemia and hypoalbuminemia (Frisbie 2010), which might serve as markers for infection.

There is Level 5 evidence (Campagnolo et al. 1994; Campagnolo et al. 1999; Furlan et al. 2006) that the immune function of persons with acute and chronic SCI is compromised compared to the able-bodied population, but there is no influence due to aging.

  • Immune function after SCI at both the acute and chronic phase is compromised compared to able-bodied controls, but age may not play an important role.

Musculoskeletal System

The musculoskeletal (MSK) changes are the most obvious external signs of aging, as most people have some wear and tear on this system as they age (Aldwin & Gilmer 2004).  Changes in the MSK system after long-term SCI may lead to upper extremity pain (Waters et al. 1993), reduced strength due to muscle atrophy (Giangregorio & McCartney 2006), and an increased risk for fractures (Lazo et al. 2001). Hence, the complications associated with a degenerating MSK system hold serious implications in terms of functionality for the person aging with SCI.

In terms of bone health, peak bone mass is achieved by the age of 30 in the general population and then declines, but the rate of decline is affected by a number of factors such as age, gender, and lifestyle (e.g., smoking). Although the risk for osteoporosis and fracture are greater among post-menopausal women over the age of 65 in the general community (Goddard & Kleerekoper 1998), there is evidence for increased risk in the SCI population (Ingram et al. 1989; Garland et al. 1992; Lazo et al. 2001).  After sustaining a SCI, there are several reports of bone loss occurring in the early months following injury (Garland et al. 1992).  These losses are regional; areas rich in trabecular bone are demineralized to the greatest degree, with the distal femur and proximal tibia bones being the most affected, followed by the pelvis and arms (Garland et al. 2001a).  However, there is some evidence that there is a continual loss of bone mass with time since injury (Demirel et al. 1998; Bauman et al. 1999), which suggests that a steady state of lower extremity bone mineral homeostasis is not reached (Craven et al. 2014).  Assuming that the rate of bone loss in the aging SCI-population is similar to that of the non-disabled population, it is likely that the degree of osteoporosis will be much more severe since they will have less skeletal mass at the onset of typical age-related declines in bone mass (Waters et al. 1993). 

As a result of bone loss associated with SCI, there is an increased risk for fracture (Garland et al. 2001a; Craven et al. 2014).  After SCI, the most common areas at risk for fracture include the distal femur and proximal tibia, and are consistent with site-specific decreases in bone mineral density around the knee (Craven et al. 2014).  The majority of fragility fractures occur following transfers or activities that involve minimal or no trauma (Ragnarsson & Sell 1981). Individuals with SCI are more at risk for osteoporosis if they are older, and the time since injury is longer (Lazo et al. 2001).  However, it is BMD, and not age per se, that is the significant predictor for risk of fracture (Lazo et al. 2001).  Interestingly, the BMD of the spine is often maintained or actually increases (Garland et al. 2001a; Sabo et al. 2001).        

Although BMD of the spine after SCI does not appear to be affected by aging, there are other age-related changes to the spine. With age the spine undergoes degeneration, which may cause deformity or nerve root compression that produces symptoms of pain radiating into the extremities, loss of sensation and/or motor function (Waters et al. 1993). Age-related degenerative changes in the spine may severely impact individuals with SCI whose functional capacities are already limited (Waters et al. 1993).  Long-term SCI is associated with scoliosis and/orCharcot spine (progressive destruction of the spine and surrounding ligament leading to major spinal instability) (Sobel et al. 1985; Park et al. 1994; Krause 2000; Vogel et al. 2002; Abel et al. 2003). Age at injury, however, may also play a role as there is some lower level evidence that the odds of developing curvature of the spine is lower in persons who are older when injured (Krause 2000).

There are a variety of musculoskeletal changes associated with aging.  In the general population, there is degeneration in the joints of the upper and lower extremities, and common sites include the shoulder, knee, and hip (Waters et al. 1993).  As well, muscle atrophy is inevitable with age, although the rate of decline varies from person to person (Loeser & Delbono 1999).  These age-related changes may lead to joint pain, stiffness, restricted range of motion, or trauma (i.e. fracture) that would not typically occur in a younger person. As a result, independence when performing daily activities may be compromised due to restricted activities of daily living, mobility. Lack of mobility may also affect temperature regulation (Aldwin & Gilmer 2004).

In addition to bone loss (see section 2.2.1), persons with SCI experience muscle atrophy (Giangregorio & McCartney 2006), especially among muscles that are denervated from complete SCI (Lam et al. 2006).  In the lower extremities, muscle degeneration typically occurs around the knee in those who are capable of ambulation but have persistent gait abnormalities, which in turn may generate pathologic forces at the knee (Waters et al. 1993). Although persons who primarily utilize wheelchairs rarely develop clinically significant degenerative problems in the lower extremities, they are more likely to have problems in the upper extremities due to overuse of muscles needed to push their wheelchairs, to transfer, and perform weight-shift maneuvers to prevent pressure ulcers (Waters et al. 1993).

Upper extremity pain is common in persons with long-term SCI, and most frequently affects the shoulder and wrist (Sie et al. 1992; Thompson & Yakura 2001; Waters & Sie 2001), and typically increases with duration of injury (Sie et al. 1992; Ballinger et al. 2000; Waters & Sie 2001). The prevalence of shoulder pain in SCI ranges between 30-100% (Curtis et al. 1999) and is likely a consequence of increased physical demands and overuse (Nichols et al. 1979; Pentland & Twomey 1991). It is unclear, however, if these findings are independent of treatment era effects or are related to environmental changes in mobility technology, accessibility, and rehabilitation practices (Adkins 2004).

Losses in strength and diminished joint capacity along with joint degeneration due to overuse can negatively impact functional ability, which makes maintaining high levels of independence difficult. Since persons with SCI are operating at a near-maximum capacity but have a low reserve capacity, declines in functionality may occur prematurely (Thompson & Yakura 2001).

In this section, 12 longitudinal studies, 1 mixed longitudinal/cross-sectional study and 23 cross-sectional studies (see Table 5) on the musculoskeletal system after SCI are reviewed.

Table 5: Musculoskeletal System

Discussion

In general, the evidence (see Table 5) supports the notion that the musculoskeletal system undergoes obvious external signs of premature aging except for a few areas.  Many studies found that there was rapid bone loss, and particularly for the pelvis and lower limbs within the acute stage post-SCI (Garland et al. 1992; Biering-Sorensen et al. 1990; Wilmet et al. 1995; Dauty et al. 2000; de Bruin et al. 2000; Frey-Rindova et al. 2000; Garland et al. 2004; Frotzler et al. 2008, Dudley-Javoroski & Shields 2010; Dionyssiotis et al. 2011).  Further, this loss may be greater for females with SCI (Garland et al. 2001b) and is evident in both bone mineral density (BMD; amount of matter per cubic centimeter of bones) and content (BMC; bone mass).  Similarly, there are bone geometric changes (Finsen et al. 1992; de Bruin et al. 2000; Giangregorio et al. 2005) that occur, which may be independent of chronological age and YPI (Slade et al. 2005). 

Some of the findings are mixed with regards to the duration of decline. One study found that bone mass continues to decline throughout the chronic phase (Finsen et al. 1992), whereas another study reporting a rapid loss with stabilization after approximately 2 years (Dudley-Javorski & Shields 2010).  A cross-sectional study with AB controls (Eser et al. 2004) and a longitudinal analysis of the same cohort of persons with complete SCI (Frotzler et al. 2008) found that tibial and femoral bone geometry and density properties reach a new steady-state within 3-8 YPI, with the time frame depending on bone parameter and skeletal site.

The use of peripheral quantitative computed tomography (pQCT) is viewed as a superior approach for investigating changes in BMD and BMC compared to dual energy X-ray absorptiometry, DXA), but there are some unresolved issues with the use of this technology in people with SCI (Dudley-Javorski & Shields 2010).  A mixed cross-sectional and longitudinal study by Dudley-Javorski & Shields (2010) who used two approaches for studying declines in BMD via pQCT found BMD values of their SCI subjects (n = 15) fell below the lowest range of control values (n = 10), suggesting that subjects lost an average of 1.7% BMD per month within the first two years post-SCI.  However, their subjects (N=4) who were followed longitudinally starting at approximately 2 years demonstrated no BMD decline over time. There is a need to better understand anatomical variations related to bone adaptive processes in order to account for SCI-related bone losses (Rittweger et al. 2010).  As such, further refinement into bone assessment are needed to help clarify some of the mixed findings noted in the literature.

There are also a number of other factors that contribute to bone loss post-SCI.  For instance, endocrine changes may be contributing to the losses in bone density (Dauty et al. 2000; Szollar et al. 1998; Finsen et al. 1992; Vaziri et al. 1994; Bauman et al. 1995).  It is thought that altered bone structure and microarchitecture due to SCI (de Bruin et al. 2000; Eser et al. 2004; Giangregorio et al. 2005; Kiratli et al. 2000; Slade et al. 2005; Frotzler et al. 2008) leads to impaired calcium and phosphate metabolism and the parathyroid hormone (PTH)-vitamin D axis (Finsen et al. 1992; Vaziri et al. 1994; Bauman et al. 1995; Szollar et al. 1998; Dauty et al. 2000).  For instance, Bauman and colleagues (1995) noted that the reduction in the bioavailability of vitamin D in persons with SCI is similar to that found in AB elderly persons.  These changes have been shown to contribute to premature onset of osteoporosis and increased risk for fracture in total and regional sites following SCI when compared to the AB population (Garland et al. 1992; Szollar et al. 1997a; Szollar et al. 1997b; Dauty et al. 2000; Kiratli et al. 2000; Garland et al. 2001b; Vlychou et al. 2003; Eser et al. 2004; Giangregorio et al. 2005; Frotzler et al. 2008, Dudley-Javoroski & Shields, 2010), which may be more related to YPI than chronological age (Bauman et al. 1999; Garland et al. 2001b).

Age of SCI onset, however, may be an influential factor on the extent of the decline in bone loss (Garland et al. 2001b; Kiratli et al. 2000; Szollar et al. 1997a).  For instance, the findings by Szollar and colleagues (1997a) provide evidence that the BMD of persons with SCI are significantly lower than the AB population, but that YPI (i.e., older adults injured at a young age) may be more influential on BMD changes in specific areas (i.e. femoral and trochanter regions), although older males may not be as severely affected.  Persons who were 60 years or older had comparable levels to their age-matched AB controls in their BMD whereas persons in the younger age categories had significant differences in their femoral regions at different intervals (Szollar et al. 1997a).  For instance, younger adults with SCI (20-39 year olds) had significantly lower BMD at 1-5 YPI and at 10-19 YPI in the femoral regions of their neck and trochanter when compared to their AB controls, and the mid-age group (40-59 year olds) only had lower BMD at 10-19 YPI in the femoral neck and trochanter regions.  These findings possibly allude to premature aging occurring at specific intervals post-injury, most notably in the first year, in the femoral region in younger persons with SCI, and are consistent with the other identified studies (Garland et al. 1992; Biering-Sorensen et al. 1990; de Bruin et al. 2005; Frey-Rindova et al. 2000; Wilmet et al. 1995; Chow et al. 1996; Szollar et al. 1997a; Szollar et al. 1997b; de Bruin et al. 2000; Kiratli et al. 2000; Eser et al. 2004; Frotzler et al. 2008).  It may be that age-related factors become less important on changes in bone mass when an individual reaches a certain chronological age threshold (i.e. 60 years).  At this point, other factors (i.e. immobilization) affecting bone mass may become more prominent.  In general,all of these changes provide additional support that premature aging is occurring.

Gender also is an influential factor on bone loss.  Garland and colleagues (2001b) provide evidence that women with a complete SCI incur a rapid bone loss in the knee, resulting in a BMD that is approximately 40% to 45% of the AB population, and that this loss is greater than the loss seen in males with comparable injuries.  Unlike the findings by Szollar and colleagues (1997a), the pattern of bone loss of the hip was linear regardless of the age at the time of injury.  The findings by Bauman and colleagues (1999), which used a cross-sectional monozygotic twin design, also shows evidence that duration of injury may be more closely associated to bone loss than current age.  Although lifestyle habits such as smoking and alcohol intake were examined and found not to be significant, the sample in Bauman et al. (1999) study was quite small, and relatively young.

As well, a study by Slade and colleagues (2005) which compared bone loss at the knee between AB and SCI women who were pre- and post-menopausal concluded that although age and estrogen effects could not be independently discerned, it was unloading (lack of weight bearing) that resulted in the deterioration of trabeculae that occurs early post-injury.  Given that SCI is less common in women, more studies are needed to further our understanding of the interaction between gender, SCI, and aging plays on bone loss.

Interestingly, the lumbar spine BMD of persons with SCI appears to increase with age regardless of YPI.  Szollar and colleagues (1997a) interpreted this finding as either being representative of the lumbar spine becoming the primary weight-bearing region or that neuropathic osetorarthropathy (i.e. spectrum of bone andjoint destructive processes associated with neurosensory deficit) may have caused diffused increased radiodensity of the spinal column.  The finding that BMD and BMC of the spine remains unaffected or increases is consistent with several other of the identified studies (Biering-Sorensen et al. 1990; Dauty et al. 2000; Chow et al. 1996; Garland et al. 2001b; Szollar et al. 1997b; Szollar et al. 1998), and are complementary to the findings by Catz and colleagues (1992).  Based on their findings, Catz et al. (1992) concluded that an SCI injury does not accelerate the aging process of the lumbar spine, and that it may even prevent some expected spinal bone changes since no significant differences were detected between their group with SCI and their AB matched control group.  However, they noted that a limitation of their study was that 10 years might be too short a duration to detect any significant effects.  As well, the sample size was small and consisted of a heterogeneous group of spinal cord etiologies (i.e. non-traumatic).  Finally, one study (Amsters & Nitz 2006) found that postural changes, such as thoracic kyphosis, might also be independent of age and YPI.

With regard to the upper extremities, the musculoskeletal system appears to decline with YPI (Siddall et al. 2003; Jensen et al. 2005; Akbar et al. 2010), with the incidence of shoulder pain increasing over time.  However, the role of chronological age may also be influential (Lal 1998; Kivimäki & Ahoniemi 2008).  The incidence of degenerative shoulder changes (Lal 1998) may be higher in persons who are older than 30 years and are less than 10 YPI, suggesting that degenerative changes may occur earlier than previously thought in persons with SCI.

In addition to the lumbar spine, there are other areas of the musculoskeletal system that are not negatively affected by aging.  For instance, handgrip strength may increase with YPI in males with paraplegia relative to AB controls (Petrofsky & Laymon 2002).  This may be due to the use of manual wheelchairs, as well as to age-related changes in muscle fibre composition, and/or to a reduction in intramuscular pressure (Petrofsky & Laymon 2002).  As well, older males with paraplegia (45 years and older) may have comparable levels of upper extremity strength to AB controls (Pentland & Twomey 1994).   

Conclusion

There is Level 4 evidence from longitudinal studies (Biering-Sorensen et al. 1990; Garland et al. 1992; Wilmet et al. 1995; de Bruin et al. 2000; Frey-Rindova et al. 2000; Garland et al. 2004; de Bruin et al. 2005; Frotzler et al. 2008, Dudley-Javorski & Shields 2010) and Level 5 evidence from 15 studies (Chow et al. 1996; Szollar et al. 1997a; Szollar et al. 1997b; Szollar et al. 1998; Bauman et al. 1999; Dauty et al. 2000; Kiratli et al. 2000; Garland et al. 2001b; Vlychou et al. 2003; Eser et al. 2004; Giangregorio et al. 2005; Slade et al. 2005; Dudley-Javorski & Shields 2010; Rittweger et al. 2010; Dionyssiotis et al. 2011) that there is a rapid loss of bone in the hip and lower extremities following SCI.

There is Level 2 evidence (Frotzler et al. 2008) and Level 5 evidence (Eser et al. 2004) that tibial and femoral bone geometry and density properties reach a new steady-state within 3-8 year post injury, with the time frame depending on bone parameter and skeletal site.

There is Level 5 evidence from three studies (Szollar et al. 1997a; Szollar et al. 1998; Garland et al. 2001b) that older males and females with SCI may not experience as rapid of a decline in bone mass compared to AB controls.

There is Level 5 evidence from two studies (Bauman et al. 1999; Garland et al. 2001b) that year YPI may be more associated with bone loss after SCI than chronological age.

There is Level 5 evidence (Slade et al. 2005) that there are differences in bone geometric indices and in structural properties in the lower extremities of women with SCIcompared to the AB women.

There is Level 5 evidence from five studies (Finsen et al. 1992; Vaziri et al. 1994; Bauman et al. 1995; Szollar et al. 1998; Dauty et al. 2000) suggesting that there are impaired biochemical and bone markers in persons with SCI compared to AB controls that persons with SCI are at greater risk for fracture due to the premature development of osteoporosis.

There is Level 2 evidence from a longitudinal study with AB controls (Catz et al. 1992), Level 4 evidence from a longitudinal study (Biering-Sorensen et al. 1990), and Level 5 evidence from five studies (Chow et al. 1996; Szollar et al. 1997a; Szollar et al. 1997b; Szollar et al. 1998; Garland et al. 2001b) that premature aging does not occur in the lumbar spine after SCI.  The possibility that the lumbar spine becomes the primary weight-bearing region, along with immobilization, may serve to protect age-related bone loss changes to this region.

There is Level 5 evidence (Amsters & Nitz 2006) that persons with SCI, regardless of age or YPI, had increased thoracic kyphosis compared to AB controls.

There is Level 5 evidence from two studies (Pentland & Twomey 1994; Petrofsky & Laymon 2002) that decreased hand grip strength does not occur in men with complete paraplegia and that continual wheelchair use may retard this aging process.

There is Level 5 evidence (Pentland & Twomey 1994) that upper limb pain in males with complete paraplegia who use manual wheelchairs may be attributed to longer YPI and not to chronological age.

There is Level 2 evidence from two longitudinal studies (Siddall et al. 2003; Jensen et al. 2005) showing that the incidence of shoulder pain increases over time in persons with SCI.

There is Level 2 evidence from a longitudinal study (Lal 1998) and Level 5 evidence (Kivimäki et al. 2008) that highlights chronological age having an important influence on developing shoulder pain..

  • Premature aging may occur in the femoral and hip regions in persons with SCI.  It may be that declines in bone mass occur rapidly following injury, and reach a new steady state within 3-8 years post-injury, depending on the bone parameter and skeletal site.

    Older males and females (< 60 years) with SCI may not experience rapid declines in bone mass in certain regions when compared to able-bodied controls.

    Duration of injury may be more associated with bone loss after SCI than chronological age.

    Women with complete SCI may be at a greater risk for fracture at the knee compared to males with SCI and the able-bodied population.

    Premature aging may not occur in the lumbar spine after SCI.

    Upper limb pain in males with complete paraplegia may be attributed to longer durations of injury and not to the aging process.

    The incidence of shoulder pain increases over time, and that age of onset may contribute to the development of pain.  Adults with SCI (< 10 years post-injury) who were 30 years and older were more likely to report shoulder pain over time than those who were less than 30 years of age.

    Premature aging may not occur in hand grip strength in men with complete paraplegia.  Rather, continual wheelchair use may retard the aging process in relation to handgrip strength.

    Regardless of age or years post-injury, persons with SCI may have increased thoracic kyphosis than the able-bodied population.

    Persons with SCI may have reduced lung capacity compared to able-bodied controls, but this reduction is due to SCI and not aging.

Respiratory System

As a consequence of SCI, especially injury to the cervical and upper thoracic parts of the spinal cord, functioning of the respiratory muscles is disrupted, and leads to lowered lung volume parameters (Linn et al. 2000), in addition to other respiratory complications, such as decreases in compliance of the chest wall, changes in breathing patterns, sleep-disordered breathing (SDB), and ventilator dependency.

For individuals with SCI who have impaired autonomic function and impaired inspiratory muscle weakness, SDB may occur (Bonekat et al. 1990).  In general, the incidence of SDB, characterized by sleep apnea, is estimated to be at least twice that reported in the general population (Schilero et al. 2009).  Respiratory complications lead to significant morbidity and mortality in people with SCI (DeVivo et al. 1993; Cotton et al. 2005). 

Among the general population, age associated changes in the respiratory system involve loss of elastic recoil of the lung. Similarly, among individuals with SCI, decreases in the compliance of the chest wall, and strength of the respiratory muscles are observed (Janssens et al. 1999; Janssens 2005).  Complications resulting from SCI may therefore hold important respiratory implications as people age.

In this section, 5 longitudinal studies and 4 cross-sectional studies (see Table 6) on the respiratory system after SCI are reviewed.

Table 6: Respiratory System

Discussion

Several of the identified studies highlight that SDB and other respiratory complications are higher in persons with SCI than in the general population and appear to increase with age (see Table 6).  In a five-year longitudinal study to assess changes in SDB, Bach and Wang (1994) measured oxygen desaturation, which is characteristic of sleep apnea, in 10 individuals with tetraplegia; six individuals had oxygen desaturation below 90%.  At the five-year follow-up, 5 of the 10 individuals had increased patterns of oxygen desaturation, leading to the conclusion that oxygen desaturation is common among people with tetraplegia and increases with age. In another longitudinal study (Berlowitz et al. 2005) sleep apnea, defined as an apnea-hypopnea index (AHI) of >10 events per hour, was found in 62% of the sample in the first month, peaking at 83% at 13 weeks, and falling to 68% and 62% at weeks 26 and 52 respectively. 

Snoring is another important indicator of sleep apnea and appears to be age related.  In a large case-control study, 29% of men (N = 331) and 21% of women with SCI (N = 77) snored daily or almost daily compared to 18.2% of the control group (N = 339) representing the normal population of Denmark (Biering-Sorensen & Biering-Sorensen 2001).  In addition, those who snored daily or almost daily in the SCI group were significantly older than those with SCI who snored less frequently.  

After SCI, there are temporal changes in pulmonary functioning.  Forced vital capacity (FVC), inspiratory capacity (IC), and maximum inspiratory mouth pressure (Pimax) are lowered in the acute stage of SCI, and then gradually improve over time.  In a five-year longitudinal study, Postma et al. (2013) showed improvements to FVC. Loveridge and colleagues (1992) showed that seated positioning imposes greater stress on the respiratory system in the acute stages of SCI than the supine position.  While breathing patterns in the supine position at all measured time points one-YPI were comparable to the controls (N= 18), breathing patterns in the seated position had to be adjusted in order to maintain minute ventilation.  Over time, however, improved breathing patterns were observed in the seated position, so much so that differences initially observed between the seated and supine positions became insignificant.  Such improved breathing pattern is speculated to be due to increased accessory muscle function, improved chest wall stability, thoraco-abdominal coupling, or a combination of these factors over time.

An increasingly shallow breathing pattern resulting from a lack of deep breaths, and other factors associated with SCI such as obesity and decreased chest wall compliance, may lead to hypercapnia, or excessive amounts of carbon dioxide in the blood, and possibly ventilatory failure (Bach & Wang 1994).  Despite these results from this prospective longitudinal study, it is unclear if breathing patterns change as a result of the injury or due to aging with SCI.  The former may be the case as the study followed adjustments only during the first YPI. 

Sustaining a SCI often leads to an initial respiratory insufficiency and necessitates a need for long-term mechanical ventilation.  In some instances, individuals may be weaned from the ventilator.  Wicks and Menter (1986) conducted a 10-year retrospective study of ventilator-dependent patients with tetraplegia (N = 134) to determine factors associated with weaning and long-term survival rate.  Despite similar levels of injury, patients over 50 years of age had a 20% mortality rate compared to 6% for those younger than 50, and that ventilator weaning is less successful for those over the age of 50.  This suggests that ventilator-dependency among SCI individuals who are older than 50 possess a much greater risk of negative health outcomes (Wicks & Menter 1986).

Although there are additional factors that can affect respiratory health long-term for the individual with SCI (i.e. level and completeness), there are several preventative activities that can be done to minimize the aging of the respiratory system, such as not smoking, minimizing exposure to polluted air, and controlling body weight (Wilmot & Hall 1993).  Further research is needed to better understand SDB in persons aging, especially in terms of their implications for for cardiovascular health.

Conclusion

There is Level 4 evidence from two longitudinal studies (Bach & Wang 1994; Berlowitz et al. 2005) support that SDB may either increase or persist with the aging process. 

There is Level 2 evidence from a longitudinal study with AB controls (Loveridge et al. 1992) that seated breathing patterns are compromised immediately post injury but recover over time.  As well, persons with tetraplegia do not take deep breaths as often as AB individuals. 

There is Level 4 evidence from a longitudinal study that adults over the age of 50 who are aging with ventilator dependency are at greater risk of death and are less likely to be weaned from their ventilators than younger adults aging with a ventilator (Wicks & Menter 1986).   

There is Level 4 evidence from one longitudinal study (Postma et al. 2013) that forced vital capacity improves 5 years after inpatient rehabilitation.

  • Sleep disordered breathing may increase or persist with the aging process in persons with SCI.

    Seated breathing patterns after tetraplegia appear compromised early post-injury but may recover over time.

    Adults who are older (50 years +) and ventilator dependent have a higher mortality rate and lower weaning rate than adults who are younger and who are ventilator dependent.

Nervous System

Characteristics of an aging nervous system include diminished strength and reaction time (Fozard et al. 1994; Lynch et al. 1999), loss of vibratory sense (Knox 1994), reduced fine coordination and agility (Pathy 1985), slowing of motor unit recruitment patterns (Tax et al. 1990), declining function of basal ganglia (Roth & Joseph 1994) and cerebellarsystems (Bickford et al. 1999), and deterioration of gait (Greenhouse 1994).  A number of anatomical and functional changes occur with aging, including deficits in long-term potentiation (the normal enhancement in signal transmission between two neurons when stimulated together), decline in expression of neurotrophic factors which promote neuronal survival and dendritic branching, and reduction in brain volume in some regions due to a decrease in synaptic density (Mora 2013).  With the exception of neurons from a few areas, there is no significant loss of neurons during the normal process of aging (Mora 2013).  Aging also impacts the peripheral and autonomic systems, which respectively result in a progressive loss of nerve conduction velocity (Verdú et al. 2000), and impaired temperature regulation (Collins et al. 1977) and baroreceptor reflexes (Duke et al. 1976).

In SCI, there is a lack of longitudinal evidence regarding the nervous system other than studies that evaluate neurological complications such as chronic pain (see Table 8).  Neuropathic chronic pain following SCI is a complex issue and results from the abnormal processing of sensory input due to damage to the nervous system (Cardenas & Rosenbluth 2001). It is often difficult to identify a specific stimulus or cause for neuropathic syndromes (Scadding 2003).  Although this pain can be identified by site (region of sensory disturbance) and by features (sharp, shooting, electric, burning, stabbing), individuals may find it difficult to describe the quality of neuropathic pain (Scadding 2003). Typically, neuropathic pain is present at or below the level of lesion, and is constant but fluctuates in intensity depending on the individual’s emotional state or level of fatigue.  SCI-related studies that have examined factors associated with the development of pain have yielded mixed results. With regards to age, some studies have found an association between chronological age and pain (e.g. Burke 1973; Anke et al. 1995; Stormer et al. 1997; Dalyan et al. 1999; Siddall et al. 1999; Putzke et al. 2000), whereas others have found none (e.g. Subbarao et al. 1995; Rintala et al. 1998; Curtis et al. 1999).

Overall, the dearth of literature on the nervous system is relatively surprising given the implications of how age may influence the recovery process following injury.  New sensory and motor deficits in persons with SCI of more than 20 YPI (Whiteneck et al. 1992) may occur due to an age-related dropout of anterior horn cells and loss of myelinated tracts (Charlifue et al. 2002).  As well, it is important to determine whether or not further deterioration in the autonomic nervous system occurs in the later decades of life, which hold implications for the gastrointestinal and genitourinary systems (Lammertse 1993). 

In this section, 4 longitudinal studies (see Table 7) on the nervous system after SCI are reviewed.

Table 7: Nervous System

Discussion

The most robust finding was that presence of pain at an earlier time point appears to be the best predictor of future pain, and that it likely does not change significantly over time (Jensen et al. 2005; Siddall et al. 2003; Putzke et al. 2002a; Rintala et al. 2004).   A limitation of most studies was the lack of clear assessments of the type and characteristics of pain being experienced by participants.  For instance, Putzke and colleagues (2002a) do not report on the quality (e.g. frequency, intensity, duration) or pain type (e.g. neuropathic, nociceptive, etc.) of their sample. Although their findings suggested that age of onset may be an important factor, pain is a complex issue that involves the interaction of biological, psycho-social, and environmental factors.      

In general, there are considerable gaps in knowledge regarding how the nervous system changes with aging with an SCI.  Although it was identified as an issue of importance more than a two decades ago (Lammertse 1993), research on the nervous system still remains incomplete and speculative at best.

Conclusion

  • Younger persons (< 30 years) may have less pain interference at one and at two years post-injury than older persons (> 60 years).

    Previous reports of pain interference after SCI, irrespective of age, may be predictive of later pain interference.

Skin and Subcutaneous Tissues

Skin undergoes structural and physiological changes resulting from both the natural aging process and being exposed to damaging environmental elements.  Over a lifetime, skin is observed to progressively degenerate.  Most notable are the changes and deterioration in the structure of the skin which are due to losses and/or a disordering of collagen, the protein primarily responsible for the tensile strength of skin, and elastin fibres (Farage et al. 2009). The elderly therefore, have an increased susceptibility to skin injuries such as pressure ulcers, and a decreased healing response.

Pressure ulcers are common among individuals with SCI, and typically occur over boney prominences, such as the ischial tuberosities and malleoli.  Damage to the skin and underlying tissue caused by pressure, shearing, and/or friction due to continuous sitting are the primary causes of pressure ulcers.  As collagen metabolism increases as a result of SCI, these individuals may be more susceptible to pressure ulcers than non-SCI individuals (Claus-Walker & Halstead 1982a; Claus-Walker & Halstead 1982b).  As a result of the combined effects of pressure, from sitting, and reduced skin integrity, due to collagen degradation, it is estimated that 85% of individuals with SCI will experience a pressure ulcer in their lifetime (Gunnewicht 1995).  Given that the mean cost of healing a wound is approximately $50,000, which translates into an annual cost of 3.6 billion dollars in the United States (Beckrich & Aronovitch 1999), there is a strong need to understand age-related changes to the skin following SCI in order to help minimize the occurrence of wounds.

In this section, 2 longitudinal studies and 2 cross-sectional studies (see Table 8) on skin and subcutaneous tissues after SCI are reviewed.

Table 8: Skin and Subcutaneous Tissues

Discussion

Over a 2 year period, one-quarter of individuals with SCI experienced a pressure ulcer (Rodriguez & Garber 1994). Understanding how skin changes post-SCI is important, not only because of the implication of pressure ulcers, but because of other non-life threatening skin complications that commonly occur after SCI, which include local fungal infection, seborrheic dermatitis, and chronic acne vulgaris (Rubin-Asher et al. 2005; Stover et al. 1994).  As well, attenuated immune response following SCI facilitates skin infections and lack of cutaneous sensation increases the incidence of pressure ulcers.

Park and colleagues (2011) found that the biomechanical skin properties were significantly altered following SCI in men, and these changes were directly influenced by regional sympathetic denervation rather than somatic sensory denervation.  They found that age significantly correlated with all biomechanical skin parameters in their AB controls.  However, in men with motor and sensory complete SCI, YPI rather than age was shown to be the most important factor influencing skin changes.  Since the amount of dermal thickening is positively correlated with YPI, Park et al. (2011) hypothesized that the thickening process following SCI may be strong enough to overwhelm the impact of aging on biomechanical skin properties.

Conclusion

There is Level 2 evidence (Vaziri et al. 1994) suggesting that plasma fibronectin, as an indicator of wound healing, may rise in SCI male patients with fast healing ulcers but not in SCI patients with poor healing ulcers. 

There is Level 5 evidence that the biomechanical skin properties are significantly influenced by sympathetic paralysis rather than somatic sensory paralysis.  Furthermore, in men with complete SCI, YPI may be the influential factor on the biomechanical properties of the skin (Park et al. 2011). 

  • Males with SCI have higher levels of collagen metabolite, glu-gal Hyl, than the able-bodied population, which may be a sign of premature aging of the skin.  Further work is needed to conclusively demonstrate this.

    Behavioural factors play a stronger role in the development of pressure ulcers in persons with SCI than either age or YPI.

    In men with complete SCI, YPI may be the influential factor on biomechanical properties of the skin.

Genitourinary and Gastrointestinal Systems

There are several normative age-related changes of the genitourinary and gastrointestinal systems that can lead to serious health problems for the elderly.  With regard to the genitourinary system, there is a progressive and structural breakdown of the kidneys with age, and problems with urinary continence that results from decreased bladder capacity and compliance, and an increase in involuntary bladder contractions (Aldwin & Gilmer 2004).  In males, enlargement of the prostate also contributes to incontinence (Dubeau 1997), and prostate cancer is one of the primary causes of death (McClain & Gray 2000).   Although urinary tract infections (UTIs) increase with age, women are at greater risk, with the incidence in males only approaching that of women when they are 60 years or older (Foxman 2002).  Unlike the genitourinary system, the gastrointestinal system retains much of its regular function, and it is unclear whether the few normal changes do affect the health of the older population.  Some potential issues include slowing in large intestine motility, and diminished gut motility, with an increase in water resorption in the colon, which contributes to hard stool and increased risk of constipation, rectal fissures, hemorrhoids, and diverticular diseases (Wilson et al. 1997).

In persons with SCI, the effects of neurogenic bladder may compound the effects of aging in persons with SCI (Madersbacher & Oberwalder 1987) since bladder management techniques, such as the use of indwelling catheters, may contribute to the occurrence of common complications such as UTIs (Charlifue et al. 1999) and for a higher risk of developing bladder cancer (Groah et al. 2002).  Similarly, neurogenic bowel may also compound aging after SCI given that persons with SCI often have higher rates of bowel-related complications compared to the general population (Cosman et al. 1993).

In this section, 9 longitudinal studies and 13 cross-sectional studies (see Table 9) on the genitourinary and gastrointestinal systems after SCI are reviewed.

Table 9: Genitourinary and Gastrointestinal Systems

Discussion

From the list of identified studies on the genitourinary system (see Table 9), there are four longitudinal studies (Viera et al. 1986; DeWire et al. 1992; MacDiarmid et al. 1995; Sekar et al. 1997) suggesting there are no differences in renal function over time among persons using various bladder management techniques.  However, the samples of these studies did incur typical SCI-related complications such as UTIs and bladder stones, and there were some indications of renal decline.  For instance, Lamid (1988) found that after 4 YPI, the number of vesicoureteral refluxes increased and progressed to grades II and IV, which caused kidney damage with caliectasis in 27 of 32 patients with SCI followed over 12 YPI.   Finally, Sekar and colleagues (1997) reported that renal function (as measured by total and individual kidney effective renal plasma flow; ERPF) decreased over time in their SCI sample (N = 1114) with a slight reversal occurring at 10 YPI.  A methodological strength of the study was the assessment of ERPF, which is thought to be a more sensitive measure of kidney function than serum creatinine (Kuhlemeier et al. 1984a).  Based on the findings of the identified studies, it may be that significant declines in renal function occur approximately at 5 YPI.   

Work regarding age of onset and the genitourinary system is also needed as the findings of a cross-sectional study by Kuhlemeier and colleagues (1984b) suggests that persons with acute SCI (N = 160) who were younger than 20 or older than 50 had comparable levels of individual and global kidney effective plasma flows compared to AB controls (N = 287), whereas persons with between 21-51 had impaired renal function.

Overall, the risk for prostate cancer appears to be lower in persons with SCI due to impaired testosterone levels, but prostate cancer screening should be encouraged given the possibility that males with SCI who do develop prostate cancer may have poorer outcomes than AB males (Scott et al. 2004).

With regard to women with SCI (n = 62), Kalpakjian and colleagues (2010) found that they experience greater symptom bother in certain areas related to menopause compared to AB controls (n = 66).  Specifically, women with SCI reported greater bother of somatic symptoms, bladder infections, and diminished sexual arousal.  However, the patterns of symptoms, transitioning through menopause, and age at final menstrual period transitions were comparable between groups.  Overall, the authors concluded that in important ways, women with SCI appear to experience menopause similarly to their peers.    

Although bowel function is clearly impaired in persons with SCI compared to AB controls, one study (Lynch et al. 2000) demonstrated that continence deteriorates with increasing age in an AB population (N = 467) but does not change with increasing age in persons with SCI (N = 467).This supports a Level 4 study that found that gastrointestinal transit times and colonic dimensions neither change during the first decade nor within the second decade post-SCI (Faaborg et al. 2011).  However, a 10-year longitudinal study (Faaborg et al. 2008) suggests persons with SCI do incur an increase in constipation-related symptoms over time. One possible reason for this occurrence is due to the evidence that high amplitude propagating contractions (HAPC) are absent in persons with SCI compared to AB controls (Ancha et al. 2010).  HAPC are often associated with colonic mass movements and are thought to be a precursor of bowel evacuation. Thus it is an important factor in the occurrence of difficulty with evacuation post-SCI. Conversely, the need fhat bowel dysfunction worsens over time for persons with SCI but three stor assistance from medications or persons does not change, while fecal incontinence decreases.  It may be tudies (Menardo et al. 1987; Krogh et al. 2000; Emmanuel et al. 2009) provide evidence that level of injury plays a primary role in the extent of bowel dysfunction.  At this time, the SCI evidence on aging and the gastrointestinal system is limited, but attention to bowel symptoms should be incorporated into routine follow-up procedures and education (Charlifue & Lammertse 2002).

Conclusion

There is Level 4 evidence (Viera et al. 1986; DeWire et al. 1992; MacDiarmid et al. 1995; Sekar et al. 1997) that there are no differences in renal functioning up to 4 YPI using various bladder management techniques with some decline occurring beyond that time.

There is Level 4 evidence (Lamid 1988) that repeated episodes of vesicoureteral reflux can cause kidney damage as early as four YPI in some persons with SCI.

There is Level 4 evidence (Sekar et al. 1997) that renal plasma flow declines until 10 YPI after SCI, at which time a slight reversal occurs. 

There is Level 5 evidence (Kuhlemeier et al. 1984b) that suggests age of SCI onset may be an important factor related to renal function, with persons with SCI who are under 20 and older than 50 having comparable renal function to AB controls, whereas persons between those ages have impaired functioning compared to the general population.

There is Level 5 evidence (Lynch et al. 2000) demonstrating a deterioration in bowel continence with increasing age in an AB population but no change with age in persons with SCI.

There is Level 4 evidence (Faaborg et al. 2008) suggesting persons with SCI do incur an increase in constipation-related symptoms and decrease in fecal incontincence over time.

There is Level 4 evidence (Faaborg et al. 2011) that gastrointestinal transit times and colonic dimensions do not change over time in persons with SCI.

There is Level 5 evidence from three studies (Menardo et al. 1987; Krogh et al. 2000; Emmanuel et al. 2009) that level of injury, and not necessarily age or YPI, plays a primary role in the extent of bowel dysfunction.

  • Various bladder management techniques (indwelling catheterization versus intermittent catheterization) may not impact renal functioning in persons with SCI over time.

    Repeated episodes of vesicoureteral reflux can cause kidney damage as early as four years post-injury.

    After SCI, renal plasma flow declines until 10 years post-injury, at which time, a slight reversal occurs.

    Age of onset may play a role in minimizing renal decline, with adults who are under 20 and older than 50 having comparable renal functioning to the able-bodied population, while those between those ages have impaired functioning.

    Bowel incontinence increased with age in the able-bodied population but does not change in persons with SCI.

    Persons with SCI may experience an increase in constipation-related symptoms and decrease in fecal incontinence over time.

    Level of injury, and not age or years post-injury, plays a primary role in the extent of bowel dysfunction.

Secondary Complications of Multiple Systems

Most individuals with SCI will develop a variety of secondary complications (Jensen et al. 2013). Common complications include pain, bowel and bladder regulation problems, muscle spasms, fatigue, esophageal symptoms, osteoporosis, cardiovascular disease, diabetes, and respiratory complications or infections (Jensen et al. 2013). As secondary health conditions negatively affect community re-integration and quality of life, the influence of the aging process on these conditions is important to consider in their management. While specific conditions have been described in previous sections (e.g. pain, bowel and bladder regulation, genitourinal and gastrointestinal problems, bone, cardiovascular disease and endocrine problems, and respiratory complications) the below section describes studies with general measures of secondary health complications or multiple health conditions, including physical and mental health (e.g. depression, fatigue and spasticity).

In this section, 1 systematic review (see Table 10) and 5 longitudinal studies (see Table 11) on secondary health complications after SCI are reviewed.

Table 10: Systematic Review of Secondary Complications of Multiple Systems

In this scoping review that examined the association between age and secondary health complications post SCI, Jensen et al. (2013) report seven key findings (i.e. evidence that is reported in at least two studies): 1) bladder problems are not associated with duration of injury; 2) spasms are not associated with duration of injury; 3) cardiovascular disease is more prevalent in older individuals; 4) diabetes is more prevalent in older individuals; 5) bone mineral density loss is higher in both older individuals and in individuals with longer duration of injury; 6) fatigue is more commonly reported by older individuals; and 7) respiratory complications/infections are more prevalent in older individuals.

The authors concluded that older age and longer SCI duration are associated with more frequent and severe health conditions. These findings support the belief that premature aging may be occurring in individuals with SCI.

The following reviews additional papers studying aging and secondary health complications after SCI.

Table 11: Aging and Secondary Health Complications after SCI

Discussion

Premature aging with a number of different organ systems appears to lead to the higher prevalence of a number of secondary health conditions compared to the normative population (Jensen et al. 2013).  Of concern is that more medical attention is required over time to address these secondary health complications (Krause et al. 2013).  As with the general population (Roy & Thomas 1986; Gaston-Johansson et al. 1996; Poluri et al. 2005), issues of fatigue and pain can limit the independence of a person with SCI.  Fatigue can be defined as an overwhelming sense of tiredness, lack of energy and often a feeling of total exhaustion (Herlofson & Larsen, 2002). Fatigue after SCI is a prevalent issue (Gerhart et al. 1999; McColl et al. 2003; McColl et al. 2004; Fawkes-Kirby et al. 2008). The findings on the associations between age and fatigue after SCI have been somewhat conflicting. For example, one study found that males with SCI reported an increased fatigue with increasing age (Pentland et al., 1995), whereas some have found greater reports of fatigue in younger persons with SCI with short durations of injury (McColl et al. 2003).

Both pain and fatigue have been both found to negatively impact on several domains of function and QoL (Rintala et al. 1998; Ingles et al. 1999; Herlofson & Larsen 2002). As well, there is some evidence of a relationship between fatigue and pain after SCI (Fawkes-Kirby et al. 2008). When examined together, the study by Charlifue and colleagues (1999) and by Putzke and colleagues (2002a) highlight chronological age as a factor that mediates the expression and/or onset of change. In the study by Charlifue et al. (1999), the youngest and oldest group reported no significant changes in fatigue between Time 1 and Time 2. Similarly, in the study by Putzke et al. (2002a) the youngest and oldest group reported the least amount of pain interference between Year 1 and Year 2; however, overall, older individuals were significantly more likely to report pain in both years than younger individuals with SCI. In terms of the influence of pain and the interference of pain on QoL over time, Putzke et al. (2002a) found that those individuals who experienced increased interference over time had decreased life satisfaction scores, whereas those whose interference subsided had increased life satisfaction. Similarly, Stensman (1994) observed over 5 years that individuals with variable pain experienced fluctuating global QoL, those with constant pain experience consistently low QoL, and those with no or little pain had consistently high or improvements to an initially low QoL over time.

The finding by Charlifue and colleagues (1999) that increasing age is associated with increased fatigue and additional physical assistance is congruent with other studies examining the effects of long-term SCI (e.g. Gerhart et al. 1993; Thompson, 1999; Liem et al. 2004). A limitation noted by Charlifue et al. (1999) was that their sample was relatively ‘young’ (M= 37.1 years), and none having lived with their SCI for more than 20 years (M= 9.3), and may not have aged enough to significantly affect overall health and functional status. However, the consistent findings for increased fatigue between Time 1 and Time 2 do highlight that there is a consistent physical decline occurring. Charlifue and colleagues (1999) recognized the systematic changes in their sample (i.e. improved health but declining functionality) but attributed them to external factors such as less contact with the healthcare system, funding changes, which lead to fewer participants reporting particular outcomes. As well, they noted the need for increased physical assistance over time in their sample may have reflected attitude changes in rehabilitation practice where maintaining functionality is preferred over complete physical independence. Although the strength of the study is its provision of several perspectives to aging with a SCI, an alternative analysis strategy might have helped to provide a more cohesive model of how the factors assessed related to one another. For instance, the increases in physical assistance between Time 1 and Time 2 were often accompanied with improvements in health but also with increases in fatigue. Reporting on associations (or lack of) between these variables may have provided additional support for their conclusions.

Conclusions

There is Level 3 evidence (Jensen et al. 2013) from a scoping review that cardiovascular disease, diabetes, bone mineral density loss, fatigue and respiratory complications or infections occur with higher frequency in older individuals or those with longer SCI duration, relative to younger individuals or those with shorter SCI duration.

There is Level 4 evidence (Ullrich et al. 2013) from one longitudinal study that co-occurrence of pain and depression is common among persons who have lived with SCI for many years and remains stable over time. There is also evidence that comorbid pain and depression are associated with higher severity of conditions, more persistent conditions over time, and more utilization of SCI specialty health-care services.

There isLevel 4 evidence (Hitzig et al. 2010; Pershouse et al. 2012) that secondary health complications increase over time in persons with SCI, (with the exception of bowel problems, which decrease).

There is Level 4 evidence from a longitudinal study (Charlifue et al. 1999) that fatigue and the need for physical assistance increases over time with SCI.

  • Fatigue and the need for physical assistance may increase over time with SCI.

    The number of secondary health complications increase with more years post injury.

    The incidence and severity of UTIs decrease over time in persons with SCI and prevalence of pressure sores remain stable.

    The co-occurrence of pain and depression is common in persons who have lived with SCI for many years.

Functional Independence

Motor and sensory impairments after spinal cord injury cause a variety of functional impairments. Functional impairments are defined as restrictions that hinder an individual’s ability to perform tasks or activities (Jette 2006). Functional tasks are often described in terms of basic activities of daily living such as walking, climbing stairs, bathing and grooming. With complete lesions, higher levels of injury cause greater motor and sensory impairment, which are associated with greater functional impairments (Aidinoff et al. 2011).  Incomplete lesions produce a more complicated pattern of motor and sensory impairments (Yilmaz et al. 2005). Individuals who have problems performing functional tasks frequently rely on a combination of assistive devices and assistance from others. Haisma et al. (2008) found that functional motor independence improved during in-patient rehabilitation and remained relatively stable one year post-discharge. Given that functional independence is a strong, significant predictor of care needs over time (Cohen et al. 2012), it is extremely important to understand the long-term functional independence of individuals with spinal cord injury. 

In this section, 1 systematic review (see Table 12) and 5 longitudinal studies (see Table 13) on functional independence after SCI are reviewed.

Table 12: Systematic Review on Functional Independence

In this systematic review, the authors report thatmotor and functional recovery decreases with advancing age for complete SCI. They also report no association between recovery and age for individuals with incomplete SCIs. Only three studies were included in this review that examined the association with age. This may indicate a dearth of evidence on the impact of aging on functional independence, and that the results should be interpreted with caution.

Table 13: Aging and Functional Independence

Discussion

All the studies report some decline in functional independence over time, although interestingly, Amsters et al. (2005) found that individuals with SCI perceived functional improvements in the first 10 years post-injury and then a subsequent decline. This study suffers from recall bias as individuals were asked to recount their function from up to 10 years post-injury.

Conclusions

There is level 4 evidence from one retrospective longitudinal study (Pershouse et al. 2012) that functional independence decreases with more years post injury for individuals who were higher functioning at one year.

There is Level 4 evidence from one longitudinal study (Amsters et al. 2005) that individuals with SCI (³20 YPI) perceive functional improvements up to 10 YPI and subsequent functional decline and greater dependence on mobility aids after 10 or more YPI.  

  • Functional independence decreases with more years post injury.

Quality of Life and Community Reintegration

In the general population, advancing into older adulthood is a period when individuals are faced with a unique array of physical, functional, and environmental stressors. This is no different for individuals aging with a traumatic SCI, who are now living an average of 30 to 40 years post-injury (YPI) (Samsa et al. 1993). As more individuals with SCI survive into their second, third, and even later decades, living with a disability becomes a life-long process for persons with SCI (Hallin et al. 2000).

Given the evidence in the previous sections of this chapter indicating that SCI represents a model for premature aging in some body systems (e.g. cardiovascular and endocrine, musculoskeletal, immune, and respiratory systems), the physical and functional declines associated with natural aging are likely to present more quickly among individuals with SCI. Such knowledge of these effects of aging however is insufficient for rehabilitation purposes without any indication of how individuals perceive the aging-related changes and how they adapt their lifestyles in response to such changes (Charlifue et al. 2010).

A key goal of rehabilitation is to enable successful community reintegration and high QoL. QoL describes the well-being and life satisfaction of an individual, and is a multi-factorial construct, which includes but is not limited to self-assessments of interpersonal relationships and social support, physical and mental health, environmental comfort, and a host of psycho-social factors (Kaplan & Erickson 2000). Community reintegration is an important construct shown to be predictive of life satisfaction in persons with SCI (e.g. Pierce et al. 1999; Richards et al. 1999; Putzke et al. 2002b; Tonack et al. 2008; Kemp & Bateham 2010). Community reintegration has been defined as returning to family and community life, engaging in normal roles and responsibilities, and actively contributing to one’s social groups and to society as a whole (Dijkers 1998). Thus successful reintegration involves resuming occupations or activities deemed important to the individual and society (i.e. self-care, employment, leisure, etc.; Yasui & Berven 2009). Environmental factors (e.g. social, institutional, cultural or physical) can either create barriers or facilitate reintegration, which impacts QoL (Anderson 2004).

In the general population, older adults frequently experience physical declines (Branch & Jette 1983) that may limit their activities of daily living (e.g., Hoyer et al. 1999), and negatively impact community reintegration and QoL. Similarly, both physical and mental health factors influence QoL in persons with SCI. For instance, poor physical health, secondary health conditions (e.g. pressure ulcers, pain, etc.), depression and stress have all been shown to negatively affect QoL (Craven et al. 2012).

With regards to aging, however, there are some mixed findings in relation to community reintegration and QoL, even within the same studies. Some studies reports that life satisfaction, QoL and community reintegration (at least in some domains) improve with years post-SCI (e.g. Zarb et al. 1990; Pentland et al. 1995; Westgren & Levi 1998; Dijkers 1999; Tonack et al. 2008), whereas other studies indicate older age is associated with poorer community reintegration and QoL (e.g. Crewe & Krause 1990; Eisenberg & Saltz 1991; Whiteneck et al. 1992; Tonack et al. 2008).  The discrepancies with aging and QoL tend to be more evident in cross-sectional analyses whereas longitudinal studies “mostly show relatively high and stable levels of QoL over long periods of time” (Kemp & Ettelson 2001, p. 119; Savic et al. 2010). An additional point to consider is that these differences may arise due to the use of different instruments, which may not all assess the same underlying QoL construct.

In this section, one systematic review (see Table 14), twenty-five longitudinal studies and two cross-sectional studies (See Table 15) on community reintegration and QoL after SCI are reviewed.

Table 14: Systematic Review on Quality of Life and Community Reintegration

Table 15: Quality of Life and Community Reintegration

Discussion

Aging is a complex process that does not only encompass biology. Environmental factors also change over time, which may be particularly important to persons with SCI, because they not only face physical limitations associated with their SCI, but also injury-related social and economic changes (Krause & Coker 2006). For example, in a series of papers reporting on the same cohort at different time points over a period of 30 years, there were significant improvements with satisfaction with employment and finances over time (Crewe & Krause 1990; Krause 1992; Krause 1998; Krause & Broderick 2005; Krause & Coker 2006), whereas satisfaction with both social and sexual relationships decreased (Krause 1997; Krause & Broderick 2005; Krause & Coker 2006). Similarly, Bushnik & Charlifue (2005) observed changes related to economics and technology, but not related to SCI or aging per se. For example, letter writing, which probably included emails, increased in the sample over time because home computing had likely become more common. Although not significant, the high percentage of persons who switched to a portable ventilator or pneumobelt from a fixed ventilator may have improved community reintegration for these individuals. As well, the finding that economic self-sufficiency steadily improved with time (e.g. Charlifue & Gerhart 2004a; Krause & Broderick 2005; Krause & Coker 2006) supports Bushnik’s (2002) speculation that increased economic standing may improve community reintegration. In the case of Bushnik’s (2002) sample, improved financial status enabled better access to adaptive equipment (e.g. modified vans).

Conversely, level of community reintegration for Charlifue & Gerhart’s (2004a) sample did not significantly change over time, but this may have been due to sample differences between the studies and that the time between data collection intervals in the other studies reviewed were further apart. As well, the individuals in Charlifue and Gerhart’s (2004a) study were at least 20 years post-injury when they entered the study. At 20 years post-injury, it is likely that routines and strategies for community participation have been well-established, and are not likely to dramatically change over 3 year periods. However, an understanding of environmental factors is important for assessing QoL since there is evidence that an individual’s adjustment over time is influenced by corresponding environmental changes (Krause & Sternberg 1997).

With regards to change in activity patterns, Bushnik and Charlifue (2005) attributed the changes to the natural progression of time utilization from external social activities associated with youth (e.g. card games with friends) to other activities (e.g. spending time with family). Further, the reported declines in activity by the SCI cohorts as they aged (e.g., Bushnik 2002, Charlifue and Gerhart 2004a, and Krause & Broderick 2005) might be similar to declines in activity patterns in the general population (Christensen et al. 1996; Bukov et al. 2002).

One of the main strengths of the studies by Krause (1997), Krause and Broderick (2005), and Krause and Coker (2006) is they assessed whether there were any differences between their current sample and those who were lost to follow-up. Based on these analyses, clear survivor effects emerged in both studies as the characteristics of respondents (persons who participated in both data collection periods) at Time 1 were younger, younger at age of SCI-onset, were less years post-injury, had higher levels of education, more likely to have cervical injuries, greater sitting tolerance, and had more social outings than non-respondents (persons who only participated in the first data collection period). These findings highlight that some care should be taken when interpreting the findings from these studies as it may only reflect survivors, and those who continued to participate.

The findings appear to provide some mixed evidence regarding the stability of QoL/life satisfaction over time. In some cases QoL/life satisfaction remained stable (i.e. Charlifue et al. 1998; Charlifue et al. 1999; Charlifue & Gerhart 2004b; Savic et al. 2010; Pershouse et al. 2012), or decreased over  time (i.e. Krause 1997; Charlifue et al. 1998). Similarly, Mitchell & Adkins 2010 that aging has greater negative influence on self-rated health in people with SCI than on those without a SCI over time. In other studies QOL/ life satisfaction improved with over (Stensman 1994; Kemp & Krause 1999; Bushnik 2002; Putzke et al. 2002b; Bushnik & Charlifue 2005; Krause & Coker 2006; van Koppenhagen et al. 2009; DeVivo & Chen 2011; Kalpakjian et al. 2011; van Leeuwen et al. 2011). Likewise, mental health has also been reported to improve longitudinally (van Leeuwen et al. 2012).

The discrepancies in these studies may potentially be attributed to theoretical and methodological differences. For instance, the study by Charlifue et al. (1998) was the only study that explicitly provided a theoretical model for assessing life satisfaction. Specifically, Charlifue and colleagues (1998) framed aging with SCI within a global thesis of function, which took into account physical, psychological, and environmental factors. Several studies with lower levels of evidence predicting life satisfaction have used other models that incorporate a variety of domains thought to impact on QoL (i.e. Pierce et al. 1999; Richards et al. 1999; Tonack et al. 2008). Unfortunately, Charlifue et al. (1998) did not provide a clear rationale for including specific predictor variables in their models. A larger theoretical concern is the issue of response shift (also known as recalibration, reprioritization, and reconceptualization; Schwartz & Spangers 2000), which refers to a dynamic process where an individual undergoes simultaneous changes in their internal standards, values, and conceptualizations of QoL in response to health and physical functioning changes (Tate et al. 2002). Ambiguous or paradoxical findings can occur because of differences among people or changes within people regarding internal standards, values, or conceptualization of health-related QoL (Schwartz et al. 2007). As a result, the psychometric properties (e.g. validity and reliability) of measurement tools can be affected (Schwartz et al. 2007).

In terms of methodological differences, because the samples in each of the studies had different mean ages and YPI it is not surprising that there are discrepancies in reported QoL. However, when examining the QoL results by an aging parameter, YPI for example, a common finding was that regardless of age, individuals with relatively new SCI (i.e.≤5 YPI) are more likely to experience improvements to their QoL (Stensman 1994; Kemp & Krause 1999; Bushnik 2002; Putzke et al. 2002b; Bushnik & Charlifue 2005; Krause & Coker 2006; van Koppenhagen et al. 2009; DeVivo & Chen 2011; Kalpakjian et al. 2011; van Leeuwen et al. 2011) than individuals with longer term SCI (i.e. ≥6 YPI) who consistently report high and stable QoL levels (i.e. Charlifue et al. 1998; Charlifue et al. 1999; Charlifue & Gerhart 2004b; Savic et al. 2010). That is, after sustaining a traumatic SCI, the QoL of these individuals may be low and have more room to improve than those individuals with longer term SCI. In fact, Dijkers (2005) noted that the wellbeing after SCI reaches a plateau at the end of the adjustment period, which is estimated to last from two to five years (Dijkers 2005). Similarly, Whalley-Hammell (2007) reported that after a four year adjustment period, individuals with SCI feel as though as they live a normal life, and have the same problems as everyone else (Whalley-Hammell 2007). In this review, there one study however that observed no changes in QoL among individuals with ≤5 YPI (Mortenson et al. 2010). Mortenson et al. (2010) argued that the individuals may have already adjusted and experienced a response shift prior to the baseline assessment.

Although age of SCI onset does not appear to limit the potential high QoL, there are likely age-related factors that may potentially influence QoL. For example, in studies with samples with mean ages in the 20s, individuals were found to have greater improvements in life satisfaction and QoL if they were students, lived independently, had a lower level injury, had overcome past medical problems, and if they had accessible vans for transportation (Barker et al. 2009; Sakakibara et al. 2012). Among individuals in their 30s, both Putzke et al. (2002b) and Stensman (1994) found QoL to be influenced by amount of pain and interference with pain (Putzke et al. 2002b; Stensman 1994),and Kalpakjian et al. (2011) found the relationship between life satisfaction and YPI to vary depending on marital status and gender (Kalpakjian et al. 2011).

Furthermore, the nature of the control group can lead to different interpretations of the results.  A strength of Kemp and Krause‟s (1999) was the use of an able-bodied, and a control group with disability (i.e., polio) when examining issues of QoL after SCI as it provides some context to the extent of some problems for persons post-SCI (i.e. levels of depression). However, the characteristics of the control groups were significantly different to the group with SCI on some key factors. For instance, the able-bodied and polio groups were significantly older (p< 0.01) and had higher levels of education than the group with SCI (p< 0.05). As well, the polio group was comprised mostly of females, had a mean pediatric age of onset, was 50.9 years post-polio, and 90% were Caucasian, whereas the SCI group was comprised of mostly males from culturally diverse backgrounds, and who had an adult age of onset, and were only 14.5 years post-injury. This limitation was addressed in the study, but highlights that the findings should be interpreted with caution since many socio-demographic and historical factors may have influenced levels of depression and life satisfaction. Nonetheless, the finding that persons with SCI have lower QoL compared to the able-bodied population is consistent with other studies that did not meet the SCIRE inclusion criteria (Kemp & Ettelson 2001).

Finally, although a couple of studies reported declines in QoL over time (Krause 1997; Charlifue et al. 1998), subsequent papers focusing on the same cohorts at longer lengths of follow-up reported different results. For example, Charlifue et al. (1998) first reported that after 3 years of observation 76% of the sample consistently rated their overall QoL as either good or excellent, but that there were significant decreases in life satisfaction, as measured by the life satisfaction index (LSI), among older individuals, those with <30 YPI and >40 YPI, and those with complete paraplegia (Charlifue et al. 1998). At a follow up thirteen years later, Savic et al. (2010) similarly reported that 76% of the sample consistently reported overall QoL as good or excellent, with the highest life satisfaction reported at the last time point (Savic et al. 2010). Similarly, over two time points 9 years apart, Krause (1997) reported diminished satisfaction related to social and sex lives, as measured by the life situation questionnaire (LSQ)* (Krause 1997).  Lower satisfaction is corroborated in papers by Krause and Broderick (2005) and Krause and Coker (2006) which used observations from the same cohort at different lengths of follow-up (Krause & Broderick 2005; Krause & Coker 2006). However, these two papers in addition to Crewe and Krause (1990), Krause (1992), and Krause (1998), all reported significant increases in satisfaction related to employment among the same cohort over various lengths of time (Crewe & Krause 1990; Krause 1992; Krause 1998). In general, the overall and common finding from studies that followed the same cohorts over time is that global QoL tends to remain high and stable over time but when considering specific areas of QoL, fluctuations exist with some domains increasing in importance (e.g. employment) and other decreasing (e.g. social and sex lives) (Krause & Bozard 2012).

*Note: Krause 1997 used a modified version of the LSQ. Using this version, the authors also observed significant declines in satisfaction related to family relationships, emotional adjustment and control over life.

Conclusion

There is level 2 evidence from one cohort study (Mitchell & Adkins 2010) that aging has greater influence on self-rated health in people with SCI than on those without a SCI.

There is Level 4 evidence from four longitudinal studies (Bushnik 2002; Bushnik & Charlifue 2005; Krause & Broderick 2005; Krause & Coker 2006) that changes in environmental factors over time (i.e. economics; technology) may influence QoL in persons with SCI rather than the aging process per se.

There is Level 4 evidence from three longitudinal studies (Charlifue & Gerhart 2004a; Bushnik & Charlifue 2005; Krause & Bozard 2012) that community reintegration and social participation declines with age after SCI. However, these changes in community reintegration may be similar as compared to the aging general population.

There is Level 4 evidence from seven longitudinal studies (Crewe & Krause 1990; Krause 1992; Krause 1997; Krause 1998; Krause & Broderick 2005; Krause & Coker 2006; Krause & Bozard 2012) that selected domains of life satisfaction change (i.e. social life, sex life, and health decrease, and employment, finances, and adjustment increase) as one ages with an SCI.  It may be that these changes in satisfaction of certain domains are comparable to changes in the general population.

There is Level 5 evidence from one cross-sectional study (Kemp & Krause 1999) that age of SCI-onset may be an influential factor on life satisfaction.

There is Level 4 evidence from one longitudinal study (Charlifue & Gerhart 2004b) that previous perceptions of life satisfaction are predictive of later perceptions of life satisfaction.

There is Level 5 evidence from two cross-sectional studies (Kemp & Krause 1999; Barker et al. 2009) that life satisfaction is lower for persons with SCI compared to the general population.

There is Level 4 evidence from two longitudinal studies (Stensman 1994; Putzke et al. 2002a) that previous reports of pain interference after SCI, irrespective of age, are predictive of later pain interference.

There is level 4 evidence from 10 longitudinal studies that individuals with ≤5 YPI have the potential to improve their QoL (Stensman 1994; Kemp & Krause 1999; Bushnik 2002; Putzke et al. 2002b; Bushnik & Charlifue 2005; Krause & Coker 2006; van Koppenhagen et al. 2009; DeVivo & Chen 2011; Kalpakjian et al. 2011; van Leeuwen et al. 2011).

There is level 4 evidence from 4 longitudinal studies that individuals with longer term SCI (i.e., ≥6 YPI) consistently report high and stable QoL levels (Charlifue et al. 1998; Charlifue & Gerhart 2004b; Savic et al. 2010). Similarly, there is Level 4 evidence from one longitudinal study (Pershouse et al. 2012) that QoL remains stable across the lifespan even in those with long-duration SCI.

  • Selected domains of life satisfaction (i.e. social life and sex life) may decline as one ages with a SCI. Other domains (i.e., employment and finances) may improve as one ages with a SCI. It may be that these changes in satisfaction of certain domains are comparable to changes in the general population.

    Changes in environmental factors over time (i.e. economics; technology) may influence QoL in persons with SCI rather than the aging process per se.

    Community participation may decline with age after SCI.  However, these changes in community participation may be similar to the aging general population.

    Individuals with new SCI (i.e. ≤ 5YPI) consistently report improvements to their QoL, whereas, individuals with longer term SCI consistently report high and stable QoL over time.

    Age of SCI-onset may be an influential factor on life satisfaction.

    Previous perceptions of life satisfaction may be predictiveof later perceptions of life satisfaction.

    Aging has greater influence on self-rated health in people with SCI than those without a SCI.

Summary

The majority of studies for all the systems provide some important findings regarding the role of chronological age (including age of SCI onset) and YPI, but there is still lack of clarity on how all of these factors affect (individually and in combination) the individual living with SCI over time, and further work is needed to determine if SCI is indeed a model for premature aging.  It appears that the field of aging with SCI has yet to make significant advances since many of the issues and questions raised over 15 years ago (Whiteneck et al. 1993) are still relevant today.

In general, longitudinal designs are the preferred method for investigating aging, but a number of longitudinal aging-related studies of SCI are limited in scope and quality due to several methodological issues (Krause 2007).  One limitation with longitudinal research designs are problems with retaining sufficient sample size over many years to observe long term changes with aging.  Problems with attrition lead to another type of cohort effect, namely survivor effects.  Survivor effects describe those individuals who may have outlived other members in their cohort due to some unusual advantage (e.g. environmental, physiological, Adkins 2001).  Persons who remain in longitudinal studies often represent those who are healthier, wealthier, and better educated whereas persons with poorer functioning drop out or have died.  Another limitation of longitudinal designs is the possibility that data collected at an earlier time point may become obsolete due to advances or changes in measurement.  Longitudinal research is also considerably more resource intensive than cross-sectional studies in terms of cost and time.

Despite the challenges associated with longitudinal research, gaining an understanding of what changes a person with SCI may undergo over time is important to identify potential problems that can be anticipated and perhaps prevented in some cases.  This in turn may contribute to continued levels of maximum independence and overall wellbeing.  The field of aging with SCI has made some tremendous strides forward, but the dearth of knowledge in some areas highlights research opportunities that will help to resolve current challenges and more importantly provide information to fill many existing gaps.   

There is level 4 evidence that the 10 year survival rate post injury is 84-87% (Rabadi et al. 2013; Pickelsimer et al. 2010).

There is Level 4 evidence (Frisbie 2010) that the mortality rate post-SCI over a 10-year period may be 15.5% to 25.8%, and level 4 evidence (Cao et al. 2013) that the mortality rate is higher for individuals with SCI than the general population.

There is Level 4 evidence (Cao et al. 2013) that mortality may be higher for persons with SCIs at the C1-4 level than other spinal cord levels.

There is Level 4 (Frisbie 2010) to Level 5 evidence (Samsa et al. 1993) that the causes of death post-SCI are beginning to approximate those of the general population.

There is Level 5 evidence (Samsa et al. 1993; Cao et al. 2013) that life expectancy for males with SCI is lower than the general male population.

There is level 4 evidence (Rabadi et al. 2013) that older age at time of injury is a predictor of SCI-related mortality.

There is Level 5 evidence from one cross-sectional study (Bauman & Spungen 2001a) that plasma homocysteine levels are higher in persons with SCI compared to the AB population, with the greatest discrepancy in older adults with SCI (> 50 years).

There is Level 5 evidence from nine cross-sectional studies (Zlotolow et al. 1992; Huang et al. 1993; Bauman & Spungen 1994; Bauman et al. 1996; Huang et al. 1998; Bauman et al. 1999; Demirel et al. 2001; Liang et al. 2007; Wang et al. 2007) that lipid profiles are altered after SCI which may contribute to the development of cardiovascular disease. 

There is Level 4 evidence (Shiba et al. 2010) that physical capacity can be maintained long-term in male athletes with SCI.

There is Level 4 evidence from one longitudinal study (de Groot et al. 2013) that lipid profiles in adults with SCI remain stable during the 5 years after inpatient rehabilitation.

There is Level 4 evidence (Apstein & George 1998) that total cholesterol (TC), total glycerides (TG), and low-density lipoproteins (LDL) increased while LDL/high-density lipoproteins (HDL) ratios decreased for males with tetraplegia and paraplegia from the acute phase until 1 YPI.  All lipid profiles were significantly depressed compared to controls.

There is Level 4 evidence (Apstein & George 1998) that persons with tetraplegia had low HDL and elevated LDL/HDL ratios, which places them at an increased risk for coronary artery disease.          

There isLevel 5 evidence (Wang et al. 2007) that C-reactive protein levels are higher in males with SCI, which could also account for the decreases in TC, LDL, and HDL.  Elevated C-reactive protein levels may also partly explain why persons with SCI are at increased risk for accelerated atherogenesis. 

There is Level 5 evidence (Orakzai et al. 2007) that persons with SCI have greater atherosclerotic burden compared to an AB reference population.

There is Level 5 evidence from two studies that men with complete paraplegia (Petrofsky & Laymon 2002) and with complete tetraplegia (Yamamoto et al. 1999) have an abnormal (absent) heart rate response to isometric exercise.

There is Level 5 evidence that men with complete tetraplegia demonstrate increased blood pressure (Yamamoto et al. 1999) response to isometric contraction.

There is Level 5 evidence (Wang et al. 1992: 63 men; Tsitouras et al. 1995; Shetty et al. 1993) that there is lower secretion of testosterone and human growth hormone levels in men with SCI compared to AB controls.

There is Level 5 evidence from two studies (Tsitouras et al. 1995; Bauman et al. 1994) that serum IGF-I levels are impaired in persons with SCI compared to the AB population, which may be a sign of premature aging.

There is Level 5 evidence from three studies (Bauman & Spungen 1994; Jones et al. 2004; Liang et al. 2007) that glucose tolerance is impaired after SCI, which may lead to an increased risk for premature diabetes mellitus.

There is Level 5 evidence (LaVela et al. 2006) that diabetes mellitus occurs prematurely in male veterans with SCI compared to AB individuals in the general population, but not veteran controls.

There is Level 5 evidence (Lewis et al. 2010) that men with SCI have slower plasma-free cortisol responses than AB controls.

There is Level 4 evidence from three longitudinal studies (de Groot et al. 2013 & 2010; Crane et al. 2011) that BMI increases significantly over time in persons with SCI.

Sevenstudies (Nuhlicek et al. 1988; Bauman et al. 1996; Bauman et al. 1999; Spungen et al. 2000; Jones et al. 2003; Jones et al. 2004; Emmons et al. 2011) provide Level 5 evidence that persons with SCI are likely to have higher levels of fat mass, and that age-related declines of lean tissue in males with SCI may occur at a significantly faster rate than the AB population.

There is Level 5 evidence from one monozygotic twin study (Bauman et al. 2004) that basal and resting energy expenditures are lower in males with SCI compared to their AB twin.

There is Level 5 evidence from one cross-sectional study (Hosier et al. 2012) that post-menopausal women with SCI have cardiometabolic risk profiles that are similar to those observed in women without SCI.

There is Level 4 evidence that persons with SCI have a prevalence of anemia and hypoalbuminemia (Frisbie 2010), which might serve as markers for infection.

There is Level 5 evidence (Campagnolo et al. 1994; Campagnolo et al. 1999; Furlan et al. 2006) that the immune function of persons with acute and chronic SCI is compromised compared to the able-bodied population, but there is no influence due to aging.

There is Level 4 evidence from 9longitudinal studies (Biering-Sorensen et al. 1990; Garland et al. 1992; Wilmet et al. 1995; de Bruin et al. 2000; Frey-Rindova et al. 2000; Garland et al. 2004; de Bruin et al. 2005; Frotzler et al. 2008; Dudley-Javorski & Shields 2010) and Level 5 evidence from 15studies (Chow et al. 1996; Szollar et al. 1997a; Szollar et al. 1997b; Szollar et al. 1998; Bauman et al. 1999; Dauty et al. 2000; Kiratli et al. 2000; Garland et al. 2001b; Vlychou et al. 2003; Eser et al. 2004; Giangregorio et al. 2005; Slade et al. 2005; Dudley-Javorski & Shields 2010; Rittweger et al. 2010; Dionyssiotis et al. 2011) that there is a rapid loss of bone in the hip and lower extremities following SCI.

There is Level 2 evidence (Frotzler et al. 2008) and Level 5 evidence (Eser et al. 2004) that tibial and femoral bone geometry and density properties reach a new steady-state within 3-8 year post injury, with the time frame depending on bone parameter and skeletal site.

There is Level 5 evidence from three studies (Szollar et al. 1997a; Szollar et al. 1998; Garland et al. 2001b) that older males and females with SCI may not experience as rapid of a decline in bone mass compared to AB controls.

There is Level 5 evidence from two studies (Bauman et al. 1999; Garland et al. 2001b) that YPI may be more associated with bone loss after SCI than chronological age.

There is Level 5 evidence (Slade et al. 2005) that there are differences in bone geometric indices and in structural properties in the lower extremities of women with SCIcompared to the AB women.

There is Level 5 evidence from five studies (Finsen et al. 1992; Vaziri et al. 1994; Bauman et al. 1995; Szollar et al. 1998; Dauty et al. 2000) suggesting that there are impaired biochemical and bone markers in persons with SCI compared to AB controls that persons with SCI are at greater risk for fracture due to the premature development of osteoporosis.

There is Level 2 evidence from a longitudinal study with AB controls (Catz et al. 1992), Level 4 evidence from a longitudinal study (Biering-Sorensen et al. 1990), and Level 5 evidence from five studies (Chow et al. 1996; Szollar et al. 1997a; Szollar et al. 1997b; Szollar et al. 1998; Garland et al. 2001b) that premature aging does not occur in the lumbar spine after SCI.  The possibility that the lumbar spine becomes the primary weight-bearing region, along with immobilization, may serve to protect age-related bone loss changes to this region.

There is Level 5 evidence (Amsters & Nitz 2006) that persons with SCI, regardless of age or YPI, had increased thoracic kyphosis compared to AB controls.

There is Level 5 evidence from two studies (Pentland & Twomey 1994; Petrofsky & Laymon 2002) that decreased hand grip strength does not occur in men with complete paraplegia and that continual wheelchair use may retard this aging process.

There is Level 5 evidence (Pentland & Twomey 1994) that upper limb pain in males with complete paraplegia who use manual wheelchairs may be attributed to longer YPI and not to chronological age.

There is Level 2 evidence from two longitudinal studies (Siddall et al. 2003; Jensen et al. 2005) showing that the incidence of shoulder pain increases over time in persons with SCI.

There is Level 2 evidence from a longitudinal study (Lal 1998) and Level 5 evidence (Kivimäki & Ahoniemi 2008) that highlights chronological age having an important influence on developing shoulder pain.

There is Level 4 evidence from two longitudinal studies (Bach & Wang 1994; Berlowitz et al. 2005) support that SDB may either increase or persist with the aging process.

There is Level 2 evidence from a longitudinal study with AB controls (Loveridge et al. 1992) that seated breathing patterns are compromised immediately post injury but recover over time.  As well, persons with tetraplegia do not take deep breaths as often as AB individuals.

There is Level 4 evidence from a longitudinal study that adults over the age of 50 who are aging with ventilator dependency are at greater risk of death and are less likely to be weaned from their ventilators than younger adults aging with a ventilator (Wicks & Menter 1986).  

There is Level 4 evidence from one longitudinal study (Postma et al. 2013) that forced vital capacity improves 5 years after inpatient rehabilitation.

There is Level 4 evidence (Putzke et al. 2002a; Siddall et al. 2003; Rintala et al. 2004; Jensen et al. 2005) that the early onset of SCI-related pain is likely to be maintained over time, with some evidence indicating that the degree of interference experienced might be affected by age of onset (Jensen et al. 2005).

There is Level 2 evidence (Vaziri et al. 1992) suggesting that plasma fibronectin, as an indicator of wound healing, may rise in SCI male patients with fast healing ulcers but not in SCI patients with poor healing ulcers.

There is Level 5 evidence that the biomechanical skin properties are significantly influenced by sympathetic paralysis rather than somatic sensory paralysis.  Furthermore, in men with complete SCI, YPI may be the influential factor on the biomechanical properties of the skin (Park et al. 2011).

There is Level 4 evidence (Viera et al. 1986; DeWire et al. 1992; MacDiarmid et al. 1995; Sekar et al. 1997) that there are no differences in renal functioning up to 4 YPI using various bladder management techniques with some decline occurring beyond that time.

There is Level 4 evidence (Lamid et al. 1988) that repeated episodes of vesicoureteral reflux can cause kidney damage as early as four YPI in some persons with SCI.

There is Level 4 evidence (Sekar et al. 1997) that renal plasma flow declines until 10 YPI after SCI, at which time, a slight reversal occurs.

There is Level 5 evidence (Kuhlemeier et al. 1984b) that suggests age of SCI onset may be an important factor related to renal function, with persons with SCI who are under 20 and older than 50 having comparable renal function to AB controls, whereas persons between those ages have impaired functioning compared to the general population.

There is Level 5 evidence (Lynch et al. 2000) demonstrating a deterioration in bowel continence with increasing age in an AB population but no change with age in persons with SCI.

There is Level 4 evidence (Faaborg et al. 2008) suggesting persons with SCI do incur an increase in constipation-related symptoms and decrease in fecal incontincence over time.

There is Level 4 evidence (Faaborg et al. 2011) that gastrointestinal transit times and colonic dimensions do not change over time in persons with SCI.

There is Level 5 evidence from three studies (Menardo et al. 1987; Krogh et al. 2000; Emmanuel et al. 2009) that level of injury, and not necessarily age or YPI, plays a primary role in the extent of bowel dysfunction.

There is Level 3 evidence (Jensen et al. 2013) from a scoping review that cardiovascular disease, diabetes, bone mineral density loss, fatigue and respiratory complications or infections occur with higher frequency in older individuals or those with longer SCI duration, relative to younger individuals or those with shorter SCI duration.

There is Level 4 evidence (Ullrich et al. 2013) from one longitudinal study that co-occurrence of pain and depression is common among persons who have lived with SCI for many years and remains stable over time. There is also evidence that comorbid pain and depression are associated with higher severity of conditions, more persistent conditions over time, and more utilization of SCI specialty health-care services.

There is Level 4 evidence (Hitzig et al. 2010; Pershouse et al. 2012) that secondary health complications increase over time in persons with SCI, (with the exception of bowel problems, which decrease).

There is Level 4 evidence from a longitudinal study (Charlifue et al. 1999) that fatigue and the need for physical assistance increases over time with SCI.

There is level 4 evidence from one retrospective longitudinal study (Pershouse et al. 2012) that functional independence decreases with more years post injury for individuals who were higher functioning at one year.

There is Level 4 evidence from one longitudinal study (Amsters et al. 2005) that individuals with SCI (³20 YPI) perceive functional improvements up to 10 YPI and subsequent functional decline and greater dependence on mobility aids after 10 or more YPI.  

There is level 2 evidence from one cohort study (Mitchell & Adkins 2010) that aging has greater influence on self-rated health in people with SCI than on those without a SCI.

There is Level 4 evidence from four longitudinal studies (Bushnik 2002; Bushnik & Charlifue 2005; Krause & Broderick 2005; Krause & Coker 2006) that changes in environmental factors over time (i.e. economics; technology) may influence QoL in persons with SCI rather than the aging process per se.

There is Level 4 evidence from three longitudinal studies (Charlifue & Gerhart 2004a; Bushnik & Charlifue 2005; Krause & Bozard 2012) that community reintegration and social participation declines with age after SCI. However, these changes in community reintegration may be similar as compared to the aging general population.

There is Level 4 evidence from seven longitudinal studies (Crewe & Krause 1990; Krause 1992; Krause 1997; Krause 1998; Krause & Broderick 2005; Krause & Coker 2006; Krause & Bozard 2012) that selected domains of life satisfaction change (i.e. social life, sex life, and health decrease, and employment, finances, and adjustment increase) as one ages with an SCI.  It may be that these changes in satisfaction of certain domains are comparable to changes in the general population.

There is Level 5 evidence from one cross-sectional study (Kemp & Krause 1999) that age of SCI-onset may be an influential factor on life satisfaction.

There is Level 4 evidence from one longitudinal study (Charlifue &Gerhart 2004b) that previous perceptions of life satisfaction are predictive of later perceptions of life satisfaction.

There is Level 5 evidence from two cross-sectional studies (Kemp & Krause 1999; Barker et al. 2009) that life satisfaction is lower for persons with SCI compared to the general population.

There is Level 4 evidence from two longitudinal studies (Stensman 1994; Putzke et al. 2002a) that previous reports of pain interference after SCI, irrespective of age, are predictive of later pain interference.

There is level 4 evidence from 10 longitudinal studies that individuals with ≤5 YPI have the potential to improve their QoL (Stensman 1994; Kemp & Krause 1999; Bushnik 2002; Putzke et al. 2002a; Bushnik & Charlifue 2005; Krause & Coker 2006; van Koppenhagen et al. 2009; DeVivo & Chen 2011; Kalpakjian et al. 2011; van Leeuwen et al. 2011).

There is level 4 evidence from 4 longitudinal studies that individuals with longer term SCI (i.e., 6 YPI) consistently report high and stable QoL levels (Charlifue et al. 1998; Charlifue & Gerhart 2004b; Savic et al. 2010). Similarly, there is Level 4 evidence from one longitudinal study (Pershouse et al. 2012) that QoL remains stable across the lifespan even in those with long-duration SCI.

Key Points

Life Expectancy

  • Life expectancy for males with SCI is likely lower than the general male population.
  • Persons injured at a younger age will likely have a longer life expectancy than persons injured at an older age.
  • Causes of death post-SCI may be similar to those of the general population.


SCI and Premature Aging

  • SCI may represent a partial model for premature aging.
  • There is strong evidence that the endocrine and musculoskeletal systems are prematurely aging, while there is limited evidence for the respiratory, skin and subcutaneous tissues, genitourinary, and gastrointestinal systems. 
  • There is weak and limited evidence that the immune and nervous system are prematurely aging.


Cardiovascular

  • Greater levels of arthersclerotic burden, higher levels of C-reactive protein levels and abnormal lipid profiles compared to the able-bodied population increases the risk for the development of cardiovascular disease in persons with SCI.
  • Men with complete SCI have abnormal heart rate and blood pressure responses to isometric exercise compared to able-bodied controls, which are indicative of altered autonomic control, but this may not represent premature aging.


Endocrine

  • Impaired secretion of both testosterone and human growth hormone in men with SCI may be due to SCI, and not from advancing age per se.
  • Serum IGF-I levels may be impaired compared to the able-bodied population, which may be a sign of premature aging.
  • Glucose tolerance and slower plasma-free cortisol responses may be impaired in persons with SCI, which may lead to an increased risk for premature diabetes mellitus.
  • Persons with SCI are at higher risk for the development of cardiovascular disease and diabetes mellitus than the able-bodied population.


Body Mass

  • Persons with SCI may have higher levels of fat mass than the able-bodied population. Although BMI increases over time in people with SCI, an active lifestyle may help to preserve physical capacity.
  • Age-related declines of lean tissue in males with SCI may occur at a significantly faster rate than the able-bodied population.
  • Body mass index increases over time in persons with SCI.


Hematological / Immunological

  • Age of onset may not influence hematologic abnormalities at the acute phase post-SCI (within first week post-injury).
  • Immune function after SCI at both the acute and chronic phase is compromised compared to able-bodied controls, but age may not play an important role.


Musculoskeletal

  • Premature aging may occur in the femoral and hip regions in persons with SCI.  It may be that declines in bone mass occur rapidly following injury, and reach a new steady-state within 3-8 years post-injury, depending on the bone parameter and skeletal site.
  • Older males and females (> 60 years) with SCI may not experience rapid declines in bone mass in certain regions when compared to able-bodied controls.
  • Duration of injury may be more associated with bone loss after SCI than chronological age.
  • Women with complete SCI may be at a greater risk for fracture at the knee compared to males with SCI and the able-bodied population.
  • Premature aging may not occur in the lumbar spine after SCI.
  • Premature aging may not occur in hand grip strength in men with complete paraplegia.  Rather, continual wheelchair use may retard the aging process in relation to handgrip strength.
  • Regardless of age or years post-injury, persons with SCI may have increased thoracic kyphosis than the able-bodied population.


Pain

  • Upper limb pain in males with complete paraplegia may be attributed to longer durations of injury and not to the aging process.
  • The incidence of shoulder pain increases over time, and that age of onset may contribute to the development of pain.  Adults with SCI (< 10 years post-injury) who were 30 years and older were more likely to report shoulder pain over time than those who were less than 30 years of age.
  • Younger persons (< 30 years) may have less pain interference at one and at two years post-injury than older persons (> 60 years).
  • Previous reports of pain interference after SCI, irrespective of age, may be predictive of later pain interference.


Respiratory

  • Persons with SCI may have reduced lung capacity compared to able-bodied controls, but this reduction is due to SCI and not aging.
  • Sleep disordered breathing may increase or persist with the aging process in persons with SCI.
  • Seated breathing patterns after tetraplegia are compromised early post-injury but recover over time. 
  • Adults who are older (50 years +) and ventilator dependent have a higher mortality rate and lower weaning rate than adults who are younger and who are ventilator dependent. 


Dermal

  • Males with SCI have higher levels of collagen metabolite, glu-gal Hyl, than the able-bodied population, which may be a sign of premature aging of the skin.  Further work is needed to conclusively demonstrate this.
  • Behavioural factors play a stronger role in the development of pressure ulcers in persons with SCI than either age or years post injury.


Genitourinary and Gastrointestinal

  • Various bladder management techniques (indwelling catheterization versus intermittent catheterization) may not impact renal functioning in persons with SCI over time.
  • Repeated episodes of vesicoureteral reflux can cause kidney damage as early as four years post-injury.
  • After SCI, renal plasma flow declines until 10 years post-injury, at which time, a slight reversal occurs.
  • Age of onset may play a role in minimizing renal decline; adults who are under 20 and older than 50 have comparable renal functioning to the able-bodied population, but those between 20 and 50 years of age have impaired functioning.
  • Bowel incontinence increased with age in the able-bodied population but does not change in persons with SCI.
  • Persons with SCI may experience an increase in constipation-related symptoms and decrease in fecal incontinence over time.
  • Level of injury, and not age or years post-injury, plays a primary role in the extent of bowel dysfunction.


Secondary Complications of Multiple Systems

  • Fatigue and the need for physical assistance may increase over time with SCI.
  • The number of secondary health complications increases with more years post injury.
  • The incidence and severity of UTIs decrease over time in persons with SCI but prevalence of pressure sores remains stable.
  • The co-occurrence of pain and depression is common in persons who have lived with SCI for many years


Functional Independence

  • Functional independence decreases with more years post injury.


Quality of Life and Community Reintegration

  • Selected domains of life satisfaction (i.e., social life and sex life) may decline as one ages with a SCI. Other domains (i.e., employment and finances) may improve as one ages with a SCI. It may be that these changes in satisfaction of certain domains are comparable to changes in the general population.
  • Changes in environmental factors over time (i.e., economics; technology) may influence QoL in persons with SCI rather than the aging process per se.
  • Community participation may decline with age after SCI. However, these changes in community participation may be similar to the aging general population.
  • Individuals with new SCI (i.e. ≤ 5YPI) consistently report improvements to their QoL, whereas, individuals with longer term SCI consistently report high and stable QoL over time.
  • Age of SCI-onset may be an influential factor on life satisfaction.
  • Previous perceptions of life satisfaction may be predictive of later perceptions of life satisfaction.
  • Aging has greater influence on self-rated health in people with SCI than those without a SCI.

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Autonomic Dysreflexia

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Abbreviations

ACE            angiotensin I-converting enzyme

AD               autonomic dysreflexia                                            

AIS              ASIA Impairment Scale

AUA            American Urological Association

BND            bladder neck disorder

BoNT-A       botulinum toxin A

BP               blood pressure

DBP            diastolic blood pressure

DESD          detrusor external sphincter dyssynergia

DVT            deep vein thrombus

ECG            electrocardiogram

FES             functional electrical stimulation

HR              heart rate

IEMG          integrated electromyography

IIQ-7            Incontinence Impact Questionnaire

IU                international unit (measurement unit of drugs)

IV                intravenous

M/F             male/female

NBD            neurogenic bowel disorder

Para            paraplegic

PDE5          phosphodiesterase type 5

QoL             quality of life

RCT            randomized controlled trial

RTX            resiniferatoxin

SBP            systolic blood pressure

SCI              spinal cord injury

Tetra           tetraplegic

TURS          transurethral sphincterotomy

UDI-6          Urogenital Distress Inventory

UUT            upper urinary tract

UTI              urinary tract infection

Introduction

Autonomic dysreflexia (AD) is a clinical emergency in individuals with spinal cord injury (SCI).  It commonly occurs in individuals with injury at level T6 and above (Mathias & Frankel 1988; Karlsson 1999; Teasell et al. 2000; Mathias & Bannister 2002).  An episode of AD is usually characterized by acute elevation of arterial blood pressure (BP) and bradycardia (slow heart rate), which, on occasion, may be replaced by tachycardia (rapid heart rate).  Objectively, an increase in systolic BP greater than 20–30mmHg is considered a dysreflexic episode (Teasell et al. 2000). Individuals with cervical and high thoracic SCI have resting arterial BPs that are approximately 15 to 20 mmHg lower than able-bodied individuals (Mathias & Bannister 2002; Claydon & Krassioukov 2006). As such, acute elevation of BP to normal or slightly elevated ranges could indicate AD in this population. Intensity of AD can vary from asymptomatic (Linsenmeyer et al. 1996), mild discomfort and headache to a life threatening emergency when systolic blood pressure can reach 300mmHg (Mathias & Bannister 2002) and symptoms can be severe.  Untreated episodes of autonomic dysreflexia may have serious consequences, including intracranial hemorrhage, cardiac complications, retinal detachments, seizures and death (Yarkony et al. 1986; Pine et al. 1991; Eltorai et al. 1992; Vallès et al. 2005).  During an episode of AD, a significant increase in visceral sympathetic activity with coronary artery constriction can result in myocardial ischemia, even in the absence of coronary artery disease (Ho & Krassioukov 2010).

It has been observed that the higher the level of the SCI, the greater the degree of clinical manifestations of cardiovascular dysfunctions (Mathias & Frankel 1992; Curt et al. 1997; Krassioukov et al. 2003). Another crucial factor affecting the severity of AD is the degree of completeness of spinal injury as only 27% of incomplete tetraplegics presented with signs of AD compared to 91% of tetraplegics with complete lesions (Curt et al. 1997).  AD is three times more prevalent in tetraplegics with a complete injury, in comparison to those with an incomplete injury (Curt et al. 1997).  It is important to note, however, that although autonomic dysreflexia occurs more often in the chronic stage of spinal cord injury at or above the 6th thoracic segment, there is clinical evidence of early episodes of autonomic dysreflexia within the first days and weeks after the injury (Silver 2000; Krassioukov et al. 2003).

Pathophysiology of AD

AD is most commonly triggered by urinary bladder or colon irritation.  However, many other causes have been reported in the literature (Teasell et al. 2000; Mathias & Frankel 2002).  AD is caused by massive sympathetic discharge triggered by either noxious or non-noxious stimuli below the level of the SCI (Krassioukov & Claydon 2006).  Numerous reports of AD have been described in the literature: episodes are usually short-lived either due to treatment or inherently self-limiting.  However, there are reports of AD triggered by a specific stimulus, which then continued to be present for a period of days to weeks (Elliott & Krassioukov 2006). 

Numerous mechanisms have been proposed for the development of AD.  It is known from animal studies that autonomic instability following SCI results from plastic changes occurring within the spinal and peripheral autonomic circuits in both the acute and chronic stages following injury (Mathias & Frankel 1988; Teasell et al. 2000; Mathias & Frankel 2002; Krassioukov 2006).  The destruction of the descending vasomotor pathways results in the loss of inhibitory and excitatory supraspinal input to the sympathetic preganglionic neurons; this is currently considered the major contributor to unstable blood pressure control following SCI (Furlan et al. 2003).  Furthermore, there is significant animal and human evidence suggesting that plastic changes within the spinal cord (specifically spinal sympathetic neurons and primary afferents) underlies the abnormal cardiovascular control and the development of AD following SCI.  Altered sensitivity of peripheral alpha-adrenergic receptors (receptors in the sympathetic nervous system) is one mechanism that may contribute to AD (Osborn et al. 1990; Arnold et al. 1995; Krassioukov & Weaver 1995, 1996; Karlsson 1999; Krassioukov et al. 1999; Krassioukov et al. 2002).

Table 1: Signs and Symptoms

Systematic Review on AD

As knowledge is growing in the field of AD management in the SCI population, it is important to regularly review the literature and ensure that the information used both in research and practice is current and evidence-based. The aim of this section is to provide an overview of the current systematic reviews available in this area related to AD management in the SCI population.

Table 2: Systematic Review on AD

Discussion

We found two systematic reviews looking at the effectiveness of AD management interventions.

Courtois et al. (2012) reported that 37 papers on the specific treatment of AD showed that nifedipine, prazosin, captopril and clonidine are candidates in the context of sexual activity. Krassioukov et al. (2009) found strong evidence that intravesical resiniferatoxin and intersphincteric anal block with lidocaine were effective inthe prevention of AD episodes. The same authors also found evidence that nifedipine is useful in the prevention of dangerous blood pressure elevation during diagnostic or therapeutic procedures. Krassioukov et al. (2009) also found that topical lidocaine is not beneficial for the management of AD in SCI population. Finally, these authors found only limited evidence supporting the use of botulinum toxin injections into the detrusor muscle and no support for the use of anticholinergicsfor AD management. Although the authors found that higher quality research assessing the management of AD in the SCI population is needed, they concluded that careful evaluation of individuals with SCI and increased awareness and early recognition of possible triggers that could result in AD remains the most effective approach in AD management.

Management

There is a well-established protocol for the management of AD developed by the Consortium for Spinal Cord Medicine (Consortium for Spinal Cord Medicine 1997).  In patients with spinal cord injury, appropriate bladder and bowel routines, in addition to pressure sore prevention are the most effective measures for the prevention of autonomic dysreflexia. However, for each individual, the identification and elimination of specific triggers for autonomic dysreflexia should also be employed to manage and prevent episodes of autonomic dysreflexia (Teasell et al. 2000; Mathias & Frankel 2002; Blackmer 2003).

There is growing evidence that education on knowledge and management of this life-threatening condition is crucial for both medical personnel and individuals with SCI (McGillivray et al. 2009).

When AD develops, the initial management of an episode involves placing the patient in an upright position to take advantage of an orthostatic reduction in blood pressure, and the loosening of any tight clothing (Consortium for Spinal Cord Medicine 1997). Throughout the episode, the blood pressure should be checked at 5 minute intervals.  It is then necessary to search for and eliminate the precipitating stimulus where one can be identified, most commonly (in 85% of cases) related to either bladder distension or bowel impaction (Teasell et al. 2000; Mathias & Frankel 2002).  The use of antihypertensive drugs should be considered as a last resort, but may be necessary if the systolic blood pressure remains at 150 mmHg or greater following the steps outlined above (Consortium for Spinal Cord Medicine 1997). The goal of such an intervention is to alleviate symptoms and avoidthe complications associated with uncontrolled hypertension (Yarkony et al. 1986; Pine et al. 1991; Eltorai et al. 1992; Valles et al. 2005).

  • The identification of the possible trigger and a decrease of afferent stimulation to the spinal cord is the most effective prevention strategy in clinical practice.

Prevention Strategies

The most effective approach to AD is the prevention of occurrence of this disabling and life threatening condition (Braddom & Rocco 1991).  This includes careful evaluation of individuals with SCI and early recognition of possible triggers that could result in AD.  Improved clinician awareness of AD and greater attention to the need to eliminate noxious stimuli in individuals with SCI is a priority.  Clinicians, family members, and caregivers should be aware that increased afferent stimulation (e.g. via surgery, invasive investigational procedures, labour and birth) to persons with SCI will increase the risk for development of AD.  A variety of procedures can be used to prevent episodes of AD.

Prevention of AD during Bladder Procedures

Urinary bladder irritation or stimulation is the major trigger of AD following SCI (McGuire & Kumar, 1986; Linsenmeyer et al. 1996; Giannantoni et al. 1998; Teasell et al. 2000; Mathias & Frankel 2002).  A bladder management program and continuous urological follow-up are important elements of the medical care of individuals with SCI (Waites et al. 1993a; Vaidyanathan et al. 1994; Vaidyanathan et al. 2004).  An established bladder management program with intermittent catheterization or an indwelling Foley catheter allows individuals with SCI to plan for bladder emptying when convenient or necessary (Consortium for Spinal Cord Medicine 2006).  However, there are no studies that specifically assess the effect of bladder management programs on the rate of occurrence of autonomic dysreflexia. 

During the last decade, urological follow-up including annual urodynamic evaluations and cystoscopy (depending on the bladder management program), have decreased the frequency of urinary tract infections and the development of renal failure in individuals with SCI (Waites et al. 1993a; Waites et al. 1993b; DeVivo et al. 1999). However, conservative management is not always successful and alternative strategies (e.g. application of Botulinum toxin, capsaicin, anticholinergics, sacral denervation and bladder and urethral sphincter surgery) are sometimes needed to decrease afferent stimulation from the urinary bladder to prevent development of AD. In addition, urodynamic procedures and cystoscopy are associated with significant activation of urinary bladder afferents and have the potential to trigger AD (Linsenmeyer et al. 1996; Dykstra et al. 1987; Snow et al. 1978; Chancellor et al. 1993) and therefore also require strategies to reduce afferent stimulation during those procedures.

Botulinum Toxin

Injection of Botulinum toxin into the detrusor muscle is a treatment for urinary incontinence secondary to neurogenic detrusor overactivity while injection into the external urethral sphincter is a treatment for detrusor-sphincter dyssynergia and high post void residual urines.

Table 3: Botulinum Toxin and AD

Discussion

Five pre-post studies (n=132) (Dykstra et al. 1988; Schurch et al. 2000; Chen et al. 2008; Kuo 2008; Chen & Kuo 2012) found injection of Botulinum toxin into the detrusor muscle or bladder sphincter to be an effective method for treating urinary incontinence or retention secondary to neurogenic detrusor overactivity and bladder sphincter dyssynergia.  In these conditions, injections of the Botulinum toxin either allowed increased urinary bladder capacity (i.e. reduced overactivity of the bladder) or facilitated improved evacuation of urine (reduced bladder sphincter dyssynergia). The duration of effect was reported to last up to 9 months (Schurch et al. 2000).  All studies were level 4 and showed positive effects. In fact, following treatment with Botulinum toxin, 3 individuals reported fewer episodes of AD (Kuo 2008), 4 individuals reported decreased frequency and intensity of AD (Chen et al. 2008), 3 individuals who experienced severe AD during bladder emptying reported disappearance of these symptoms altogether (Schurch et al. 2000), 3 individuals reported AD was completely resolved (Chen & Kuo 2012), and 18 individuals experienced improvement in AD symptoms (Chen & Kuo 2012).  While the evidence suggests that Botulinum toxin may be a viable treatment for neurogenic detrusor overactivity, the evidence supporting the application of Botulinum toxin specifically for the prevention of AD is inconclusive.

Conclusion

  • There is level 4 evidence (from 5 pre-post studies) (Dykstra et al. 1988; Schurch et al. 2000; Chen et al. 2008; Kuo 2008; Chen & Kuo 2012) that Botulinum toxin injections into the detrusor muscle or external urethral sphincter seem to be a safe and valuable therapeutic option in SCI patients who perform clean intermittent self-catheterization and have incontinence resistant to anticholinergic medications.

  • Botulinum toxin injections into the detrusor muscle or external urethral sphincter seem to be a safe and valuable therapeutic option in SCI patients who perform clean intermittent self-catheterization and have incontinence resistant to anticholinergic medications. Its use in the prevention of AD is less well defined.

Intravesical Capsaicin

Capsaicin is an extract from red pepper and exerts a selective action on certain sensory nerves, most notably those involved in reflex contractions of the bladder after spinal cord injury.

Table 4:  Capsaicin

Discussion

One RCT (n=23) (Giannantoni et al. 2002) and one pre-post study (n=7) (Igawa et al. 2003) evaluated the effect of capsaicin.  Capsaicin exerts a selective action on those sensory nerves involved in reflex contractions of the bladder after SCI. In their pre-post study, Igawa et al. (2003) demonstrated that intravesical capsaicin decreased episodes of AD in patients with SCI during catheterization, thereby suggesting the therapeutic potential of intravesical capsaicin for both AD and detrusor hyperreflexia in SCI patients (Igawa et al. 2003).   Giannantoni et al. (2002) in a high quality RCT (PEDro=6) used an analogue of capsaicin (resiniferatoxin RXT) that is more than 1,000 times more potent in desensitizing C-fiber bladder afferents and found reduced episodes of AD (Giannantoni et al. 2002). In addition, investigators found that intravesical administration of resiniferatoxin was superior to that of intravesical capsaicin in terms of urodynamic results and clinical benefits in SCI patients within 60 days of treatment and did not cause the inflammatory side effects associated with capsaicin. Long-term effects of capsaicin or resiniferatoxin on AD, however, have not been evaluated.

Conclusion

There is level 4 evidence (from 1 pre-post study) (Igawa et el. 2003) that intravesical capsaicin is effective for reducing episodes of AD in SCI.

There is level 1 evidence (from 2 RCTs) (Kim et al. 2003; Giannantoni et al. 2002) that intravesical resiniferatoxin is effective for reducing episodes of AD in patients with SCI.

There is level 1 evidence (from 1 RCT) (Giannantoni et al. 2002) that intravesical resiniferatoxin is more effective than intravesical capsaicin.

  • Capsaicin and its analogue, resiniferatoxin, are effective in reducing the episodes of AD in patients with SCI.

Anticholinergics

Anticholinergics are a class of medications that inhibit the binding of the neurotransmitter acetylcholine to its receptors.  Acetylcholine is released by the parasympathetic nerve fibers innervating the urinary bladder and contributes to detrusor contraction and activation of the bladder afferents.  These afferent stimuli activate spinal sympathetic circuits that trigger AD.  In theory, anticholinergic agents could therefore decrease afferent activation, and consequently AD.

Table 5:  Anticholinergics

Discussion

Only one study, employing an observational cross-sectional design (n=48), has examined the use of anticholinergics (Giannantoni et al. 1998).  These authors did not observe a correlation between anticholinergic drugs and reduced incidence of AD, unless treatment resulted in detrusor areflexia.

Conclusion

  • There is level 5 evidence that anticholinergics (from 1 observational study) (Giannantoni et al. 1998) are not associated with reduced incidence of AD episodes.

  • Anticholinergics do not appear to be sufficient for the management of AD in SCI.

Sacral Denervation

When detrusor hyperreflexia post SCI does not respond to conservative treatment, and patients are not eligible for ventral sacral root stimulation for electrically induced micturition, sacral bladder denervation may be considered as a stand-alone procedure to treat urinary incontinence and AD.

Table 6: Sacral Denervation

Discussion

Three level 4 studies (aggregate n=459) (Schurch et al. 1998; Hohenfellner et al. 2001; Kutzenberger 2007) examining sacral denervation have reported conflicting results in response to this procedure.  Hohenfellner et al. reported that sacral bladder denervation is a valuable treatment option for eliminating detrusor hyperreflexia and AD in all 9 of their subjects (Hohenfellner et al. 2001).  However, in Schurch et al.’s 10 subjects, it was shown that complete bladder deafferentation does not abolish AD during bladder urodynamic investigations. In a review of 440 patients, Kutzenberger saw sacral deafferentation eliminate AD in 438 of them.

Conclusion

  • Sacral deafferentation may reduce AD during urodynamic investigations.

Bladder and Urethral Sphincter Surgery

The association between episodes of AD and the presence of detrusor sphincter dyssynergia, high intravesical pressure and urethral pressure has led to the development of surgical procedures to alleviate voiding dysfunctions and consequently AD.

Table 7:  Bladder and Urethral Sphincter Surgery

Discussion

Four surgical studies (Barton et al. 1986; Sidi et al. 1990; Perkash 2007; Ke & Kuo 2010) included indicators of AD (e.g. blood pressure changes).  An older study by Barton et al. (1986) demonstrated reduced AD with an external sphincterotomy. A long-term follow-up of patients treated with transurethral sphincterotomies showed the procedure provided subjective relief of AD and was correlated with a significant decrease in blood pressure (Perkash 2007). Additionally, post-void residual urine decreased significantly after surgery (Perkash 2007).  Similar results were found by Ke & Kuo in 2010. Patients reported decreased severity in the degree of AD during micturition, as well as significant decrease of post-void residual urine andimprovement in quality of life (QoL) indexafter bladder surgical augmentations.    

Sphincterotomies are now rarely performed due to their association with significant risks, including hemorrhage, erectile dysfunction (Ahmed et al. 2006) and the need for repeat procedures (Secrest et al. 2003).  Alternatives including intraurethral stents and Botulinum toxin injections have been investigated and shown some success (Ahmed et al. 2006; Seoane-Rodriguez et al. 2007; Pannek et al. 2011; van der Merwe et al. 2012). Augmentation enterocystoplasty has demonstrated long-term success based on urodynamic evaluation and has been found to reduce symptoms of AD (Sidi et al. 1990).  Enterocystoplasty with a Mitrofanoff procedure has become a more frequent choice of bladder augmentation in individuals with SCI due to more favorable long-term outcomes.  Memokath stent placement in the external sphincter region has demonstrated a significant reduction in post-void residual urine as well as in UTI symptoms (Pannek et al. 2011; van der Merwe et al. 2012).  Dual flange Memokath stent placement over the internal and external urethral sphincters in 28 patients with neuropathic bladder dysfunction was shown by van der Merwe et al. (2012) to reduce severe AD from 17 cases to 7 cases after stent placement.

Conclusions

  • There is level 4 evidence (based on four pre-post/case series studies) (Barton et al. 1986; Sidi et al. 1990; Perkash 2007; Ke & Kuo 2010) that urinary bladder surgical augmentations may result in a decrease of intravesical and urethral pressure and therefore diminish or resolve episodes of AD. 

    There is level 4 evidence (based on 2 case series) (van der Merwe et al. 2012; Seoane-Rodriguez et al. 2007) that an intraurethral stent decreases incidence of AD and may be an effective means for the long-term management of detrusor-sphincter dysynergia for SCI patients, including those who have previously undergone sphincterotomy.

  • Urinary bladder surgical augmentations may diminish or resolve episodes of AD.

Prevention of AD during Anorectal Procedures

The second most common cause of AD is pain or irritation within the colorectal area. Constipation, hemorrhoids, and anal fissures, all frequently observed in patients with SCI, contribute to episodes of AD (Teasell et al. 2000; McGuire & Kumar 1986; Hawkins et al. 1994; Teichman et al. 1998).  Digital stimulation, a common component of bowel routines in individuals with SCI, can also trigger AD (Furusawa et al. 2007), especially in the presence of hemorrhoids and/or anal fissures.  In addition, rectosigmoid distension and anal manipulation are common iatrogenic triggers of AD (Cosman & Vu 2005).

Table 8:  Prevention of AD during Anorectal Procedures

Discussion

In two small RCTs (n=70) (Cosman & Vu 2005; Cosman et al. 2002), investigators compared the effect of topical local anesthesia of the anorectal area to a nonmedicated control gel for the prevention of AD during anorectal procedures.  They found that anoscopy, which involves stretching the anal sphincters, was a more potent stimulus for AD than flexible sigmoidoscopy, which involves gaseous distention of the rectosigmoid.  In one randomized, double-blind, placebo-controlled trial, AD was not abolished by topical lidocaine in the rectum during the anorectal procedure (Cosman et al. 2002).  However, the same investigators in a later RCT demonstrated that intersphincteric anal block with lidocaine was effective in limiting anorectal procedure-associated AD (Cosman & Vu 2005). In one small RCT (n=25) (Furusawa et al. 2009) investigators found that topical lidocaine applied to the rectum prior to digital bowel stimulation significantly reduced systolic blood pressure and reports of AD over the duration of the bowel program when compared to the control group.

Conclusion

There is level 1 evidence (from 1 RCT) (Cosman & Vu 2005) that lidocaine anal block significantly limits the AD response in susceptible patients undergoing anorectal procedures.

There is level 1 evidence (from 1 RCT) (Cosman et al. 2002) that topical lidocaine does not limit or prevent AD in susceptible patients during anorectal procedures.

There is level 1 evidence (from 1 RCT) (Furusawa et al. 2009) that topical lidocaine may help to prevent AD during gentle bowel stimulation.

  • Lidocaine anal block can limit the AD response in susceptible patients
    undergoing anorectal procedures.

    Topical lidocaine may prevent AD during digital bowel stimulation but does not prevent AD during anorectal procedures.

Prevention of AD during Pregnancy and Labour

In North America, women represent a third of the SCI population (Ackery et al. 2004).  Approximately 3,000 American women of childbearing age are affected by SCI (Cross et al. 1992).  The ability of women to have children is not usually affected by SCI once their menstrual cycle resumes (Jackson & Wadley 1999).  There are increasing numbers of women with SCI who have healthy babies (Cross et al. 1992).  However, during labour and delivery, susceptible women with SCI are at high risk of developing uncontrolled AD (Sipski 1991; Sipski & Arenas 2006).  Recognition and prevention of this life threatening emergency is critical for managing labour in women with SCI (McGregor & Meeuwsen 1985). The majority of women with SCI above T10 experience uterine contractions as only abdominal discomfort, an increase in spasticity and AD (Hughes et al. 1991).

Table 9:  Prevention of AD during Pregnancy and Labour

Discussion

Numerous observational studies, case reports and expert opinions recommend adequate anesthesia in women with SCI during labour and delivery despite the apparent lack of sensation.  However, there are only five studies (n=59) (Cross et al. 1992; Hughes et al. 1991; Cross et al. 1991; Ravindran et al. 1981; Skowronski & Hartman 2008) with observational evidence recording the management specific to AD during labour.  The American College of Obstetrics and Gynecology emphasized that it is important that obstetricians caring for these patients be aware of the specific problems related to SCI (American College of Obstetrics and Gynecology 2002).  

Conclusion

There is level 4 evidence that women with SCI may safely give birth vaginally.  With vaginal delivery or when Caesarean delivery or instrumental delivery is indicated, adequate anesthesia (spinal or epidural if possible) is needed to reduce the episodes of AD associated with birth. 

There is level 4 and 5 evidence (from 2 case series and 2 observational studies) (Cross et al. 1992; Hughes et al. 1991; Cross et al. 1991; Showronski & Hartman 2008) that epidural anesthesia is preferred and effective for most patients with AD during labour and delivery.

  • Adequate anesthesia (spinal or epidural if possible) is needed with vaginal delivery,
    Caesarean delivery or instrumental delivery.

    Epidural anesthesia is preferred and effective for most women
    with AD during labour and delivery.

Prevention of AD during General Surgery

Despite the partial or total loss of sensation below the level of injury, surgical procedures or manipulations can potentially initiate episodes of AD.  Anesthesiologists and surgeons performing surgery on SCI patients must be aware of the interactions of the anesthetic and its effects on AD and how to prevent or manage AD during these procedures.

Table 10: Prevention of AD during Surgery

Two observational studies (Lambert et al. 1982; Eltorai et al. 1997) presented evidence that AD is a common complication during general surgery in individuals with SCI.  Up to 90% of individuals undergoing surgery with topical anesthesia or no anesthesia developed AD.  Both studies concluded that patients at risk for AD could be protected by either general or spinal anesthesia.

Discussion

Two observational studies (Lambert et al. 1982; Eltorai et al. 1997) presented evidence that AD is a common complication during general surgery in individuals with SCI.  Up to 90% of individuals undergoing surgery with topical anesthesia or no anesthesia developed AD.  Both studies concluded that patients at risk for AD could be protected by either general or spinal anesthesia.

Conclusion

There is level 5 evidence (from 2 observational studies) (Lambert et al. 1982; Eltorai et al. 1997) that indicates that patients at risk for autonomic dysreflexia are protected from developing intraoperative hypertension by either general or spinal anesthesia.

  • Anesthesiologists and surgeons dealing with SCI patients must know how to recognize the AD syndrome, how to prevent its occurrence and how to manage it.

    Anesthesia should be used during surgical procedures in individuals with SCI despite apparent lack of sensation.

Prevention of AD during FES Exercise

Functional electrical stimulation (FES) is a widely-used modality in the rehabilitation of individuals with SCI (Sampson et al. 2000; Wood et al. 2001).  Similar to any non-noxious or noxious stimuli below the level of injury, FES itself may also lead to significant afferent stimulation and trigger the development of AD (Ashley et al. 1993; Matthews et al. 1997).

Table 11: Prevention of AD during FES Exercise

Discussion

One RCT (n=7) assessed the effect of topical anaesthetic and placebo creams applied to the skin area over the quadriceps muscle 1 hour prior to FES on two different days (Matthews et al. 1997).  As cardiovascular and AD responses during FES were unaffected by topical anaesthetic cream application at the stimulation site, the authors suggested that mechanisms other than skin nociception contributed to FES-induced AD.

Conclusion

  • There is level 1 evidence (from one RCT) (Matthews et al. 1997) supporting no effect of topical anesthetic for the prevention of AD during FES.

  • Topical anesthetic is not effective for the prevention of AD during FES.

Prevention of AD with Stoma

Neurogenic bowel dysfunction is increasingly recognized as a major barrier to increasing quality of life in people with SCI. Bowel management difficulties include constipation, abdominal pain, faecal incontinence, prolonged transit time, and AD. The treatment of neurogenic bowel dysfunction with stoma usually takes place when other interventions such as transanal irrigation, pharmacological agents, etc. have failed.

Table 12: Prevention of AD with Stoma

Discussion

One cross-sectional study (n=92) completed a retrospective analysis participants who had stomas. Following stoma surgery, significantly fewer respondents reported AD associated with bowel management (37% before, 18% after).

Conclusion

There is level 4 evidence (Coggrave et al. 2012) that AD associated with bowel management decreases following stoma surgery.

Prevention of AD in Acute Care

The primary mechanisms of SCI are irreversible, therefore, prevention of AD in acute care are mainly focused on the attenuation of the effects of secondary injuries which are delayed, prolonged, and reversible.

Table 13: Prevention of AD in Acute Care

Discussion

One prospective study (Chen et al. 2012, n=295) examined differences in morbidity of AD in patients with acute SCI treated with surgical decompression at different times (urgent, early and delayed). The study found that patients in the urgent and early surgical decompression groups had lower AD incidence post-operatively and at 6 months follow-up.

Conclusion

There is level 4 evidence from one prospective study (Chen et al. 2012) that earlier surgical decompression after acute SCI results in decreased AD incidence as compared to delayed surgical compression.

Management of Acute AD Episodes

Despite appropriate preventative strategies, AD remains common among individuals with SCI.  As previously noted, especially in individuals with cervical or high thoracic injuries, episodes of AD, even accompanied by a significant increase in arterial blood pressure, can be asymptomatic (Linsenmeyer et al. 1996; Ekland et al. 2008; McGillivray et al. 2006).The Guidelines of the Consortium for Spinal Cord Medicine for management of AD recommends employing non-pharmacological measures initially; if they fail, and systolic blood pressure continues to be at or above 150 mmHg in adults, 120 mmHg in children under 5 years old, 130 mmHg in children 6-12 years old, and 140 mmHg in adolescents, pharmacological agents should be initiated (Consortium for Spinal Cord Medicine 2006).

Non-Pharmacological Management of AD

The initial management of an episode of AD involves placing the patient in an upright position to take advantage of an orthostatic reduction in blood pressure (Consortium for Spinal Cord Medicine 2001). While there are no studies that evaluate the effect of a sit-up position on blood pressure during the episodes of AD, significant decreases in resting blood pressure have been shown during a tilt or sit-up test from supine position in individuals with SCI (Claydon & Krassioukov 2006; Krassioukov & Harkema 2006; Sidorov et al. 2007). It is proposed that an upright posture will induce pooling of blood into the abdominal and lower extremity vessels as peripheral vasoconstriction is compromised or lost following SCI; thus arterial blood pressure is reduced.  The next step is to loosen any tight clothing and constrictive devices (Consortium for Spinal Cord Medicine 2001).  This procedure will also allow more blood to pool into the vessel beds below the level of injury as well as removal of a possible trigger of peripheral sensory stimulation.  Blood pressure should be checked at a minimum of 5 minute intervals until the individual is stable (Consortium for Spinal Cord Medicine 2001), at which time it is necessary to search for and eliminate the precipitating stimulus, which in 85% of cases can be found to relate to either bladder distention or bowel impaction (Teasell et al. 2000; Mathias & Bannister 2002). The use of antihypertensive drugs should be considered as a last resort and used if the systolic blood pressure remains at 150 mmHg or greater following the steps outlined above (Consortium for Spinal Cord Medicine 2001). The goal of such an intervention is to alleviate symptoms and avoidthe complications associated with uncontrolled hypertension (Yarkony et al. 1986; Pine et al. 1991; Eltorai et al. 1992; Valles et al. 2005).

Pharmacological Management of AD

Episodes of AD in individuals with SCI can vary in severity, but in some cases can be asymptomatic and be managed by the individual once they are familiar with their own triggers and symptoms (Linsenmeyer et al. 1996).  However, in some individuals it is difficult to find the trigger for the acute blood pressure elevation and immediate medical attention is required (Elliott & Krassioukov 2006). Antihypertensive drugs with a rapid onset and short duration of action should be used in the management of acute episodes (Blackmer 2003). The Consortium for Spinal Cord Medicine recommends that if non-pharmacological measures fail and arterial blood pressure remains 150 mmHg or greater, pharmacological management should be initiated (Consortium for Spinal Cord Medicine 2001). However, the Consortium for Spinal Cord Medicine (2001) does not identify any particular medication for management of AD. Numerous pharmacological agents (e.g. nifedipine, nitrates, captopril, terzaosin, prazosin, phenoxybenamine, Prostaglandin E2, sildanefil) have been proposed for management of episodes of AD (Consortium for Spinal Cord Medicine; Blackmer 2003; Naftchi & Richardson 1997). The majority of the recommendations are based on the clinical management of hypertensive crises in able-bodied populations, as well as case reports and anecdotal evidence.  Characteristics and outcomes of studies assessing pharmacological interventions for the management of AD are presented in the following sections.

The literature supporting pharmacological management of AD using fast-acting antihypertensive drugs is specific to SCI.  Although the use of fast-acting anti-hypertensives is strongly discouraged in able-bodied populations, there is a clinical need for immediate action in individuals with SCI, due to the mechanisms of hypertensive crisis and a result of the emergent risk of intracranial bleed, myocardial infarction or death (Ho & Krassioukov 2010; Yoo et al. 2010). Episodes of AD are typically short lasting events, and could thus be well controlled with the use of short acting antihypertensive medications. Therefore, the use of these medications at a low dose and only as needed is less likely to result in the deleterious effects observed in the able bodied population when initially prescribed for the management of hypertension.

Nifedipine (Adalat, Procardia)

Nifedipine, a calcium ion influx inhibitor (Ca-channel blocker), selectively inhibits calcium ion influx across the cell membrane of cardiac muscle and vascular smooth muscle while maintaining serum calcium concentrations.  In humans, Nifedipine decreases peripheral vascular resistance and creates a modest fall in systolic and diastolic pressure (5-10mm Hg systolic although sometimes larger).  Nifedipine is generally given using the "bite and swallow" method, in a dose of 10 mg.

Table 14:  Nifedipine (Adalat, Procardia)

Discussion

Five studies (n=59) (Steinberger et al. 1990; Lindan et al. 1985; Thyberg et al. 1994; Kabalin et al. 1993; Dykstra et al. 1987) have evaluated the effects of Nifedipine; two level 2 controlled but not randomized trials (Steinberger et al. 1990; Lindan et al. 1985), and three level 4 studies (Thyberg et al. 1994; Kabalin et al. 1993; Dykstra et al. 1987).  Four of these five studies saw a reduction or alleviation of AD with nifedipine (Steinberger et al. 1990; Thyberg et al. 1994; Kabalin et al. 1993; Dykstra et al. 1987). In their non-randomized control trial, Steinberger and co-investigators (1990) reported that sublingual nifedipine decreased peak systolic, diastolic, and mean blood pressure in SCI individuals undergoing electroejaculation.  Braddom and Rocco (1991) surveyed 86 physicians with an average of 16.8 years of experience in managing AD in patients with SCI. While pharmacologic treatment of AD varied greatly from physician to physician, antihypertensive medications were the most frequently used medications with Nifedipine being a drug of choice for 48% of physicians for minor AD cases and for 58% of physicians for severe symptomatic AD cases.  Although nifedipine has been the most commonly used agent for management of AD in individuals with SCI (Thyberg et al. 1994; Dykstra et al. 1987; Esmail et al. 2002; Braddom & Rocco 1991), its use has declined recently (Frost 2002; Anton & Townson 2004). There have beenno reported adverse events from the use of nifedipine in thetreatment of AD (Blackmer 2003), although all studies had a very small sample size.  However, a review of nifedipine for the management of hypertensive emergencies not specific to SCI found serious adverse effects such as stroke, acute myocardial infarction, death and numerous instances of severe hypotension (Grossman et al. 1996). Due to several reports of serious adverse reactions occurring after administration of immediate-release nifedipine, the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure (1997) has discouraged use of this drug.

Conclusion

There is level 2 evidence (from 2 prospective controlled trials) (Steinberger et al. 1990; Lindan et al. 1985) that Nifedipine may be useful to prevent dangerous blood pressure reactions, e.g. during cystoscopy and other diagnostic or therapeutic procedures in SCI injured patients with AD. 

There is level 5 evidence (from clinical consensus) (Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure 1997), that serious adverse effects from Nifedipine may occur and these have been reported in other populations.

  • Nifedipine may be useful to prevent or control AD in SCI individuals; however, serious adverse effects from may occur similar to those reported in other populations.

Nitrates (Nitroglycerine, Depo-Nit, Nitrostat, Nitrol, Nitro-Bid)

Nitrates are used for the management of an acute episode of AD as they relax vascular smooth muscle, thus producing vasodilator effects on peripheral arteries and veins.  Dilation of post-capillary vessels, including large veins, promotes peripheral pooling of blood and reduces venous return to the heart, thereby reducing left ventricular end-diastolic pressure (pre-load) and arterial blood pressure.  On the other hand, arteriolar relaxation reduces systemic vascular resistance, which leads to reduced arterial pressure (after-load).  If sildenafil has been used within the previous 24 hours in an individual with SCI presenting with acute AD, use of an alternative short acting, rapid-onset antihypertensive agent is recommended.  Nitrates are the second most commonly used agent after nifedipine for management of AD in individuals with SCI (Consortium for Spinal Cord Medicine 2001; Braddom & Rocco 1991).  However, with the exception of one case report with intravenous use of nitroprusside (Ravindran et al. 1981) and expert opinions (Consortium for Spinal Cord Medicine 2001), no studies exist to support their use in SCI.  There is level 5 evidence (clinical consensus) (Consortium for Spinal Cord Medicine 2001; Braddom & Rocco 1991), but no clinical studies which support the use of nitrates in the acute management of AD in SCI.

Discussion

There is level 5 evidence (clinical consensus) (Consortium for Spinal Cord Medicine 2001; Braddom & Rocco 1991), but no clinical studies which support the use of nitrates in the acute management of AD in SCI.

Conclusion

  • Nitrates are commonly used in the control of AD in SCI; however, no studies have been done to show their effectiveness or safety in SCI.

Captopril

Captopril is a specific competitive inhibitor of angiotensin I-converting enzyme (ACE).  During an episode of AD, 25mg of captopril is recommended for sublingual administration.

Table 15: Captopril

Discussion

From one pre-post study (n=26) (Esmail et al. 2002), captopril was safe and effective in 4 out of 5 episodes for AD management.  This prospective open labeled study and numerous experts’ opinion suggest the use of the captopril as a primary medication in management of AD (Consortium for Spinal Cord Medicine 2001; Frost 2002; Anton & Townson 2004).

Conclusion

  • There is level 4 evidence (from one pre-post study) (Esmail et al. 2002) for the use of captopril in the acute management of AD in SCI.

  • Preliminary evidence suggests that captopril is effective for the management of AD in SCI.

Terazosin

Terazosin is a long-acting, alpha-1adrenoceptor selective blocking agent.  Selective alpha 1 blockade has been suggested as a good pharmacological choice in the management of AD because of its dual effect at the bladder level (inhibition of urinary sphincter and relaxation of the smooth muscles of blood vessels).

Table 16: Terazosin

Discussion

Regular doses of Terazosin over weeks or months were evaluated in three level 4 experimental studies (n=57) (Vaidyanathan et al. 1998; Swierzewski et al. 1994; Chancellor et al. 1994) in which it appears to be effective in preventing AD without erectile function impairment.  Patients reported moderate to excellent improvement (Chancellor et al. 1994) or even complete termination of the dysreflexic symptoms (Vaidyanathan et al. 1998) during a 3-month period of Terazosin administration.

Conclusion

  • There is limited evidence for the use of Terazosin as an agent for control

    of AD in SCI individuals.

Prazosin (Minipress)

Prazosin, a postsynaptic alpha-1 adrenoceptor blocker, lowers blood pressure by relaxing blood vessels. Prazosin has a minimal effect on cardiac function due to its alpha-1 receptor selectivity. The recommended starting dose in adults is 0.5 or 1 milligram (mg) taken two or three times a day.

Table 17: Prazosin (Minipress)

Discussion

In a small (n=15) (Krum et al. 1992), but high quality RCT, Prazosin twice daily was well tolerated and did not affect the baseline blood pressure; AD episodes were also less severe and shorter in duration over a 2 week period.

Conclusion

  • There is level 1 evidence (from one RCT) (Krum et al. 1992), that Prazosin is superior to placebo in the prophylactic management of AD.
  • Prazosin can prophylactically reduce severity and duration of AD episodes in SCI.

Phenoxybenzamine (Dibenzyline)

Phenoxybenzamine, a long-acting, adrenergic, alpha-receptor blocking agent, can increase blood flow to skin, mucosae, and abdominal viscera and lower supine and erect blood pressures.  The initial dose is 10 mg of Dibenzyline (phenoxybenzamine hydrochloride) bid with increases once daily, usually up to 20-40 mg 2-3 times/days. 

Table 18: Phenoxybenzamine (Dibenzyline)

Discussion

McGuire et al. (1976) reported that hypertension, headache and anxiety of AD could no longer be provoked with bladder filling (but sweating continued to occur) in the six subjects who took phenoxybenzamine (dose range from 10 to 20mg) daily. This result is opposite to Lindan et al.’s (1985) fingings. They reported that after talking phenoxbenzamine for 4 or more days, blood pressure still rose with bladder distension in ten subjects and remained at the base level in only two subjects.

Conclusion

  • There is level 4 evidence (from one pre-post study and one case series study) for use of Phenoxybenzamine in the management of AD; however, the results are conflicting with no effects seen in one study (Lindan et al. 1985) and positive effects in another (McGuire et al. 1976).

  • It is not known whether Phenoxybenzamine is effective for the management of AD in SCI.

Prostaglandin E2

Prostaglandin E2 is a group of hormone-like substances that contribute to a wide range of body functions including the contraction and relaxation of smooth muscle, the dilation and constriction of blood vessels and control of blood pressure.

Table 19: Prostaglandin E2

Discussion

Frankel and Mathias (1980) studied five subjects; 3 subjects underwent administration with and without Prostaglandin E2 and showed that the level of BP recorded during electrical ejaculation decreased with the drug.

Conclusion

  • There is level 2 evidence from a very small prospective controlled study (Frankel & Mathias 1980) which used subjects as their own controls and showed that the level of BP recorded during electrical ejaculation was substantially reduced with Prostaglandin E2.

  • Prostaglandin E2 is effective for reducing BP responses during eletroejactulation.

Sildenafil (Viagra)

Sildenafil inhibits phosphodiesterasetype5 (PDE5), relaxes smooth muscle, and increases levels of cGMPin, and inflow of bloodto, the corpuscavernosum.  Sildenafil at recommended doses has no effectin the absence of sexualstimulation.  The recommended doseis 50 mgtaken, as needed, approximately 1 hour before sexualactivity, but it may be taken anywhere from 0.5 hour to 4 hours before sexualactivity. Sildenafil is known to enhancethe hypotensiveeffects of nitrates. Thus, nitrates in any form are contraindicated with sildenafil use.

Table 20: Sildanefil (Viagra)

Discussion

The effect of sildenafil on AD was reported in one small RCT with 13 subjects (Sheel et al. 2005).  Although sildenafil decreased resting BP, no effect on magnitude of AD resulting from penile vibrostimulation in men with SCI was observed.

Conclusion

  • There is level 2 evidence (from 1 RCT) (Sheel et al. 1995) that sildenafil citrate had no effect on changes in BP during episodes of AD initiated by vibrostimulation in men with SCI.

  • Sildenafil has no effect on AD responses in men with SCI during ejaculation.

Other Pharmacological Agents Tested for Management of AD

While other pharmacological agents have been used to manage AD in individuals with SCI and their use has been reported in the literature (e.g. expert opinion, case report), they currently do not have sufficient evident to warrant recommendation.  These include the use of Phenazopyridine for AD associated with cystitis (Paola et al. 2003), magnesium sulfate for AD associated with labour (Maehama et al. 2000) or life-threatening AD in intensive care (Jones & Jones 2002), Diazoxide (Hyperstat) (Erickson 1980) for acute AD episodes and intrathecal baclofen for AD associated with spasticity (Kofler et al. 2009).  In addition, there have been reports of the use of beta blockers (Pasquina et al. 1998), Mecamylamine (Inversine) (Braddom & Rocco 1991) and Hydralzine (Apresoline) (Erickson 1980) for the general management of AD symptoms in individuals with SCI.  

Table 21: Other Pharmacological Agents Tested for Management of AD

Summary

  • There is level 4 evidence (from 5 pre-post studies) (Dykstra et al. 1988; Schurch et al. 2000; Chen et al. 2008; Kuo 2008; Chen & Kuo 2012) that Botulinum toxin injections into the detrusor muscle or external urethral sphincter seem to be a safe and valuable therapeutic option in SCI patients who perform clean intermittent self-catheterization and have incontinence resistant to anticholinergic medications.

    There is level 4 evidence (from 1 pre-post study) (Igawa et el. 2003) that intravesical capsaicin is effective for reducing episodes of AD in SCI.

    There is level 1 evidence (from 2 RCTs) (Kim et al. 2003; Giannantoni et al. 2002) that intravesical resiniferatoxin is effective for reducing episodes of AD in patients with SCI.

    There is level 1 evidence (from 1 RCT) (Giannantoni et al. 2002) that intravesical resiniferatoxin is more effective than intravesical capsaicin.

    There is level 5 evidence that anticholinergics (from 1 observational study) (Giannantoni et al. 1998) are not associated with reduced incidence of AD episodes.

    There is level 4 evidence (from one pre-post study and one case series study) (Hohenfellner et al. 2001; Kutzenberger 2007) that sacral deafferentation may be effective in preventing AD.

    There is level 4 evidence (based on four pre-post/case series studies) (Barton et al. 1986; Sidi et al. 1990; Perkash 2007; Ke & Kuo 2010) that urinary bladder surgical augmentations may result in a decrease of intravesical and urethral pressure and therefore diminish or resolve episodes of AD. 

    There is level 4 evidence (based on 2 case series) (van der Merwe et al. 2012; Seoane-Rodriguez et al. 2007) that an intraurethral stent decreases incidence of AD and may be an effective means for the long-term management of detrusor-sphincter dysynergia for SCI patients, including those who have previously undergone sphincterotomy .

    There is level 1 evidence (from 1 RCT) (Cosman & Vu 2005) that lidocaine anal block significantly limits the AD response in susceptible patients undergoing anorectal procedures.

    There is level 1 evidence (from 1 RCT) (Cosman et al. 2002) that topical lidocaine does not limit or prevent AD in susceptible patients during anorectal procedures.

    There is level 1 evidence (from 1 RCT) (Furusawa et al. 2008) that topical lidocaine may help to prevent AD during gentle bowel stimulation.

    There is level 4 evidence that women with SCI may give birth vaginally.  With vaginal delivery or when Caesarean delivery or instrumental delivery is indicated, adequate anesthesia (spinal or epidural if possible) is needed to reduce the episode of AD associated with birth.

    There is level 4 and 5 evidence (from 2 case series and 2 observational studies) (Cross et al. 1992; Hughes et al. 1991; Cross et al. 1991; Showronski & Hartman 2008) that epidural anesthesia is preferred and effective for most patients with AD during labor and delivery.

    There is level 5 evidence (from 2 observational studies) (Lambert et al. 1982; Eltorai et al. 1997) that indicate that patients at risk for autonomic dysreflexia are protected from developing intraoperative hypertension by either general or spinal anesthesia.

    There is level 1 evidence (from one RCT) (Matthews et al. 1997) supporting no effect of topical anesthetic for the prevention of AD during FES. 

    There is level 4 evidence (Coggrave et al. 2012) that AD associated with bowel management decreases following stoma surgery.

    There is level 4 evidence from one prospective study (Chen et al. 2012) that earlier surgical decompression after acute SCI results in decreased AD incidence as compared to delayed surgical compression.

    There is level 2 evidence (from 2 prospective controlled trials) (Steinberger et al. 1990; Lindan et al. 1985) that Nifedipine may be useful to prevent dangerous blood pressure reactions, e.g. during cystoscopy and other diagnostic or therapeutic procedures in SCI injured patients with AD. 

    There is level 5 evidence (from clinical consensus) (Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure 1997), that serious adverse effects from Nifedipine may occur and these have been reported in other populations.

    There is level 5 evidence (clinical consensus) (Consortium for Spinal Cord Medicine 2001; Braddom & Rocco 1991), but no clinical studies which support the use of nitrates in the acute management of AD in SCI.

    There is level 4 evidence (from one pre-post study) (Esmail et al. 2002) for the use of captopril in the acute management of AD in SCI.

    There is level 4 evidence (from 3 pre-post studies) (Vaidyanathan et al. 1998; Swierzewski et al. 1994; Chancellor et al. 1994) that regular use of Terazosin may have positive effects on incontinence and AD.

    There is level 1 evidence (from one RCT) (Krum et al. 1992), that Prazosin is superior to placebo in the prophylactic management of AD.

    There is level 4 evidence (from one pre-post study and one case series study)  for use of Phenoxybenzamine in the management of AD; however, the results are conflicting with no effects seen in one study (Lindan et al. 1985) and positive effects in another (McGuire et al. 1976).

    There is level 2 evidence from a very small prospective controlled study (Frankel & Mathias 1980) which used subjects as their own controls which showed that the level of BP recorded during electrical ejaculation was substantially reduced with Prostaglandin E2.

    There is level 2 evidence (from 1 RCT) (Sheel et al. 1995) that sildenafil citrate had no effect on changes in BP during episodes of AD initiated by penile vibrostimulation in men with SCI.

Key Points

  • The identification and removal of the possible trigger and subsequent decrease of afferent stimulation to the spinal cord is the most effective prevention strategy in clinical practice.

    Botulinum toxin injections into the detrusor muscle or external urethral sphincter seem to be a safe and valuable therapeutic option in SCI patients who perform clean intermittent self-catheterization and have incontinence resistant to anticholinergic medications. Its use in the prevention of AD is less well defined.

    Capsaicin and its analogue, resiniferatoxin, are effective in the management of AD in patients with SCI.

    Anticholinergics do not appear to be sufficient for the management of AD in SCI.

    Sacral deafferentation may reduce AD during urodynamic investigations.

    Urinary bladder surgical augmentations may diminish or resolve episodes of AD.

    Lidocaine anal block can limit the AD response in susceptible patients undergoing anorectal procedures.

    Topical lidocaine may prevent AD during digital bowel stimulation but does not prevent AD during anorectal procedures.

    Adequate anesthesia (spinal or epidural if possible) is needed with vaginal delivery, Caesarean delivery or instrumental delivery.

    Anesthesiologists and surgeons dealing with SCI patients must know how to recognize the AD syndrome, how to prevent its occurrence and how to manage it.

    Epidural anesthesia is preferred and effective for most women with AD during labour and delivery.

    Anesthesia should be used during surgical procedures in individuals with SCI despite apparent lack of sensation.

    Topical anesthetic is not effective for the prevention of AD during FES.

    Nifedipine may be useful to prevent or control AD in SCI individuals; however, serious adverse effects from its use may occur similar to those reported in other populations.

    Nitrates are commonly used in the control of AD in SCI; however, no studies have been done to show their effectiveness or safety in SCI.

    Preliminary evidence suggests that captopril is effective for the management of AD in SCI.

    There is limited evidence for the use of Terazosin as an agent for control of AD in SCI individuals.

    Prazosin can prophylactically reduce severity and duration of AD episodes in SCI.

    It is not known whether Phenoxybenzamine is effective for the management of AD in SCI.

    Prostaglandin E2 is effective for reducing BP responses during eletroejaculation.

    Sildenafil has no effect on AD responses in men with SCI during ejaculation.

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Bladder Management

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Introduction

Bladder dysfunction in persons with spinal cord injury (SCI) can be disabling medically, physically, and socially. Most people with SCI have some degree of bladder dysfunction.

Normally, the bladder is able to store urine with detrusor (bladder wall muscle) relaxation, at low pressures, until it is socially appropriate to void. At the appropriate time, volitional sphincter muscles relaxation, detrusor contraction, and bladder emptying is achieved in a low pressure, coordinated manner. This coordinated function is achieved by the pons micturition centre and timing is controlled by the frontal cortex. The ability to fill the bladder under low pressure is of utmost importance in maintaining health of the kidneys and maintaining continence. The ability to empty the bladder completely on a regular basis in a low pressure manner is also important in maintaining kidney health and preventing urinary tract infections.

After SCI, neural connectivity to the pons and cortex are disrupted, hence the loss of coordinated bladder filling and emptying. The main goals of bladder dysfunction management following SCI are as follows: achieving regular bladder emptying and avoiding stasis; avoiding high filling and voiding pressures; maintaining continence and avoiding frequency and urgency; and preventing and treating complications such as urinary tract infections (UTIs), stones, strictures and autonomic dysreflexia.

In the present chapter, the literature has been classified into sections pertaining to type of bladder dysfunction i.e., neurogenic overactivity (hypperreflexia) or areflexia, and then methods of treating these either pharmacologically or non-pharmacologically. This includes a section describing literature addressing various bladder management methods. Prevention of complications is best achieved with proper management of the bladder dysfunction type. The last section focuses on UTI prevention and treatment.

Types of Bladder Dysfunction in SCI

 

There are two main types of bladder dysfunction in SCI: 1) neurogenic detrusor overactivity, usually associated with sphincter dysynergia (Detrusor external spincter dyssynergia: DESD) and 2) detrusor areflexia. Occasionally detrusor overactivity secondary to SCI is seen without associated sphincter dysynergia which can result in difficulty with continence. Methods to improve continence in those with or without DESD are often similar and as such, are addressed in the sections on enhancing bladder volumes in DESD.

Detrusor Overactivity Associated with Sphincter Dysynergia (DESD)

This type of dysfunction tends to be seen in those with injuries of the spinal cord affecting the upper motor neurons. In these cases, the lack of coordination of the sphincter and the detrusor is caused by lack of coordination from the pontine micuturition centre due to the spinal cord injury. Both the detrusor and the sphincter are overactive due to lack of control and descending inhibition from the pons and cortex, and both sphincter and detrusor contract reflexively when stretched. The detrusor becomes overactive, reflexively contracting at small volumes against an overactive sphincter, resulting in high bladder pressures. This leads to incontinence (when the detrusor contracts hard enough to overcome the sphincter contraction), incomplete emptying (due to sphincter co-contraction), and reflux (due to high bladder pressures) with resultant recurrent bladder infections, stones, hydronephrosis, pyelonephritis, and renal failure.

Detrusor Areflexia

In the case of a flaccid bladder, loss of detrusor muscle tone prevents bladder emptying and leads to bladder wall damage from over-filling, urine reflux and an increase in infection risk due to stasis. The sphincter tone also tends to be flaccid (at least the external sphincter) causing incontinence, especially with maneuvers that increase intraabdominal pressure (so-called “Valsalva” maneuvers) including straining during transfers, coughing and sneezing. Internal sphincter tone may be intact due to the higher origin of sympathetic innervation, thus complete emptying, even with externally applied suprapubic pressure, may be difficult.

Compared to DESD, patients with detrusor areflexia comprise a much smaller proportion of the SCI population and there is very little literature examining the effectiveness of interventions for this patient subpopulation (patients with detrusor areflexia). Therefore, in the present review the focus is on the literature addressing DESD therapy. In some cases, individual papers may include persons with detrusor areflexia and individual treatments or management methods may still be appropriate for, and applied to those with an areflexic bladder.

DESD Therapy in SCI

Due to the small capacity bladder seen with neurogenic detrusor overactivity, the potential for high bladder pressures leading to reflux, hydronephrosis, and kidney damage, and also due to the potential for incontinence, the goals of therapy are twofold: 1) to enhance bladder volume while lowering bladder filling pressures, and 2) to empty the bladder regularly in a low pressure manner, usually with intermittent catheterization in people with an intact external sphincter, or external drainage in people that have had a procedure to physically or chemically obliterate the external sphincter. Methods to enhance bladder volumes will be discussed first. Note that this pertains to people usually on concomitant intermittent catheterization for drainage. Occasionally the volume enhancing treatments below will be used in combination with an indwelling catheter to avoid leakage around the catheter.

Enhancing Bladder Volumes Pharmacologically

Anticholinergic Therapy for SCI-Related Detrusor Overactivity

The body of the detrusor is comprised of smooth muscle that contains muscarinic receptors triggered by acetylcholine to cause muscle contraction. Therefore, to relax the detrusor and allow it to fill with higher volumes under lower pressure, anticholinergics may be used. Common marketed medications in this class for overactive bladder include oxybutynin (available as Ditropan, Ditropal XL, Oxytrol, Uromax, etc), tolterodine (available as Detrol, Detrol LA), fesoterodine (marketed as Toviaz), and more recently, trospium chloride (Trosec), propiverine hydrochloride (Mictonorm) and M3-receptor specific medications darifenacin (Enablex) and solifenacin (Vesicare). 

Table: Summary Table of Oral Anticholinergics

Discussion

Although there are numerous anticholinergics available for use in overactive bladder, few have actually been used in clinical trials for people with SCI and neurogenic detrusor overactivity. Only those that have been used for SCI-related neurogenic bladder are presented here.

Propiverine has both anticholinergic and calcium channel blocking properties, thus decreasing involuntary smooth muscle contractions. In the SCI population, a double-blind, placebo-controlled, randomized, multicentre (n=124 with 113 completers) study, utilizing 15mg tid administration of propiverine over 2 weeks yielded significant improvement of SCI detrusor hyperreflexia represented by increased maximal cystometric bladder capacity (Stohrer et al. 1999). A subsequent increase in residual urine volume was found, as is the goal in those on concurrent intermittent catheterization. Side effects (primarily dry mouth) were considered tolerable. 

Oxybutynin is an anticholinergic agent used extensively and clinically to treat overactive bladder, yet few studies have been performed on the neurogenic bladder population with this medication. Newer versions of oxybutynin in longer acting forms have sparked renewed research interest in this medication with the hopes of reducing side effects observed with the short acting oxybutynin. O’Leary et al. (2003), in a small (n=10) pre-post trial showed that controlled-release oxybutynin was efficacious for SCI individuals with detrusor hyperreflexia as reflected by significantly increased bladder volume with decreased mean number of voids per 24 hours. However, post-void residual volumes, nocturia and weekly incontinence episodes did not change significantly.

Although oxybutynin is commonly chosen to treat overactive bladder, it is accompanied by bothersome side effects such as dry mouth. A newer anticholinergic that causes less dry mouth, tolterodine, has also been shown to be efficacious for the treatment of neurogenic bladder dysfunction. In a RCT, tolterodine was shown to be significantly better at increasing intermittent catheterization (IC) volumes (p<0.0005) and reducing incontinence (p<0.001) but was similar in its effects on cystometric bladder capacity when compared to placebo (Ethans et al. 2004). This trial was small, thus at risk for type 2 error. As part of the eligibility criteria for this study, subjects were using oxybutynin and intermittent catheterization prior to a 4-day washout in advance of randomization to the tolterodine vs placebo study. This design allowed for a comparison between oxybutynin and tolterodine where the difference in effectiveness of the two drugs were found to be equivocal with respect to IC volumes, degree of incontinence and bladder capacity. Horstmann (2006) found that compared to baseline tolterodine improved reflex volumes, cystometric capacity, and maximum detrusor pressures. Although this study also evaluated trospium, the two medications were only evaluated in a pre-post manner rather than head to head comparison.

Although available in Europe for many years, trospium chloride (an anticholinergic medication that is reported not to cross the blood-brain barrier) has been approved in North America only recently for use in overactive bladder. The efficacy of trospium chloride (20mg bid) in SCI with detrusor hyperreflexia was confirmed by Stohrer et al. (1991) in a RCT. Highly significant (p<0.001) responses were found in favour of trospium chloride vs placebo for increased bladder capacity and compliance, and decreased bladder pressure with low side effects and no effect on flow rate and residual urine volumes. Horstmann et al. (2006) found that trospium chloride improved reflex volumes, cystometric capacity, and maximum detrusor pressures. Presumably the cognitive changes seen on psychometric testing with medications such as oxybutinin are not seen with this medication as it does not cross the blood brain barrier, but this has not been examined specifically in persons with SCI.

More recent investigations have been conducted to provide comparison information about the relative efficacy and presence of side effects associated with these anticholinergic options (Amend et al. 2008; Stohrer et al. 2007). Stohrer et al. (2007) showed similarities in efficacy in a comparison study of propiverine vs oxybutynin that employed a double-blind, randomized, controlled study design. Both treatments significantly improved bladder capacity and reduced maximum detrusor pressure although fewer side effects (most notably dry mouth) were evident in subjects in the propiverine group. Of note, Amend et al. (2008) examined 3 combinations of anti-cholinergics in subjects (n=27) whose initial symptoms of incontinence did not completely resolve – even with dosages doubled from manufacturer recommendations (i.e., Horstmann et al. 2006). These authors added a second anti-cholinergic medication such that participants took either: 1) tolterodine / oxybutynin, 2) trospium / tolterodine or 3) oxybutynin / trospium and demonstrated that 85% of patients were treated successfully, despite having mostly unsatisfactory outcomes with a single medication. Each initial medication was maintained at thehigh (i.e., double dose) and there were no clear combinations that were superior to the other in terms of either effectiveness or side effect profile. It should be noted that there is a concern when administering doses of mixed anti-cholinergics for their potential consequences on heart rythm which would be detected with an electrocardiogram (ECG). Neither of studies reported conducting an ECG, which raises concerns about potential abnormalities and issues incurred by those receiving a mixed dose.

In addition, Kennelly et al. (2009) reported that a transdermal method of oxybutinin was effective in increasing the proportion of clean intermittent catheterizations without leaking as well as improving various urodynamic measures (e.g., reflex volume, amplitude of detrusor contraction, maximum bladder capacity, residual urine volume) in a pre-post investigation (n=24). These positive effects were seen and more importantly there were fewer side effects than typically seen with oral delivery, even at up to three times the standard dose.   

Conclusion

  • Level 1 evidence from two RCTs supports the use of propiverine in the treatment of detrusor hyperreflexia resulting in significantly improved bladder capacity, with one of these trials showing equivalent results to oxybutinin but fewer side effects, notably dry mouth.
  • Level 1 evidence from a single RCT supports the use of tolterodine vs placebo to significantly increase intermittent catheterization volumes and decrease incontinence in neurogenic detrusor overactivity.
  • Level 2 evidence from a small single open label prospective controlled trial that tolterodine and oxybutynin are equally efficacious in SCI patients with neurogenic detrusor overactivity except that tolterodine results in less dry mouth.
  • Level 4 evidence from single pre-post trials support the potential benefits of controlled-release oxybutynin as well as a transdermal system for oxybutinin administration, the latter with reduced side effect profile.
  • Level 4 evidence from a single study suggests benefits such as reduced incontinence and increased bladder capacity from combination treatments of two of oxybutinin, trospium or tolterodine, even in patients with unsatisfactory outcomes following a trial with one of these medications.
  • Level 1 evidence from a single RCT supports the use of trospium chloride to increase bladder capacity and compliance, and decrease bladder pressure with very few side effects in SCI individuals with neurogenic bladder.
  • Propiverine, oxybutynin, tolterodine and trospium chloride are efficacious anticholinergic agents for the treatment of SCI neurogenic bladder.

    Treatment with 2 of oxybutynin, tolterodine or trospium may be effective for the treatment of SCI neurogenic bladder in those not previously responding to one of these medications.

    Tolterodine, propiverine, or transdermal application of oxybutinin likely result in less dry mouth but are similarly efficacious to oral oxybutynin in terms of improving neurogenic detrusor overactivity.

Toxin Therapy for SCI-Related Detrusor Overactivity

Botulinum toxin A (BTx-A) has been used for many disorders including strabismus, focal spasticity, hyperhydrosis, cosmetic disorders (wrinkles) and others. A newly approved indication in the USA and Canada is for neurogenic detrusor overactivity treatment in individuals with SCI and multiple sclerosis. The advantage of botulinum toxin over systemic administration of medications such as anti-cholinergics is the botulinum toxin is used focally in the bladder, thus avoids systemic side effects for the most part. There are various types of botulinum toxin available, including various types of botulinum toxin type A. When evaluating the literature in this area, one must be aware that although Dysport and Botox are both derived from botulinum toin type A, they are very different and units cannot be compared or interchanged.

The use of capsaicin (CAP), a vanilloid, as a topical temporary analgesic is not uncommon as evidenced by over-the-counter ointments available for purchase in local pharmacies, and is used in the form of a topical patch for allodynia pain in Europe. Capsaicin induced localized and reversible antinociception by capsaicin is a result of induced C-fibre conduction and subsequent neuropeptide release inactivation (Dray 1992). Although C-fibers are not involved in normal voiding, neuroplastic changes to C-fiber bladder afferent growth account for injury emergent C-fiber mediated voiding reflex (i.e., spinal detrusor hyperreflexia; deGroat 1995). Resiniferatoxin (RTX) is another vanilloid which has been studied for its similar beneficial effects, with less irritation to the bladder and is thus better tolerated. By chemically decreasing C-fiber bladder afferent influence with intravesical vanilloids (i.e., CAP, RTX) bladder contractility is decreased and bladder capacity is increased (Evans 2005). 

Table: Toxin Therapy for SCI-Related Detrusor Overactivity

Discussion

Botulinum toxin

In 2005, Schurch et al. published a trial evaluating the efficacy of onabotulinum toxin A (oBTX-A), Botox, injections into the detrusor muscle in people with SCI to reduce incontinence and increase bladder capacity. This landmark rigorous RCT evaluated botulinum toxin for neurogenic overactive bladder. The study evaluated the effects of 200 IU, 300 IU, or placebo injected into the detrusor wall. The results revealed a significant decrease in incontinence by about half for both oBTX-A groups, and a significant drop in maximum detrusor pressure. Baseline maximum detrusor pressures were 92.6cm H2O and 77.0 cm H2O in the 300 IU and 200 IU groups, respectively, and by 2 weeks had dropped to 41.0 cm H20 and 31.6 cm H20), respectively. Dramatic improvements were seen in cystometric capacity with baseline being 293 cc and 260cc in the 300 and 200 group respectively, and improving by 2 weeks to 479cc and 482 cc respectively. Mean reflex detrusor volume improved at 6 weeks in the 300 U oBTX-A group and at 24 weeks in the 200 U oBTX-A group (p<0.021). The significant improvements were mostly maintained out to 6 months, at which point the study follow-up was terminated - thus, the true duration of effect of the injection is unknown.

Ehren et al. (2007) studied a different form of abobotulinum toxin A (abBTX-A), Dysport, using 500 IU in a placebo controlled study. These authors also found improved continence, cystometric capacity, and decreased pressures. In addition, concomitant anti-cholinergic use, tolterodine, was found to be less in the botulinum toxin group.

Schurch and colleagues (2000) were also the first group to publish a large prospective trial on the use of onabotulinum toxin for neurogenic detrusor overactivity to improve incontinence and increase bladder capacity. This first trial was not placebo controlled, but given the impressive changes in objective measures such as urodynamic measures, it bears considerable significance. Pre-injection, the subjects had detrusor hyperreflexia and urge incontinence resistant to high-dose oral anticholinergic treatment and emptied their bladders by intermittent self-catheterization. By 6 weeks post injection, ninety percent of subjects were continent between catheterizations in conjunction with markedly decreased or withdrawn anticholinergic drug administration. Post-void residuals were significantly increased, which is the goal with people on intermittent catheterizations, and significant increases in cystometric bladder capacity as well as decreases in maximum detrusor voiding pressure were found. Autonomic dysreflexic hypertensive crises were abolished in the 3 patients with a history of autonomic dysreflexia. This group reported that a dose of 300 units of oBTX-A was required for successful treatment of detrusor overactivity lasting at least 9 months per injection. These results were amplified by a large scale study (n=200 - 167 with SCI) involving a retrospective case series design across 10 European centres (Reitz et al. 2004). This study showed significant improvements in a wide variety of urodynamic-related measures that were maintained for up to 36 weeks following a single procedure of botulinum toxin injections to the detrusor. Several smaller open-label studies have had similar promising results (Hajebraimi 2005, Klaphajone 2005, Patki 2006, Tow 2007, Akbar 2007, Kuo 2008, Grosse 2009, Giannantoni et al. 2009). In all of these studies, incontinence was reduced and bladder capacity increased with botulinum toxin. The unique aspects of each of these will be noted below.

Klaphajone (2005) addressed the question of low compliance bladders in people with SCI. People with poor bladder compliance had been excluded in previous large trials. In this open-label trial, the authors found that bladder compliance, bladder capacity, and reflex detrusor volume all increased and maximum detrusor pressure decreased. However, most of these effects were only seen out to 16 weeks and not to 36 weeks (or longer) as has been shown in other studies in people with compliant but spastic bladders. An evaluation between these two points of 16 weeks and 36 weeks would have been helpful to learn how long to expect effects to last in this type of neurogenic bladder.

Abobotulinum toxin, at 1000 IU, was similiarly found to have beneficial effects (Patki 2006) in an open-label trial of 37 people with SCI and drug resistant neurogenic detrusor overactivity. At mean follow up of 7 months the maximum cystometric capacity, maximal detrusor pressure, quality of life and incontinence were significantly improved, and 86% were able to stop anticholinergics.

In 2006, Kuo evaluated the effects of suburothelial injections of onabotulinum toxin A instead of intradetrusor muscle injection, in hopes of reducing risk of urinary retention in those with neurogenic bladder dysfunction who continue to exhibit voiding dysfunction (frequency, urgency, and incontinence). The proposed mechanism for effect is addressing the afferent system with known effects on the P2X3 and TRYP V1 receptors, thus presumably decreasing the reflexic activity by targeting these receptors on the afferent loop. These subjects were not on intermittent catheterization at time of enrolment although perhaps some should have been as 58% of the people with SCI had baseline post-void residual values of >150ml at baseline. Only 8/24 of the subjects had SCI, and were incomplete or complete, with levels from C6-S2. Similar beneficial effects to the other studies were seen, with 92% of subjects with SCI becoming continent, but post-void residual increased by 4 times the baseline value. Thus, although the goal of subendothelial injections was to reduce the degree of urinary retention, this goal was not achieved, and no additional benefits were seen over those seen in studies with intra-muscular injection. Head to head comparisons would be required to indicate which type of injection is better. Certainly one cannot conclude from this study that suburothelial injections protect against worsening urinary retention.

Tow et al. (2007) assessed onabotulinum toxin in an open-label fashion and added frequency of catheterizations to the outcomes. This was significantly improved at the 6 week point but not at 24 weeks. Other measures seen in the previous studies were similarly improved, but this study, as did the 2000 Schurch study, followed subjects for 9 months. Only the improvement in catheterized volumes was maintained to the 9 month mark, while most of the other improvements persisted only until the 6 month mark. This study was small (n=15) and not placebo controlled. Perhaps the reason for not reaching statistical significance for changes out to 9 months was small sample size, as Schurch et al. (2000) did find many of these same parameters attained significance at 9 months.

Giannantoni et al. (2009) prospectively followed 17 persons with motor complete SCI and bladder dysfunction due to neurogenic detrusor overactivity over a period of 6 years as they were treated with 300U of intravesical onabotulinum toxin with re-injections as required. In addition to the prolonged follow-up period, which showed continued effectiveness and minimal side effects associated with ongoing treatment, this investigation incorporated an assessment of incontinence-related quality of life. Improvements in this measure were maintained throughout the treatment period.

Akbar et al. (2007) used abobotulinum toxin in an open-label fashion with the objective of reporting effects of repeated use of botulinum toxin to the detrusor. Some of these patients had systemic weakness after injections of 1000 IU, but when reducing the dose to 750 IU this side effect subsided. The subjects were reinjected with abobotulinum when their symptoms returned or when urodynamic studies revealed a return to baseline. The repeat injections were 7.8-8.0 months apart for the first 3 injections, then 9 months for the subsequent injection, although fewer patients continued in the study to this point (11 as compared to 41 receiving 3 injections). Compliance, maximum detrusor pressure, and capacity all improved significantly with respect to baseline with all reinjections. All these numbers showed a slight gradual improvement with each subsequent injection, but statistical analysis was not performed to show if this modest improvement was significant. The same results were found in a more recent retrospective case series where the treatment was botulinum toxin type A (Pannek et al. 2009). Notably, this study was the first to indicate decreased detrusor contractility in patients may occur with repeated injections (Pannek et al. 2009).

Hori (2009) addressed patient satisfaction with detrusor injections of botulinum toxin A by way of a 5-minute questionnaire conducted via telephone. Ninety percent of people who had botulinum toxin A injections for neurogenic detrusor overactivity stated they would consider staying on this treatment long-term. This group has had a low annual withdrawal rate from this long-term treatment and a high annual new patient starting rate, prompting the authors to conclude that health care systems would be advised to incorporate this new treatment option as part of routine service provision.

A retrospective trial (Grosse 2009) compared the effects of abobotulinum toxin in doses 500-1000 IU to onabotulinum toxin in doses 200-400 IU. The different doses of abobotulinum toxin had no difference at follow up of 3.8 months, and comparison of the abobotulinum toxin group to the onabotulininum toxin group revealed no difference at 3 months. Although the effect lasted 9.5 months in the abobotulinum toxin 500 group compared to 16.1 months in the abobotulinum toxin 1000 group, this was not judged to be statistically significant, but seems to have clinical significance. The difference does raise the question of whether larger dosing may have longer lasting effects, and certainly has potential for future studies. Note in this study 9/28 in abobotulinum toxin group did not respond compared to 7/28 in the onabotulinum toxin group. One subject who received abobotulinum toxin 750 IU experienced transient hypoasthenia.

Capsaicin

deSeze et al. (1998) has provided level 1 evidence in support of the ability of CAP to improve bladder function (decrease frequency and leakages) by increasing bladder capacity. These authors found that 30 days after instillation, CAP was superior to placebo in decreasing 24h voiding freq (p=0.016), decreasing 24h leakages (p=0.0008), increasing maximal cystometric capacity (p=0.01), and decreasing maximal detrusor pressure. However, these differences were not significant and they found similar side effects in each group. This study offers soe support to other small, non-RCT studies that reported significant CAP-induced increases in bladder capacity (Das et al. 1996; Dasgupta et al. 1998).

George et al. (2007) reported use a one time instillation and reported that the “efficacy” of cystometric capacity was significant. However, when evaluating the data, it seems the significant difference was actually a significant decline in capacity at 3 hours (pre=224.6 cc, 3 hr post=139.6 cc, p=0.015) and a non-significant decline at 1 week (174.2 cc at 1 week, p=0.059). The authors claim that there was a marked, progressive and overall improvement following capsaicin except for leak point pressure. But the statistical results do not support this claim, and only leak volume was improved statistically at 2 weeks. Autonomic dysreflexia, a significant side effect, was reported in 2 patients following CAP. Although this study included blinded evaluations of oxybutynin vs propantheline instillation, CAP evaluations could not be blinded and therefore, discussion of oxybutynin vs propantheline results were undertaken separately.

The Dasgupta group (1998) confirmed presence of metaplasia, dysplasia, and flat carcinoma in situ after treatment with Intravesical capsaicin.  All biopsies were determined to be benign but some showed signs of chronic inflammation. However, neither papillary nor solid invasive cancer was detected after 5 years of follow-up. Further surveillance is required up to 10 years when chemical carcinogenic morphologies typically present.

Resiniferotoxin

deSeze et al. (2004) established that RTX was similarly effective in increasing bladder capacity when compared to CAP. CAP was significantly more effective at increasing urgency delay (p<0.01) but there was only a trend to greater maximum bladder capacity in favour of CAP. There was also a statistically significant increase with CAP, suprapubic pain, although it was clinically tolerable and brief (p<0.04). The increase in persistent clinical improvements due to RTX over CAP at 90 days follow-up was not statistically significant.

The efficacy of RTX vs placebo was confirmed in an RCT conducted by Silva et al. (2005) where they found that RTX was responsible for significantly increased volume of first involuntary detrusor contraction (FDC; 143±95mL vs184±93mL; p=0.03), maximum cystometric capacity (MCC; 115±61mL vs 204±92mL; p=0.02), decreased urinary frequency (p=0.01) and incontinence (p=0.03) with similar side effects as compared to placebo. Kim et al. (2003) confirmed the improvements in SCI bladder function and further investigated the effect of dose (single 100 ml instillation of 0.005, 0.025, 0.05, 0.10, 0.2, 0.5, 1.0 microM RTX or placebo). Despite the small sample size in each dose category, MCC increased by 53% and 48% for the two highest dosages by 3 weeks post-treatment. Similarly, incontinence episodes decreased by 51.9% and 52.7%.

Nociception/orphanin phenylalanine glutamine

Nociception/orphanin phenylalanine glutamine (N/OFG) is a heptadecapeptide (Meunier et al. 1995; Reinscheid et al. 1995) that acts on sensory innvervation of the lower urinary tract in a similar fashion to CAP and RTX. It activates the G protein coupled receptor nociceptin orphan peptide and thus has an inhibitory effect on the micturition reflex in the rat (Lecci et al. 2000). Following a successful preliminary human study, Lazzeri et al. (2003) confirmed that N/OFG versus placebo is responsible for a significant increase in bladder capacity (p<0.001) and threshold volume of detrusor overactivity (p<0.001), and a non-significant decrease of maximum bladder pressure of the dysfunctional neurogenic bladder. These results were verified in an additional small-scale RCT (n=18) of a 10 day course of N/OFG treatment vs placebo (saline). Statistically significant improvements to bladder capacity (assessed by daily voiding diary) and urine leakage episodes were seen in the treated group but not with placebo (Lazzeri et al. 2006). The authors conclude that this inhibition of the micturition reflex supports nociceptin orphan peptide receptor agonists as a possible new treatment for neurogenic bladders of SCI patients.

Conclusion

  • Level 1 evidence based on two RCTs supports the use of Onabotulinum toxin A injections into the detrusor muscle to provide targeted treatment for neurogenic detrusor overactivity and urge incontinence resistant to high-dose oral anticholinergic treatments with intermittent self-catheterization in SCI. Numerous level 3 and 4 studies confirm the efficacy and safety.
  • Level 4 evidence based on a single case series indicates detrusor contractility may be decreased through repeated BoNT-A injection, though prospective study and higher levels of evidence is needed to confirm.
  • Level 1 evidence supports the use of vanillanoid compounds such as capsaicin or resiniferatoxin to increase maximum bladder capacity and decrease urinary frequency and leakages in neurogenic detrusor overactivity of spinal origin.
  • Level 4 evidence exists to suggest that intravesical capsaicin instillation in bladders of SCI individuals does not increase the rate of common bladder cancers after 5 years of use.
  • Level 1 evidence based on two small-scale RCTs supports the use of N/OFG, a nociceptin orphan peptide receptor agonist for the treatment of neurogenic bladder in SCI.

Intravesical Instillations for SCI-Related Detrusor Overactivity

Intravesical instillations are intended as a means for increasing bladder capacity, lowering pressures, and decreasing incontinence, with the potential for decreased systemic side effects compared to oral medications. Capsaicin and resiniferotoxin have been discussed under toxins, but in fact may also be administered as an intravesical instillation. Other medications used in this manner are the anticholinergics such as oxybutynin and propantheline which are presented below. Most of these protocols consist of dissolving the medication in a liquid solution, and instilling the medication after emptying the bladder by intermittent catheterization, then leaving it in place until the next scheduled intermittent catherization. 

Table: Intravesical Instillations for SCI-Related Detrusor Overactivity

Discussion

George et al. (2007) described results with a pre-post trial with both propantheline and oxybutynin. This group also reported effects of capsaicin, but will not be reported as comparative data here due to the different treatment schedule used for capsaicin. Unfortunately, the data is not compared directly between propantheline and oxybutynin, as it was noted that overall the treatments resulted in a significant decrease in leak volume and leak frequency with no significant change in cystometric capacity, leak point pressures and intermittent catheterization volumes. In separate evaluations of propantheline and oxybutynin, it seems only propantheline resulted in significant change in leak frequency, and all other parameters were not changed for either medications before and after therapy. Two of the patients with the oxybutynin instillations developed systemic side effects (e.g., dry mouth) typical of those on oral medications.

Vaidyananthan et al. (1998) reported a pre-post trial (n=7) for which individuals originally managed by condom catheterization were switched to intermittent catheterization for a period of time, followed by another period when an intra-vesical instillation of oxybutynin was also administered. Although no group statistical results were reported, all subjects showed improved continence with intermittent catheterization and even more so when oxybutynin was added. Quality of life scores were mixed with intermittent catheterization alone but showed a definite improvement when oxybutynin was added. This may have been partly due to a reduced incidence of UTIs with the combination of intermittent catheterization and intra-vesical oxybutynin. The real implications of the instillations of oxybutynin alone are not known from this study.

Singh and Thomas (1995) presented a pre-post study with oxybutynin instillations, and were unable to show any significant improvements. Ersoz et al. (2010) challenge these results however by showing a significantly improved bladder volume for patients using indwelling catheters who are treated simultaneously with oral and intravesical oxybutynin. In this study, however, 52.6% of patients were lost to attrition and reports of intravesical instillation of oxybutynin were common (Ersoz, 2010). Given the equivocal results noted in most studies (e.g., lack of effect and presence of possible systemic side effects) and difficulty in administering treatment, caution is warranted in considering intra-vesical instillation of oxybutynin. When performed, combined oral and intravesical instillation may be preferred.

Conclusion

There is level 4 evidence from 3 studies that instillations with oxybutinun or propantheline have equivocal benefits for neurogenic bladder in people with SCI. There is level 4 evidence from1 study that combined oral and intravesical installation of oxybutinin significantly improves bladder volume. There is level 4 evidence suggesting systemic absorption may occur with this therapy, resulting in systemic side effects.

  • Intravesical instillations with oxybutinun or propantheline alone are ineffective for treating neurogenic bladder in people with SCI.

Other Pharmaceutical Treatments for SCI-Related Detrusor Overactivity

There are other therapies reported to decrease neurogenic detrusor overactivity that have not been mentioned nor fit into the categories noted above. In particular, medications that have been traditionally used for treating spasticity of skeletal muscles in spinal cord injury, i.e., intrathecal baclofen and intrathecal clonidine, have been reported to be helpful in the area of decreasing spasticity of the bladder in the same population. Intrathecal therapy has been used since the early 1990’s for treating spasticity, and better spasticity control can be achieved with fewer systemic side effects as compared to oral administration

Table: Intrathecal Baclofen and Clonidine for SCI-Related Detrusor Overactivity

Discussion

Chartier-Kastler et al. (2000) specifically used test bolus intrathecal injections of clonidine (ITC) to investigate its effects on SCI neurogenic detrusor overactivity, in patients otherwise resistant to a combination of oral treatment and self-clean intermittent catheterization (SCIC). After the test bolus injection, 6 of 9 subjects elected to have permanent pump implantation for the treatment of severe detrusor overactivity. Further confirmatory study of this proposed alternative treatment is needed as the sample size was small and no objective outcome measures were used.

Steers et al. (1992) investigated the use of intrathecal baclofen (ITB) specifically for the treatment of genitourinary function in 10 SCI patients with severe spasticity. Compared with placebo, involuntary bladder contraction induced incontinence was eliminated and 1 patient was able to convert from indwelling urethral catheterization to intermittent self-catheterization. Bladder capacity was increased by a mean of 72% while detrusor-sphincter dyssynergia was eliminated in 50% of patients. These authors recommend the use of ITB for SCI genitourinary dysfunction when oral pharmacological interventions are insufficient to improve bladder function. However, in light of the documented effectiveness of Botulinum toxin described above, the relative ease and temporary nature of treatment with Botulinum toxin, and the absence of significant adverse effects, it is unlikely that clinicians would chose intrathecal treatments over toxin therapy except in cases when intrathecal therapy is required for other problems (eg. spasticity)

Conclusion

  1. There is level 1 evidence from a single small RCT (n=10) that intrathecal baclofen may be beneficial for bladder function improvement in individuals with SCI when oral pharmacological interventions are insufficient.
  2. Level 4 evidence is available from a single, small (n=9), case series study for the use of intra-thecal clonidine to improve detrusor overactivity in individuals with SCI when a combination of oral treatment and sterile intermittent catheterization are insufficient.
  • Intrathecal baclofen and clonidine may be beneficial for bladder function improvement but further confirmatory evidence is needed.

Enhancing Bladder Volumes Non-Pharmacologically

Electrical Stimulation to Enhance Bladder Volumes

Electrical stimulation, most notably anterior sacral root stimulation, has been used to enhance bladder volume and induce voiding (Egon et al. 1998; Brindley et al. 1982). Typically, this approach has involved concomitant dorsal sacral rhizotomy and implantation of a sacral nerve stimulator. The combined effect of this is a more compliant bladder with more storage capacity under lower pressure and triggered voiding resulting in reduced incontinence, without the need to catheterize. As the focus of many of the studies involving electrical stimulation is on both of these functions (i.e., increased bladder capacity and control of bladder emptying), we will describe the evidence for these and other methods of electrical stimulation for improving bladder outcomes in a single subsequent subsection (see Section 13.3.4.7 Electrical Stimulation for Bladder Emptying (and Enhancing Volumes)). 

Surgical Augmentation of the Bladder to Enhance Volume

Bladder augmentation or augmentation cystoplasty is a surgical repair to the bladder typically suggested when conservative approaches such as anticholinergics with intermittent catheterization have failed to create an adequate bladder volume under low pressure for storage (Chartier-Kastler et al. 2000; Quek & Ginsberg 2003). Intolerable incontinence, renal deterioration, and/or local erosions or infections related to the use of catheters are common final pathways that may lead the clinician to consider definitive urological surgery. There are several approaches that have been described in the SCI literature with a common method being variations of the “clam-shell” ileocystoplasty in which the bladder is opened up like a clam and isolated intestine (ileum) are patched in to create a larger bladder (Chartier-Kastler et al. 2000; Nomura et al. 2002; Quek & Ginsberg 2003; Chen & Kuo, 2009). Surgical techniques that are focused on urinary diversion away from the bladder and subsequent drainage (e.g., cutaneous ileal conduit diversion) are discussed in the section on incontinent urinary diversion in the section that is focused on drainage (see 13.3.4.6 Continent Catheterizable Stoma and Incontinent Urinary Diversion).

Table: Surgical Augmentation of the Bladder to Enhance Volume

Discussion

As is the case for most surgical approaches, the evidence for surgical augmentation of the bladder exists in the form of clinical experience from individual centres as is described in retrospective chart reviews (e.g., Nomura et al. 2002; Quek & Ginsberg 2003; Chen & Kuo 2009; Reyblat et al. 2009) or more rarely may be found in prospective studies that are limited to non-controlled, non-randomized pre-post (cohort) study designs (e.g., Chartier-Kastler et al. 2000). Long-term retrospective results associated with ileocystoplasty in persons with traumatic and non-traumatic SCI (or spina bifida) were reported over a mean period of 5.5 and 8 years by Nomura et al. (2002) (n=21) and Quek and Ginsberg (2003) (n=26) respectively. Chartier-Kastler et al. (2000) conducted a prospective evaluation of 17 persons with traumatic longstanding SCI who underwent enterocystoplasty (i.e., ileocystoplasty) with systematic follow-up at 1, 3, 6, 12 months and then yearly for a mean follow-up of 6.3 years. Chen & Kuo (2009) reported on 40 adults with SCI. In all cases, this was conducted in individuals with overactive bladder and/or detrusor-sphincter dyssynergia with reflex incontinence which failed to respond to conservative treatment. Across all these studies, at follow-up, bladder capacity increased dramatically with near or complete resolution of incontinence in the vast majority of patients. Chartier-Kastler et al. (2000) conducted systematic urodynamic investigations and showed a significant increase in maximal cystometric capacity by 191% (174.1 to 508.1 ml, p<0.05) with a concomitant decrease in maximal filling pressure of 72% (65.5 60 18.3 cm H2O, p<0.05). These results are similar to those reported by Nomura et al. (2002) and Quek and Ginsberg (2003). Reyblat et al. (2009) compared an “extraperitoneal” approach (small peritoneotomy and standard ‘clam’ enteroplasty) vs. the standard intraperitoneal approach in which the extraperitoneal approach was found to result in shorter operative time, shorter hospital stay, and eventual return of bowel function. No serious complications were noted across the studies, and other complications were noted in only a few individuals (e.g., transient paralytic ileus, vesicoureteral reflux, wound infection, urethral stricture of unknown cause, recurrent pyelonephritis possibly due to non-compliance with intermittent catheterization and use of Crede maneuver) with the vast majority of these responding well to conservative treatment (Chartier-Kastler et al. 2000; Nomura et al. 2002; Quek & Ginsberg 2003). Subsequent subjective assessment of patient satisfaction with the procedure was reported to be extremely high (Quek & Ginsberg 2003) which is consistent with other similar investigations in SCI patients (Khastgir et al. 2003). Chen & Kuo (2009) noted, however, that issues with UTI, reservoir calculi and new onset upper-tract urolithiasis that commonly follow the ileoplasty still require resolution. Reyblat et al. (2009), in a retrospective chart review, reported equivocal postoperative continence using an extraperitoneal (small peritoneotomy and standard ‘clam’ enteroplasty) vs. the standard intraperitoneal augmentation. The extraperitoneal approach resulted in shorter operative time, shorter length of stay, and ore rapid return of bowel function. There was a potential for selection bias in this study that was mitigated with a subgroup analysis in an effort to control for a significant confounding variable of higher rates of prior abdominal surgery in the intraperitoneal group (Reyblat et al. 2009).

Conclusion

  • There is level 4 evidence from four studies that surgical augmentation of bladder (ileocystoplasty) may result in enhanced bladder capacity under lower filling pressure and improved continence in persons with SCI who previously did not respond well to conservative approaches for overactive bladder.
  • There is level 3 evidence from a single study that extraperitoneal (vs intraperitoneal) augmentation enterocystoplasty produces equivocal postoperative continence with easier early postoperative recovery.
  • Surgical augmentation of bladder may result in enhanced bladder capacity under lower filling pressure and improved continence in persons with SCI.

    Extraperitoneal vs intraperitoneal augmentation enterocystoplasty may result in better postoperative recovery.

Enhancing Bladder Emptying Pharmacologically

As noted previously, normal voiding process occurs through a pathway between the pontine and sacral micturition centers. These centers work synergistically to allow for bladder storage or drainage. However, in individuals with SCI lesions this process can be interrupted. This causes impairment of voiding function, which can be classified into two categories: impairment in storing and impairment in emptying (Hanno 2001).

Enhancing bladder storage, as discussed earlier in the chapter, involves relaxing the detrusor muscle and allowing for increased bladder volumes. Individuals with impairment of bladder emptying are those whose sphincter is unable to relax or who have weak or nonexistent detrusor muscle contractions, both causing failure to empty. These individuals can be treated pharmacologically with oral alpha adrenergic blockers and botulinum toxin (injected into the sphincter). Both interventions are intended to improve voiding but also may increase the tendency towards incontinence, a point not highlighted in the studies presented below. However, in those male patients who already have incontinence, and are using condom drainage, but have persistently elevated residuals, alpha blockers or Botulinum toxin (injected into the sphincter) may result in more complete emptying.

Alpha-adrenergic Blockers for Bladder Emptying

A variety of alpha adrenergic blockers have been used to treat SCI bladder dysfunction. These drugs have been used to target alpha adrenoreceptor blocker subtypes which may be implicated in a variety of mechanisms including bladder neck dysfunction, increased bladder outlet resistance, detrusor-sphincter dyssynergia, autonomic hyperreflexia or upper tract stasis.

Table: Summary of Alpha Adrenergic Blockers

Discussion

Tamsulosin is an alpha1 adrenoreceptor antagonist that has been used to treat SCI bladder neck dysfunction by causing smooth muscles in the bladder neck to relax and improve urine flow rate. A large scale (n=263) study conducted by Abrams et al. (2003), provided evidence for decreased micturition frequency and improvement in urinary leakage parameters for individuals with SCI. This study consisted of a 4 week RCT followed by a longer-term open-label period conducted over a year in persons with overactive bladder with or without dyssynergia. Maximal urethral pressure determined via urethral pressure profilometry was reduced significantly with the longer-term trial (p<0.001) although only a trend was apparent during the one month RCT with 0.4 mg dose (p=0.183) but not with a dose of 0.8 mg (p=0.443). In the 1 year open-label investigation tamsulosin also was associated with several improved cystometry parameters related to bladder storage and emptying, and also resulted in increased mean voided volume values as reported in a patient diary. Given that most positive outcomes were more apparent with the open-label phase, which consisted of a pre-post trial design, this trial has been assigned as level 4 evidence.

Moxisylyte is an alpha adrenoreceptor blocker used commonly in the treatment of Raynaud’s disease where narrowing of the blood vessels in the hands causes numbness and pain in the fingers. Costa et al. (1993) in an n=20 RCT investigated the off-label use of moxisylyte in the treatment of SCI bladder neck dysfunction. With its smooth muscle relaxant property, the decrease in urethral closure pressure was found to be dose related and significant when compared to placebo, with the maximum reduction of 47.6% occurring at 10 minutes after 0.75mg/kg in individuals with SCI.

Terazosin is often used to treat hypertension. However, this alpha-adrenergic blocker is also useful in treating bladder neck dysfunction by relaxing the bladder neck muscles and easing the voiding process. Perkash (1995) reported that although 82% of patients (N=28), with absent detrusor sphincter dyssynergia, perceived improvement in voiding; only 42% registered meaningful objective decreases in maximum urodynamic voiding pressure. Side effects, tolerance and required additional urodynamic monitoring may be deterrents to the wide-spread adoption of terazosin as an alternative treatment for bladder neck dysfunction in SCI individuals. The specificity of terazosin action on the bladder neck, exclusive of the external sphincter, was demonstrated by Chancellor et al. (1993) in a subgroup of SCI patients who had persistent voiding difficulty after previous sphinterotomy subsequent to failed initial terazosin treatment.

Phenoxybenzamine is an antihypertensive usually chosen to treat autonomic symptoms of pheochromocytomas such as high blood pressure or excess sweating. Al-Ali et al. (1999) undertook to utilize the autonomic effects of phenoxybenzamine to treat bladder dysfunction which is in part under autonomic control. Treatment with phenoxybenzamine (n=46 with 41 completers) resulted in a reduction of bladder outlet resistance, detrusor-sphincter dyssynergia or autonomic hyperreflexia in some subjects while no benefits were recorded for areflexive bladders. Phenoxybenzamine can be beneficial as an adjunct treatment for neuropathic bladder following SCI, when tapping or crede is unable to achieve satisfactory residual urine volumes of <100 mL. The lack of efficacy in those with bladder neck dysfunction was specifically noted in this study. Since statistically significant results were not reported in this study, further appropriately sized RCTs would be helpful in providing sufficient evidence for the use of phenoxybenzamine in the treatment of SCI neuropathic bladder.

The pyelouretheral smooth muscle responsible for urethral peristalsis and movement of the urine from the kidneys to the bladder via the ureters is also a potential site of action for alpha 1-receptor antagonist therapy. Linsenmeyer et al. (2002), in a small (n=10) retrospective chart review found that in men with upper tract (i.e. kidneys and ureters) stasis secondary to SCI at or above T6, 6 months of alpha1-blocker therapy provided improvement in upper tract stasis in 80% of subjects who used reflex voiding to manage their bladder as measured by significant decreases of the duration of uninhibited bladder contractions. Firm conclusions about effectiveness and the optimum duration of treatment can only be validated with further RCT trials.

Conclusion

  • Level 1 evidence from a single study suggests that moxisylyte decreases maximum urethral closure pressure by 47.6% at 10 minutes after an optimum dose of 0.75mg/kg in individuals with SCI.
  • There is level 4 evidence from a single study that suggests that tamsulosin may improve bladder neck relaxation and subsequent urine flow in SCI individuals.
  • There is level 4 evidence (two studies, n=28 & 9) that supports terazosin as an alternative treatment for bladder neck dysfunction in SCI individuals provided that side effects and drug tolerance are monitored.
  • There is level 4 evidence derived from a single, case series study involving 46 subjects (41 completers) that indicates some potential for phenoxybenzamine as an adjunct treatment for neurogenic bladder following SCI, when tapping or crede is insufficient to achieve residual urine volume of <100mL. Further evidence is required.
  • Level 4 evidence from 1 small retrospective chart review suggests that 6 months of alpha 1-blocker therapy may improve upper tract stasis secondary to SCI in men by decreasing the duration of involuntary bladder contractions.
     
  • Tamsulosin may improve urine flow in SCI individuals with bladder neck dysfunction.

     

    Mosixylyte is likely able to decrease maximum urethral closure pressure at
    a dose of 0.75mg/kg in individuals with SCI.

     

    Terazosin may be an alternative treatment for bladder neck dysfunction in individuals with SCI. but side effects and drug tolerance should be monitored.

     

    Phenoxybenzamine may be useful as an adjunct therapy for reducing residual
     urine volume in SCI neuropathic bladders maintained by crede or tapping.

     

    Six months of alpha 1-blocker therapy in male SCI patients may improve upper tract stasis.

Botulinum Toxin for Bladder Emptying

Botulinum toxin is an exotoxin produced by the bacteria Clostridium botulinum. As noted previously (see 3.1.2 Toxin therapy for SCI-related Detrusor Overactivity), it has been used for many conditions associated with muscular overactivity and specifically for neurogenic detrusor overactivity. In SCI individuals with sphincter overactivity causing drainage impairment, botulinum toxin may also be administered into the external urethral sphincter causing the muscle to relax resulting in improved drainage (deSeze et al. 2002). The toxin works by inhibiting acetylcholine release at the neuromuscular junction and relaxing the muscle, an effect that gradually wears off over the months following injection. Injections of botulinum toxin A into the sphincter may improving emptying and, if possible, eliminate the need for catheterization for some individuals with neurogenic bladder. 

Table: Bladder Emptying through Botulinum Toxin

Discussion

DESD and associated high bladder pressures, vesicoureteral reflux, and frequent UTI are associated with poor long-term outcomes for patients. These patients may develop upper tract deterioration and/or suffer incontinence and poor quality of life. Injection into the external urethra with botulinum toxin has been shown to reduce bladder pressures, improve incidence of UTI, and in some patients, normalize bladder emptying (Tsai et al. 2009, Kuo 2008). The important impact of increased incontinence after sphincter injection, along with urodynamic parameters were studied by Kuo. While this author cautions that QoL can decrease due to the increased incontinence experienced by some individuals, careful patient selection may allow some to benefit from the clearly evident improvement in urodynamic parameters and UTI incidence. Tsai et al. (2009) showed statistically significant improvement in quality of life post injection, but did not reveal data on incontinence.

The improvement found in post voiding residual volume demonstrated by the Kuo and Tsai studies was initially shown in the study by deSeze et al. (2002) who conducted a randomized, controlled, double blind study using lidocaine as a control injection (n=8) compared to botulinum toxin A (BTxA) as the active treatment (n=5). This study found BTxA improved post void residual volume in individuals with SCI significantly better than lidocaine. One month after BTxA was injected into the external sphincter, post-voiding residual volume decreased significantly by 159.4 mL to 105.0 mL and all patients who previously presented with autonomic dysreflexia no longer exhibited symptoms.

Other studies also showed a decrease in symptoms of autonomic hyperreflexia in at least 60% of patients (Tsai et al. 2009, Kuo 2008, Dykstra et al. 1988; Dykstra & Sidi 1990; Petit et al. 1998; Schurch et al.1996). Almost all patients showed post-injection sphincter denervation on electromyography; resulting in temporary relief of these symptoms for about 2-3 months leading to the need for subsequent BTxA injections to maintain results (Dykstra et al. 1988; Dykstra & Sidi 1990).

Schurch et al. (1996) compared the effectiveness of transurethral versus transperineal botulinum toxin A injections through a prospective controlled study.  The study found that transurethral botulinum toxin injections were significantly more effective in reducing urethral pressure than transperineal injections. However, other symptoms were improved through either injection method. Tsai in 2009 described a method of transperineal sphincter injections using fluoroscopic guidance and EMG that resulted in excellent effects on bladder emptying, with most patients returning to voiding. Patients were able to avoid frequent intermittent catheterization, and three patients were able to discontinue indwelling catheterization altogether.

Schurch et al (1996) also revealed the additive effects of recurrent BTx injections resulting from prolonged inhibition of acetylcholine release. After 3 monthly injections, the therapeutic effects of BTx lasted for as long as 9 months compared to only 2 – 3 months with 1 injection.

Phelan et al. (2001) were the first to demonstrate the successful use of botulinum toxin A in women. This study of 13 females showed that all but 1 patient was able to spontaneously void after botulinum A injection. Women, as a result of anatomial differences, often have greater difficulty performing self-catheterization than do men. Therefore voiding “normalization” as a result of sphincter injection with botulinum toxin may have an even more significant role in the urologic management of females with SCI. More study on the long term outcome of “spontaneous voiding” after sphincter injection in women is required.

Chen et al. (2010) evaluated the effects of a single transrectal ultrasound (TRUS)-guided transperineal injection of 100U oBTX-A to the external urethral sphincter (EUS) to treat DESD. As the prostate gland represented a key landmark in the TRUS-guided injection, the study was limited to male subjects. Video-urodynamic results obtained at an average of 33.3 days postinjection showed significant reduction in dynamic urethral pressure, integrated electromyography (iEMG), and static urethral pressure. The oBTX-A injection did not produce a significant decrease in maximal detrusor pressure. This was the first study to demonstrate the effect of TRUS-guided transperineal oBTX-A injection into the EUS and the potential for achieving outcomes similar to transurethral injection.

While not specifically mentioned in the above studies, a group of patients likely to benefit from injections of BTx into the sphincter are those men who have persistently elevated bladder volumes while using condom drainage. Sometimes such patients have chosen condom drainage because of reluctance to perform self catheterization while other times this bladder drainage option is chosen because of persistent incontinence on intermittent catheterization regimes despite adequate trials of anticholinergic medication. These patients could theoretically benefit from improved drainage, as residual urine is a common cause of UTI, and can also accompany elevated bladder pressures, that put upper tracts at risk. Whether or not such patients actually resume “voiding” to allow for the discontinuation of condom drainage altogether has not been addressed.

Botulinum toxin therapy has the advantage of avoiding major surgical procedures and their associated risks. Botulinum toxin therapy injection relaxes the external sphincter resulting in a decrease in post-voiding residual urine volume, and in 70% of patients, acceptable voiding pressures (Tsai et al. 2009). This improvement further seems to result in decreasing other symptoms such as autonomic dysreflexia and UTI incidence. However, due to transient sphincter denervation, it has the disadvantage of requiring repeated injections to maintain its therapeutic results. Also, post injection urodynamic studies should be done to prove that resultant voiding pressures are in the acceptable range. For those individuals with SCI with neurogenic bladder that do not experience unacceptable incontinence, botulinum toxin injection into the external sphincter is effective in assisting with more effective bladder emptying. Whether or not recurrent sphincter injection related improvements in voiding pressure and UTI incidence results in better long term upper tract outcomes requires further study.  Furthermore, clarity over the patient characteristics best suited to maximize the benefits of sphincter injections without subsequent unacceptable incontinence is needed in future studies to ensure widespread clinical uptake.

Conclusion

There is level 1 evidence from a single RCT with support from several additional controlled and uncontrolled trials that botulinum toxin injected into the external urinary sphincter may be effective in improving outcomes associated with bladder emptying in persons with neurogenic bladder due to SCI.

  • Botulinum toxin injected into the sphincter is effective in assisting with bladder emptying for persons with neurogenic bladder due to SCI.

Other Pharmaceutical Treatments for Bladder Emptying

Beyond the typical Alpha adrenergic and botulinum toxin approaches to improving bladder emptying, other pharmaceutical interventions have been explored. While these approaches still total few in number, this section describes primarily the use of tadalafil (Taie et al. 2010), a phosphodiesterse-5 (PDE5) inhibitor (Taie et al. 2010) and 4-Aminopyridine, (Grijalva et al. 2010). 4-Aminopyridine prepared in various commercial formulations for the treatment of MS related walking difficulties is also known fampridine [ampyra, fampyra] Most SCI specific studies involving 4-Aminopyridine assess bladder sensation and/ or control with respect to outcomes relevant to bladder management; often conducting more global assessments of function following treatment. This section reports only on bladder specific outcomes.

Table: Other Pharmaceutical Treatments for Bladder Emptying

Discussion

With respect to bladder management, phosphodiesterase-5 inhibitors (PDE5) inhibitors are postulated to promote relaxation of the detrusor muscle, thereby decreasing overactivity and increase capacity and compliance. This was confirmed in work by Taie et al. (2010) in male participants with supra sacral SCI where bladder compliance and capacity increased, and maximum voiding detrusor pressure and filling pressure decreased significantly following a single dose of 20mg oral tadalafil. As the evidence in this area is limited to a single study, further research is warranted before recommending this treatment.

4-Aminopyridine is a potassium channel blocker, prolonging action potentials and increasing neurotransmitter release at the neuromuscular junction (NMJ). Only one study to date, Grijalva et al. (2010), has explicitly commented on bladder function following administration of fampridine. During the open-label portion of the study where dosage levels of fampridine peaked, 3/12 participants regained both sensation and control of the bladder sphincter, and 1/12 regained sensation only. The paucity of literature in this area does not yet warrant fampridine as a primary treatment of bladder management in SCI.

Conclusion

There is level 4 evidence from a single study that PDE5 inhibitors may be effective in improving outcomes associated with bladder emptying in persons with neurogenic bladder due to SCI.

There is level 4 evidence from a single study that 4-aminopyridine, at sufficient dosage, may be effective in restoring sensation and/ or control of the bladder sphincter.

  • A single dose of oral tadalafil is effective in improving urodynamic indices in males with supra sacral SCI; more evidence is needed to support this as a treatment option.

    4-Aminopyridine at sufficient dosage may return sensation and control of the bladder sphincter following SCI; more evidence is needed to support this as a treatment option.

Enhancing Bladder Emptying Non-Pharmacologically

Comparing Methods of Conservative Bladder Emptying

Bladder emptying must be conducted under low pressure conditions in order to prevent upper urinary tract complications which may lead to renal failure. The choice of bladder management method must also result in continence, be acceptable to the individual with neurogenic bladder, and facilitate the greatest independence. During rehabilitation, most people with SCI are evaluated and consulted for the most suitable bladder management technique, taught how to manage the chosen method, and are advised as to complications and alternatives. In order to counsel patients appropriately, it is helpful for the clinician to understand the data related to bladder management method and complications. The section below reviews several papers that review the outcome of groups of patients treated with the most commonly chosen conservative methods of bladder management. Further papers addressing outcomes are included in the indwelling and intermittent catheterization sections.

Management methods discussed with the patient initially are based on clinical problems – eg. incomplete emptying, incontinence, dysreflexia, etc.  – and on the functional ability of the patient. The conservative methods for bladder management include the following: Intermittent catheterization, indwelling urethral catheterization, or condom catheterization (males only). If bladder function permits, spontaneously “triggered” or expression voiding without the need for an external drainage system may also be an option, although the disadvantages with these approaches have been outlined in a review (Wyndaele et al. 2001). Suprapubic catheterization is occasionally chosen in the subacute period given that there is no disturbance to the urethra.  However, the complication rate remains high for this invasive technique and thus it becomes a more suitable option in the chronic period.  Urodynamic studies provide information on bladder storage and emptying pressure, presence of reflux, and are essential in the management of the patient as the data is useful in influencing the choice of bladder management method.  Whether or not, and why, patients change their bladder management method are also topics of importance. Green (2004), Drake et al. (2005), and Yavuser et al. (2000), address these issues, listing some of the common complications as reason for change:  frequent UTI’s, upper tract deterioration, increased post void residual urine volume, bladder or kidney stones, functional decline and patient request. The section below presents data on retrospective studies which attempt to clarify the type and incidence of complications associated with the above methods of bladder management. For the most part, these approaches are considered in advance of other options involving bladder augmentation surgery or stimulator implantation, subjects of later sections.

Table: Comparison Studies of Conservative Bladder Emptying

Discussion

Several authors have examined the frequency of a variety of urological and renal complications associated with various forms of chronic bladder management (Ord et al. 2003; Weld & Dmochowski 2000; Hackler 1982). These authors have all employed retrospective chart reviews to examine complication rates associated with long-term follow-up data. In general, these authors concur that the greatest numbers of complications occur with long-term use of indwelling suprapubic and urethral catheters. In particular, of these investigations, Weld and Dmochowski (2000) employed a large sample (N=357) and examined the greatest range of complications. These authors noted that long-term urethral catheterization was associated with the largest overall number of complications, with long-term suprapubic catheterization ranked next. Depending on the specific complication, one of these two methods was associated with the highest incidence. Urethral catheter users had the highest rates for epididymitis, pyelonephritis, upper tract stones, bladder stones, urethral strictures and periurethral abscess. Suprapubic catheter users had the highest rates for vesicoureteral reflux and abnormal upper tracts. It should be noted that these authors did not account for changing bladder management methods, preferring to simplify the analysis by classifying the results by the most predominate bladder management method.

Ord et al. (2003), on the other hand, also examined a relatively large dataset (n=467) but examined all the combinations of changing methods. However, these authors limited their analysis to the effect of various bladder management techniques on the risk of bladder stone formation. Similar to Weld and Dmochowski (2000), these authors also found a slightly greater incidence of bladder stones for indwelling urethral catheterscompared to suprapubic catheters. Each of these methods, however, resulted in a greater incidence of bladder stones than intermittent catheterization. Ord et al. (2003) reported hazard ratios relative to intermittent catheterization of 10.5 for suprapubic catheters and 12.8 for indwelling urethral catheters. In contrast, Hackler (1982) reported comparisons between long-term complication rates among those with condom (Texas), urethral (Foley) and suprapubic catheterization and found markedly higher rates for those managed with suprapubic catheters even though the follow-up period for these patients was only 5 years as compared to 20 years for those managed with the other 2 methods. However, these findings reflected a much smaller series of patients (N=31) and the comparisons were made from patients from different time periods reflecting different “generations” of care.

It should be noted that even though the data favor intermittent catheterization or triggered spontaneous voiding, it is not always possible to use these methods. Lack of independence for catheterization can limit the use of intermittent catheterization in tetraplegics and in women, while spontaneous voiding may not be possible given the state of bladder function (Yavuzer et al. 2000). While every effort is made to start patients on intermittent catheterization programs, some patients change to other methods with time. Drake et al. (2005) reported a 28.8% incidence in change of bladder management method, while Yavuzer et al. (2000) found that up to 60% of patients changed from intermittent to indwelling catheter use. In Green’s Model System’s study (2004), only 25% changed to indwelling catheters over 15 years. The primary reasons indicated for changing methods were a greater dependence on care-givers than originally thought, presence of severe spasticity, incontinence and inconvenience with intermittent catheterization (females only). Thus assisting patients in choosing the most optimal method of bladder management is important. If less optimal methods of management are used post-injury, appropriate or increased surveillance must continue, given the described complication rates.  

Conclusion

There is level 4 evidence that indwelling urethral catheterization is associated with a higher rate of acute urological complications than intermittent catheterization. 

There is level 4 evidence that prolonged indwelling catheterization, whether suprapubic or urethral, may result in a higher long-term rate of urological and renal complications than intermittent catheterization, condom catheterization or triggered spontaneous voiding. 

There is level 4 evidence that intermittent catheterization, whether performed acutely or chronically, has the lowest complication rate. 

Results are conflicting about the complications associated with chronic use of spontaneous triggered voiding but some authors present level 4 evidence that this method has comparable long-term complication rates to intermittent catheterization.

There is level 4 evidence that those who use intermittent catheterization at discharge from rehabilitation may have difficulty continuing, especially those with tetraplegia and complete injuries. Females also have more difficulty than males in maintaining compliance with IC procedures.

  • Intermittent catheterization, whether performed acutely or chronically, has the lowest complication rate.

    Indwelling catheterization, whether suprapubic or urethral or whether conducted acutely or chronically, may result in a higher long-term rate of urological and renal complications than other management methods.

    Persons with tetraplegia and complete injuries, and to a lesser degree females, may have difficulty in maintaining compliance with intermittent catheterization procedures following discharge from rehabilitation.

Intermittent Catheterization

Intermittent catheterization is the preferred method of bladder management likely due to a reduced incidence of renal impairment, reflux, stone disease, bladder cancer and possibly UTI compared to other methods of bladder management (Groah et al. 2002; Weld & Dmochowski 2000; Ord et al. 2003). The present section outlines those studies focusing on specific aspects of intermittent catheterization, including timing of catheterization and catheter selection, (Polliack et al. 2005; Waller et al. 1997; De Ridder et al. 2005; Giannantoni et al. 2001; Kovindha et al. 2004; Sarica et al. 2010). Effectiveness of intermittent catheterization in emptying the bladder is addressed in Jensen et al. (1995). Long-term follow-up data of patients managed by intermittent catheterization is provided in the articles by Ku et al. (2006), Perrouin-verbe et al. (1995) and Nanninga et al. (1982).

Table: Intermittent Catheterization

Discussion

Intermittent catheterization (IC) is the mode of bladder management generally associated with the fewest long-term complications (Groah et al. 2002; Weld & Dmochowski 2000; Ord et al. 2003).  However, there are some complications that occur with higher frequency in patients who intermittently catheterize.  For example, increased urethral complications (19% incidence) may lead to urosepsis and epididymorchitis (28.5% incidence) and may result in increased morbidity and reduced fertility (Ku et al. 2006).  Despite these IC related higher rates of complications, there is good consensus among the larger retrospective studies available that intermittent catheterization programs are still preferred for the protection of the upper urinary tract through regular emptying with low bladder pressures (Giannantoni et al. 2001).  Episodes of pylonephritis and UTI are also reduced when bladder emptying is conducted consistently and completely in the absence of indwelling catheters (Groah et al. 2002; Weld & Dmochowski 2000; Ord et al. 2003; Giannantoni et al. 2001). Perrouin-Verbe et al. (1995) showed that patients most likely to continue with intermittent catheterization would be those who are able to independently catheterize and those who have an acceptable level of continence. In line with this finding, Pannek & Kullik (2009) showed that in patients who employ self IC and have optimal bladder function, perceived quality of life is higher than those with suboptimal function.  Thus it is essential to consider an individual’s activities of daily living, psychological factors (and other concurrent comorbidities) and potential caregiving needs when intermittent catheterization is being introduced early after SCI.

A very low incidence of bladder stones and hydronephrosis were reported in Perouin-Verbe et al. (1995) (2%), consistent with previously discussed studies. However, Nanninga et al. (1982), reported upper tract changes in 33% of patients. While this range is large, it is possible that management of patients in 1982 involved less stringent control of high bladder pressures which is the cause of upper tract disease in many cases (Nanninga et al. 1982). Nanninga noted that high bladder pressures may occur even in patients who remain continent or nearly continent between catheterizations, and that the problem can at least be partially avoided by increasing the frequency of catheterization. Other options for patients with persistently elevated pressures already on intermittent catheterization programs are detrusor Botox injections and/or anticholinergic medications.  It is important to note that regular follow-up of these patients including tests of bladder physiology and upper tract function is recommended to monitor for changes and for increasing incidence of complications with time (Perrouin-Verb et al. 1995; Nanninga et al. 1982). 

There are several trials investigating varying properties of catheters used for IC (De Ridder et al. 2005; Giannantoni et al. 2001; Waller et al. 1997; Sarica et al. 2010). For example, Giannantoni et al. (2001) demonstrated a reduction in the incidence of UTIs and in the presence of asymptomatic bacteriuria for a pre-lubricated catheter versus a conventional PVC catheter. Of note are 3 subjects initially requiring assistance with a conventional catheter transitioning to independence with a pre-lubricated catheter. However, the order of cather use by type was not reported. In terms of general satisfaction, subjects rated the pre-lubricated catheter significantly higher than the conventional catheter with respect to comfort, ease of insertion, extraction, and handling. Reduced incidence of UTIs was reported by De Ridder et al. (2005) in favour of hydrophilic catheters when compared to conventional PVC catheters. Although this multi-centre investigation employed a RCT design (N=123) results should be cautiously interpreted given a 54% drop-out rate. A third investigation examining catheter properties investigated the effect of osmolality on two different hydrophilic catheters. Waller et al. (1997) demonstrated reduced friction with the high-osmality catheter vs the other, a finding corroborated by nursing reports of fewer catheter “stickings”. These differences did not translate into clinically significant results for differences in the incidence of UTIs with either hydrophilic catheter type. Sarica et al. (2010) found gel lubricated non-hydrophilic cathethers to be superior to hydrophilic coated and PVC catheters in terms of reduced urethral microtrauma and pyuria, and increased patient satisfaction, despite higher cost. Finally, a study by Kovindha et al. (2004), provides data on a reusable (average of 3 years of usage) silicone catheter. The frequency of UTIs reported for the reuseable catheter is comparable to that reported for standard disposable catheters (3-7 days of usage), but inferior to frequencies reported for prelubricated catheters. Kovindha et al. (2004) stated that the long-term silicone catheter is an economical option for those in developing countries. In developing countries, the high cost of the single use, prelubricated catheters is prohibitive outside of exceptional situations.

It should be noted that some assistive devices that may enhance compliance with intermittent catheterization for those with impaired hand function do exist, but are likely not in widespread use. For example, Adler and Kirshblum (2003) reported a series of 9 individuals with C5-C7 SCI, originally unable to perform intermittent catheterization, that were subsequently satisfied and successful with a device to help performance of intermittent catheterization.  

Conclusion

  • There is Level 1 evidence based on 1 RCT that pre-lubricated hydrophilic catheters are associated with fewer UTIs and reduced incidence of urethral bleeding and microtrauma as compared to conventional Poly Vinyl Chloride catheters.
  • There is Level 2 evidence based on 1 lower quality RCT that fewer UTIs, but not necessarily urethral bleeding may result with the use of hydrophilic catheters as compared to conventional PVC catheters.
  • There is Level 2 evidence based on 1 lower quality RCT that urethral microtrauma and pyuria is reduced with use of gel-lubricated non-hydrophilic catheter, with higher patient satisfaction, as compared to hydrophilic-coated or PVC catheters
  • There is level 4 evidence that urethral complications and epididymoorchitis occurs more frequently in those using IC programs for bladder emptying, but the advantages of improved upper tract outcome over those with indwelling catheters outweigh these disadvantages.
  • There is level 4 evidence that using a portable ultrasound device reduces the frequency and cost of intermittent catheterizations. 
  • Although both pre-lubricated and hydrophilic catheters have been associated with reduced incidence of UTIs as compared to conventional Poly Vinyl Chloride catheters, less urethral microtrauma with their use may only be seen with pre-lubricated catheters.

    Urethral complications and epididymoorchitis occur more frequently in those using intermittent catheterization programs.

    Portable ultrasound device can improve the scheduling of intermittent catheterizations.

Triggering-Type or Expression Voiding Methods of Bladder Management

Individuals with SCI undergoing inpatient rehabilitation are sometimes taught various maneuvers in order to initiate or attempt spontaneous voiding, termed “expression voiding” as well as to provide a “trigger” to initiate voiding (Wyndaele et al. 2001). As noted previously, these involve methods to increase intra-abdominal pressure so as to facilitate voiding. Only 1 study examining these methods met the criteria for inclusion in the present review.

Table: Triggering-Type or Expression Voiding Methods

Discussion

Greenstein et al. (1992) documented the use of Valsalva and Crede maneuvers to initiate spontaneous voiding in a small case series of 5 males with paraplegia. In his review, Wyndaele et al. (2001) states that bladder “voiding” by this method utilizes C-fibre activation,  to trigger the sacral reflex resulting in involuntary and non-sustained bladder contraction. Wyndaele et al. (2001) cautions readers that DESD may occur in a high percentage of patients who can activate bladder emptying in this manner, resulting in the potential for upper tract changes, as well as incomplete emptying. Greenstein et al. intended to examine the potential for long-term complications in those who employed these techniques over an extended period of time. High intravesical pressure was documented during voiding. The authors suggested that long-term monitoring for these individuals is advisable and intermittent catheterization should replace these methods in the event of urological complications. Triggered voiding and use of the crede maneuver to initiate “voiding” should only be considered in patients with normal upper tracts, provided that urodynamic studies demonstrate low pressure storage and “voiding”, and that there is a low incidence of UTI.

Conclusion

There is level 4 evidence that triggering mechanisms such as the Valsalva or Crede maneuvers may assist some individuals with neurogenic bladder in emptying their bladders without catheterization. However, high intra-vesical voiding pressures can occur which could conceivably lead to renal complications.

  • Valsalva or Crede maneuver may assist some individuals to void spontaneously but produce high intra-vesical pressure, increasing the risk for long-term complications.

Indwelling Catheterization (Indwelling or Suprapubic)

Urethral catheterization may be the bladder management method of choice for a variety of reasons including the following: ease of management, inadequate hand function for Intermediate catherizations, severe spasticity, low bladder capacity with high detrusor pressures and/or persistent incontinence especially in women, and pressure ulcers (Yavuzer et al. 2000). Suprapubic catheterization, first described in SCI by Cook and Smith (1976), is the preferred choice for those patients who require an indwelling catheter but have severe urethral disease. Weld and Dmochowski (2000) presented data showing a lower overall complication rate from suprapubic catheter use than from urethral catheter use (44.4% vs 53% respectively). Since indwelling catheterization is sometimes unavoidable, becoming familiar with the various potential complications and appropriate monitoring is important for clinical and self-management of neurogenic bladder.

Based on a series of case review studies (most described earlier in Section 13.4.3.1) comparing various bladder management methods, long-term use of indwelling catheters is associated with generally higher rates of complications (Wyndaele et al. 1985; Gallien et al. 1998; Weld & Dmochowski 2000) in contrast to other methods (especially Intermeiadite catherizations). For example, Ord et al. (2003) noted a significantly greater chance of having bladder stones with long-term suprapubic catheter or urethral indwelling catheter use as indicated by hazard ratios of 10.5 and 12.8 relative to intermittent catheterization respectively. Indwelling catheterization has also been linked to significantly higher rates of bladder cancer development (Groah et al. 2002; Kaufman et al. 1977) and upper tract deterioration (Weld & Dmochowski 2000) as compared to those who use long-term intermittent catheterization.

Table: Indwelling Catheterization

Discussion

Although Intermediate catherizations are the first choice for neurogenic bladder management, some patients with subacute SCI are managed with indwelling catheters due to prolonged high urine output states, frequent intercurrent medical illnesses or surgical complications, or severe incontinence. Suprapubic catheterization is occasionally considered during this early period if urethral damage has occurredas a result of prolonged urethral catheter use. Later, in chronic situations, suprapubic catheterization may also be favored by individuals with SCI who are obese, have severe lower extremity spasticity, inadequate hand function, persistent incontinence, urethral stricture or erosion, or because of perceived increased ability to engage in sexual relations (Weld & Dmochowski 2000; Peatfield et al.1983). Prostatitis and orchiepidymitis occur less frequently in those with suprapubic catheterization but upper tract deterioration remains a concern (Gallien et al. 1998; Weld & Dmochowski 2000; Sugimura et al. 2008).

Hackler (1982) has suggested that upper tract deterioration may be reduced with concomitant use of anticholinergic medication. MacDiarmid et al. (1995) hypothesized that clinical factors may also reduce the complication rate. They attributed the low incidence of complications during the year-long data collection period to strict adherence to a catheter protocol with regular follow-up and close surveillance utilizing a dedicated medical and nursing team and informed primary care practitioners. Sugimura et al. (2008) also noted that upper tract complication rates resulting from suprapubic catheterization may be lower than earlier studies suggested and reported a 13.4% renal complication rate associated with a mean follow-up period of 68 months. Furthermore, Sherriff et al. (1998) conducted a satisfaction survey regarding suprapubic catheter use which indicated 70-90% satisfaction based on questions such as impact on life, pleasure with the switch, and “would you do it again”, etc.

Several of the studies described above on suprapubic catheterization contain a relatively short follow-up period (e.g., < 10 years). The specific concerns regarding indwelling catheter use centre on the potential for urological complications with long-term use. Many patients are injured as young adults, and may live for greater than 50 years and therefore the target for safety monitoring regarding bladder management choice should emulate SCI life expectancy. According to the prospective study by Kaufman et al. (1977), the risk of bladder cancer with indwelling urethral catheters increase significantly with duration of use. Interestingly, his data suggest that routine screening with bladder biopsy may be indicated in addition to cystoscopy for those at highest risk of bladder cancer. Research since this time suggests, however, that there is no good evidence for screening cystoscopy in this population; the requirements of a test to be a good screening tool have not met (Yang et al., 1999). Kaufman et al. (1977) did not include a significant number of suprapubic catheter users, but Groah et al. (2002) did include both types of indwelling catheter users, and clearly showed a higher incidence of bladder cancer in such patients compared to those not managing their bladders with indwelling catheters. Stone disease, upper tract deterioration, reflux, and chronic infection remain additional long term concerns in those who resort to indwelling catheter use, with a slightly lower overall incidence reported in those with suprapubic vs. urethral catheters (Weld & Dmochowski 2000).

Conclusion

  • There is level 4 evidence, despite an associated significant incidence of urological and renal complications, acute and chronic indwelling suprapubic catheterization may still be a reasonable choice for bladder management for people with poor hand function, lack of care-giver assistance, severe lower limb spasticity, urethral disease, and persistent incontinence with urethral catheterization.
  • There is level 4 evidence that those with indwelling catheters are at higher risk for bladder cancer compared to those with non-indwelling catheter management programs. Screening for cancer may require routine biopsy as well as cytoscopy.
  • With diligent care and ongoing medical follow-up, indwelling suprapubic catheterization may be an effective and satisfactory bladder management choice for some people, though there is insufficient evidence to report lifelong safety of such a regime.

    Indwelling catheter users are at higher risk of bladder cancer, especially in the second decade of use, though risk also increases during the first decade of use.

Condom Catheterization

A viable option for bladder management in males is condom catheterization. As noted above, condom catheterization is associated with relatively fewer complications than indwelling methods but more complications than intermediate catherization (Ord et al. 2003; Hackler 1982). However, complications may still arise, as described by Newman & Price 1985). Of greatest concern is incomplete drainage, which may lead by persistently high bladder pressures, recurrent UTIs and the likelihood of glomerular filtration rate deterioration described below. Sometimes this situation necessitates adjuvant daily or twice daily catheterization, medications, or sphincterotomy. Medications to improve drainage, such as alpha blockers can improve emptying by reducing outlet resistance, and sometimes by reducing pressures. Newman & Price (1985) raise practical issues such as cleanliness and proper use of appliances. Application difficulties with condom catheterization are likely problematic in the event of impaired hand function. Slippage of the condom can result in leaks. Perkash et al. (1992) describe the use of penile implants, in part as a means to circumvent this issue with condom application. 

Table: Condom Catheterization

Discussion

Bladder management through condom drainage is often chosen to oversome persistent incontinence that may occur with other methods of bladder management. However, periodic monitoring for bladder “residuals” and complete emptying, as emphasized by Newman and Price (1985) following a review of 60 SCI patients with external catheters. Elevated residuals should raise the possibility of excessive bladder pressure resultsing from incomplete emptying ads a spastic sphincter. This is a situation that can easily be assessed by urodynamic studies. Though Newman and Price (1985) indicated a high prevalence of bladder trabeculation, and implied that this occurred secondary to high pressure, no corroborating urodynamic data was provided. Sphincterotomy is a surgical procedure that eliminates outlet resistance and one that almost 30% of the study group in Newman and Price (1985) had undergone. Another problem commonly described with condom drainage is infection. It is difficult to make conclusions in this area based on the rather generalized description of a positive culture (“any organism growing”) as presented by Newman and Price (1985).

Some patients prefer condom drainage for convenience, as there is usually no need or reduced need to catheterize, compared to regimes that involve sole use of clean intermittent catheterization. However, this convenience can be offset by accidental leaks, and skin problems at the site of condom attachment. Perkash et al. (1992) conducted a retrospective analysis of 79 male patients with penile implants in place over a mean time of 7.08 years. A primary reason for obtaining a penile implant in these patients, among others, was to provide a stable penile shaft to hold a condom for external urinary drainage. In addition, penile implantation allowed some to switch to a more effective and safer bladder management method (i.e. 18% no longer required an indwelling catheter). All patients reported improved continence as reflected in the general observation that it was easier to keep themselves clean and dry.

Conclusion

  • There is level 4 evidence that condom drainage may be associated with urinary tract infection and upper tract deterioration.
  • There is level 4 evidence that penile implants may allow easier use of condom catheters, thereby reducing incontinence and improving sexual function.
  • Patients using condom drainage should be monitored for complete emptying and for low pressure drainage, to reduce UTI and upper tract deterioration. Sphincterotomy may eventually be required.

    Penile implants may allow easier use of condom catheters and reduce incontinence.

Continent Catheterizable Stoma and Incontinent Urinary Diversion

People with tetraplegia, especially females often have difficulty performing clean intermittent catherization. In addition, females are more troubled by persistent incontinence. The surgical methods described in this section can result in the ability to self-catheterize, allowing the individual to benefit from intermittent rather than indwelling bladder catheterization, the latter being associated with a higher rate of complications. The mitrofanoff channel involves the use of an autologous tubular structure, usually the appendix, as a cutaneous catheterizable stoma. Implantation in the bladder via a submucosal tunnel provides continence to the conduit (Sylora et al. 1997). The stoma can be hidden in the umbilicus. While performed often in children, the procedure has less commonly been performed in adults. Long term followup is unknown, particularly with respect to the potential for malignancies. Karsenty et al. (2008) describes a similar procedure, performed in 13 patients with incontinence and inability to self-catheterize.

Ileal conduit diversion, another surgical approach more commonly performed in females, is also often considered for reasons of lack of manual dexterity or ease of care and convenience (Pazooki et al. 2006; Chartier-Kastler et al. 2002). This technique aims to establish low-pressure urinary drainage by diverting urine prior to entering the bladder and connecting the ureters to an external urinary collection system via a catheter passed through the ileal lumen. This procedure is sometimes conducted along with removal of the bladder as well (Chartier-Kastler et al. 2002; Kato et al. 2002).

Table: Continent Catheterizable Stoma and Incontinent Urinary Diversion

Discussion

Continent Catheterizable Stoma

Despite small sample sizes, the results of the above studies are very promising. High levels of continence, independence, and the ability to manage the bladder with intermittent catheterization are reported in all three studies. The stability of serum creatinine has implications for upper tract function (Karsenty et al. 2008). Hakenberg et al. (2001) reported safe urodynamic bladder storage pressures (20-44 mm H20) on patients that underwent appendicovesicostomy with cutaneous stoma. Participants in this study and the study by Sylora et al. (1997) were kept on anticholinergic medication, a consideration that ensures low pressure storage in those with persistent hyperreflexia and dyssynergia, and contributes to ongoing continence. Complications occur, most concerning of which are those requiring surgical procedures (pelvic abscess, bowel occlusion, stomal revision for stenosis). Larger sample sizes would be necessary to determine true incidence. Length of follow-up ranged from 20 – 44 months, which does not provide sufficiently long term safety and effectiveness data. However, given the importance of the clinical achievements (i.e., independent use of intermittent catheterization; continence) further study with larger sample sizes is warranted.

Incontinent Urinary Diversion

Ileal conduit diversion is another surgical procedure noted with some frequency in the literature. Chartier-Kastler et al. (2002) and Kato et al. (2002) have reported separate case series (N=33 and N=16 respectively) examining this approach. Chartier-Kastler et al. (2002) reported all patients became continent after initially being incontinent prior to surgery and Kato et al. (2002) reported that most patients were more satisfied with the procedure than their previous management method upon survey a few months after the operation. Both authors also reported several long-term complications (e.g., pyocystitis, suprapubic collection – genital secretions), chronic urethral leakage, acute pyelonephritis). However, it is uncertain if these high complication rates would be comparable in the event individuals had continued with their previous form of bladder management, as often surgical procedures are performed only if other more conservative methods are unsuccessful. Controlled trials (e.g., case control study design) would be beneficial to address this issue.

Colli & Lloyd (2011) evaluated a series of cases (N=35) involving bladder neck closure (BNC) which was paired with permanent suprapubic catheter (SPC) diversion as opposed to other forms of urinary diversion, such as ileovesicotomy or continent catheterizable stoma. Their results suggest that BNC in conjunction with SPC diversion offers urethral continence with a reasonable complication rate (17%). A straightforward operative approach without violation of the peritoneum, no need for enteric reconstruction, and possible reduction of bowel complications are additional advantages conferred by this technique. Specific disadvantages, such as a reduced likelihood of success in very low bladder capacity patients were noted.

Conclusion

  • There is level 4 evidence that most individuals who receive catheterizable stomas become newly continent and can self-catheterize. It appears possible that this surgical intervention could protect upper tract function. Larger studies are needed to better evaluate true incidence of complications, and long-term bladder and renal outcome.
  • There is level 4 evidence that most individuals undergoing cutaneous ileal conduit (ileo-ureterostomy) diversion became newly continent and were more satisfied than with their previous bladder management method. Long-term follow-up demonstrated the presence of a high incidence of urological or renal complications. 
  • Catheterizable abdominal stomas may increase the likelihood of achieving continence and independence in self-catherization, and may result in a bladder management program that offers more optimal upper tract protection.

    Cutaneous ileal conduit diversion may increase the likelihood of achieving continence but may also be associated with a high incidence of various long-term complications.

Electrical Stimulation for Bladder Emptying (and Enhancing Volumes)

Although electrostimulation to enhance bladder volume and induce voiding has been studied since the 1950’s it was not until the development of the Brindley anterior sacral nerve root stimulator, and subsequent implantation of the first device in a human in 1978 that widespread clinical applications have been available (Egon et al. 1998; Brindley et al. 1982). Others have noted the important role of Tanagho and Schmidt (1982) in developing this approach – also termed sacral neuromodulation – by conducting a series of experiments to elucidate the neuroanatomical basis of electrical stimulation in enhancing bladder function (Hassouna et al. 2003). Although there are several configurations,[1] Creasey et al. (2001) described the system employed in most investigations (i.e., the Finetech-Brindley system), as consisting of an implanted internal stimulator-receiver which is controlled and powered via telemetered radio transmission by an external controller-transmitter. Cables and electrodes are also implanted which are held in contact with sacral nerves (i.e., often S2-S4). This system allows programmable stimulation patterns and permits control of both bowel and bladder function. Often dorsal sacral rhizotomy is performed at the same time as stimulator implantation (Vastenholt et al. 2003; Creasey et al. 2001; Egon et al. 1998; Martens et al. 2011).

Various investigators have examined other forms of stimulation including direct bladder stimulation (Madersbacher et al. 1982; Radziszweski et al. 2009) or employing stimulators intended for other purposes such as enhancing muscle functions for improving movement, spasticity or muscle strength (Katz et al. 1991; Wheeler et al. 1986). In addition, multi-functional stimulators may be configured to provide similar stimulation patterns to similar targets as the bladder-specific stimulators. As noted previously (Section 13.3.2.1 Electrical Stimulation to Enhance Bladder Volumes), the present section describes studies that assess outcomes associated with both bladder emptying and bladder storage as appropriately configured stimulation may result in improvements in both of these functions.

Table: Electrical Stimulation to Trigger Bladder Emptying and Enhance Bladder Volume

Discussion

Sacral neuromodulation or sacral anterior root stimulation combined with sacral deafferentation is the most well studied method of triggering bladder emptying via electrical stimulation techniques with many investigators incorporating retrospective case series or prospective pre-post study designs comprising level 4 evidence (Robinson et al. 1988; Van Kerrebroeck et al. 1996; Van Kerrebroeck et al. 1997[1]; Egon et al. 1998; Creasey et al. 2001; Vastenholt et al. 2003; Kutzenberger et al. 2005; Kutzenberger 2007; Lombardi & Del Popolo 2009; Possover 2009). Typical participant characteristics for these studies include: detrusor overactivity; incomplete bladder emptying and frequently recurrent UTI; incontinence; and vesicoureteric reflux, refractory to conservative treatment. In each of these studies, a large percentage of subjects did become continent and were able to successfully void with these devices, whereas this was typically not the case for most participants with whatever bladder management method was used prior to implantation. These findings appear to persist in that several reports have noted continued improvement with successful continence rates of 73-88% over an average follow-up period up to 8.6 years (Egon et al. 1998; Vastenholt et al. 2003; Kutzenbergen et al. 2005; Kutzenberger 2007; Lombardi & Del Popolo 2009). Of note, Lombardi and Del Popolo (2009) conducted a study that included patients with underactive bladder (n=13) in addition to those with overactive bladder (n=11) and reported similar results for both groups (i.e., reduction in incontinence and increased voiding volume). However, 30.8% of persons in the underactive bladder group had a loss of efficacy over the follow-up period (mean of 60.7 months) as compared to none in the overactive bladder group.

Several of these investigators reported a significant decrease in UTIs (Van Kerrebroeck et al. 1996; Egon et al. 1998; Vastenholt et al., 2003; Creasey et al. 2001; Kutzenberger et al. 2005; Kutzenberger 2007; Martens et al. 2011) and autonomic dysreflexia (Van Kerrebroeck et al. 1996; Egon et al. 1998; Creasey et al. 2001; Kutzenberger et al. 2005; Kutzenberger 2007; Possover 2009) among participants, even after long-term use. Some investigators performed satisfaction surveys and reported that most participants remained satisfied with the device, even after many years. In particular, Vastenholt et al. (2003) and Martens et al. (2011) conducted a Qualiveen questionnaire for assessing the bladder health-related quality of life and impact of urinary problems. In the Vastenholt et al. (2003) study, the top 3 advantages noted by stimulator users was a reduction in UTIs (68% reporting), improved social life (54%) and improved continence (54%). Martens et al. (2011) reported improved quality of life scores (Qualiveen and SF-36), a significantly better Specific Impact of Urinary Problems score and continence rate, in addition to reduced UTIs for patients undergoing a Brindley procedure.

Posterior rhizotomy was performed in addition to implantation of a sacral root stimulator in most reports (Creasey et al. 2001; Van Kerrebroeck et al. 1996; Egon et al. 1998; Kutzenberger et al. 2005; Kutzenberger 2007; Martens et al. 2011). The stated benefit of this deafferentation is the abolition of dyssynergia and high intravesical pressures, reduced risk of hydronephrosis and reflex incontinence. The cost is the loss of bowel reflexes and reflex erections. Nonetheless, most authors report improved bowel management in many of their patients (since the stimulator is activated during the bowel routine), and a great improvement in autonomic dysreflexia (Van Kerrebroeck et al. 1996; Egon et al. 1998; Creasey et al. 2001; Kutzenberger 2007). In Robinson et al. (1988) sphincterotomies were performed on 3 patients with persistent reflex incontinence, and/or upper tract deterioration, while 3 patients were given sphincterotomies pre-implantation to prevent anticipated autonomic dysreflexia. Thus, sphincterotomy has shown some success as an option for producing some of the benefits attributed to posterior rhizotomy.

A primary purpose of posterior rhizotomy is the attainment of an areflexic bladder, thus allowing a more compliant reservoir with the potential for greater bladder capacity under lower pressure. Results from all investigations measuring capacity have shown this to be true with significant increases in bladder capacity at lower pressures associated with combined sacral anterior root stimulation and sacral deafferentation (Creasey et al. 2001; Van Kerrebroeck et al. 1996; Egon et al. 1998; Kutzenberger et al. 2005, 2007). Several investigations have been conducted using different approaches aimed at conditioning the bladder with different forms of stimulation so as to achieve the same effect of increasing bladder capacity under low-pressure conditions in persons with SCI with overactive bladder and intact dorsal sacral nerves (Madersbacher et al. 1982; Kirkham et al. 2002; Kirkham et al. 2002; Bycroft et al. 2004; Hansen et al. 2005). Additionally, rhizotomy alone (without a stimulator) has shown to result in higher quality of life scores over matched controls (Martens et al. 2011).

Of note, Kirkham et al. (2002) implanted the same sacral anterior root stimulator used in the majority of investigations (i.e., Finetech-Brindley stimulator) in a small group of patients (n=5) without posterior rhizotomies and therefore configured the stimulator to deliver both anterior and posterior sacral root stimulation. The conditioning posterior root stimulation was effective in producing increased bladder capacity in 3 of 5 subjects and the anterior root stimulation was able to elicit bladder emptying, but with significant residual volumes. (Note: the 2 remaining subjects sustained posterior root damage and were not included in post-operative testing.) This preliminary trial suggests there is a possibility of achieving success with sacral anterior root stimulation without necessitating the destructive posterior root ablation.

Others have conducted more mechanistic investigations of conditioning stimuli delivered to the pudenal, dorsal penile or clitoral nerve (Spinelli et al 2005; Kirkham et al. 2001) or magnetic stimulation applied over the sacral nerves (Bycroft et al. 2004) and achieved demonstrations of detrusor inhibition or increased bladder capacity under lower pressure. Further developmental work would be required before these or modified approaches could be incorporated clinically as an approach that permits bladder stimulation in the absence of deafferentation.

Recently, Possover (2009) reported a new surgical technique applied to persons with SCI involving laparoscopic transperitoneal implantation of neural electrodes to pelveoabdominal nerves, which they have termed the ‘‘LION procedure’’ (i.e., laparoscopic implantation of neuroprosthesis). With this method, which is far less invasive than the traditional dorsal approach for stimulator implantation, the risk associated with immediate or long-term complications (e.g., meningitis, encephalitis, infections) is significantly reduced. In addition, the destructive procedures of rhizotomy and laminectomy are not necessary. Possover (2009) conducted this procedure on a series of 8 persons previously having an explanted Brindley-Finetech stimulator, 6 of whom had viable sacral nerves. This resulted in adequate detrusor contractions enabling complete bladder emptying still present at follow-up (3-27 months). Patients undergoing this procedure returned home after only a 3-5 day hospital stay and there were no reported complications.

Another approach has been to apply stimulation to the bladder itself, most appropriately done during initial rehabilitation (Madersbacher et al. 1982; Radziszweski et al. 2009). Radziszweski et al. (2009) applied daily 15 minute bouts of transcutaneous electrical stimulation directly to the bladder for 30 days in patients seen by the Rehabilitation Department of a Military Hospital (time since injury not reported). These authors demonstrated significant increases in bladder capacity and peak flow velocity and a significant decrease in residual urine volume immediately following stimulation and persisting at 2 months follow-up compared to baseline. A similar approach was reported by Madersbacher et al. (1982) in which stimulation, in the form of impulse packages applied to a saline filled bladder, was administered over a variable treatment period after which the treatment effect persisted up to one year when most subjects reported a definite waning of the benefits. Unlike other studies involving sacral neuromodulation, this was conducted on those more recently injured with 17 of 29 becoming continent and 10 others becoming socially dry without need for pads and urinals. This study involved a case series design but would have been much more powerful with the inclusion of a control group, given the potential for natural bladder recovery in individuals with more recent injuries. Further research would also be needed to examine safety information related to bladder pressure during voiding, and follow-up of any potential renal changes before considering this intervention.

Sievert et al. (2010) also capitalized on the concept of neural plasticity through early (upon confirmation of bladder acontractility) sacral neromodulation (SNM) and reported no instances of detrusor overactivity and urinary incontinence with normal bladder capacity, reduced UTI rates and improved bowel and erectile functionality without nerve damage. Although follow-up was reported for greater than 2 years, further investigations are needed to augment the small sample size (nSNM=10) and involve fMRI to confirm plastic changes within the brain of those patients undergoing SNM vs those pharmacologically treated.

Other investigators have examined the effects on the urinary system associated with stimulation directed towards other targets For example, Katz et al. (1991) tested the effect of epidural dorsal spinal cord stimulation, intended primarily for spasticity relief, at T1 (for those with tetraplegia) or T11-T12 (for those with paraplegia). Wheeler et al. (1986) investigated the effect of 4 to 8 weeks of quadriceps muscle reconditioning by surface electrical stimulation (FES) bilaterally, intended primarily for strength and spasticity. In each case, these techniques had marginal effects on bladder function. However, in the latter experiment it was noted that some subjects did achieve beneficial changes in bladder function and that these tended to be most noticeable in the same subjects that showed positive improvements in strength and spasticity.

Conclusion

  • There is level 4 evidence from eight studies and level 5 evidence from a single study that ongoing use of sacral anterior root stimulation (accompanied in most cases by posterior sacral rhizotomy) is an effective method of bladder emptying resulting in reduced incontinence for the majority of those implanted. This is associated with increased bladder capacity and reduced post-void residual volume.
  • There is level 4 evidence from five studies and level 5 evidence from a single study (UTIs only) that sacral anterior root stimulation (accompanied in most cases by posterior sacral rhizotomy) may be associated with reducing UTIs and autonomic dysreflexia.
  • There is level 4 evidence from two studies that direct bladder stimulation may result in reduced incontinence, increased bladder capacity and reduced residual volumes but requires further study as to its potential clinical use.
  • There is level 4 evidence from various single studies that other forms of neuroanatomically-related stimulation (e.g., electrical conditioning stimulation to posterior sacral, pudenal, dorsal penile or clitoral nerve or surface magnetic sacral stimulation) may result in increased bladder capacity but require further study as to their potential clinical use. Further development involving some of these approaches may permit sacral anterior root stimulation without the need for posterior root ablation.
  • There is limited level 2 evidence from a single small study that reports early sacral neuromodulation may improve management of lower urinary tract dysfunction. Further investigation is required to confirm the results and substantiate the hypothesis of resultant plastic changes of the brain.
  • There is level 4 evidence from a single study that epidural dorsal spinal cord stimulation at T1 or T11 originally intended for reducing muscle spasticity may have little effect on bladder function.
  • There is level 4 evidence from a single study that a program of functional electrical stimulation exercise involving the quadriceps muscle originally intended for enhancing muscle function and reducing muscle spasticity has only marginal (if any) effects on bladder function.
  • Sacral anterior root stimulation (accompanied in most cases by posterior sacral rhizotomy) enhances bladder function and is an effective bladder management technique though the program (surgery and followup) requires significant expertise.

    Direct bladder stimulation may be effective in reducing incontinence and increasing bladder capacity but requires further study.

    Posterior sacral, pudenal,dorsal penile or clitoral nerve stimulation may be effective to increase bladder capacity but requires further study.

    Early sacral neural modulation may improve management of lower urinary tract dysfunction but requires further study.

Sphincterotomy, Artificial Sphincters, Stents and Related Approaches for Bladder Emptying

Transtherurethral sphincterotomy and related procedures such as insertion of artificial sphincters, sphincteric stents or balloon dilation of the external urinary sphincter provide a means to overcome persistent dysynergia (Chancellor et al. 1999; Juma et al. 1995; Chancellor et al. 1993a; Chancellor et al. 1993b; Patki et al. 2006; Seoane-Rodriguez et al. 2007). Often these are performed when intermittent catheterization is not an option because of lack of manual dexterity and when more conservative options have proven unsuccessful (Chancellor et al. 1999; Juma et al. 1995).

Table: Sphincterotomy, Intraurethral Stent Insertion and Related Approaches for Bladder Emptying

Discussion

A common surgical method of treating bladder outlet obstruction or detrusor-sphincter dyssynergia has been transurethral sphincterotomy usually done in anticipation of emptying the bladder with condom drainage with reflex “voiding”. Autonomic dysreflexia (AD), a common complication of high volume storage and/or high pressure “voiding” or leaking in SCI patients with spinal lesions typically above T12, can be diagnosed with blood pressure (BP) monitoring during cystometrogram and urodynamic studies and subsequently better managed after successful transurethral sphincterotomy (Perkash 2007). Perkash (2007) noted a highly significant (p<0.0001) decrease in systolic and diastolic BP after transurethral sphincterotomy as well as improved voiding and post-void residuals. However, although diminished symptoms of AD were reported, mean maximum voiding pressures changes were not significant.

Juma et al. (1995) reported a case series of 63 individuals who had received 1 or more sphincterotomies with a mean follow-up time of 11 (range 2-30) years. This study was directed at describing the risk for long-term complications following this procedure. Although more than half of these individuals had normal upper tract imaging studies a significant proportion had complications - with 25/63 having some upper tract pathology (i.e., 12 renal calculi, 11 renal scarring, 1 atrophic kidney, 1 renal cyst). Nineteen of these were deemed significant. Risk of significant upper tract complications in presence or absence of bacteria was 38% and 13% respectively. Thirty out of 63 had lower tract complications (5 bladder calculi, 10 recurrent UTI, 3 urethral diverticula, 6 urethral stricture or bladder neck stenosis and 6 recurrent epididymitis). These authors noted that the most reliable urodynamic measure for predicting potential complications following sphincterotomy appeared to be an increase in leak point pressure. Complication rates of 50% were noted for those with leak point pressure of > 70 cm H2O, whereas rates were reduced to 25% when leak point pressure was < 30 cm H2O.

Despite possible upper renal tract protection and extended periods of satisfactory bladder function (i.e., 81 months), long-term outcome data (Pan et al. 2009) caution that high rates of recurring bladder dysfunction symptoms (68%) require approaching sphincterotomy as a staged intervention given that 36% (30/84) of patients required a second procedure to achieve the mean extended period of satisfactory bladder function. When considering these studies, it is uncertain if these high complication rates would be comparable in the event individuals had continued with their previous form of bladder management as often surgical procedures are performed only if other more conservative methods are unsuccessful. A controlled trial is required to address this issue. For cases where DESD is paired with with bladder neck dyssynergia (which should be confirmed with videourodynamic study), Ke & Kuo (2010) have shown that transurethral incision of the bladder neck (TUI-BN) may restore contractility of the detrusor. PVR decreased and QMax increased significantly after TUI-BN and an open urethral sphincter was noted in 19 of 22 patients studied postoperatively. In addition, autonomic dysreflexia during micturition was also reduced or eliminated in 15 of the 17 patients with AD preoperatively (Ke & Kuo 2010).

One alternative to sphinterotomy is placement of a stent passing through the external sphincter thereby ensuring an open passage. Several studies have been conducted examining the long-term outcomes associated with different types of stents including a wire mesh stent (UroLume) (Chancellor et al.1993a, Abdill et al. 1994, Chancellor et al. 1995; Abdul-Rahman et al. 2010) and a nickel-titanium alloy tightly coiled stent (Memokath) (Mehta & Tophill 2006). Long-term outcomes of each of these stents were also investigated in a retrospective case series study of 47 consecutive male patients (Seoane-Rodriguez et al. 2007). All of these studies involved either retrospective case series reviews or prospective pre-post study designs and demonstrated effective treatment of incontinence initially while the stent was in place although some studies also showed the necessity for stent removal due to migration or other complications. In particular, Mehta and Tophill (2006), in a case series of 29 persons with SCI with a follow-up of up to 47 months suggested that the “working life” of the Memokath stent was 21 months. They noted that complications most commonly leading to removal included stent blockage by encrustation, migration (especially in single-ended models), UTIs and persistent haematuria. Others have noted similar issues but typically have reported lower rates of complications leading to stent removal (Abdill et al. 1994, Chancellor et al. 1995, Seoane-Rodriguez et al. 2007; Abdul-Rahman et al. 2010). Despite these issues, when the stents are in place they appear to be effective, resulting in significant reductions in voiding pressure and post-void residual urine volumes although no significant changes have been noted in bladder capacity (Chancellor et al.1993a; Abdill et al. 1994; Chancellor et al. 1995; Seoane-Rodriguez et al. 2007; Abdul-Rahman et al. 2010). In addition, reduced incidence of UTIs and autonomic dysreflexia has typically been reported (Chancellor et al.1993a; Seoane-Rodriguez et al. 2007). Game et al. (2008) advocate for a trial period with a temporary stent early post-injury based on the percentage of patients (~30%) not choosing placement of a permanent stent or in whom the stent did not provide the expected results. This reversible management option is however, limited by the available materials for temporary stenting.

Chancellor and colleagues (1999) also conducted a RCT (n=57) comparing the outcomes associated with sphincterotomy as compared to placement of the stent (UroLome) prosthesis (Chancellor et al. 1999). This study was deemed a low quality RCT, largely because blinding and concealed allocation was not possible given the nature of the intervention. Similar measurement procedures and overall findings were noted as reported for the studies above (i.e., Chancellor et al. 1993c) with significant decreases in voiding detrusor pressure and post-void residual urine volumes and no significant changes reported for bladder capacity and no differences noted between sphincterotomy and stent for any measure at any time point (i.e., 3, 6, 12 and 24 months). The need for catheterization, initially required in 50% of the sphincterotomy group (n=26) and 71% of the stent group (n=31), was reduced to just 3, 4, 1, & 1 and 1, 0, 1 & 2 individuals respectively at 3, 6, 12 and 24 months respectively. There was little difference in subjective assessment of impact of bladder function on quality of life or in the incidence of complications between the treatment groups although those in the stent group spent less time in the hospital for the procedure.

Chancellor et al. (1993b) also have examined another procedure with similar rationale as that associated with sphincterotomy. This investigation involved a pre-post trial design (n=17) of transurethral balloon dilation of the external urinary sphincter. Again, similar methods were employed as the studies noted above and findings were also similar. Of all 17 patients previously managed by indwelling Foley catheter, 15 used condom catheters post-procedure and 2 voided on their own. Significant decreases were noted in voiding pressure (p=0.008) at all follow-up times (i.e., 3, 6 and 12 months). No changes were seen in bladder capacity (p=0.30) and significant reductions in post-void residual urine volumes (p<0.05) were seen at all follow-up times. Positive urine cultures (i.e., UTI) were noted in 15/17 prior to surgery but only in 5, 8 and 4 of the patients at 3, 6 and 12 months respectively. Subjective autonomic dysreflexia improved in all 9 individuals who had previously complained of this.

More recently, Patki et al. (2006) reported a small retrospective case series investigation (n=9) of implantation of an artificial urinary sphincter (AUS; American Medical System 800). This device has evolved over the years to where it is now easier to implant surgically, has a longer life and a higher success rate in achieving incontinence (~80% with more recent models). In this trial, all patients achieved successful incontinence with no self-reported leakage upon activation of the system. However, by 3 month follow-up, 2 patients reported significant recurrrent incontinence, with one implant being removed and the other being revised and by a mean follow-up of 105.2 months 5 of 9 implants have been successful with no revisions. Overall, more than half of the patients with working implants recorded higher maximum detrusor pressures although no upper tract change or deterioration in renal function was noted in any patient. A retrospective analysis in 2009 by Bersch et al. of individuals (n=51) who underwent implantation of an artificial sphincter at the bladder neck using a port instead of a pump suggested this approach to be highly successful, reliable, safe and cost-effective treatment option (even with implant revisions). Additionally, a retrospective review by Chartier-Kastler et al. (2011) determined an AUS device was effective in restoring urinary continence in males, in the majority of cases reviewed, with a decrease in urethral erosion by placement of the device around the bladder neck, providing more credence to consideration for SCI patients.

Conclusion

  • There is level 4 evidence from a single case-series study that sphincterotomy is effective in reducing episodes of autonomic dysreflexia associated with inadequate voiding.
  • There is level 4 evidence from a single case-series study that sphincterotomy, as a staged intervention, can provide long-term satisfactory bladder function.
  • There is level 2 evidence from a single low-quality RCT but supported by level 4 studies that both sphincterotomy and implantation of a sphincteric stent are effective in reducing incontinence, with little need for subsequent catheterization, and both treatments are associated with reduced detrusor pressure and reduced post-void residual volume but not with changes in bladder capacity. The only significant difference in these 2 treatments was the reduced initial hospitalization associated with the stent, given the lesser degree of invasiveness.
  • There is level 4 evidence that implantation of a sphincteric stent may result in reduced incidence of UTIs and bladder-related autonomic dysreflexia over the short-term although several studies have demonstrated the potential for various complications and subsequent need for re-insertion or another approach over the long-term.
  • There is level 4 evidence from a single long-term follow-up study of those having a previous sphincterotomy that the incidence of various upper and lower tract urological complications may be quite high.
  • There is level 4 evidence from a single case-series study that advocates for placement of a temporary stent early after injury as a reversible option that allows patients to choose from the range of permanent stent placement to less invasive bladder management methods such as intermittent catheterization.
  • There is level 4 evidence based on a single study that transurethral balloon dilation of the external sphincter may permit removal of indwelling catheters in place of condom drainage, and also may result in reduced detrusor pressure and post-void residual volume but not with changes in bladder capacity.
  • There is level 4 evidence based on 2 studies that implantation of an artificial urinary sphincter may be useful in the treatment of incontinence in SCI but further study is required.
  • There is level 4 evidence from a single pre-post study that transurethral incision of the bladder neck may be useful in bladder neck and voiding dysfunction. 
  • Surgical and prosthetic approaches (with a sphincterotomy and stent respectively) to allow bladder emptying through a previously dysfunctional external sphincter both seem equally effective resulting in enhanced drainage although both may result in long-term upper and lower urinary tract complications.

    Artificial urinary sphincter implantation and transurethral balloon dilation of the external sphincter may be associated with improved bladder outcomes but require further study.

Other Miscellaneous Treatments

In addition to those noted in the previous sections, there are a variety of other approaches that have been investigated to address the consequences of neurogenic bladder associated with SCI. These include the use of desmopressin acetate (DDAVP) as an adjuvant therapy to manage the effects of an overactive bladder otherwise refractory to conventional treatment such as nocturnal enuresis (i.e., night-time emission of urine) or the requirement for too frequent catheterizations. DDAVP is a synthetic analogue of antidiuretic hormone (ADH) most commonly administered by intravenous infusion for treatment of bleeding disorders. It can also be taken in the form of a pill or intranasal spray for reducing urine production as in the present application (Chancellor et al. 1994; Zahariou et al. 2007). DDAVP is thought to bind to V2 receptors in renal collecting ducts to increase water reabsorption.

Others have employed alternative approaches such as electroacupuncture (Cheng et al. 1998) or nerve crossover surgery / spinal root anastomoses (Livshits et al. 2004; Lin et al. 2008; Lin et al. 2009) to enhance recovery of bladder function.

Table: Other Miscellaneous Treatments

Discussion

Zahariou et al. (2007) and Chancellor et al. (1994) conducted a pre-post (n=11) and a case series (n=7) investigation retrospectively to investigate the use of intranasal DDAVP as an alternative therapy to reduce urine production in the hopes of reducing nocturnal emissions or reducing the need for overly frequent catheterization during the day. In each case, DDAVP was employed as an adjuvant therapy in addition to standard therapies of anticholinergics and intermittent catheterization which had resulted in less than satisfactory results. With use of DDAVP just before bedtime, Zahariou et al. (2007) reported a statistically significant increase in urine production rate during the day (p<0.001) and a decrease in nocturnal urine production (p<0.001). After DDAVP treatment, participants had reduced or complete elimination of nocturnal enuresis (Chancellor et al. 1994; Zahariou et al. 2007). In addition, the proportion of persons requiring clean intermittent catheterizations in the night while still maintaining continence was greatly reduced (Zahariou et al. 2007) and 3 individuals used DDAVP during the day at work and were able to achieve an additional 3.5 hours between catheterizations (Chancellor et al. 1994). These improvements persisted for a mean of 12 months. These small scale studies provides only preliminary evidence and encourages further study, although DDAVP is in fairly widespread use for SCI-related neurogenic bladder.

Another adjunctive therapy that has been investigated is the use of electroacupuncture. For example, Cheng et al. (1998) conducted a RCT (n=60) investigating the effectiveness of electroacupuncture administered in combination with conventional bladder management method (i.e., intermittent catheterization, tapping and trigger point stimulation) as compared to those not receiving electroacupuncture. Their primary outcome measure was the time to achieve bladder balancing which was defined as the time when 1) the patient could easily pass adequate urine at low pressure, 2) residual urine of approximately 100 ml or less and 3) absent UTIs. Although employing a randomized, controlled design, some limitations (i.e., lack of blinding, concealed allocation or intent to treat) constrained the level of evidence assigned to this trial (i.e., Level 2). Regardless, those receiving electroacupuncture had a reduced time to achieve bladder balancing for both those with upper motor lesions (p<0.005) and lower motor neuron lesions (p<0.01). In addition, if electroacupuncture was started within 3 weeks of SCI, bladder balancing was achieved sooner than those which started after 3 weeks (p<0.005).

Reports regarding microanastamosis to reinnervate the paralyzed bladder reveal recovery of neurogenic bladder dysfunction. These include surgical anastomosis of the intercostal nerve (Livshits et al 2004; n=11), T11 nerve root (Lin et al 2008, n=10), L5 nerve root (Xiao et al 2003, n=15) or the S1 nerve root (Lin et al 2009, n=12) to the S2 or S3 spinal nerve roots. Mean follow-up of patients was between 2 to 3 years and restitution of bladder function was observed in the majority of patients. Significant results were reported for pre and post-surgical findings including reduced bladder capacity with increased urine volume under increased force of detrusor contractions and increased voiding pressure. There was also reduced residual urine volume and both detrusor tone and sphincter resistance were increased. Results from individual subjects in Livshits et al (2004) were presented for each of these showing consistency across these measures although statistical analysis techniques were inappropriate consisting of individual Wilcoxon signed rank tests for each variable. Patient self-report measures showed increases within a few months following surgery. Similar findings were evident in 100/67/75% of patients undergoing T11/L5/S1 microanastamosis respectively (Lin et al 2009, Xiao et al 2003, Lin et al 2008). Full recovery of renal function and an absence of urinary tract infections was observed at follow-up (i.e., 6-18 months). Important considerations of this surgical approach are that it is far more invasive than other approaches (i.e., indwelling catherization); and patients do not regain the bladder sensation that contributes to quality of life (i.e., sensing urgency and timing of micturition). In particular, accidental voiding may be triggered by unintentional dermatomal stimulation or Achilles tendon stretch. Furthermore, considering the potential for up to 30% failure rates and serious side effects (i.e. neuromas) this invasive procedure must be weighed cautiously against other approaches to treatment of bladder dysfunction.

Conclusion

  • There is level 2 evidence from a single study that early treatment with electroacupuncture may shorten the time that it takes to develop low pressure voiding /emptying with minimal residual volume, when combined with conventional methods of bladder management.
  • Level 4 evidence from two studies suggests that intranasal DDVAP may reduce nocturnal urine production with fewer night-time emissions and also may reduce the need for more frequent catheterizations in persons with SCI with neurogenic bladder that is otherwise unresponsive to conventional therapy.
  • There is level 4 evidence from four studies that nerve crossover surgery (anastomosis of more rostral ventral nerve roots to S2-S3 spinal nerve roots) may result in improved bladder function in chronic SCI. 
  • Early electroacupuncture therapy as adjunctive therapy may result in decreased time to achieve desired outcomes.

    Intranasal DDVAP may reduce nocturnal urine emissions and decrease the frequency of voids (or catheterizations).

    Anastomosis of the T11, L5 or S1 to the S2-S3 spinal nerve roots may result in improved bladder function in chronic SCI.

Detrusor Areflexia

Detrusor areflexia is seen most commonly in cauda equina lesions where the sacral reflex is disrupted. It can occasionally occur at other levels of spinal lesions. The clinical manifestation of this results in an inability for the bladder to empty completely or at all, leading to overdistension and stasis. Additionally, there is frequently incontinence due to lack of external sphincter tone, most often due to increased abdominal pressure on the bladder (i.e. stress incontinence). This can be especially problematic in persons with paraplegia that may require high valsalva forces for activities such as transferring from wheelchairs.

Unfortunately, there is a great paucity of research examining the impact and treatment of detrusor areflexia. Although the goals remain the same as with overactive bladder in SCI, (i.e., avoiding incontinence, stasis, UTI’s, and upper urinary tract damage, etc.), these goals may be achieved differently. In general, the goal is either: 1) stopping leakage and improving storage with medications and intermittent catheterization, or 2) improving emptying, either voluntarily in the incomplete injury, and/or into condom drainage in the person with more severe neurogenic bladder impairments. However, further discussion on detrusor areflexia will not occur in this chapter given the extremely sparse evidence base. It should be noted that in some studies described in the sections pertaining to DESD therapy there may have been mixed samples in which a few subjects with detrusor areflexia might have participated in addition to those with detrusor overactivity. In one instance, subjects with detrusor areflexia comprised all study participants providing level 4 evidence from a single case series (n=10) for the surgical anastomosis of the T11 ventral nerve root to the S2-S3 ventral nerve roots in improving bladder function (e.g., Lin et al. 2008 in Table 13.16 for Other Miscellaneous Treatments). 

Urinary Tract Infections

Defining Urinary Tract Infections

Urinary tract infections (UTIs) are a common secondary health condition following SCI and a major cause of morbidity (Charlifue et al. 1999; Vickrey et al. 1999). There are numerous ways that UTIs have been defined within individual studies with respect to either identifying the presence of UTIs and/or establishing treatment success. Although this diversity exists across studies, the criteria identified at the National Institute on Disability Rehabilitation Research (NIDRR) sponsored National Consensus Conference on UTI (1992) have become generally accepted standards for UTI definition. These designate a UTI as indicative of significant bacteriuria with tissue invasion and resultant tissue response with some or all of the following signs and / or symptoms:

  • Leukocytes in the urine generated by the mucosal lining,
  • Discomfort or pain over the kidneys or bladder, or during urination,
  • Onset of urinary incontinence,
  • Fever,
  • Increased spasticity,
  • Autonomic hyperreflexia,
  • Cloudy urine with increased odor,
  • Malaise, lethargy, or sense of unease.

Significant bacteriuria varies according to the method of urinary drainage and is defined by the following criteria: ≥102 colony-forming units of uropathogens per milliliter (cfu/mL) in catheter specimens from persons on intermittent catheterization, (b) ≥104 cfu/mL in clean-voided specimens from catheter-free men using condom catheters, c) any detectable concentration of uropathogens in urine specimens from indwelling or suprapubic catheters, and d) ≥105 cfu/mL for spontaneous management. Treatment of asymptomatic bacteriuria is not recommended as it has been shown not to be effective and can actually create antimicrobial resistance.

Detecting and Investigating UTIs

Detecting a UTI is the first stage towards successful treatment. Identification of symptoms by the patient is a critical first step in this detection; however, in a prospective case review undertaken by Linsenmeyer and Oakley (2003) only 61% (90/147) of patients were able to correctly predict the presence of a UTI based on their symptoms. Other methods of detection include urine chemical dipsticks which provide an indication of the presence of nitrites and leukocytes with the benefit of a providing a quick turnaround (Faarvang et al. 2000; Hoffman et al. 2004). However, the primary approach and gold standard is the microbiological evaluation of urine bacterial culture. As noted above, organizations such as NIDRR have defined UTIs at least in part on the results of laboratory investigations documenting the presence, amount and type of bacterial growth that occurs with an infection. This also results in the identification of the antibiotic(s) for which the bacteria species may be susceptible (i.e., sensitivity). Furthermore, it has been noted that 33% of SCI UTIs are polymicrobial (Dow et al. 2004). The clinician must then decide between a limited or full microbial investigation in selecting the appropriate treatment. The obvious benefit of a full microbial investigation (i.e. accuracy) is offset by potentially adverse effects due to the time delay for the bacterial sensitivity results and the cost of a full investigation. The studies reviewed in the present section examine specific issues associated with the laboratory investigation of UTIs and how these might impact treatment. 

Table: Investigating UTIs

Discussion

As noted above, laboratory investigation of suspected UTI using microbiological analysis of urine cultures is important for diagnosing UTI and also for guiding treatment. For example, Shah et al. (2005), Hoffman et al. (2004) and Tantisiriwat et al. (2007) reporting centre-based results under a variety of study designs, noted Enteroccoccus species, K. pneumonia, E coli, Pseudomonas aerginosa, Staphlococcus aureus and Proteus mirabilis as among the most common species of bacteria present in urine from those suspected of having a UTI. Antibiotic sensitivity tests are then conducted to determine if these bacteria are susceptible to specific antibiotics. For example, Tantisiriwat et al. (2007) noted that of the antibiotics tested, E. coli was most susceptible to amikacin (96.1%), ceftazidime (88.9%), and cetriaxone (75%). The efficacy of specific antibiotics investigated in the SCI literature will be summarized in subsequent sections.

However, given the cost and the time spent before results can be obtained with bacterial culture (e.g., from 18-48 hours), simpler screening methods have been developed for assessing the presence of a UTI. One of these methods involves using a urine “dipstick” which signifies the presence of nitrates or the presence of leukocyte esterase (LE) respectively as a potential indicator of UTI. The results of investigations into the sensitivity and specificity of these dipstick tests in predicting UTI in patient populations other than SCI have been mixed so Hoffman et al. (2004) conducted an investigation to compare dipstick results for Nitrites and LE to urine culture results where each test was conducted monthly over a 5 year period in a community-based SCI sample (n=56). Using NIDRR criteria for UTI, 81% of the total 695 samples collected over the study period met criteria for bacteriuria, and of these, 36% met criteria for a positive UTI. In general, sensitivity (i.e., the ability to correctly identify significant results) was relatively low at 63% even when either the LE or nitrate dipstick was positive and specificity (i.e., the ability to correctly identify samples without significant bacteria) was 89% or higher for any combination of test. When compared to the ability to predict UTIs, the dipstick sensitivity remained relatively low at 63% and specificity was also low at 52% for any combination of dipstick test. Overall results suggest using dipstick testing as a treatment guide could result in inappropriate or delayed treatment and the study authors suggested that individuals with SCI with suspected UTI should be evaluated with urine culture and not dipstick testing (Hoffman et al. 2004). However, a separate investigation comparing positive and negative predictive values for dipstick testing as compared to leukocyte microscopy relative to culture-derived bacteriuria determined that either method was equally effective with reasonable prediction rates of approximately 80% for each alone or in combination (Faarvang et al. 2000).

Practicality and cost savings in UTI prevention and treatment may not have been the prime motive in an investigation by Darouiche et al. (1997), but they did find that an adequate clinical response to treatment was not significantly different as a result of limited vs full microbial investigation. Limited investigations were conducted by examining colony morphology, appearance on Gram-stain, catalase test and oxidase test without organism identification and antibiotic susceptibilities. Rather, antibiotic selection was based on recognized hospital-based patterns of antibiotic susceptibilities. As well, the cost savings, at an average of $183 US per patient, was not significantly less but indicated a trend (p=0.18) associated with limited vs full investigation. Although this provides level 1 evidence in favour of deferring to a limited microbial investigation for SCI UTI treatment selection, the sample size was small (N=15) and warrants further study. It is also unclear from this study if the results are transferable to anything but an inpatient hospital unit (i.e., not community-based patients) and if treatment is determined in part by relying on the experience of the clinical team in determining treatment.

The results of clinical laboratory analysis are also prone to contamination from a variety of practical issues. For example, sample deterioration between the time of sampling and processing is controversial. Horton et al. (1998) conducted a blinded RCT to investigate the effects of refrigeration on urinalysis and culture results. Samples were split and analyzed at 4 (“fresh”) and 24 (“refrigerated”) hours post-refrigeration. The bacterial counts of “mixed” organisms (p=0.10) and Staph aureus (p=0.66) were altered with refrigeration but no changes in colony counts would have altered the treatment regimen chosen based on urinalysis or culture results. This level 1 evidence provides a level of confidence for urine samples refrigerated (up to 24 hours) prior to analysis.

In another investigation of a narrower issue involving potential contamination, Shah et al. (2005) demonstrated that the number of clinically significant organisms (≥105 cfu/mL) detected by urine culture were reduced in SCI inpatients with indwelling or suprapubic catheters suspected of having a UTI when the catheter was changed just prior to urine collection as compared to those where it was left unchanged (p=0.01). This practice also resulted in a savings of $15.64 per patient.

Conclusion

  • Level 1 evidence based on a single RCTon SCI inpatients suggests that both limited and full microbial investigation result in adequate clinical response to UTI treatment with antibiotics. Therefore the cost savings attributed to a limited microbial investigation favours this practice in the investigation of UTI although more rigorous investigation of the patient outcomes and attributed costs is needed.
  • There is limited level 1 evidence from a single investigation that refrigeration (up to 24 hours) of urine samples prior to sample processing does not significantly alter urinalysis or urine culture results in SCI patients.
  • There is limited level 2 evidence from a single investigation that fewer false positive tests showing bacteriuria occur if indwelling or suprapubic catheters are changed prior to collection for urine culture analysis.
  • There is conflicting level 4 evidence from two investigations concerning whether dipstick testing for nitrates or leukocyte esterase is recommended to guide treatment decision-making.
  • Both limited and full microbial investigation may result in adequate clinical response
    to UTI treatment with antibiotics.

    Indwelling or suprapubic catheters should be changed just prior to urine collection so as to limit the amount of false positive urine tests.

    Urinalysis and urine culture results of SCI patients are not likely to be affected by sample
    refrigeration (up to 24 hours).

    It is uncertain if dipstick testing for nitrates or leukocyte esterase is useful in screening for bacteriuria to assist treatment decision-making.

Non-Pharmacological Methods of Preventing UTIs

The method of bladder management one selects is a primary factor in reducing the risk of UTI in persons with SCI (Trautner & Darouiche 2002). The method chosen should minimize access to the urinary system by foreign bodies and reduce their potential for continued residence by draining the bladder effectively. Most SCI-related research for UTI prevention by these means has been conducted on various techniques for intermittent catheterization and these types of studies are summarized in Table 13.18. Different coatings have been applied to catheters to minimize various complications associated with catheterization and neurogenic bladder and Table 13.19 outlines studies investigating the effect of hydrophilic catheters on UTI prevention. Finally, Table 13.20 summarizes studies that compare intermittent catheterization to other bladder management methods or use aids to augment the use of a particular bladder management method with a goal of preventing UTIs. 

Table: Intermittent Catheterization and Prevention of UTIs

Discussion

During inpatient rehabilitation, intermittent catheterization is the preferred method of bladder management for most cases and several prospective studies have compared sterile techniques with traditional or clean techniques of intermittent catheterization (Charbonneau-Smith 1993; Prieto-Fingerhut et al.1997; Moore et al. 2006). Notably, Moore et al. (2006) and Prieto-Fingerhut et al. (1997) employed RCT designs and showed no statistically significant differences in the number of UTIs occurring in patients using the sterile technique vs the clean technique. Conversely, Charbonneau-Smith (1993) conducted a prospective trial and did find significantly reduced UTI rates for a sterile “no-touch” method as compared to historical controls undergoing a traditional sterile method, although the nature of the historical comparison provides the possibility of confounding variables also affecting this result. Each author noted the greater expense associated with the sterile approach, making it the less attractive option in the absence of evidence for improved positive outcomes.

As with all aspects of rehabilitation, a primary goal of bladder training within an inpatient stay is the goal of patient independence and self-care. Wyndaele and De Taeye (1990) conducted a case control study (n= 73) in which the incidence of UTIs was examined following introduction of an initiative to promote self-catheterization among those with paraplegia on an SCI unit. Prior to this, catheterization was conducted by a specialized catheter health care team using a non-touch technique. Neither UTI rates nor the proportion of people achieving a state of bladder balance or those encountering complications of urethral trauma were significantly different between these 2 approaches. Interestingly, the introduction of patient self-catheterization also seemed to be a factor in the patients being ready for home visits much sooner in their rehabilitation stay.

Less information exists on the continued use of intermittent catheterization for individuals as they move into the community and live with SCI for a prolonged period of time. A case control investigation was conducted by Yadav et al. (1993) comparing UTI incidence rates between those using a clean intermittent catheterization technique during inpatient rehabilitation with another group of patients continuing to use the same bladder management method and living in the community for 1-12 years. Similar rates of UTI (termed acceptably low by the authors) were found in both samples although there were differences in the types of bacteria causing UTIs between the SCI rehabilitation unit and the community.

Regardless of the approach to bladder management, and even if intermittent catheterization is used, the rate of UTI in the SCI population is still elevated relative to a population with neurologically normal functioning bladders This is thought to be partly due to the residual volume of urine that may persist in the bladder following intermittent catheterization. Jensen et al. (1995) conducted a study in inpatient rehabilitation (n=12) correlating UTI incidence over the rehabilitation period with the average residual urine volume after intermittent catheterization. Correlations between UTIs and residual volumes were low and suggested little relationship or as the authors point out it may have been that residual volumes would have had to be reduced to negligible values before UTI incidence would have been reduced as opposed to the mean values of 40 ± 11 ml (hyperactive bladder) or 19 ± 7 ml (hypoactive bladder) seen in this study.

Conclusion

  • Level 2 evidence based on two RCTs suggests no difference in UTI rates between sterile vs clean approaches to intermittent catheterization during inpatient rehabilitation, however, using a sterile method is significantly more costly.
  • There is limited level 4 evidence from a single study that there is no difference in UTI rates between intermittent catheterization conducted by the patients themselves or by a specialized team during inpatient rehabilitation.
  • There is limited level 4 evidence from a single study that similar rates of UTI may be seen for those using clean intermittent catheterization during inpatient rehabilitation as compared to those using similar technique over a much longer time when living in the community.
  • There is limited level 4 evidence from a single study that differences in residual urine volume ranging from 0-153 ml were not associated with differences in UTI during inpatient rehabilitation.
  • Sterile and clean approaches to intermittent catheterization seem equally effective in minimizing UTIs in inpatient rehabilitation.

    Similar rates of UTI may be seen with intermittent catheterization as conducted by the patients themselves or by a specialized team during inpatient rehabilitation.

    Similar rates of UTI may be seen with intermittent catheterization, whether conducted in the short-term during inpatient rehabilitation or in the long-term while living in the community.

    UTIs were not associated with differences in residual urine volumes after intermittent catheterization.

Table: Intermittent Catheterization using Specially Coated Catheters for Preventing UTIs

Discussion

Another approach used to reduce the incidence of UTI associated with catheterization in patients with neurogenic bladder involves the application of coatings to the catheter (Giannantoni et al. 2001; Vapnek et al. 2003; De Ridder et al. 2005; Cardenas & Hoffman 2009; Cardenas et al. 2011). For example, Giannantoni et al. (2001) employed a double-blind, crossover RCT design (n=18) to examine the difference between a pre-lubricated, nonhydrophilic Instantcath catheter as compared to a conventional polyvinyl chloride (PVC) silicon-coated Nelaton catheter with respect to the occurrence of UTIs and urethral trauma. The subjects were randomized to 1 of 2 groups which tried each catheter for a period of 7 weeks in an A-B, B-A design. Both incidence of UTIs (p=0.3) and presence of asymptomatic bacteriuria (p=0.024) were significantly reduced for the pre-lubricated catheter vs the conventional PVC catheter. Perhaps most interesting, 3 subjects requiring assistance with the conventional catheter became independent with the pre-lubricated catheter, although it was not reported if these individuals were in the group using the conventional catheter initially or lastly. The existence of an order effect (or not) for any of the measures was not reported. In terms of general satisfaction with use, subjects rated the pre-lubricated catheter significantly higher than the conventional catheter with respect to comfort, ease of inserting and extracting, and handling.

A similar finding of reduced incidence of UTIs (p=0.02) was reported by De Ridder et al. (2005), but in this case the reduction was associated with a hydrophilic catheter as compared to the conventional PVC catheter. This multi-centre investigation also employed a RCT design (N=123) but had several methodological problems that likely constrained the potential utility of the results. Most significant was a high drop-out rate (54%) with slightly more individuals not completing the study from the hydrophilic catheter group. A probable cause for many of these drop-outs was the lengthy treatment period of 1 year during which many individuals were likely to improve bladder function such that intermittent catheterization was no longer required. There were no other significant differences noted between the two groups including the number of bleeding episodes or occurrence of hematuria, leukocyturia and bacteriuria. More individuals expressed greater satisfaction with various aspects of the hydrophilic catheter, although these differences were also not significant. A reduced incidence of hematuria and a significant decrease in UTI incidence was also reported by Vapnek and Maynard (2003), when hydrophilic vs non-hydrophilic catheter use was compared in a 12 month study of 62 patients (n=49 completed).

Reduced numbers of treated UTIs were reported by Cardenas & Hoffman (2009) with the use of hydrophilic catheters vs standard nonhydrophlic catheters even though no difference was reported between the 2 groups of self-IC SCI patients for number of symptomatic UTIs. Furthermore, lubrication was more beneficial for men since women on self-IC were more likely to develop UTIs regardless of catheter type. Although this study may have been underpowered, it is important to note that the drop out rate was just under 20% as compared to almost 54% in the DeRidder et al (2005) study with only 57/123 subjects remaining at the end of year 1. The Cardenas & Hoffman (2009) study also included women which allowed for potential gender differentiation in the effect of hydrophilic catheter use. Although females accounted for 29% of the participants, an n=16 should invoke caution when interpreting the data.

More recently, Cardenas et al.(2011) showed that time to the first antibiotic-treated symptomatic UTI in acute SCI patients (less than 3 months injured for inclusion) could be delayed by opting for a hydrophilic coated catheter as compared to an uncoated catheter. However effects disappeared when first months after institutional discharge were included in the analysis. Participants and/ or caregivers reported significantly higher satisfaction (P=0.007) with the hydrophilic coated catheter versus the uncoated however no differences were found in a similar evaluation by nursing staff. This largest RCT to date on this topic

Conclusion

  • There is level 1 evidence based on 1 RCT that pre-lubricated nonhydrophilic catheters are associated with fewer UTIs as compared to conventional Poly Vinyl Chloride catheters.
  • There is conflicting level 2 evidence based on 1 RCT that fewer UTIs may result with the use of hydrophilic catheters as compared to conventional PVC catheters.
  • There is level 2 evidence based on 2 RCTs that use of hydrophilic vs non-hydrophilic catheters are associated with fewer symptomatic UTIs treated with antibiotics even though the number of symptomatic UTIs are similar between groups.
  • A reduced incidence of UTIs or reduced antibiotic treatment of symptomatic UTIs have been associated with pre-lubricated or hydrophilic catheters as compared to standard non-hydrophilic catheters.

Table: Other Issues Associated with Bladder Management and UTI Prevention

Discussion

In addition to intermittent catheterization, the effects of other bladder management methods have been investigated with respect to their impact in preventing UTIs. In particular, intermittent catheterization has been compared to indwelling catheterization. Joshi and Darouiche (1996) report following a prospective controlled trial that the response to antibiotic, as indicated by reduced pyuria, is improved and can be assessed earlier in patients who utilize intermittent catheterization over those whose bladder drainage is reliant on suprapubic or indwelling foley catheters. All patients (n=29) experienced relief from appropriate antibiotic therapy after 3-4 days, but the level of residual pyuria was lowest at mid-therapy and after therapy completion in those patients using intermittent catheterization.

In another comparison study, Nwadiaro et al. (2007) conducted a retrospective comparison of indwelling urethral catheterization and suprapubic cystostomy on UTI prevalence in a predominately illiterate and impoverished population where intermittent catheterization is a less preferred option. Prevalence of UTI was significantly less in the group having a suprapubic versus indwelling urethral catheter (p<0.05). In addition, there was significantly less mortality with the suprapubic catheter (p<0.05) at 1 year post admission with UTI-related septicaemia the number one cause of death in these patients. Sugimura also looked at the incidence of complications in patients using suprapubic catheterization, and reported a 29% incidence of UTI’s, though there was no comparison group in this study. However, in Ku et al. (2005) no bladder management technique was found to be superior in protecting against pyelonephritis (simple UTI was not tracked as an outcome); instead, the presence of vesicoureteral reflux led to a 2.8 fold higher risk of pylonephritis than those without reflux. Reflux is most often associatiated with high pressure urine storage due to low compliance or high pressure voiding due to sphincter spasticity and obstruction. Thus actual bladder pathophysiology may have the largest affect on clinically significant infections with the caveat that in this study, the group with urethral catheterization did experience more total upper tract deterioration than other bladder management groups.

Lloyd et al. (1986) conducted a case control investigation reviewing a group of 204 SCI patients grouped according to urological management techniques as follows: A) intermittent catheterization within 36h of injury, B) suprapubic trocar drainage within 36 h of injury, C) urethral catheter drainage for >36h prior to intermittent catheterization, D) indwelling urethral catheter drainage throughout and after discharge from hospital and E) intermittent catheterization placed in community hospital. Overall, these authors found that the method of initial bladder management does not affect the incidence of UTI, genitourinary complications or frequency of urological procedures at 1 year after injury. The only exception was group D who had a greater rate of UTIs as a result of the prolonged placement of indwelling urethral catheter drainage throughout and after discharge from hospitalization. It should be noted that individual variations in bladder management methods following the initial method and up to the one year follow-up were not accounted for in this investigation representing a potential major confound.

As noted in several of these comparative investigations, complications occur most frequently in those with urethral catheterization. Despite this, many patients resort to using urethral catheterization for convenience or necessity, if hand dexterity is insufficient, or care givers unaffordable. Some investigators have suggested an approach to minimizing UTI when urethral catheterization is determined to be the most viable management approach. Darouiche et al. (2006) conducted a multicentre RCT of hospital inpatients (n=118) in which the effect of securing indwelling catheters with a device called the Statlock as compared to traditional means of catheter securement (i.e., tape, velcro strap, cath-secure, or nothing) was assessed. In addition to SCI, 10 subjects had multiple sclerosis. In this trial, there was a statistically non-significant trend for a lower rate of symptomatic UTI (p=0.16) and also a lower incidence of symptomatic UTI per 1000 device days (p=0.16) for those using this Statlock device versus the control group.

Condom catheters also can be a source of bacterial colonization, especially of the perineum, which has been suggested by Sanderson and Weissler (1990b) to be significantly correlated with bacteriuria in SCI individuals. By discontinuing night time use of an external condom drainage system in a prospective controlled trial involving SCI rehabilitation inpatients (n=119), Pseudomonas colonization of the urethra was found to be significantly reduced where Klebsiella colonization was not significantly affected (p<0.05) (Gilmore et al. 1992). Further, a 3rd group of patients did not use a condom drainage system at any time and colonization rates for both Pseudomonas and Klebsiella were significantly lower in this group at all sites tested (urethra, perineum and rectum) as compared to those using the external drainage system (p<0.05). However, the prevalence of bacteriuria caused by either gram-negative bacilli, was not reduced with either night-time or continuous disuse of an external condom drainage system.

Conclusion

  • There is level 2 evidence based on a single prospective controlled trial and supported by a case control study that intermittent catheterization may lead to a lower rate of UTI as compared to other bladder management techniques such as use of indwelling or suprapubic catheter.
  • There is level 3 evidence based on a single case control study that bladder management with a suprapubic as opposed to indwelling catheter may lead to a lower rate of UTI and reduced mortality in a poor, illiterate population where intermittent catheterization may not be viable as an approach to bladder management.
  • There is weak level 2 evidence based on a single low quality RCT that suggests that use of the Statlock device to secure indwelling and suprapubic catheters may lead to a lower rate of UTI.
  • There is level 2 evidence based on a single prospective controlled trial that suggests that removal of external condom drainage collection systems at night or for 24 hours/day might reduce perineal, urethral or rectal bacterial levels but have no effect on bacteriuria.
  • There is level 4 evidence based on a single case series that no bladder management method is advantageous in preventing pyelonephritis (though indwelling urethral catheterization does have the highest incidence of upper tract deterioration). However, the presence of reflux results in a 2.8 fold higher incidence of pyelonephritis.
  • Intermittent catheterization is associated with a lower rate of UTI as compared to use of indwelling or suprapubic catheter.

    The Statlock device to secure indwelling and suprapubic catheters may lead to a lower rate of UTI.

    Removal of external condom drainage collection systems at night or for 24 hours/day may reduce perineal, urethral or rectal bacterial levels but has no effect on bacteriuria.

    The presence of vesicoureteral reflux likely has a greater impact on development of significant infections than the choice of bladder management.

Pharmacological and Other Biological Methods of UTI Prevention

There are a variety of approaches that involve pharmaceuticals and other biological agents that have been examined for UTI prevention in persons with SCI - as is noted in several reviews on this topic (Biering-Sorensen 2002; Garcia Leoni & Esclarin De Ruz 2003). These include pharmacological approaches such as bacterial interference or antibiotic prophylaxis, the use of other biological agents such as antiseptic cleansing agents or the use of nutraceuticals such as cranberry in one form or another. 

Table: Bacterial Interference for Prevention of UTIs

Discussion

Bacterial interference has been touted as a promising approach to UTI prevention for the future (Biering-Sorensen 2002). In this approach, a group of bacteria that do not cause UTIs are introduced into the bladder which acts to limit the ability of other pathogens to effectively colonize the bladder and cause a symptomatic UTI. To date, the specific approach employed in studies in persons with SCI has been to colonize the bladder with E. coli 83972 (Hull et al. 2000; Darouiche et al. 2005; Prasad et al. 2009). Most notably, Darouiche et al. (2005) conducted a prospective, randomized, placebo-controlled, double-blind trial (n=27) in which they randomized persons with SCI of greater than 1 years duration and with a history of symptomatic UTIs to receive bladder inoculation of either E. coli 83972 or sterile normal saline at a 3:1 ratio. This was preceded by a one-week course of empirically selected antibiotics as it has been noted that successful colonization is more likely achieved with a sterile bladder (Hull et al. 2000). Patients were monitored over the following year with monthly urine cultures. The number of UTIs experienced by those with successful E. coli 83972 colonization had significantly fewer UTIs than those with saline inoculation or unsuccessful E. coli inoculation (1.6 vs 3.5 episodes/year, p =0.036). The period during which the bladder remained colonized by E. coli 83972 was variable among study participants with only 13 of 21 patients being successfully colonized for at least 1 month, 4 of these remaining colonized for the entire 1 year study period and 9 losing E. coli after an average of 3.5 months. It should be noted that statistical comparisons were made between those with successful colonization (n=13) vs those inoculated with saline (n=6) combined with those not successfully inoculated (n=8). Only 1 of the 13 participants successfully inoculated developed a UTI while E. coli 83972 was in the bladder and this was associated with another organism (P. aeruginosa). No adverse events were obtained with the E. coli 83972 inoculations although 1 person in the saline group developed autonomic dysreflexia which subsided post-inoculation.

Prasad et al. (2009) using a less robust pre-post study design, also reported that preinoculation antibiotics improved inoculation rates, that rates of UTI went down during the period of colonization, and that colonization with E.coli 83972 is safe.

A longer period of colonization was achieved in the pre-post trial conducted by Hull et al. (2000) in which 21 individuals with longstanding SCI (> 18 months) with a history of symptomatic UTI over the preceding year were inoculated with E. coli 83972 following a course of appropriate antibiotics for 5-7 days. Persistent colonization of greater than 1 month was achieved in 13 study participants with mean colonization duration of 12.3 months (range 2-40 months). No participant sustained a UTI while colonized with E. coli even though these same individuals had a mean of 3.1 UTIs over the previous year. UTIs were noted in 4 of 7 persons not successfully colonized and at a rate of 3.5 UTIs/year for the months following loss of colonization in those where E. coli 83972 was no longer found in the bladder. The overall results from these three studies point to a strong effectiveness associated with this approach while the bladder remains colonized but that more work is required to enhance the rate of successful inoculation and to examine methods for sustaining the period of colonization.  

Conclusion

There is level 1 evidence based on a single RCT and supported by two level 4 investigations that bacterial interference in the form of E. coli 83972 bladder inoculation may prevent UTIs.

  • E. coli 83972 bladder inoculation may prevent UTIs.

Table: Antibiotic Prophylaxis of UTIs

Discussion

Several investigations have been conducted which explore the effectiveness of a prophylactic antibiotic approach although cost and conflicting results along with issues of adverse events and increasing likelihood of enhancing resistant organisms have led reviewers to not recommend this approach for routine use (Garcia Leoni & Esclarin De Ruz 2003). Although researchers and clinicians have reservations about this approach, an obvious and important variable is the specific antibiotic that is used for prophylaxis. For the most part investigations in SCI patients have involved different dosages and regimens of orally administered ciprofloxacin or co-trimoxazole (trimethoprim-sulfamethoxazole or abbreviated as TMX-SMX) as prophylactic measures.

An RCT comparing low-dose, long-term treatment with ciprofloxacin (100mg each night) vs placebo concluded that ciprofloxacin prophylaxis for up to 39 months resulted in a marked reduction from the pre-study infection rate. (p<0.00005, corrected) with no severe side effects and only 1 instance of ciprofloxacin resistant E. coli found in the feces of 1 patient (Biering-Sorensen et al. 1994). Another RCT involved a 3 day course of ciprofloxacin (500 mg bid) or suitable placebo as a pre-cursor to urodynamic investigation (Darouiche et al. 1994), which has been associated with subsequent development of UTI (Pannek & Nehiba 2007). Of those receiving ciprofloxacin, none had a symptomatic UTI at the study follow-up visit (3-5 days post urodynamic testing), whereas 3 of 22 study participants (14%) in the placebo group developed a symptomatic UTI. This finding was statistically nonsignificant (p=0.24), but the trend for reduced UTI incidence and the fact that no subjects in the treatment group actually developed a UTI suggests that a study with greater power would be required to demonstrate the benefit of pre-urodynamic testing prophylaxis more conclusively.

Conflicting results have been obtained across separate controlled trials conducted in individuals undergoing acute SCI inpatient rehabilitation of sustained (i.e., > 3 months) prophylaxis with TMP-SMX. Gribble and Puterman (1993) reported that oral administration of a TMP (40mg) - SMX (200mg) formulation once daily was found to significantly reduce frequency and relapse rates of bacteriuria (p=0.0001) and symptomatic urinary tract infection (p=0.0003) in persons with recent SCI using intermittent catheterization for bladder management (n=129). Conversely, Sandock et al. (1995) reported on an investigation of patients at least 6 months post-injury within an inpatient SCI rehabilitation program in which the standard of care was to prescribe TMP-SMX liberally as a prophylaxis. This practice was stopped for the purpose of conducting a prospective controlled trial in 1 of 2 units and it was noted that there was no significant difference in the number of symptomatic UTIs between those stopping vs those continuing suppressive therapy (0.043 vs 0.035 UTIs/week, p>0.5). In addition, there was a significant decrease in the emergence of TMP-SMX resistant asymptomatic bacteriuria in the patients stopping suppressing therapy (78.8% vs 94.1%, p<0.05). This latter finding was also consistent with that noted by Gribble and Puterman (1993) who noted this, along with TMP-SMX related adverse events as serious limitations of TMP-SMX prophylaxis therapy. Reid et al. (1994b) also showed an inability of a higher dose of TMP (160mg)-SMX(800mg) to reduce rates of symptomatic UTI within a prospective controlled trial conducted on a rehabilitation unit in patients using intermittent catheterization for bladder management.

Given the conflicting findings noted above and in other patient groups, a novel approach to UTI prevention in SCI patients was undertaken by Salomon et al. (2006). After a prospective, pre-post study with 2 year follow-up, they concluded that a weekly oral cyclic antibiotic (WOCA) program was beneficial in preventing UTI in SCI patients, decreasing antibiotic consumption and decreasing the number and length of hospitalizations, without severe adverse events or the emergence of multi-drug resistant (MDR) bacteria. The WOCA regimen involved alternating between two antibiotics, administered once per week over at least 2 years. The specific antibiotics selected as prophylaxis were customized to the patient, chosen based on allergy and antimicrobial susceptibility. The most frequent combination of antibiotics utilized were trimethoprim / sulfamethoxazole and cefixime (30%) followed by cefixime and nitrofurantoin (25%). The combination of antibiotics was modified in 40% of the patients once, 20% twice and 10% on three occasions during the follow-up. Salomon et al. (2009) expanded on earlier work specifically to employ a WOCA program in pregnant women with SCI. In this study, UTI rate during pregnancy (which is commonly elevated) was significantly reduced, no complications were observed during delivery, and all newborns were a healthy weight (Salomon et al. 2009). This level 4 evidence for the effectiveness of WOCA in SCI UTI prevention, treatment and cost, and would serve well as guidance in design of a randomized, double-blind, placebo-controlled study to confirm these results.

Conclusion

  • There is level 1 evidence from a single RCT that low-dose, long-term ciprofloxacin may prevent symptomatic UTI.
  • There is level 1 evidence from a single RCT that TMP-SMX as prophylaxis may reduce symptomatic UTI rates although conflicting findings were obtained from 2 prospective controlled trials. The potential for emergence of drug resistant bacteria and TMP-SMX related adverse events further limit the potential use of TMP-SMX for prophylaxis.
  • There is level 4 evidence from a single study that suggests weekly oral cyclic antibiotic use, customized as to individual allergy and antimicrobial susceptibility, may be effective for UTI prevention in SCI patients, and UTI reduction in pregnant patients.
  • Ciprofloxacin may be indicated for UTI prophylaxis in SCI but further research is needed to support its use.

    Long-term use of TMP-SMX is not recommended for sustained use as a suppressive therapy for UTI prevention.

    A weekly oral cyclic antibiotic, customized to the individual, may be beneficial in preventing UTI in SCI.

Table: Antiseptic and Related Approaches for Preventing UTIs

Discussion

It is generally accepted that good hygiene practices are an important element in UTI prevention. Therefore, it is a natural extension to expect that antiseptic agents applied either directly to the bladder or to potential vectors of indirect transference might be effective in UTI prevention. Accordingly, Sanderson and Weissler (1990b) found that perineal colonization of SCI individuals was significantly correlated with bacteriuria and may be associated with contamination of the environment and indirectly of the hands of patients and staff. As a result of this finding, this group further examined the effect of chlorhexidine antisepsis on bacteriuria, perineal colonization and environmental contamination in spinally injured patients requiring intermittent catheterization (Sanderson & Weissler 1990a). In male patients not receiving antibiotics, daily body washing in chlorhexidine and application of chlorhexidine cream to the penis after every catheterization significantly reduced bacteriuria to 60% from 74% in patients who were only washed with standard soap, although the effect was not as strong as that delivered by treatment with appropriate antibiotics. Chlorhexidine antisepsis alone did not affect perineal coliform colonization or contamination of the environment although there was a trend for this effect (p<0.1). In essence, this antiseptic effect acted to amplify the bacteria-reducing effects of antibiotics.

Acidifying urinary pH for the prevention of UTIs is based on the established fact that pH reduction to ≤5.0 will inhibit growth of urinary E. coli (Shohl & Janney 1917), a prevalent pathogen in the urinary tract. An RCT conducted by Waites et al. (2006) on participants having indwelling or suprapubic catheter with existing bacteriuria and pyuria (n=89) compared sterile saline, acetic acid and neomycin-polymyxin solution bladder irrigants and demonstrated no effect on the degree of bacteriuria/pyuria, or development of antimicrobial resistance. Moreover, the twice daily bladder irrigation for 8 weeks resulted in a significant increase in urinary pH (p=0.01) for all groups to a range that was more favourable for the growth of E. coli (i.e., pH 6.0-7.0). Similarly, 2 weeks of phosphate supplementation or 2 gram per day of ascorbic acid for unspecified duration in SCI neurogenic bladder managed with IC or indwelling catheter have proved ineffective in acidifying urine or altering UTI rates (Schlager et al. 2005; Castello et al. 1996).

Feasibility of treatment is a valid issue for consideration as evidenced by the study conducted by Pearman et al. (1988). These investigators compared the use of trisdine with kanamycin-colistin, a medicated bladder instillation previously demonstrated to be effective to prevent bacteriuria and UTI in SCI (Pearman 1979). In this trial (n=18), they found no difference between incidence of bacteriuria in catheterized patients yet concluded that trisdine was preferred based on its stability at room temperature, association with a reduced likelihood for antibiotic-resistant bacteria and reduced cost compared to kanamycin-colistin. Although the latter are important factors for treatment choice, this study presents no evidence for preferential beneficial effects based on incidence of bacteriuria.

Another solution shown to have some promise in UTI prevention was studied as a combination therapy, both with antiseptic properties. Krebs et al. (1984) investigated the potential of a 5% hemiacidrin solution instilled as an intravesicular acidifying agent at each intermittent catheterization combined with oral administration of methenamine mandelate (2 mg) qid in persons undergoing SCI inpatient rehabilitation. As compared to individuals undergoing no bacterial prophylaxis, the pH of urine was significantly reduced (p<0.01) and there was a lower rate of symptomatic UTI (p<0.05) and less bacteriuria as indicated by a reduced number of positive cultures (p<0.001). The role of hemiacidrin solution alone in these findings remains uncertain.

 In contrast to these findings, as part of a double-blind, placebo-controlled RCT (n=305) conducted by Lee et al. (2007), oral methenamine hippurate (another formulation of methenamine as an antiseptic) was generally ineffective in preventing symptomatic UTIs. In this well-conducted large sample trial, active and placebo formulations (oral tablet) of both methenamine hippurate and a cranberry preparation were compared as to the occurrence of asymptomatic UTI (up to 6 months) as a primary end-point. There were no statistically significant effects with either treatment alone or in combination as compared to placebo.

These various conflicting results suggest the specific antiseptic agent, alone or in combination with others, and its mode of administration might be important in determining clinical effectiveness and that the practice of antiseptic bladder instillation along with other methods of delivery, dismissed as ineffective by some or in general practice by others (Pearman et al. 1988; Castello et al. 1996; Schlager et al. 2005; Lee et al. 2007), requires further study.

Conclusion

  • There is level 1 evidence based on a single RCT that oral methenamine hippurate, either alone or in combination with cranberry, is not effective for UTI prevention.
  • There is level 2 evidence from separate studies that bladder irrigation with trisdine, kanamycin-colistin or a 5% hemiacidrin solution combined with oral methenamine mandelate (2 mg qid) may be effective for UTI prevention.
  • There are varying levels of evidence that bladder irrigation with neomycin/polymyxin (level 1), acetic acid (level 1), ascorbic acid (level 2) or phosphate supplementation (level 4) is not effective for UTI prevention.
  • There is level 2 evidence based on a single low quality RCT that supports the use of daily body washing with chlorohexidine and application of chlorhexidine cream to the penis after every catheterization versus using standard soap to reduce bacteriuria and perineal colonization.
  • Oral methenamine hippurate, either alone or in combination with cranberry, is not effective for UTI prevention.

    The antiseptic agents delivered via bladder irrigation (5% hemiacidrin solution combined with oral methenamine mandelate) may be effective for UTI prevention, whereas others are not (i.e., trisdine, kanamycin-colistin, neomycin/polymyxin, acetic acid, ascorbic acid and phosphate supplementation).

    Daily body washing with chlorohexidine and application of chlorhexidine cream to the penis after every catheterization instead of using standard soap may reduce bacteriuria and perineal colonization.

Table: Cranberry for Preventing UTIs

Discussion

Cranberry (in various forms) is in widespread use for UTI prevention and many clinicians recommend it for this purpose. This remains the fact despite uncertainty as to its effectiveness, especially in persons requiring ongoing catheterization as reported in a recent Cochrane systematic review (Jepson & Craig 2008). However, also in 2008, Hess et al. conducted a study in which subjects were given either cranberry tablets or placebo for 6 months, and then crossed to the opposite arm, showing a significant reduction in UTI incidence for those on cranberry treatment. These authors chose a robust definition of UTI (see above), and explained in their conclusion that they presume the treatment effect arose from an effect on cell wall adherence to the uroepithelial cell wall, an effect that they propose takes > 1 month to develop. As such, shorter studies may fail to note benefit from cranberry treatment (see Linsemeyer et al. 2004). While Reid et al. 2001 is a short study, significant results were noted in biofilm load and bacterial adhesion (though this study was not designed to determine effect on significant UTI). These hypotheses help build our understanding of the potential mechanisms of action cranberry may have in preventing UTI.

As noted in the section on antiseptic agents above, Lee et al. (2007) conducted a well-designed double-blind, placebo-controlled RCT (n=305) that examined the effectiveness of cranberry tablets (1600 mg) for UTI prevention alone or in combination with oral methenamine hippurate (2 g). Neither treatment alone or in combination was effective in preventing symptomatic UTIs as assessed over a 6 month study period. This rigorous study incorporated intention-to-treat and multiple analysis methods including survival analysis and multivariate analysis using Cox proportional hazards regression and investigated outcomes associated with both symptomatic UTIs (primary) and bacteriuria (secondary).

These results were confirmed by two additional RCTs. Linsenmeyer et al. (2004) found that cranberry tablets (400 mg) were not effective in changing bacterial or white blood cell (WBC) counts of 21 participants who underwent a 9 week placebo-controlled, crossover trial. Similar results were obtained by Waites et al. (2004) in community residing persons with SCI of greater than 1 years duration (n=48) which showed no difference between cranberry extract or placebo taken for 6 months in reducing bacteriuria or pyuria nor for reducing symptomatic UTI rates.

In contrast to these findings, a prospective controlled trial (n=15) conducted by Reid et al. (2001) showed that cranberry juice intake significantly reduced the adhesion of bacteria to bladder cells whereas water intake did not significantly reduce the bacterial adhesion or biofilm presence in individuals with SCI. These conflicting conclusions may be influenced by the variation in “dose” and formulation of cranberry product (i.e., tablet vs juice) and the outcome measures used across the various studies. Notably, this study (Reid et al. 2001) was not designed or intended to assess the effect of cranberry on asymptomatic UTI.

Hess et al. (2008) comment in their discussion that subjects in the Waites study may have been non-compliant given that study medication was mailed to subjects, that the UTI definition may not have been as robust, and that there was an imbalance in bladder management methods between groups. It is important to be note that Hess, Linsenmeyer, and Waites lack intent-to-treat statistical analyses which therefore reduces the quality of these investigations. The lack of consistency between results underscores the need for yet further efforts to convincingly prove or disprove the potential value of cranberry prophylaxis.

Conclusion

There is conflicting level 1 evidence across 4 RCTs (1 +ive, 3 –ive) to support the effectiveness of cranberry in preventing UTI in patients with neurogenic bladder due to SCI.

  • It is uncertain if cranberry is effective in preventing UTIs in persons with SCI.

Educational Interventions for Maintaining a Healthy Bladder and Preventing UTIs

SCI patients with neurogenic bladder typically receive education while in initial rehabilitation to assist with bladder management and maintain a healthy bladder. This may continue as their bladder function changes following rehabilitation discharge.

Table: Individual Studies of Educational Interventions

Discussion

Health care providers have an excellent opportunity to provide proper bladder management education during inpatient rehabilitation to significantly affect the quality of bladder management after discharge with the goal of assisting clients in maintaining a healthy bladder, often manifest through prevention of UTIs. Anderson et al. (1983) reported on a case-control study where patients completed a special urinary tract care education program consisting of classes, reading material, written examinations, and demonstration of acquired skills. With this approach 71% of patients were asymptomatic of UTI at 6 month follow-up. Only 32% of patients had no symptoms when a group of patients, tested 4 years earlier in 1975, did not undergo the education program. Furthermore, as a result of the education program only 5% of the educated group lost time from their usual daily activities compared to 23% of the non-educated group losing time. However, both groups registered the same incidence of confirmed or suspected UTI (62-63%). Therefore, the benefit translated into early detection and definitive action resulting in less impairment and less lost time due to the UTI. This study was assessed as comprising Level 4 evidence due to inadequate control of potential confounds between the education and non-education group among other limitations.

Once discharged, some SCI patients experience unacceptable recurrence of UTIs. Cardenas et al. (2004) examined the effectiveness of an educational program in an RCT of 56 community-dwelling SCI patients with a self-reported history of UTIs. The educational intervention included written material, a self-administered test, a review by nurse and physician, and a follow-up telephone call. The control group did not receive the intervention and final interventional data was compared to an equivalent baseline period. A significant decrease in urine bacterial colony count (but not in UTI incidence) and increased Multidimensional Health Locus of Control scale score reflected the beneficial effects of UTI educational intervention in improving bladder health and the patient’s perception of control over their own health behaviour.

These results were amplified by Hagglund et al. (2005) and Barber et al. (1999), who each examined participants with longstanding SCI and conducted their investigations in conjunction with outpatient rehabilitation follow-up services. Positive benefits of reduced UTI occurrences were seen following a 6 hour physician-mediated educational workshop conducted as part of a prospective controlled trial with 6 month follow-up periods (n=60) (Hagglund et al. 2005). Of note, Hagglund et al. (2005) directed their educational intervention at the consumer-personal assistant dyad.

Barber et al. (1999) identified 17 high risk patients (i.e., ≥ 2 UTI/6months) over 1000 consecutive outpatient SCI clinic days. These authors found that 11 (65%) of these patients were able to reduce their number of UTIs to be reclassified as not high-risk with intensive counseling on proper bladder management technique and hygiene, although 8 required multiple counseling sessions to realize an effective reduction of number of UTIs. The remaining patients in this series required pharmaceutical prophylaxis for UTI prevention although there were some issues with compliance when treatment was extended over 1 year. The authors suggested that education intervention by a clinic nurse is a simple, cost-effective means of decreasing the risk of UTIs in at-risk SCI individuals, although the sample size was small and the study was neither randomized nor controlled.

Conclusion

  • There is level 1 evidence from a single RCT that a single educational session conducted by SCI specialist health professionals with accompanying written materials and a single follow-up telephone call can result in reduced urine bacterial colony counts in community-dwelling individuals with prior history of SCI.
  • The beneficial effects of education mediated by SCI specialist health professionals on reducing UTI risk in community-dwelling individuals with SCI are supported by a single level 2 study and two level 4 studies incorporating different features such as one-on one or group workshops, demonstrations, practice of techniques and written materials.
  • There is no evidence assessing the relative effectiveness of different educational approaches for reducing UTI risk. 
  • A variety of bladder management education programs are effective in reducing UTI risk in community-dwelling persons with SCI, although limited information exists as to the most effective approaches.

Pharmacological Treatment of UTIs

UTIs in persons with SCI with neurogenic bladder are termed “complicated UTIs” which refers to the presence of a UTI in a functionally, metabolically, or anatomically abnormal urinary tract or that are caused by pathogens that are resistant to antibiotics (Stamm & Hooton 1993). Complicated UTIs may be caused by a much wider variety of pathogens in persons with SCI and are often polymicrobial. It is generally recommended that persons with SCI be treated for bacteriuria only if they have symptoms, as many individuals especially with indwelling or suprapubic catheters typically have asymptomatic bacteriuria (Biering-Sorensen et al. 2001). Once symptomatic UTI is confirmed, the first line of empirical treatment is via antibiotics and the most common antibiotics chosen for UTI treatment include fluorquinolones (e.g. ciprofloxacin), trimethorprin, sufamethoxazole, amoxicillin, nitrofurantoin and ampicillin. Fluorquinolones are often chosen because of their effectiveness over a wide spectrum of bacterial strains (Waites et al. 1991; Garcia Leoni & Esclarin De Ruz 2003). Although much experience with treating UTIs in SCI has been gleaned from other indications, there are several studies that are reviewed below which have investigated a variety of antibiotic agents in this population.

Table: Antibiotics in Treatment of UTIs

Discussion

The range of effective antibiotic treatment duration can vary widely depending on the specific microorganism causing the infection, the antibiotic used and the patients’ UTI history. Dow et al. (2004) conducted a RCT (n=60) to compare a 14 vs 3 day course of ciprofloxin treatment in SCI patients with UTI symptoms or microbially documented bacteriuria and concluded that a 14 day Ciprofloxin treatment results in improved clinical and microbiological outcomes.  Microbiological relapse rates were significantly lower for those patients treated for 14 vs 3 days. Although, this high quality level 1 evidence advocates for the use of a 14 vs 3 day course of ciprofloxacin in SCI UTI, as the author notes, it does not address the optimal treatment period which may be 5, 7 or 10 days nor does it examine the question of whether a higher dose might have been more effective with the shorter therapy.

Ofloxacin is a fluoroquinolone antibiotic shown to be promising in its ability to penetrate and eradicate bacterial biofilms in the bladder in vitro and in SCIpatients (Reid et al. 1994a; Reid et al. 1994b). Bacterial biofilms are colonies of microorganisms along with their extracellular products that may form on surfaces as a structured community that enables the pathogens to resist antibiotics and persist in the urinary tract thereby potentially causing recurrent UTI (Biering-Sorensen et al. 2003). Reid et al. (2000) employed a randomized, double blind design (n=42) to assess the relative effectiveness of a 7 day course of ofloxacin as compared to trimethoprim-sulphamethoxazole (TMP-SMX) or other more appropriate antibiotics as detected by culture sensitivity. Study participants had symptomatic UTI and clinical cure rates, defined as patients becoming asymptomatic with sterile urine, were assessed at day 4 and day 7. Clinical cure rate was significantly greater for Ofloxacin as compared to TMP-SMX or other antibiotic at day 4 (90% vs 48%, p=0.003) and day 7 (90% vs 57%, p=0.015). In addition, both treatments were effective at reducing bacterial biofilms at day 4 and 7 (p<.001) although the biofilm eradication rate was significantly higher with Ofloxacin vs TMP-SMX or other antibiotic at day 4 (62% vs 24%, p=.005); and day 7 (67% vs 35%, p=.014). This finding was supported by an earlier study (Reid et al. 1994a) noting that fluoroquinolone therapy was more effective at reducing bladder cell adhesion counts in 63% of asymptomatic SCI UTIs vs 44% of SCI subjects treated with trimethoprim-sulfamethoxazole.    

Reid et al. (2000) suggested that a 3-day regimen in the treatment of SCI UTI could be sufficient based on significant biofilm eradication detected in bladder epithelial cells in patients treated with Ofloxacin compared to TMP-SMX. Shorter courses of antibiotic treatment are currently considered by clinicians and patients who are concerned with side effects, cost and antimicrobial resistance due to longer term use. Treatment course durations as short 3 days are not uncommon while the more common treatment duration is 14 days. The difference in effective treatment duration, compared to the findings of Dow et al. (2004), is due, in part, to the difference in anti-microbial used. However, further study comparing the 2 antimicrobials (and others) and differing treatment durations are required to clarify the question of optimum treatment duration for the antimicrobial being considered for use.

Gram-negative bacteria such as Pseudomonas, Acinetobacter, Enterobacter and mycobacteria are susceptible to aminoglycosides such as tobramycin and amikacin which may be chosen for complicated UTI treatment. Due to their toxicity and inconvenient route of administration (i.e. intramuscular injection), their use is limited. To investigate the effectiveness of a lower dose of these aminoglycosides, Sapico et al. (1980) compared infection, persistence and reinfection rates of SCI UTI against a standard dose. An overall low rate of success and no differences between the dose strengths and between tobramycin and amikacin even though high antibiotic concentrations were found in the urine of all subjects suggested that alternative antimicrobial agents would be better to consider for use in this population.

Although Waites et al. (1991) showed norfloxacin, another fluoroquinolone, to be 73% effective in eradicating UTIs by mid-treatment, the rate of reinfection was 84% after 8 to 12 weeks post initial eradication. Furthermore, 16% of strains isolated after eradication became resistant to norfloxacin. This trial, employing a pre-post study design (n=78) with a 14 day course of treatment, enrolled participants with symptomatic UTI and the equivocal results point to the utility of controlled study designs when assessing antibiotic effectiveness. The authors concluded that norfloxacin is a reasonable treatment choice for SCI UTI but the subsequent and problematic emergence of resistance must be monitored (as with other antimicrobials).  

In addition to decisions on selecting the most appropriate antibiotic, the clinician is sometimes faced with additional treatment option challenges when multi-drug resistant bacteria or the patient’s allergy to the appropriate antibiotic are encountered. Although conflicting results have been obtained with the use of antiseptic agents as part of a prophylactic strategy to lower urine pH and thereby assist in the prevention of UTIs, Linsenmeyer et al. (1999) used a case series review (n=10) to investigate the use of medicated bladder irrigation as a method to alter the existing antimicrobial resistance. They found that intermittent neomycin/polymyxin bladder irrigation was effective in altering the resistance of the offending bladder organism(s) to allow for appropriate antibiotic treatment, therefore proving preliminary evidence advocating for a short course treatment of neomycin/polymyxin irrigant to alter existing antimicrobial resistance.

Conclusion

  • There is level 1 evidence from a single RCT that supports the use of 14 vs 3 days of Ciprofloxcin for improved clinical and microbiological outcomes in the treatment of UTI in persons with SCI.
  • There is level 1 evidence from a single RCT suggesting that 3 or 7 day Ofloxacin treatment is more effective than trimethoprim-sulfamethoxazole in treating UTI and results in significant bladder bacterial biofilm eradication in persons with SCI patients.
  • Level 4 evidence from a single study suggests that norfloxacin may be a reasonable treatment choice for UTI in SCI but subsequent resistance must be monitored.
  • A low success rate of aminoglycosides in the treatment of SCI UTI is supported by level 1 evidence from a single RCT.
  • Optimum antimicrobial treatment duration and dosage is uncertain due to the lack of comparative trials in persons with SCI.
  • Level 4 evidence is reported for intermittent neomycin/polymyxin bladder irrigation being effective in altering the resistance of the offending bladder organism(s) to allow for appropriate antibiotic treatment.
  • Ciprofloxin administered over 14 (vs 3) days may result in improved clinical and microbiological SCI UTI treatment outcome.

    Ofloxacin administered over either a 3 or 7 day treatment regimen may result in significant SCI UTI cure and bladder bacterial biofilm eradication rate, moreso than trimethoprim-sulfamethoxazole.

    Norfloxacin may be a reasonable treatment choice for UTI in SCI but
    subsequent resistance must be monitored.

    Aminoglycosides have a low success rate in the treatment of SCI UTI.

    Intermittent neomycin/polymyxin bladder irrigation may be effective in altering the resistance of the offending bladder organism(s) to allow for appropriate antibiotic treatment.

Summary

  • Level 1 evidence from two RCTs supports the use of propiverine in the treatment of detrusor hyperreflexia resulting in significantly improved bladder capacity, with one of these trials showing equivalent results to oxybutinin but fewer side effects, notably dry mouth.

    Level 1 evidence from a single RCT supports the use of tolterodine vs placebo to significantly increase intermittent catheterization volumes and decrease incontinence in neurogenic detrusor overactivity.

    Level 2 evidence from a small single open label prospective controlled trial that tolterodine and oxybutynin are equally efficacious in SCI patients with neurogenic detrusor overactivity except that tolterodine results in less dry mouth.

    Level 4 evidence from single pre-post trials support the potential benefits of controlled-release oxybutynin as well as a transdermal system for oxybutinin administration, the latter with reduced side effect profile.

    Level 4 evidence from a single study suggests benefits such as reduced incontinence and increased bladder capacity from combination treatments of two of oxybutinin, trospium or tolterodine, even in patients with unsatisfactory outcomes following a trial with one of these medications.

    Level 1 evidence from a single RCT supports the use of trospium chloride to increase bladder capacity and compliance, and decrease bladder pressure with very few side effects in SCI individuals with neurogenic bladder.

    Level 1 evidence based on two RCTs supports the use of Onabotulinum toxin A injections into the detrusor muscle to provide targeted treatment for neurogenic detrusor overactivity and urge incontinence resistant to high-dose oral anticholinergic treatments with intermittent self-catheterization in SCI. Numerous level 3 and 4 studies confirm the efficacy and safety.

    Level 4 evidence based on a single case series indicates detrusor contractility may be decreased through repeated BoNT-A injection, though prospective study and higher levels of evidence is needed to confirm.

    Level 1 evidence supports the use of vanillanoid compounds such as capsaicin or resiniferatoxin to increase maximum bladder capacity and decrease urinary frequency and leakages in neurogenic detrusor overactivity of spinal origin.

    Level 4 evidence exists to suggest that intravesical capsaicin instillation in bladders of SCI individuals does not increase the rate of common bladder cancers after 5 years of use.

    Level 1 evidence based on two small-scale RCTs supports the use of N/OFG, a nociceptin orphan peptide receptor agonist for the treatment of neurogenic bladder in SCI.

    There is level 4 evidence from 3 studies that instillations with oxybutinun or propantheline have equivocal benefits for neurogenic bladder in people with SCI. There is level 4 evidence from1 study that combined oral and intravesical installation of oxybutinin significantly improves bladder volume. There is level 4 evidence suggesting systemic absorption may occur with this therapy, resulting in systemic side effects.

    There is level 1 evidence from a single small RCT (n=10) that intrathecal baclofen may be beneficial for bladder function improvement in individuals with SCI when oral pharmacological interventions are insufficient.

    Level 4 evidence is available from a single, small (n=9), case series study for the use of intra-thecal clonidine to improve detrusor overactivity in individuals with SCI when a combination of oral treatment and sterile intermittent catheterization are insufficient.

    There is level 4 evidence from four studies that surgical augmentation of bladder (ileocystoplasty) may result in enhanced bladder capacity under lower filling pressure and improved continence in persons with SCI who previously did not respond well to conservative approaches for overactive bladder.

    There is level 3 evidence from a single study that extraperitoneal (vs intraperitoneal) augmentation enterocystoplasty produces equivocal postoperative continence with easier early postoperative recovery.

    Level 1 evidence from a single study suggests that moxisylyte decreases maximum urethral closure pressure by 47.6% at 10 minutes after an optimum dose of 0.75mg/kg in individuals with SCI.

    There is level 4 evidence from a single study that suggests that tamsulosin may improve bladder neck relaxation and subsequent urine flow in SCI individuals.

    There is level 4 evidence (two studies, n=28 & 9) that supports terazosin as an alternative treatment for bladder neck dysfunction in SCI individuals provided that side effects and drug tolerance are monitored.

    There is level 4 evidence derived from a single, case series study involving 46 subjects (41 completers) that indicates some potential for phenoxybenzamine as an adjunct treatment for neurogenic bladder following SCI, when tapping or crede is insufficient to achieve residual urine volume of <100mL. Further evidence is required.

    Level 4 evidence from 1 small retrospective chart review suggests that 6 months of alpha 1-blocker therapy may improve upper tract stasis secondary to SCI in men by decreasing the duration of involuntary bladder contractions.

    There is level 1 evidence from a single RCT with support from several additional controlled and uncontrolled trials that botulinum toxin injected into the external urinary sphincter may be effective in improving outcomes associated with bladder emptying in persons with neurogenic bladder due to SCI.

    There is level 4 evidence from a single study that PDE5 inhibitors may be effective in improving outcomes associated with bladder emptying in persons with neurogenic bladder due to SCI.

    There is level 4 evidence from a single study that 4-aminopyridine, at sufficient dosage, may be effective in restoring sensation and/ or control of the bladder sphincter.

    There is level 4 evidence that indwelling urethral catheterization is associated with a higher rate of acute urological complications than intermittent catheterization.

    There is level 4 evidence that prolonged indwelling catheterization, whether suprapubic or urethral, may result in a higher long-term rate of urological and renal complications than intermittent catheterization, condom catheterization or triggered spontaneous voiding.

    There is level 4 evidence that intermittent catheterization, whether performed acutely or chronically, has the lowest complication rate.

    Results are conflicting about the complications associated with chronic use of spontaneous triggered voiding but some authors present level 4 evidence that this method has comparable long-term complication rates to intermittent catheterization.

    There is level 4 evidence that those who use intermittent catheterization at discharge from rehabilitation may have difficulty continuing, especially those with tetraplegia and complete injuries. Females also have more difficulty than males in maintaining compliance with IC procedures.

    There is Level 1 evidence based on 1 RCT that pre-lubricated hydrophilic catheters are associated with fewer UTIs and reduced incidence of urethral bleeding and microtrauma as compared to conventional Poly Vinyl Chloride catheters.

    There is Level 2 evidence based on 1 lower quality RCT that fewer UTIs, but not necessarily urethral bleeding may result with the use of hydrophilic catheters as compared to conventional PVC catheters.

    There is Level 2 evidence based on 1 lower quality RCT that urethral microtrauma and pyuria is reduced with use of gel-lubricated non-hydrophilic catheter, with higher patient satisfaction, as compared to hydrophilic-coated or PVC catheters

    There is level 4 evidence that urethral complications and epididymoorchitis occurs more frequently in those using IC programs for bladder emptying, but the advantages of improved upper tract outcome over those with indwelling catheters outweigh these disadvantages.

    There is level 4 evidence that using a portable ultrasound device reduces the frequency and cost of intermittent catheterizations.

    There is level 4 evidence that triggering mechanisms such as the Valsalva or Crede maneuvers may assist some individuals with neurogenic bladder in emptying their bladders without catheterization. However, high intra-vesical voiding pressures can occur which could conceivably lead to renal complications.

    There is level 4 evidence, despite an associated significant incidence of urological and renal complications, acute and chronic indwelling suprapubic catheterization may still be a reasonable choice for bladder management for people with poor hand function, lack of care-giver assistance, severe lower limb spasticity, urethral disease, and persistent incontinence with urethral catheterization.

    There is level 4 evidence that those with indwelling catheters are at higher risk for bladder cancer compared to those with non-indwelling catheter management programs. Screening for cancer may require routine biopsy as well as cytoscopy.

    There is level 4 evidence that condom drainage may be associated with urinary tract infection and upper tract deterioration.

    There is level 4 evidence that penile implants may allow easier use of condom catheters, thereby reducing incontinence and improving sexual function.

    There is level 4 evidence that most individuals who receive catheterizable stomas become newly continent and can self-catheterize. It appears possible that this surgical intervention could protect upper tract function. Larger studies are needed to better evaluate true incidence of complications, and long-term bladder and renal outcome.

    There is level 4 evidence that most individuals undergoing cutaneous ileal conduit (ileo-ureterostomy) diversion became newly continent and were more satisfied than with their previous bladder management method. Long-term follow-up demonstrated the presence of a high incidence of urological or renal complications.

    There is level 4 evidence from eight studies and level 5 evidence from a single study that ongoing use of sacral anterior root stimulation (accompanied in most cases by posterior sacral rhizotomy) is an effective method of bladder emptying resulting in reduced incontinence for the majority of those implanted. This is associated with increased bladder capacity and reduced post-void residual volume.

    There is level 4 evidence from five studies and level 5 evidence from a single study (UTIs only) that sacral anterior root stimulation (accompanied in most cases by posterior sacral rhizotomy) may be associated with reducing UTIs and autonomic dysreflexia.

    There is level 4 evidence from two studies that direct bladder stimulation may result in reduced incontinence, increased bladder capacity and reduced residual volumes but requires further study as to its potential clinical use.

    There is level 4 evidence from various single studies that other forms of neuroanatomically-related stimulation (e.g., electrical conditioning stimulation to posterior sacral, pudenal, dorsal penile or clitoral nerve or surface magnetic sacral stimulation) may result in increased bladder capacity but require further study as to their potential clinical use. Further development involving some of these approaches may permit sacral anterior root stimulation without the need for posterior root ablation.

    There is limited level 2 evidence from a single small study that reports early sacral neuromodulation may improve management of lower urinary tract dysfunction. Further investigation is required to confirm the results and substantiate the hypothesis of resultant plastic changes of the brain.

    There is level 4 evidence from a single study that epidural dorsal spinal cord stimulation at T1 or T11 originally intended for reducing muscle spasticity may have little effect on bladder function.

    There is level 4 evidence from a single study that a program of functional electrical stimulation exercise involving the quadriceps muscle originally intended for enhancing muscle function and reducing muscle spasticity has only marginal (if any) effects on bladder function.

    There is level 4 evidence from a single case-series study that sphincterotomy is effective in reducing episodes of autonomic dysreflexia associated with inadequate voiding.

    There is level 4 evidence from a single case-series study that sphincterotomy, as a staged intervention, can provide long-term satisfactory bladder function.

    There is level 2 evidence from a single low-quality RCT but supported by level 4 studies that both sphincterotomy and implantation of a sphincteric stent are effective in reducing incontinence, with little need for subsequent catheterization, and both treatments are associated with reduced detrusor pressure and reduced post-void residual volume but not with changes in bladder capacity. The only significant difference in these 2 treatments was the reduced initial hospitalization associated with the stent, given the lesser degree of invasiveness.

    There is level 4 evidence that implantation of a sphincteric stent may result in reduced incidence of UTIs and bladder-related autonomic dysreflexia over the short-term although several studies have demonstrated the potential for various complications and subsequent need for re-insertion or another approach over the long-term.

    There is level 4 evidence from a single long-term follow-up study of those having a previous sphincterotomy that the incidence of various upper and lower tract urological complications may be quite high.

    There is level 4 evidence from a single case-series study that advocates for placement of a temporary stent early after injury as a reversible option that allows patients to choose from the range of permanent stent placement to less invasive bladder management methods such as intermittent catheterization.

    There is level 4 evidence based on a single study that transurethral balloon dilation of the external sphincter may permit removal of indwelling catheters in place of condom drainage, and also may result in reduced detrusor pressure and post-void residual volume but not with changes in bladder capacity.

    There is level 4 evidence based on 2 studies that implantation of an artificial urinary sphincter may be useful in the treatment of incontinence in SCI but further study is required.

    There is level 4 evidence from a single pre-post study that transurethral incision of the bladder neck may be useful in bladder neck and voiding dysfunction.

    There is level 2 evidence from a single study that early treatment with electroacupuncture may shorten the time that it takes to develop low pressure voiding /emptying with minimal residual volume, when combined with conventional methods of bladder management.

    Level 4 evidence from two studies suggests that intranasal DDVAP may reduce nocturnal urine production with fewer night-time emissions and also may reduce the need for more frequent catheterizations in persons with SCI with neurogenic bladder that is otherwise unresponsive to conventional therapy.

    There is level 4 evidence from four studies that nerve crossover surgery (anastomosis of more rostral ventral nerve roots to S2-S3 spinal nerve roots) may result in improved bladder function in chronic SCI.

    Level 1 evidence based on a single RCTon SCI inpatients suggests that both limited and full microbial investigation result in adequate clinical response to UTI treatment with antibiotics. Therefore the cost savings attributed to a limited microbial investigation favours this practice in the investigation of UTI although more rigorous investigation of the patient outcomes and attributed costs is needed.

    There is limited level 1 evidence from a single investigation that refrigeration (up to 24 hours) of urine samples prior to sample processing does not significantly alter urinalysis or urine culture results in SCI patients.

    There is limited level 2 evidence from a single investigation that fewer false positive tests showing bacteriuria occur if indwelling or suprapubic catheters are changed prior to collection for urine culture analysis.

    There is conflicting level 4 evidence from two investigations concerning whether dipstick testing for nitrates or leukocyte esterase is recommended to guide treatment decision-making.

    Level 2 evidence based on two RCTs suggests no difference in UTI rates between sterile vs clean approaches to intermittent catheterization during inpatient rehabilitation, however, using a sterile method is significantly more costly.

    There is limited level 4 evidence from a single study that there is no difference in UTI rates between intermittent catheterization conducted by the patients themselves or by a specialized team during inpatient rehabilitation.

    There is limited level 4 evidence from a single study that similar rates of UTI may be seen for those using clean intermittent catheterization during inpatient rehabilitation as compared to those using similar technique over a much longer time when living in the community.

    There is limited level 4 evidence from a single study that differences in residual urine volume ranging from 0-153 ml were not associated with differences in UTI during inpatient rehabilitation.

    There is level 1 evidence based on 1 RCT that pre-lubricated nonhydrophilic catheters are associated with fewer UTIs as compared to conventional Poly Vinyl Chloride catheters.

    There is conflicting level 2 evidence based on 1 RCT that fewer UTIs may result with the use of hydrophilic catheters as compared to conventional PVC catheters.

    There is level 2 evidence based on 2 RCTs that use of hydrophilic vs non-hydrophilic catheters are associated with fewer symptomatic UTIs treated with antibiotics even though the number of symptomatic UTIs are similar between groups.

    There is level 2 evidence based on a single prospective controlled trial and supported by a case control study that intermittent catheterization may lead to a lower rate of UTI as compared to other bladder management techniques such as use of indwelling or suprapubic catheter.

    There is level 3 evidence based on a single case control study that bladder management with a suprapubic as opposed to indwelling catheter may lead to a lower rate of UTI and reduced mortality in a poor, illiterate population where intermittent catheterization may not be viable as an approach to bladder management.

    There is weak level 2 evidence based on a single low quality RCT that suggests that use of the Statlock device to secure indwelling and suprapubic catheters may lead to a lower rate of UTI.

    There is level 2 evidence based on a single prospective controlled trial that suggests that removal of external condom drainage collection systems at night or for 24 hours/day might reduce perineal, urethral or rectal bacterial levels but have no effect on bacteriuria.

    There is level 4 evidence based on a single case series that no bladder management method is advantageous in preventing pyelonephritis (though indwelling urethral catheterization does have the highest incidence of upper tract deterioration). However, the presence of reflux results in a 2.8 fold higher incidence of pyelonephritis.

    There is level 1 evidence based on a single RCT and supported by two level 4 investigations that bacterial interference in the form of E. coli 83972 bladder inoculation may prevent UTIs.

    There is level 1 evidence from a single RCT that low-dose, long-term ciprofloxacin may prevent symptomatic UTI.

    There is level 1 evidence from a single RCT that TMP-SMX as prophylaxis may reduce symptomatic UTI rates although conflicting findings were obtained from 2 prospective controlled trials. The potential for emergence of drug resistant bacteria and TMP-SMX related adverse events further limit the potential use of TMP-SMX for prophylaxis.

    There is level 4 evidence from a single study that suggests weekly oral cyclic antibiotic use, customized as to individual allergy and antimicrobial susceptibility, may be effective for UTI prevention in SCI patients, and UTI reduction in pregnant patients.

    There is level 1 evidence based on a single RCT that oral methenamine hippurate, either alone or in combination with cranberry, is not effective for UTI prevention.

    There is level 2 evidence from separate studies that bladder irrigation with trisdine, kanamycin-colistin or a 5% hemiacidrin solution combined with oral methenamine mandelate (2 mg qid) may be effective for UTI prevention.

    There are varying levels of evidence that bladder irrigation with neomycin/polymyxin (level 1), acetic acid (level 1), ascorbic acid (level 2) or phosphate supplementation (level 4) is not effective for UTI prevention.

    There is level 2 evidence based on a single low quality RCT that supports the use of daily body washing with chlorohexidine and application of chlorhexidine cream to the penis after every catheterization versus using standard soap to reduce bacteriuria and perineal colonization.

    There is conflicting level 1 evidence across 4 RCTs (1 +ive, 3 –ive) to support the effectiveness of cranberry in preventing UTI in patients with neurogenic bladder due to SCI.

    There is level 1 evidence from a single RCT that a single educational session conducted by SCI specialist health professionals with accompanying written materials and a single follow-up telephone call can result in reduced urine bacterial colony counts in community-dwelling individuals with prior history of SCI.

    The beneficial effects of education mediated by SCI specialist health professionals on reducing UTI risk in community-dwelling individuals with SCI are supported by a single level 2 study and two level 4 studies incorporating different features such as one-on one or group workshops, demonstrations, practice of techniques and written materials.

    There is no evidence assessing the relative effectiveness of different educational approaches for reducing UTI risk.

    There is level 1 evidence from a single RCT that supports the use of 14 vs 3 days of Ciprofloxcin for improved clinical and microbiological outcomes in the treatment of UTI in persons with SCI.

    There is level 1 evidence from a single RCT suggesting that 3 or 7 day Ofloxacin treatment is more effective than trimethoprim-sulfamethoxazole in treating UTI and results in significant bladder bacterial biofilm eradication in persons with SCI patients.

    Level 4 evidence from a single study suggests that norfloxacin may be a reasonable treatment choice for UTI in SCI but subsequent resistance must be monitored.

    A low success rate of aminoglycosides in the treatment of SCI UTI is supported by level 1 evidence from a single RCT.

    Optimum antimicrobial treatment duration and dosage is uncertain due to the lack of comparative trials in persons with SCI.

    Level 4 evidence is reported for intermittent neomycin/polymyxin bladder irrigation being effective in altering the resistance of the offending bladder organism(s) to allow for appropriate antibiotic treatment.

Key Points

DESD Therapy in SCI: Enhancing Bladder Volumes Pharmacologically

Anticholinergic Therapy for SCI-Related Detrusor Overactivity

Propiverine, oxybutynin, tolterodine and trospium chloride are efficacious anticholinergic agents for the treatment of SCI neurogenic bladder.

  • Treatment with 2 of oxybutynin, tolterodine or trospium may be effective for the treatment of SCI neurogenic bladder in those not previously responding to one of these medications.
  • Tolterodine, propiverine, or transdermal application of oxybutinin likely result in less dry mouth but are similarly efficacious to oral oxybutynin in terms of improving neurogenic detrusor overactivity.

Intravesical Instillations for SCI-Related Detrusor Overactivity

  • Intravesical instillations with oxybutinun or propantheline alone are ineffective for treating neurogenic bladder in people with SCI.

Other Pharmaceutical Treatments for SCI-Related Detrusor Overactivity

  • Intrathecal baclofen and clonidine may be beneficial for bladder function improvement but further confirmatory evidence is needed.

 

DESD Therapy in SCI: Enhancing Bladder Volumes Non-Pharmacologically

Surgical Augmentation of the Baldder to Enhance Volume

  • Surgical augmentation of bladder may result in enhanced bladder capacity under lower filling pressure and improved continence in persons with SCI.
  • Extraperitoneal vs intraperitoneal augmentation enterocystoplasty may result in better postoperative recovery.

 

DESD Therapy in SCI: Enhancing Bladder Emptying Pharmacologically

Alpha-adrenergic Blockers for Bladder Emptying

  • Tamsulosin may improve urine flow in SCI individuals with bladder neck dysfunction.
  • Mosixylyte is likely able to decrease maximum urethral closure pressure at a dose of 0.75mg/kg in individuals with SCI.
  • Terazosin may be an alternative treatment for bladder neck dysfunction in individuals with SCI but side effects and drug tolerance should be monitored.
  • Phenoxybenzamine may be useful as an adjunct therapy for reducing residual urine volume in SCI neuropathic bladders maintained by crede or tapping.
  •  months of alpha 1-blocker therapy in male SCI patients may improve upper tract stasis.

Botulinum Toxin for Bladder Emptying

  • Botulinum toxin injected into the sphincter is effective in assisting with bladder emptying for persons with neurogenic bladder due to SCI.

Other Pharmaceutical Treatments for Bladder Emptying

  • A single dose of oral tadalafil is effective in improving urodynamic indices in males with supra sacral SCI; more evidence is needed to support this as a treatment option.
  • 4-Aminopyridine at sufficient dosage may return sensation and control of the bladder sphincter following SCI; more evidence is needed to support this as a treatment option.

 

DESD Therapy in SCI: Enhancing Bladder Emptying Non-Pharmacologically

Comparing Methods of Conservative Bladder Emptying

  • Intermittent catheterization, whether performed acutely or chronically, has the lowest complication rate.
  • Indwelling catheterization, whether suprapubic or urethral or whether conducted acutely or chronically, may result in a higher long-term rate of urological and renal complications than other management methods.
  • Persons with tetraplegia and complete injuries, and to a lesser degree females, may have difficulty in maintaining compliance with intermittent catheterization procedures following discharge from rehabilitation.
  • Intermediate Catheterization
  • Although both pre-lubricated and hydrophilic catheters have been associated with reduced incidence of UTIs as compared to conventional Poly Vinyl Chloride catheters, less urethral microtrauma with their use may only be seen with pre-lubricated catheters.
  • Urethral complications and epididymoorchitis occur more frequently in those using intermittent catheterization programs.
  • Portable ultrasound device can improve the scheduling of intermittent catheterizations.

Triggering-Type of Expression Voiding Methods of Bladder Management

  • Valsalva or Crede maneuver may assist some individuals to void spontaneously but produce high intra-vesical pressure, increasing the risk for long-term complications.

Indwelling Catheterization (Indwelling or Suprapubic)

  • With diligent care and ongoing medical follow-up, indwelling suprapubic catheterization may be an effective and satisfactory bladder management choice for some people, though there is insufficient evidence to report lifelong safety of such a regimen
  • Indwelling catheter users are at higher risk of bladder cancer, especially in the second decade of use, though risk also increases during the first decade of use.

Condom Catheterization

  • Patients using condom drainage should be monitored for complete emptying and for low pressure drainage, to reduce UTI and upper tract deterioration. Sphincterotomy may eventually be required.
  • Penile implants may allow easier use of condom catheters and reduce incontinence.
  • Continent Catheterizable Stoma and Incontinent Urinary Diversion
  • Catheterizable abdominal stomas may increase the likelihood of achieving continence and independence in self-catherization, and may result in a bladder management program that offers more optimal upper tract protection.
  • Cutaneous ileal conduit diversion may increase the likelihood of achieving continence but may also be associated with a high incidence of various long-term complications.

Electrical Stimulation for Bladder Emptying (and Enhancing Volumes)

  • Sacral anterior root stimulation (accompanied in most cases by posterior sacral rhizotomy) enhances bladder function and is an effective bladder management technique though the program (surgery and followup) requires significant expertise.
  • Direct bladder stimulation may be effective in reducing incontinence and increasing bladder capacity but requires further study.
  • Posterior sacral, pudenal,dorsal penile or clitoral nerve stimulation may be effective to increase bladder capacity but requires further study.
  • Early sacral neural modulation may improve management of lower urinary tract dysfunction but requires further study.

Sphincterotomy, Artificial Sphincter, Stents and Related Approaches for Bladder Emptying

  • Surgical and prosthetic approaches (with a sphincterotomy and stent respectively) to allow bladder emptying through a previously dysfunctional external sphincter both seem equally effective resulting in enhanced drainage although both may result in long-term upper and lower urinary tract complications.
  • Artificial urinary sphincter implantation and transurethral balloon dilation of the external sphincter may be associated with improved bladder outcomes but require further study.

 

DESD Therapy in SCI: Other Miscellaneous Treatments

  • Early electroacupuncture therapy as adjunctive therapy may result in decreased time to achieve desired outcomes.
  • Intranasal DDVAP may reduce nocturnal urine emissions and decrease the frequency of voids (or catheterizations).
  • Anastomosis of the T11, L5 or S1 to the S2-S3 spinal nerve roots may result in improved bladder function in chronic SCI.

 

Urinary Tract Infections: Detecting and Investigating UTIs

  • Both limited and full microbial investigation may result in adequate clinical response to UTI treatment with antibiotics.
  • Indwelling or suprapubic catheters should be changed just prior to urine collection so as to limit the amount of false positive urine tests.
  • Urinalysis and urine culture results of SCI patients are not likely to be affected by sample
  • refrigeration (up to 24 hours).
  • It is uncertain if dipstick testing for nitrates or leukocyte esterase is useful in screening for bacteriuria to assist treatment decision-making.

 

Urinary Tract Infections: Non-Pharmacological Methods of Preventing UTIs

Intermittent Catheterization NS Prevention of UTIs

  • Sterile and clean approaches to intermittent catheterization seem equally effective in minimizing UTIs in inpatient rehabilitation.
  • Similar rates of UTI may be seen with intermittent catheterization as conducted by the patients themselves or by a specialized team during inpatient rehabilitation.
  • Similar rates of UTI may be seen with intermittent catheterization, whether conducted in the short-term during inpatient rehabilitation or in the long-term while living in the community.
  • UTIs were not associated with differences in residual urine volumes after intermittent catheterization.

Intermittent Catheterization using Specially Coated Catheters for Preventing UTIs

  • A reduced incidence of UTIs or reduced antibiotic treatment of symptomatic UTIs have been associated with pre-lubricated or hydrophilic catheters as compared to standard non-hydrophilic catheters.

Other Issues Associated with Bladder Management and UTI Prevention

  • Intermittent catheterization is associated with a lower rate of UTI as compared to use of indwelling or suprapubic catheter.
  • The Statlock device to secure indwelling and suprapubic catheters may lead to a lower rate of UTI.
  • Removal of external condom drainage collection systems at night or for 24 hours/day may reduce perineal, urethral or rectal bacterial levels but has no effect on bacteriuria.
  • The presence of vesicoureteral reflux likely has a greater impact on development of significant infections than the choice of bladder management.

 

Urinary Tract Infections: Pharmacological and Other Biological Methods of UTI Prevention

Bacterial Interferences for Prevention of UTIs

  • E. coli 83972 bladder inoculation may prevent UTIs.

Antibiotic Prophylaxis of UTIs

  • Ciprofloxacin may be indicated for UTI prophylaxis in SCI but further research is needed to support its use.
  • Long-term use of TMP-SMX is not recommended for sustained use as a suppressive therapy for UTI prevention.
  • A weekly oral cyclic antibiotic, customized to the individual, may be beneficial in preventing UTI in SCI.

Antiseptic and Related Approaches for Preventing UTIs

  • Oral methenamine hippurate, either alone or in combination with cranberry, is not effective for UTI prevention.
  • The antiseptic agents delivered via bladder irrigation (5% hemiacidrin solution combined with oral methenamine mandelate) may be effective for UTI prevention, whereas others are not (i.e., trisdine, kanamycin-colistin, neomycin/polymyxin, acetic acid, ascorbic acid and phosphate supplementation).
  • Daily body washing with chlorohexidine and application of chlorhexidine cream to the penis after every catheterization instead of using standard soap may reduce bacteriuria and perineal colonization.

Cranberry for Preventing UTIs

  • It is uncertain if cranberry is effective in preventing UTIs in persons with SCI.

Urinary Tract Infections: Educational Intervention for Maintaining a Healthy Bladder and Preventing UTIS

  • A variety of bladder management education programs are effective in reducing UTI risk in community-dwelling persons with SCI, although limited information exists as to the most effective approaches.

 

Urinary Tract Infections: Pharmacological Treatments of UTIs

Antibiotic in Treatments of UTIs

  • Ciprofloxin administered over 14 (vs 3) days may result in improved clinical and microbiological SCI UTI treatment outcome.
  • Ofloxacin administered over either a 3 or 7 day treatment regimen may result in significant SCI UTI cure and bladder bacterial biofilm eradication rate, moreso than trimethoprim-sulfamethoxazole.
  • Norfloxacin may be a reasonable treatment choice for UTI in SCI but  subsequent resistance must be monitored.
  • Aminoglycosides have a low success rate in the treatment of SCI UTI.
  • Intermittent neomycin/polymyxin bladder irrigation may be effective in altering the resistance of the offending bladder organism(s) to allow for appropriate antibiotic treatment.

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Bone Health

Craven C, Lynch CL, Eng JJ (2014). Bone Health Following Spinal Cord Injury. In Eng JJ, Teasell RW, Miller WC, Wolfe DL, Townson AF, Hsieh JTC, Connolly SJ, Noonan VK, Loh E, McIntyre A, editors. Spinal Cord Injury Rehabilitation Evidence. Version 5.0. Vancouver: p 1- 37.


Abbreviations

AB                   able-bodied

aBMD              areal bone mineral density

ABT                 activity-based therapy

AIS                  ASIA Impairment Scale

ASA                 acetylsalicylic acid

BALP               bone-specific alkaline phosphatase

BMC                bone mineral content

BMD                bone mineral density

BMI                  body mass

BP                   bisphosphonate

BW                  body weight

CE                   cycle ergometer

CSA                 cross-sectional area

CT                   Type I collagen C-telopeptide levels

CTX                 collagen C-telopeptide

DPA                 dual energy photon absorptiometry

DOI                  duration of injury

DXA / DEXA    dual energy X-ray absorptiometry

EMS                electromyostimulation

ES                   electrical stimulation

FES                 functional electrical stimulation

HR                   high resolution

IGF1                insulin-like growth factor-1

IV                     intravenous

NMES              neuromuscular electrical stimulation

NTX                 N-telopeptide

OC                   osteocalcin

PINP                serum procollagen type I N propeptide

pQCT              peripheral quantitative computed tomography

PTH                 parathyroid hormone

QUS                quantitative ultrasound

RCT                 randomized controlled trial

RGO                reciprocating gait orthosis

SLOP              sublesional osteoporosis

TSI                  time since injury

vBMD              volumetric bone mineral density

Introduction

A significant decline in hip and knee region bone mineral density (BMD) occurs after motor complete spinal cord injury (SCI) which leads to a lifetime increased risk of lower extremity fragility or low trauma fracture.  Preserving bone mass and maintaining bone architecture are crucial to decrease the risk of lower extremity fragility fractures.  Within the first few days following SCI there is an increase in excreted calcium (known as hypercalciuria) that is 2-4 times that of individuals without SCI who are confined to prolonged bed rest (Bauman & Spungen 2001) and reflects excessive bone resorption.  Longitudinal studies also highlight a higher rate of hypercalcemia (excessive calcium in the blood) for people after SCI that reflects rapid bone mineral loss in the first 4-6 months that slows for the remainder of the first year post-injury (Hancock et al. 1980; Frey-Rindova et al. 2000).  Early studies also suggest that bone mineral density (BMD) stabilizes by 1-2 years after SCI (Griffiths et al. 1976; Hancock et al. 1980; Garland et al.1992) at 25-50% below that of able-bodied peers in the hip and knee region.  Other investigations support a continual loss of bone mass with time since injury (Demirel et al. 1998; Bauman et al. 1999; Eser et al. 2005) and suggest that lower extremity bone mineral homeostasis is not reached.

The immediate and excessive loss of bone mass post-SCI is believed to result from a decrease in mechanical loading as a result of reduced or complete loss of muscle function and/or weight-bearing activities.  Autoimmune, neural, vascular, hormonal and nutritional changes may also negatively affect bone, but the relative contributions of these factors are unknown (Jiang et al. 2006).  The reader is referred to two recent review articles which characterize the regional changes in bone density and architecture (Jiang et al. 2006; Craven et al. 2008). Furthermore, an inadequate dietary calcium intake (Tomey et al. 2005) or insufficient vitamin D may contribute to the rate and severity of BMD decline (Bauman et al. 1995).  Aging and inactivity accentuate bone resorption further, resulting in site-specific decreases in bone mineral content (that is, trabecular bone experiences larger decreases in mineral content than cortical bone). Additionally, women with motor complete SCI experience regional declines in hip and knee region BMD during menopause that are greater than age-matched able-bodied women (Garland et al. 2001).  These changes in bone density and bone architecture all contribute to the increased risk of fragility fractures in people with SCI. Fractures after SCI often result in delayed union or non-union and/or complications of immobilization (DVT, pressure sore, cellulitis). These fractures are associated with an increase in direct and indirect medical expenses, as well as the individual’s morbidity and mortality.

Systematic Review

Table 1: Systematic Review

Fracture Risk following SCI

There is overwhelming evidence that supports the importance of addressing bone health issues early after SCI.  A higher incidence of fragility fractures exist in people who sustain SCI (Table 2); the majority of fragility fractures occur following transfers or activities that involve minimal or no trauma (Comarr et al. 1962; Ragnarsson & Sell; 1981; Freehafer 1995).  The distal femur and proximal tibia (knee region) are most at risk, consistent with site-specific decreases in BMD to such a degree that fractures of the distal femur were previously referred to as ‘the paraplegic fracture’ (Comarr et al. 1962). 

Risk factors for fragility fracture after SCI include: sex, age at injury, time post injury, type of impairment, low BMI, low knee region BMD, and use of anticonvulsants, heparin, or opioid analgesics.  Women are at greater risk compared to men (Vestergaard et al. 1998; Lazo et al. 2001; Nelson et al. 2003; Garland et al. 2004).  Increasing age and longer time since injury (Frisbie 1997; McKinley et al.1999; Garland et al. 2004; Garland et al. 2005) increases fracture risk which rises significantly at 10 years post injury.  Further, people with paraplegia have more fractures (Frisbie 1997) and those with complete injuries have greater bone mass loss compared with those with incomplete injuries (Garland et al. 2004; Garland et al. 2005). 

BMD fracture thresholds are values below which fragility fractures begin to occur, whereas fracture breakpoints are values below which the majority of fractures occur (Garland et al. 2005). Knee region aBMD and vBMD thresholds for fracture and breakpoint have been identified (Mazess 1990; Eser et al. 2005; Garland et al. 2005). The use of heparin (HR 1.48, CI 1.20-1.83), opioid analgesics (HR 1.80, CI 1.57-2.06), or anticonvulsants (HR 1.35, CI 1.18-1.54), especially the benzodiazepine sub-class (HR 1.45, CI 1.27-1.65), is associated with an increased risk of lower extremity fragility fractures in men with chronic (≥ 2 yrs injury duration) SCI (Carbone et al. 2013a, 2013b).In a large retrospective cohort study of men with chronic SCI (N = 6969, ≥ 2 yrs post-injury), the use of thiazide-type diuretics was associated with a 25% reduction in the risk of lower extremity fragility fractures (Carbone et al. 2013c). In the general population, individuals with a prior history of fragility fracture or a maternal history of fracture have an elevated fracture risk; these risk factors should also be considered during a fracture risk assessments among patients with SCI. Men with chronic SCI are at a slightly increased risk of lower extremity fragility fractures when exposed to proton pump inhibitors (HR 1.08, CI 0.93-1.25), selective serotonin reuptake inhibitors (HR 1.05, CI 0.90-1.23), or thiazoledinediones (HR 1.04, CI 0.68-1.61) (Carbone et al. 2013a, 2013b). However, these drugs are known risk factors for the development of osteoporosis in the general population, and should therefore be considered when assessing fracture risk in SCI patients. 

Table 2: Fractures and Risk Factors for Fragility Fractures after SCI

  • Fragility fractures, especially around the knee, are common in people with SCI.

We recommend documenting your patient’s fracture risk by completing the risk factor profile checklist (Craven et al. 2008; Craven et al. 2009). We propose that the presence of ≥ 3 risk factors implies a moderate fracture risk, while ≥ 5 risk factors implies a high fracture risk (Table 3).

Table 3: Risk Factors for Lower Extremity Fragility Fracture after SCI

Sublesional Osteoporosis (SLOP) Detection and Diagnosis

In order to assess and understand your patient’s bone health, it is important to measure their BMD and document their fracture risk.   We advocate diagnosing the presence of SLOP based on the following DXA criteria (Table 4).

Table 4: Definition of Sublesional Osteoporosis (SLOP)

Bone Outcome Measures

There are multiple methods for assessing bone health. Commonly used tools include:

Imaging Modalities

Bone imaging is typically used to assess bone mineral density (BMD), morphology, or microstructure. Imaging modalities that are used for bone health assessment include dual energy X-ray absorptiometry (DXA), dual-energy photon absorptiometry (DPA), and standard and high-resolution peripheral quantitative computed tomography (pQCT, HR-pQCT).

Dual-Energy Absorptiometry (DXA, DPA)

BMD assessment by dual energy X-ray absorptiometry (DXA) imaging is considered by the World Health Organisation as the “gold standard” to diagnose osteoporosis and is the most widely used assessment technique for determining treatment effectiveness. DXA is a non-invasive, relatively safe modality for measuring areal BMD (aBMD), which is defined as bone mineral content per unit area in g/cm2. DPA is an older technology for measuring aBMD that is sometimes reported in studies conducted prior to the 1990’s.

Increases in areal BMD (aBMD) are presumed to be a suitable surrogate outcome for fracture risk reduction when assessing the effectiveness of SLOP therapy. “Optimal therapeutic outcome” would be defined as an increase in knee region BMD above the fracture threshold in the absence of fragility fracture.

There are several established methods for measuring BMD at the knee (Garland et al. 1993; Moreno et al. 2001; Eser et al. 2004; Morse et al. 2009). Regardless of the methodology chosen, assessment of knee region BMD is crucial as it best predicts knee region fracture risk after SCI (Eser et al. 2005; Garland et al. 2005; Lala et al. 2013).

Peripheral Quantitative Computed Tomography (pQCT, HR-pQCT)

Peripheral QCT is another non-invasive, relatively safe imaging modality that can be used to diagnose osteoporosis. Whereas DXA measures areal BMD, pQCT measures volumetric BMD (vBMD), which is defined as bone mineral content per unit volume in g/cm3. vBMD stands alongside aBMD as a surrogate outcome for fracture risk reduction. In addition to assessing volumetric bone density, pQCT can also differentiate cortical bone from trabecular bone and quantify architecture. However, pQCT is available as a clinical diagnostic tool in only a few countries.

High-resolution pQCT (HR-pQCT) improves upon the resolution of standard pQCT imaging, and is now available with as fine as 80 µm resolution. This imaging modality gives detailed information on the microarchitecture of peripheral bone, but is not widely available outside of research applications.

Biochemical Markers

Biochemical markers of bone turnover can be used as an adjunct to DXA in the assessment of bone health among patients with SCI. Serum and urine markers provide useful insight into bone metabolism at specific time points after injury and are an effective tool for selecting patients who would benefit from therapy and monitoring response to therapy. The current therapeutic utility of bone turnover markers is limited by day-to-day, diurnal, inter-individual, and inter-assay variability. For urine markers, results need to be corrected for creatinine (Reiter et al. 2007).

Markers of bone formation include bone-specific alkaline phosphatase (BALP), osteocalcin (OC), N-terminal propeptide of type I collagen (PINP), and C-terminal propeptide of type I collagen (PICP). Markers of bone resorption include urinary free and total pyridinoline (Pyr) and deoxypyridinoline (DPD) crosslinks, type 1 collagen C-telopeptide (CTX), and N-telopeptide (NTX). Pyr and DPD are molecules that provide stability to collagen and, along with CTX and NTX, are released when collagen is degraded during bone resorption (Brown et al. 2009).

For a bone marker to be useful in assessing the rate of bone turnover and/or monitoring therapy effectiveness, the difference in the rate of bone turnover before and after SCI, as well as the early period versus the late period after SCI, needs to be discernible. Consensus regarding which biomarkers are best to monitor bone turnover is needed in the SCI community. Several authors have suggested candidate biomarkers including sclerostin (Morse et al. 2013) and adiponectin (Doherty et al. 2014). Alignment of the choice of biomarkers across future bone health studies may allow for cross-study comparison or future meta-analyses.

Histomorphometry

Histomorphometry are measurements from bone biopsies to provide an in-depth understanding of bone.  There are two types of bone histomorphometry, dynamic and static.  Dynamic histomorphometry involves using substances such as tetracycline to measure tissue growth. Static histomorphometry involves determining the size and types of cells; measurements include length, area or cell counts. 

Although bone histomorphometry is considered an important tool, it is not always feasible because it requires surgically obtaining bone specimens from consenting participants. As biomarker technology continues to improve, the use of histomorphometry in live human subjects will likely be supplanted by this less invasive testing modality.

Clinical Guide

In the following sections, prevention and treatment interventions for maintaining bone health after SCI are discussed. Two distinct clinical questions can be posed regarding bone loss after SCI: (1) What is the best way to prevent acute regional declines in bone mineral density in the early post-injury period (10-90 days post injury)? and (2) What are the best treatments for established low bone mass and increased fracture risk of the hip and knee region for individuals  with chronic (>2 years) SCI?

Bone loss is greatest in the first year post-SCI. Therefore, this review classifies intervention studies as either prevention studies (i.e. the participants are less than 6 months post-SCI) or treatment studies (i.e. study participants are ≥1 year post-SCI). Within the prevention and treatment categories, this review discusses (a) pharmacological intervention studies, (b) non-pharmacological intervention studies, and (c) studies of combination interventions (e.g. drug therapy concurrent with a rehabilitation intervention).

When selecting a treatment to offer patients, clinicians seek the best available evidence to support their practice.  Ideally, one would like to see three randomized control trials (Level 1 evidence) from separate centres demonstrating the efficacy of a therapy prior to routine implementation.  Having highlighted this issue, the diversity of interventions, study design and outcome measures make interpretation of the SCI bone health literature challenging and subject to controversy. The following sections attempt to identify the best available literature to address specific clinical questions.

Pharmacological Therapy: Bisphosphonates

Within weeks after SCI, there is a marked increase in bone resorption (breaking bone down) with a decrease in bone formation (adding new bone). These phenomena are responsible for the significant loss of bone mass that occurs after SCI. Bisphosphonates are a group of medications that are used to prevent declines in bone mass or treat low BMD; they act to slow down excessive bone resorption. They are generally divided into two types, those with or without nitrogen; each type has a different mechanism of action. Etidronate (Didrocal, Didronel), clodronate (Bonefos, Ostac) and tiludronate (Skelid) do not contain nitrogen while pamidronate (Aredia), alendronate (cholecalciferol, Fosamax, Fosamax Plus D, Fosavance), ibandronate (Boniva), risedronate (Actonel, Actonel with Calcium) and zoledronate (zoledronic acid, Aclasta, Reclast, Zomera, Zometa) contain nitrogen. Etidronate, alendronate and risedronate are oral bisphosphonates that are currently approved for the treatment of postmenopausal osteoporosis in Canada (Brown et al. 2002).  Clodronate is available intravenously (IV) and orally for the treatment of osteoporosis.  Tiludronate is available in oral form in the United States.  Zoledronate is a newer once yearly bisphosphonate which is administered via IV infusion.  Concurrent supplementation with calcium and vitamin D have been important additions to bisphosphonate therapy for post-menopausal osteoporosis (Brown et al. 2002). The concurrent administration of calcium, vitamin D, and bisphosphonates has not been prospectively evaluated in the SCI population, but should nonetheless be considered when prescribing oral bisphosphonates for SLOP based on the post-menopausal osteoporosis literature.

Pharmacologic Therapy: Prevention of Bone Loss (within 12 Months of Injury)

Table 5: Studies of Pharmacologic Therapy for Prevention of Bone Loss in the First Year after SCI

Discussion

Evidence for pharmacological prevention of SCI bone loss includes 8 randomized controlled trials (RCT) (n=152 participants) and 1 non-randomized trial (n=24) (Table 5).  These studies were difficult to interpret as a group due to the variability in selection of the pharmacological treatment, primary outcome measure, relatively short durations of follow-up, small sample sizes, and the lack of stratification based on impairment level.  Preventing bone loss immediately following SCI is challenging given the rapid bone resorption especially in AIS A patients.  The majority of studies found bisphosphonates resulted in a reduction of bone loss compared with a control group.  The two studies which report that first generation bisphosphonates (Clodronate) can maintain bone were short in duration (3 month intervention) and participants had less severe injury (paraplegia, incomplete SCI) (Minaire et al. 1981,1987).  In the studies by Pearson and colleagues (1997) and Nance and colleagues (1999), both groups continued to lose bone, except AIS D participants who had bone density preservation in the lower extremity with bisphosphonates while participants with AIS A had the greatest decline in both studies.  A recent study which used a second-generation version of the bisphosphonate, Pamidronate, and a longer intervention period found no significant differences between groups for bone loss after 1 year (Bauman et al. 2005a).  Gilchrist and colleagues (2007) noted a significant difference in BMD at the hip with once weekly Alendronate. Shapiro and colleagues (2007) tested the effect of once yearly IV Zoledronate with significant improvement in BMD at the hip at 6 months that returned to baseline values at 12 months; the control group on the placebo treatment lost bone over the 12 months.  Bubbear et al. (2011) also showed that once yearly IV Zolendronate resulted in less bone loss at the spine and hip over 12 months.  The investigators also highlighted the added benefits of a once yearly IV administration of bisphosphonate, as this eliminates issues surrounding poor patient adherence and the adverse gastrointestinal effects associated with alternate oral therapies. Although there is evidence that bisphosphonates may reduce bone resorption, current medications do not totally prevent BMD decline.  Nonetheless, there is a window of opportunity soon after injury where SLOP prevention may be effective, and there is sufficient evidence of moderate prevention efficacy that patients should be counseled on the available therapies and allowed to ­­make their own decision regarding treatment.

Conclusions

There is level 1 evidence (from 3 RCTs) (Minaire et al. 1981, 1987; Chappard et al. 1995) that oral Tiludronate and Clodronate prevent a decrease in BMD of the hip and knee region with no adverse effects on bone mineralization in men with paraplegia.

There is level 1 evidence (from 1 RCT) (Pearson et al. 1997) that oral Etidronate prevents a decrease in BMD of the hip and knee region in people with incomplete paraplegia or tetraplegia (AIS D impairment) who return to walking within 3 months of the SCI.

There is level 1 evidence (from 1 RCT) (Gilchrist et al. 2007) that once weekly oral Alendronate maintains hip region BMD.

There is level 1 evidence (from 2 RCTs) (Shapiro et al. 2007; Bubbear et al. 2011) that a one-time IV infusion of Zoledronate may reduce bone loss in the hip region during the 12 months following administration.

There is level 1 evidence (from 1 RCT) (Bauman et al. 2005a) that Pamidronate 60mg IV seven times per year and level 2 evidence (from 1 non-randomized prospective controlled trial) (Nance et al. 1999)that Pamidronate 30 mg IV six times per yearis not effective for the prevention of BMD loss at the hip and knee region early after SCI in men and women who have motor complete paraplegia or tetraplegia.

  • Bone health management should begin early following SCI, given the significant declines in hip and knee region bone mass in the first year and the associated lifetime increased fracture risk.

    The efficacy of drug interventions appears to be greater when medications are administered early after SCI onset.

  • Oral tiludronate and clodronate prevent a decrease in BMD of the hip and knee region with no adverse effects on bone mineralization in men with paraplegia.

    Oral etidronate prevents a decrease in BMD of the hip and knee region in people
    with incomplete paraplegia or tetraplegia who return to walking.

    Oral alendronate once weekly maintains BMD at the hip.

    Once yearly IV infusion zoledronate may reduce bone loss at the hip during the 12 months following administration.

  • Pamidronate 30 mg IV or 60 mg IV 4x/year is not effective for the prevention of BMD loss at the hip and knee region early after SCI people with motor complete paraplegia or tetraplegia.

Pharmacologic Therapy: Treatment (1 Year Post-Injury and Beyond)

Table 6: Studies of Pharmacologic Therapy for Treatment of Bone Loss in Chronic SCI

Discussion

Evidence for pharmacological treatment of SLOP includes 3 RCTs (Zehnder et al. 2004; Bauman et al. 2005b; Moran de Brioto et al. 2005) (n=124 participants).  In these studies, the treatment group experienced improvement or maintenance in bone health at various sites.  For the two studies that tested Alendronate, the extent of improvement was greater in the study by Zehnder et al. (2004) who found an increase in BMD at the spine with maintenance of BMD at the hip and tibia.  In contrast, Moran de Brioto et al. (2005) only found a non-significant increase in BMD in the upper extremity and a significant increase in total BMD.  The difference in response of outcomes could be a result of the younger participants with less severe injuries in the work by Zehnder and coworkers (2004).  Bauman and colleagues noted positive results in leg BMD for participants who received vitamin D.

This review has provided conflicting support for using first and second generation oral bisphosphonates for prevention of low bone mass and some support for treatment of low bone mass.  Despite the benefits of these medications, they are not without their complications.  Oral bisphosphonates must be ingested on an empty stomach, with 4-8oz of water, followed by sitting up for one-hour post ingestion, prior to taking any other food or medication.  About 1% of the ingested oral bisphosphonate is absorbed in the upper intestine, yet it remains in the body in an inactive form for several months or years thereafter.  Oral bisphosphonate therapy can cause side effects; joint pain, stomach upset and diarrhea being the most frequently reported adverse effects.  Intravenous formulations of bisphosphonates are available in monthly, quarterly and annual preparations, and have a greater relative potency.  Although their common short-term side effects include fever, low serum calcium and transient decrease in white blood cells, IV preparations are attractive due to the flexibility in dosing regimens, assured adherence to therapy and the reduced relative risk of an adverse upper gastrointestinal event.

Bisphosphonates should be used with caution in pre-menopausal women due to the unknown teratogenic effects of these medications on the fetus during pregnancy.  Patients taking acetylsalicylicacid (ASA), corticosteroids or NSAIDS may require gastrointestinal prophylaxis as these medications in combination with bisphosphonates increase the relative risk of developing a gastric ulcer or bleeding.  Many questions regarding the safety of these medications among people with SCI and the optimal duration of therapy remain.  Zolendronate, an IV bisphosphonate, has been reported to increase the incidence of serious atrial fibrillation resulting in hospitalization or disability among 1-3% of elderly non-SCI patients (HORIZON study, Black et al. 2007).  Zolendronate should be used with caution in elderly patients or patients with premorbid atrial fibrillation or arrhythmia secondary to autonomic dysfunction after SCI.  The risk of osteonecrosis of the jaw is highest among people with a prior history of cancer or radiotherapy.  Both osteonecrosis of the jaw and arrhythmia should be discussed during consent for oral or IV bisphosphonate therapy.

It has been shown that oral bisphosphonates may be taken safely without adverse effects on bone metabolism for 10 years in postmenopausal women (Bone et al. 2004).  Data from postmenopausal non-SCI women suggests BMD should be monitored at least alternate years in patients who stop taking oral bisphosphonates; those with a rapid decline in BMD of >10% in two years or >5% from baseline should be switched to alternate treatment or resume bisphosphonate therapy (Colon-Emeric 2006).

Conclusion

There is level 1 evidence (from 1 RCT) (Zehnder et al. 2004) that Alendronate 10 mg daily and calcium 500mg orally 3x/day is effective for the maintenance of BMD of thetotal body, hip and knee region for men with paraplegia.

There is level 1 evidence (from 1 RCT) (Bauman et al. 2005b) that vitamin D analog is effective for maintaining leg BMD.

  • Alendronate 10 mg daily and calcium 500 mg orally 3x/day is effective for the maintenance of BMD of the total body, hip and knee region for men with paraplegia.

    Vitamin D analog is effective for maintenance of BMD in the leg.

Non-Pharmacologic Therapy: Rehabilitation Modalities

Rehabilitation options for bone health after SCI focus on stimulating muscles and encouraging weight-bearing. This section includes six modalities: functional electrical stimulation (FES), electrical stimulation (ES), standing and walking, treadmill training, ultrasound and physical activity.  FES is an important option to stimulate muscle with the goal of increasing regional BMD, and involves the use of surface or implanted electrodes to facilitate stimulation-induced standing, ambulation or bicycling (cycle ergometry).  An FES cycle ergometer uses a series of electrodes placed over the hamstrings, quadriceps and gluteal muscles of the legs to stimulate a cycling pattern.  Weight-bearing activities are also used for bone health after SCI; these modalities include either passive (tilt-table or standing frame) or active weight-bearing activities with or without assistance from FES.  Many FES studies have enrolled participants with both acute and chronic injuries and are therefore difficult to classify as pure prevention or treatment interventions.  For the purpose of this review, studies that enrolled participants that ranged from the acute phase to > 1 year were included with the treatment literature, as the majority of their participants were in the chronic phase.

Non-Pharmacologic Therapy: Prevention (within 12 Months of Injury)

Table 7: Studies of Rehabilitation Modalities for Prevention of Bone Loss in the First Year after SCI

Discussion

Evidence for non-pharmacological prevention of sublesional osteoporosis includes data from sixteen investigations (n=264 participants).  This includes four RCTs (80 participants), five non-randomized controlled trials (116 participants) and three pre-post studies (22 participants) (Table 7). As with pharmacological studies, there were difficulties with interpretation because of low numbers of participants and variability with the primary outcome measures. For each of the five different modalities there is limited evidence available and there was variability in the selection of the primary outcomes. The therapeutic ultrasound study by Warden and coworkers (2001) found no significant improvement in bone health after a 6 week intervention. Although prospective observational data (Frey-Rindova et al. 2000) highlight the loss of bone in the early phase (first 6-months post SCI), there was no significant influence of self-reported physical activity level.  Overall, the evidence suggests that rehabilitation modalities did not prevent bone mass decline in the acute phase after SCI.

Conclusion

There is level 1 evidence (from one RCT) (Warden et al. 2001) that short-term (6 weeks) ultrasound is not effective for treating bone loss after SCI.

There is level 2 evidence (from 1 non-randomized prospective controlled trial) (Shields et al. 2006a) that ES reduced the decline in BMD in the leg.

There is level 2 evidence (from 1 non-randomized prospective controlled trial) (Eser et al. 2003) that FES cycling did not improve or maintain bone at the tibial midshaft in the acute phase.

There is level 4 evidence (from 1 pre-post study) (Giangregorio et al. 2005) that walking and level 1 evidence (from 1 RCT) (Ben et al. 2005) that standing in the acute phase did not differ from immobilization for bone mass decline at the tibia.

There is level 4 evidence (from 1 pre-post study) (Astorino et al. 2013) that activity-based training 2-3 hours/day for a minimum of 2 days a week for 6 months increased spine BMD.

  • Short term (6 weeks) therapeutic ultrasound is not effective for preventing
    bone loss after SCI.

    FES-cycling does not improve or maintain bone at the tibial midshaft in the acute phase.

    Activity-based training (6 months) is effective for increasing spine BMD.

Non-Pharmacologic Therapy: Treatment (1 Year Post-Injury and Beyond)

In this section, non-pharmacological rehabilitation treatment modalities are divided into six sub-sections: Electrical stimulation, vibration, functional electrical stimulation (FES) cycle ergometry, standing and walking, and physical activity (Tables 8, 9, 10, 11).  Both ES and FES use cyclical patterns of electrical stimulation that simulate muscular activity.  However, FES is directed towards the attainment of purposeful tasks such as cycling or walking.  Electrical stimulation, on the other hand, is focused on producing muscle contractions (isometric, isotonic).  In some interventions, ES techniques are used as a training stimulus to prepare muscles for a subsequent FES training regimen.

Electrical Stimulation

Table 8: Treatment Studies Using Electrical Stimulation for Bone Health after SCI

Discussion

Although there were no randomized controlled trials that assessed the effect of electrical stimulation, Bélanger et al. (2000) produced impressive results with a level 2, non-randomized trial which used 1 limb as the treatment and the other as the control limb.  Following training, the BMD recovered close to 30% of bone loss when compared with able-bodied values.  Stimulation effects only occur over the areas of stimulation and return to baseline within months once stimulation is stopped (Mohr et al. 1997).

Conclusion

  • There is level 2 evidence (from 1 prospective controlled trial) (Bélanger et al. 2000) that electrical stimulation either increased or maintained BMD over the stimulated areas.

  • Electrical stimulation can maintain or increase BMD over the stimulated areas.

Vibration

Table 9: Studies of Vibration Treatment for Bone Loss in Chronic SCI

Discussion

Vibration training is a relatively new treatment option used for potential benefits to muscle and/or bone health.

Conclusion

  • There is level 4 evidence (from 1 pre-post study) (Melchiorri et al. 2007) that vibration training did not improve or maintain BMC in the arms.

FES Cycle Ergometry

Table 10: Treatment Studies Using FES Cycle Ergometry for Bone Health after SCI

Discussion

For FES-Cycling there are mixed results for bone outcomes.  Three studies found an increase in BMD (Mohr et al.1997; Chen et al. 2005Frotzler et al. 2008) at the proximal tibia or distal femur while there was no significant within-participant BMD change at the hip in 3 pre-post studies (Pacy et al. 1988; Leeds et al.1990; and BeDell et al.1996)  The FES-cycling studies which reported a positive effect on bone parameters used protocols that were at least 3 sessions/week for 6 months in duration, and increased bone parameters over areas directly affected by stimulated muscles (e.g. quads, distal femur and proximal tibia).  Although one study showed that FES-cycling intervention needed to be maintained or bone gains were lost (Chen et al. 2005), Frotzler and colleagues found BMD and BMC were preserved at the distal sites for some participants at 12 months.  FES shows promise as an effective treatment around the knee; however the limited availability of cycle ergometry for home or longitudinal use may limit its generalizability if the therapy cannot be sustained outside a clinical trial scenario.

Conclusion

  • FES cycle ergometry may increase lower extremity BMD over areas stimulated.

Standing

Table 11: Treatment Studies Using Standing or Walking for Bone Health after SCI

Discussion

There is inconclusive evidence for Reciprocating Gait Orthosis, long leg braces or passive standing as a treatment for low bone mass after SCI. One mixed cross-sectional and longitudinal study (Dudley-Javoroski et al. 2012) found that participants who underwent quadriceps activation in stance with 150% body weight compressive load had significantly higher BMD than participants who underwent quadriceps activation in stance with 40% body weight compressive load and passive standing. One cross-sectional study (Goemaere et al. 1994) used a self-report physical activity measure to highlight the potential for standing to reduce bone loss at the femoral shaft; patients with long leg braces had a significantly higher trochanter and total BMD compared with standing frame or standing wheelchair.  In contrast, another cross-sectional investigation of bone outcomes and self-report physical activity measures found no effect of activity on lower extremity bone parameters (Jones et al. 2002).

Conclusion

  • There is inconclusive evidence for Reciprocating Gait Orthosis, long leg braces, passive standing or self-reported physical activity as a treatment for low bone mass.

    There is level 4 (Dudley-Javoroski et al. 2012) evidence for quadriceps activation in stance with 150% body weight compressive load to increase BMD.

  • There is inconclusive evidence for Reciprocating Gait Orthosis, long leg braces, passive standing or self-reported physical activity as a treatment for low bone mass.

Physical Activity

Table 12: Treatment Studies Using Physical Activity for Bone Health after SCI

Discussion

There is no evidence to support physical activity as a treatment for low bone mass after SCI. One cross-sectional study (Chain et al. 2012) used a self-report physical activity measure to highlight the differences in BMD between self-reported “active” and “sedentary” patients; active patients did not differ from sedentary patients in any bone parameter and the sedentary group actually had significantly higher lumbar spine BMD.

Conclusion

There is no evidence to support physical activity as a treatment for low bone mass after SCI.

Combination Interventions

As this chapter goes to press, the first generation of studies of combination interventions for treatment of bone loss in chronic SCI are being completed. These studies evaluate the concurrent administration of pharmacological therapy with non-pharmacological rehabilitation interventions. Some examples of registered trials include studies of zoledronate in combination with FES rowing, and recombinant parathyroid hormone (rPTH, Forteo) in combination with weight bearing. Table 13 describes the early results from one such trial.

Table 13: Studies of Combination Interventions for Treatment of Bone

Discussion

One study of concurrent teriparatide and body-weight supported treadmill stepping did not provide evidence in support of this combination intervention for treatment of bone loss in SCI. However, this study used a convenience sample with a small N, and was not powered to detect significant intervention effects.

Conclusion

There is no evidence to support concurrent treatment of low bone mass with teriparatide and body-weight supported treadmill training.

Interventions with Bone Biomarker Outcomes

As biomarker science improves, the utility of urinary and serum biomarkers of bone turnover continues to increase. While BMD is considered the gold standard outcome measure for bone health interventions, this outcome is not always available. In particular, retrospective studies may not have access to BMD data, and may therefore report only biomarker outcomes. Table 14 describes several such studies.

Table 14: Studies of Bone Health Interventions with Biomarker Outcome

Discussion

Two retrospective case series studies (Chen et al. 2001; Mechanick et al. 2006) provide Level 4 evidence supporting the use of calcitriol-pamidronate therapy to reduce urinary excretion of calcium and NTx in acute SCI, which are biomarkers of bone resorption. Single-dose infusion of pamidronate was associated with increased incidence of fever compared to infusion on three consecutive days. However, single-dose pamidronate may be a more efficient use of patients’ time during ever-shorter inpatient rehabilitation stays.

One study (Bauman et al. 2009) provided Level 4 evidence that calcium gluconate infusion may reduce transient bone collagen catabolism in men with chronic SCI.

Conclusion

There is Level 4 evidence (Chen et al. 2001; Mechanick et al. 2006) to support the use of calcitriol-pamidronate therapy to reduce bone resorption in acute SCI.

General Discussion

The risk for fragility fractures after SCI has been established and low bone mass is an important factor to be considered.  In 2002, the Canadian Medical Association published clinical practice guidelines for prevention and treatment of bone health (Brown et al. 2002).  Currently, these guidelines do not specifically address persons with spinal cord injury.  While, they do provide a resource for osteoporosis diagnosis, prevention and treatment, the lack of SCI-specific, consensus-based guidelines forSLOP, has resulted in diverse SLOP screening, prevention, and treatment practices among SCI clinicians (Morse et al. 2008; Ashe et al. 2009).  Hopefully future national guidelines will provide recommendations for people who have SCI and diverse impairments that lead to reduced weight-bearing, muscle activity and physical activity levels.  Recently a decision guide has been published for rehabilitation professionals on the identification and management of bone health related issues for people with SCI (Craven et al. 2008, Craven et al. 2009).

In this review we note some support for pharmacological agents, but less support for rehabilitation modalities for the prevention and management of bone health in people with SCI.  Our results have some similarities with the recent systematic review by Bryson and Gourlay (2009).  Our results for the non-pharmacological treatment of bone health are consistent with the review by Bering-Sorensen and colleagues (2009) highlighting promise with some modalities. However, this review differs by reporting evidence for early (acute) and late (>12 months) intervention with rehabilitation modalities and therefore provides a description of the results based on whether the goal of therapy is prevention or treatment of SLOP.  In the past 40 years there have been a number of interventions (both pharmacological and rehabilitation modalities) aimed to maintain or slow down bone mass decline after SCI yet consistent methodological oversights have emerged including: small sample sizes and broad inclusion criteria that do not always account for sex, time since injury or impairment differences between participants.

The pharmacological interventions (either prevention or treatment interventions) discussed here report stronger methodologies— all except one were RCTs with PEDro scores ranging from 6-10 indicating moderate to high quality.  In contrast, the studies employing rehabilitation modalities had low numbers of participants and only 3 of the 31 studies were RCTs.  These factors contribute to difficulties drawing generalizable conclusions regarding the impact of rehab interventions on bone parameters.  Nonetheless, despite the lack of evidence to establish the effectiveness of these rehab modalities on bone parameters, it does not negate these treatments as beneficial to other body systems.  For example, FES-cycling may have small effects on bone, but this modality has been shown to have large effects on cardiovascular health (Jacobs & Nash 2004).

There are a few key points to consider when interpreting the results from interventions designed to maintain and/or improve bone parameters after SCI.  These include biological differences in bone development and maintenance between men and women, the natural decline in bone mass with aging and the selected primary outcome measure.  Age-related changes in bone mass affect both women and men but the pattern of change is different because estrogen plays such a dominant role in bone remodeling.  Consequently in women, the loss of estrogen at menopause initiates a rapid loss of bone that eventually slows but continues throughout life.  Men generally do not experience the rapid phase of bone loss with aging rather, only a slower phase of bone loss is observed.  Therefore, keeping in mind that bone mass declines over time, a study that reports no significant difference in BMD between two time periods 6 months apart may be interpreted as positive because of the anticipated loss.

Due to the diversity of primary outcomes (BMD bydual photon absorptiometry [DPA], DXA or pQCT, urine or blood markers) it is difficult to pool the results from multiple studies.  When measuring parameters such as urine or blood biomarkers, studies of short duration may yield significant results.  However, using imaging, cortical bone remodeling can take at least 9 months in order to observe changes within participants over time.  Consequently, investigations that did not maintain an intervention for at least 6 months may not show changes, and the results cannot be interpreted as negative.  Importantly, all primary outcomes for bone health after SCI are surrogate measures, that is, there has yet to be a study published in this area that investigates the effect of an intervention (either pharmacological or non-pharmacological) on fracture reduction. Fracture reduction studies are somewhat infeasible due to cost and the large number of participants that would needed and followed longitudinally.  Consequently, the clinical significance of the interventions based on fractures for this population remains to be determined.  Prospective multicentre intervention studies using common interventions and outcome assessments are urgently needed.

Conclusion

There is a significant risk for fragility fractures after SCI; the risk increases for women, people with motor complete injuries (AIS A and B), longer duration of injury, and with use of benzodiazepines, heparin, or opioid analgesia.  Early assessment and ongoing monitoring of bone health are essential elements of SCI care. 

There is Level 1 evidence for the prevention and treatment of bone loss using medications; however, non-pharmacological evidence for preventing a decline in bone mass and treating low bone mass is poor.  Interpretation and pooling of bone health studies is limited by small samples, diverse treatment protocols, heterogeneous samples (in terms of impairment and injury duration) and short treatment durations given the time required to detect improvements in bone parameters and variability associated with different imaging technologies.  As noted in two publications (Craven et al. 2008, Ashe et al. 2009), a consensus regarding the ideal duration of therapy and choice of outcome measures would advance the field.

  • Early assessment and monitoring of bone mass after SCI are essential to identify low bone mass and quantify risk of lower extremity fragility fracture.

    Prevention with oral bisphosphonates (Tiludronate, Clodronate and Etidronate) may slow the early decline in hip and knee region bone mass after SCI. There is limited evidence that treatment with oral bisphosphonates maintains hip and knee region bone mass late after SCI.

Summary

  • There is level 1 evidence (from 3 RCTs) (Minaire et al. 1981, 1987; Chappard et al. 1995) that oral Tiludronate and Clodronate prevent a decrease in BMD of the hip and knee region with no adverse effects on bone mineralization in men with paraplegia.

    There is level 1 evidence (from 1 RCT) (Pearson et al. 1997) that oral Etidronate prevents a decrease in BMD of the hip and knee region in people with incomplete paraplegia or tetraplegia (AIS D impairment) who return to walking within 3 months of the SCI.

    There is level 1 evidence (from 1 RCT) (Gilchrist et al. 2007) that once weekly oral Alendronate maintains hip region BMD.

    There is level 1 evidence (from 2 RCTs) (Shapiro et al. 2007; Bubbear et al. 2011) that a one-time IV infusion of Zoledronate may reduce bone loss in the hip region during the 12 months following administration.

    There is level 1 evidence (from 1 RCT) (Bauman et al. 2005) that Pamidronate 60mg IV seven times per year and level 2 evidence (from 1 non-randomized prospective controlled trial) (Nance et al. 1999) that Pamidronate 30 mg IV six times per yearis not effective for the prevention of BMD loss at the hip and knee region early after SCI in men and women who have motor complete paraplegia or tetraplegia.

    There is level 1 evidence (from 1 RCT) (Zehnder et al. 2004) that Alendronate 10 mg daily and calcium 500mg orally 3x/day is effective for the maintenance of BMD of thetotal body, hip and knee region for men with paraplegia.

    There is level 1 evidence (from 1 RCT) (Bauman et al. 2005b) that vitamin D analog is effective for maintaining leg BMD.

    There is level 1 evidence (from 1 RCT) (Warden et al. 2001) that short-term (6 weeks) ultrasound is not effective for treating bone loss after SCI.

    There is level 2 evidence (from 1 non-randomized prospective controlled trial) (Shields et al. 2006a) that ES reduced the decline in BMD in the leg.

    There is level 2 evidence (from 1 non-randomized prospective controlled trial) (Eser et al. 2003) that FES cycling did not improve or maintain bone at the tibial midshaft in the acute phase.

    There is level 4 evidence (from 1 pre-post study) (Giangregorio et al. 2005) that walking and level 1 evidence (from 1 RCT) (Ben et al. 2005) that standing in the acute phase did not differ from immobilization for bone mass decline at the tibia.

    There is level 4 evidence (from 1 pre-post study) (Astorino et al. 2013) that activity-based training 2-3 hours/day for a minimum of 2 days a week for 6 months increased spine BMD.

    There is level 2 evidence (from 1 prospective controlled trial) (Bélanger et al. 2000) that electrical stimulation either increased or maintained BMD over the stimulated areas.

    There is level 4 evidence (from 1 pre-post study) (Melchiorri et al. 2007) that vibration training did not improve or maintain BMC in the arms.

  • There is level 4 evidence (Mohr et al.1997; Chen et al. 2005Frotzler et al. 2008) that FES cycle ergometry increased regional lower extremity BMD over areas stimulated.

    There is inconclusive evidence for Reciprocating Gait Orthosis, long leg braces, passive standing or self-reported physical activity as a treatment for low bone mass.

    There is level 4 evidence for quadriceps activation in stance with 150% body weight compressive load to increase BMD.

    There is no evidence to support physical activity as a treatment for low bone mass after SCI.

    There is no evidence to support concurrent treatment of low bone mass with teriparatide and body-weight supported treadmill training.

    There is Level 4 evidence (Chen et al. 2001; Mechanick et al. 2006) to support the use of calcitriol-pamidronate therapy to reduce bone resorption in acute SCI.

Key Points

Bone Health & Fracture

  • Fragility fractures, of the distal femur and proximal tibia, are common in people with SCI.
  • Bone health management should begin early following SCI, given the significant declines in hip and knee region bone mass in the first year and the associated lifetime increased fracture risk. The efficacy of drug interventions appear greater when medications are administered early after SCI onset
  • Individuals with chronic SCI and increased risk for lower extremity fragility fractures can be readily identified based on completion of a clinical history and risk factor profile.
  • Measurement and monitoring of hip and knee region BMD after SCI are essential to identify low bone mass and quantify lower extremity fracture risk.
  • Biomarkers provide clinical insight into the metabolic activity of bone, while imaging techniques provide insight into bone density, quality and architecture.

Pharmacologic Therapy for Prevention of Sublesional Osteoporosis (SLOP)

  • Oral tiludronate and clodronate prevent a decrease in BMD of the hip and knee region with no adverse effects on bone mineralization in men with paraplegia.
  • Oral etidronate prevents a decrease in BMD of the hip and knee region in people with incomplete paraplegia or tetraplegia who return to walking.
  • Oral alendronate once weekly maintains BMD at the hip.
  • Once yearly IV infusion zoledronate may reduce bone loss at the hip during the 12 months following administration.
  • Pamidronate 30 mg IV or 60 mg IV 4x/year is not effective for the prevention of BMD loss at the hip and knee region early after SCI people with motor complete paraplegia or tetraplegia.
  • In summary, there is limited evidence that bisphosphonates prevent declines in hip and knee region bone mass after SCI. However, bisphosphonates are moderately effective at ameliorating the rate of hip and knee region bone mass resorption.

Pharmacologic Therapy for Treatment of SLOP

  • Alendronate 10 mg daily and calcium 500 mg orally 3x/day is effective for the maintenance of BMD of the total body, hip and knee region for men with paraplegia.
  • Vitamin D analog is effective for maintenance of BMD in the leg.

Non-pharmacologic Therapy for Prevention and/or Treatment

  • Short term (6 weeks) therapeutic ultrasound is not effective for preventing
  • bone loss after SCI.
  • FES-cycling does not improve or maintain bone at the tibial midshaft in the acute phase.
  • Activity-based training (6 months) is effective for increasing spine BMD.
  • Electrical stimulation can maintain or increase BMD over the stimulated areas.
  • FES cycle ergometry may increase lower extremity BMD over areas stimulated.
  • There is inconclusive evidence for Reciprocating Gait Orthosis, long leg braces, passive standing or self-reported physical activity as a treatment for low bone mass.
  • There is a lack of definitive evidence supporting non-pharmacological interventions for either prevention or treatment of bone loss after a SCI.

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Bowel Dysfunction and Management

Coggrave M, Mills P, Willms R, Eng JJ, (2014). Bowel Dysfunction and Management Following Spinal Cord Injury. In Eng JJ, Teasell RW, Miller WC, Wolfe DL, Townson AF, Hsieh JTC, Connolly SJ, Noonan VK, Loh E, McIntyre A, editors. Spinal Cord Injury Rehabilitation Evidence. Version 5.0. Vancouver: p 1- 48.

We would like to acknowledge previous contributors: Andrei Krassioukov & Bonnie Venables


Abbreviations

ACE                        Antegrade Colonic Enema                                             

DIE                          Difficult Intestinal Evacuation

DGN                        Dorsal Genital Nerve

FES                         Functional Electrical Stimulation

FMS                        Functional Magnetic Stimulation

GE                          Gastric Emptying

GI                            Gastrointestinal

HVB                        Hydrogenated Vegetable-oil Base

LMN                        Lower Motor Neuron

MACE (or ACE)      Malone Antegrade Continence Enema

NBD                        Neurogenic Bowel Dysfunction

PGB                        Polyethylene Glycol Base

SARS                      Sacral Anterior Root Stimulator

SNM                        Sacral Nerve Modulator

SNS                        Sacral Nerve Stimulation

TAI                          Transanal Irrigation

UMN                       Upper Motor Neuron

Introduction

Bowel dysfunction due to spinal cord injury (SCI) results in fecal incontinence and severe constipation termed ‘neurogenic bowel dysfunction’ (NBD) and is very damaging to quality of life (Emmanuel 2010; Byrne et al. 2002; Correa & Rotter 2000; Stiens et al. 1997; Glickman & Kamm 1996; Longo et al. 1995).

Even when a bowel routine to manage the problem is effective it can be onerous and time consuming, and may take up to 1-2 hours per session, repeated every day or alternate days throughout post-injury life. It can interfere significantly with the individual’s education, work and social life and presents a major challenge to quality of life, independence and community reintegration after SCI. Loss of bowel control may have greater impact than loss of ability to ambulate (Frost et al. 1993) and is a source of anxiety and distress (Ng et al. 2005; Glickman & Kamm 1996; Coggrave et al. 2009, Coggrave & Norton 2010). Ineffective bowel care results in social isolation (Byrne et al. 2002), inability to work and admissions to acute services for treatment of fecal impaction and bowel obstruction when constipation escalates. Treatment of bowel dysfunction rates highly for patients in both clinical and research domains (Anderson 2004; Glickman & Kamm 1996).