Abstract
Bladder and bowel distention are primary triggers of autonomic dysreflexia in individuals with spinal cord injury (SCI), with reports of systolic blood pressure (SBP) rising by more than 20 mmHg and remaining elevated, with intolerable symptoms. The goal of the current study was to quantify the degree of cardiovascular changes, as well as the presence/absence and type of symptomatic indices, in a controlled laboratory setting during bladder filling (urodynamics) and bowel distention (anorectal manometry [ARM]). A total of 56 individuals (35 males and 21 females) with SCI participated in the study, with injury levels ranging from C2 to L3 and American Spinal Injury Association Impairment Scale grades A–D. Filling cystometry (CMG) and ARM were conducted on separate days, and continuous arterial blood pressure (BP) was acquired throughout. International SCI datasets for bladder and bowel function were also completed. The data indicate that 90.9% of individuals had a maximum change in SBP above 20 mmHg during CMG (group mean of 45 mmHg) and 85.4% of individuals had a maximum change in SBP above 20 mmHg during ARM (group mean of 37 mmHg). One or two symptoms (goosebumps, sweating, flushing, chills, tingling, and headache) occurred in 43.6% of participants during CMG and 23.6% during ARM, with higher rates reported in the dataset questionnaires. The maximum changes in SBP typically occurred at maximum vesicle pressure and/or at first sensation during CMG, and during balloon catheter insertion or withdrawal during the ARM procedure. These data, taken together, indicate that urodynamic and bowel assessments in individuals with SCI should include measures of BP and be considered in daily management practices, as the frequent triggering of cardiovascular changes likely impacts health and well-being.
Introduction
Cardiovascular complications associated with autonomic dysregulation 1–4 are listed as the leading causes of morbidity and mortality in patients with chronic spinal cord injury (SCI).5–7 However, there are few clinical standards of care that have been established for individuals with these abnormalities. 8 Injuries above the T6 spinal level, resulting in a disconnection between the brain and spinal autonomic nuclei, often manifest as a syndrome known as autonomic dysreflexia (AD) due to an unregulated sympathetic cascade that is triggered by either noxious or innocuous stimuli below the injury level.9–13 The focal vasoconstriction and a rise in blood pressure (BP) can be evoked multiple times a day and, if poorly managed, may place individuals at risk for stroke, seizures, retinal detachment, or even death.14–16
Overdistension of the bladder and bowel is the most common trigger of AD post-SCI.17,18 Urodynamic studies, recognized as the gold standard for assessing neurogenic lower urinary tract (LUT) dysfunction,19,20 are known to precipitate AD in individuals with SCI.21–23 Bladder and bowel dysfunctions consistently rank as one of the top disorders affecting quality of life after SCI. Information regarding the triggering of AD during bladder filling and bowel evacuation is critical in the development of strategies to reduce bladder and bowel dysfunction in individuals with SCI. The goal of the current study was to quantify, in a controlled laboratory setting, cardiovascular changes during bladder filling (cystometry [CMG]) versus bowel distention (anorectal manometry [ARM]) in the same individuals with chronic SCI, with a focus upon degree of change, triggering events, and the extent of symptomatic indices. A better understanding of common daily triggers that elevate BP will likely contribute to improvements in management and utilization of effective strategies for prevention, ultimately improving overall health and quality of life.
Methods
Participants
The recruitment process was conducted through informational sessions with participants consenting to an interventional study in our SCI Center, as well as through our secure research database, which includes over 6,000 individuals registered with SCI (search limited to individuals living within a radius of 250 miles from our center). All potentially eligible research participants were invited to discuss the complete protocol, including risks and benefits, with the principal investigator and/or designated research staff. The recruitment goal was 60 participants. The study was registered on ClinicalTrials.gov (NCT04193709).
Each potential research participant was screened for medical eligibility by a study physician and for scientific eligibility by the principal investigators. Inclusion criteria were male and female adults, American Spinal Injury Association Impairment Scale (AIS) classification A–D, presence of neurogenic bladder and bowel dysfunction, and non-progressive supra-sacral SCI. Exclusion criteria were prior Botox injections to the bladder, bladder augmentation surgery, and/or colostomy. After study eligibility was determined and consent procedures were implemented, the study physician completed a medical history and neurological examination for each SCI individual for medical eligibility. All research participants signed an informed consent that had been approved by the University Institutional Review Board prior to entering the study. Each subject was assigned a subject identification number to designate all evaluations. All participants underwent an International Standards for Neurological Classification of SCI evaluation 24 by a licensed physical therapist prior to assessments for bladder (urodynamics/CMG) and bowel (ARM) function.
All assessments were done in a controlled laboratory setting and performed by the same registered nurse. Two testing sessions were done per participant on separate days: one involving bladder filling (90-min session) and the other involving bowel distention (45-min session). All procedures were discussed with the research participant, including any risks and potential side effects not limited to infection and/or bleeding. Continuous arterial BP was acquired throughout the assessments using a finger cuff placed around the left middle or index finger, or thumb (Finapres NOVA; Finapres Medical Systems, Netherlands). Manual arterial BP measurements were taken periodically with a digital BP measurement device (Welch Allyn) for calibration purposes. Any signs or self-reported symptoms of AD were documented and observed throughout testing.
Bladder filling cystometry
The methods followed our previously published protocols and complied with established guidelines, standards, and recommendations of the International Continence Society.25–28 Using the Aquarius® LT Urodynamic Investigation system (Laborie Model, Canada), CMG was performed in a dedicated temperature-controlled room (22°C) in a seated position. A single-sensor, dual-channel catheter (7 Fr, T-DOC® Air-Charged™, Laborie, Williston, VT) was used for continuous filling with sterile, body-temperature water (37°C). Abdominal pressure was measured via a rectal balloon catheter (7 Fr, T-DOC Air-Charged, Laborie, Williston, VT), and pelvic floor electromyography (EMG; Neotrode II; Laborie) was recorded using surface patch EMG electrodes (a grounding pad was placed on a bony prominence, usually the hip or knee).
After emptying the bladder immediately prior to the start of filling at a fixed rate of 20 mL/min, each research participant was asked to cough to verify intra-abdominal catheter position. Participants were instructed to communicate when they felt the first sensation of a full bladder, the desire to urinate (first urge to void), and when they could no longer wait to void (maximum capacity). The volume of water and detrusor pressures (calculated by subtracting the intra-abdominal pressure from the intravesical pressure) were recorded at each event.
Per previous protocols,29–32 bladder filling was ceased if any of the following occurred: spontaneous urine leakage, infused volume reaching 600 mL, high intravesical pressure (≥40 cm H2O), or a sustained systolic blood pressure (SBP) recording of ≥20 mmHg from baseline, with or without intolerable symptoms of AD.
At the end of testing, the bladder was emptied through the experimental dual-channel catheter to quantify residual volume. A post-fill BP recording was captured to ensure that values had returned to baseline. AD did not persist; however, if it had, it would have been managed according to established guidelines.33,34
Anorectal manometry
The Aquarius LT system was also used, following established guidelines,35,36 to provide a comprehensive assessment of pressure activity in the rectum and anal sphincter region together with an assessment of rectal sensation, rectoanal reflexes, and rectal compliance. Procedurally, with the participant in the left lateral decubitus position, a 19 Fr T-DOC Air-Charged Anorectal Manometry Catheter (Laborie), with a pre-attached 300 mL balloon and incremental markings at 1 cm intervals, was inserted 5 cm into the rectum. The four phases of ARM included pull-through, rectoanal inhibitory reflex (RAIR), sensation to balloon distension, and expulsion testing. For the pull-through phase, starting at 5 cm, the participant was asked to rest, squeeze, and push for 10 sec each while pressure was measured in four quadrants (four sensors are directional and feature advanced membrane sensor technology). The catheter was then manually retracted in 1 cm steps until five rest/squeeze measurements were obtained (1–5 cm locations). The balloon was then moved to the maximum squeeze pressure level for the RAIR test, which involves rapid inflation of the balloon catheter with air, followed by deflation and evaluation of the reflexive pressure drop. At the same rectal level, the balloon attached to the catheter was slowly inflated with air (2 cc/sec), as the participant was asked to note rectal sensations (first sensation, urge, and maximal tolerance), up to maximum tolerance or 200 cc distension volume, after which the balloon was deflated. The balloon was then adjusted to the anal verge and inflated to a volume of 50 mL of water to mimic the size of a fecal bolus for the expulsion phase of ARM. A measurement of time to expel the balloon was then conducted, and if attempts during a 3-min window were unsuccessful, the catheter was manually removed.
Patient-reported health data questionnaires
At the time of assessments, participants were administered the International SCI Dataset for LUT function 37 and bowel function, 38 which included reporting awareness of the need to empty their bladder or defecate. Selection of indirect indicators included examples of abdominal cramping or discomfort, abdominal muscle and/or lower extremity muscle spasms, and AD symptoms such as perspiration, piloerection, headache, and chills.
Data collection and analysis
Data were collected using our customized acquisition software system. Data analysis programs include Uro-BP (BP during urodynamics/CMG) and ARM-BP (BP during ARM). The Uro-BP analyzes continuous beat-to-beat BP and heart rate (HR) during CMG assessments and generates graphs and Excel files for export. After importing synchronized data acquired from LabChart (software used to record BP, HR, and comments) and Laborie (a system used to record vesicle pressure, infusion volume, and comments), the Uro-BP program allows the user to either enter brachial BP manually or select a time interval from beat-to-beat BP for analysis (i.e., mean or maximum systolic BP). Events during which BP and HR were analyzed included resting during sitting prior to catheters, resting during sitting with catheters, beginning of infusion, maximum vesical pressure, bladder sensation(s) during filling, maximum BP during filling (if no sensation), non-void contraction(s), point of end fill, resting post-void or emptying, and resting during sitting after catheter removal.
The ARM-BP program analyzes continuous beat-to-beat BP and HR during ARM assessments and generates graphs and Excel files for export. After importing synchronized data, the ARM-BP program allows the user to either enter brachial BP manually or select a time interval from beat-to-beat BP for analysis. All events were automatically extracted from the comments of Laborie data, except for catheter insertion and removal, which were selected manually. Maximum BP was obtained during catheter insertion, during the four phases of ARM (pull-through, RAIR, sensation, and expulsion tests), and during catheter removal.
Continuous outcomes were evaluated for normality using the Shapiro–Wilk test. Normally distributed outcomes were summarized as mean + standard deviation and compared using the t-test between males and females, and the analysis of variance between neurological level of injury categories and AIS levels. Non-normally distributed variables were summarized using the median with the first and third quartiles (Q1 = 5th, Q3 = 75th percentiles) and compared using the Brown–Mood test between males and females, between neurological level of injury categories, and between AIS levels. Categorical outcomes were summarized as percentages and compared across different categories including sex, neurological level, and AIS using the chi-square test. All tests were two-sided, and the significance level was set at 5%. Correlations between normally distributed outcomes were calculated with Pearson correlation, and non-normally distributed outcomes using Spearman correlation. The proportion of observations of AD symptoms during assessments versus self-reported indirect symptoms on the questionnaire was compared using the chi-square test. Statistical analyses of the effects of sex, level of injury, and AIS grade were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA). Correlation analyses were performed using R (version 4.4.2).
Results
A total of 56 participants (35 males and 21 females) were enrolled in the study (ClinicalTrials.gov NCT04193709), with injury levels ranging from C2 to L3 and AIS grades A–D. The enrollment period was from May 11, 2020, to April 9, 2025. Due to study interruptions during COVID-19 and subsequent restrictions that impacted recruitment, retrospective data were also used from prior participants in other studies conducted in our SCI Center’s adult translational program who met the following benchmarks: (1) met all study inclusion and exclusion criteria; (2) completed both urodynamics and anorectal manometry assessments prior to any intervention (baseline); and (3) had continuous BP recordings throughout the assessments, including at least two arm cuff measurements for calibration. Of the 56 participants, 25 were retrospective (dated back to August 16, 2018), and 31 were prospective.
Demographics for the study participants are provided in Table 1. Bladder filling CMG and ARM were conducted on separate days. An example from one participant illustrating the various phases of each procedure is shown in Figure 1. Continuous beat-to-beat arterial BP was acquired pre, post, and during CMG and ARM. Note the maximum rise in SBP in response to the increase in detrusor pressure during bladder filling (Fig. 1A) and movement of balloon catheter during ARM (Fig. 1B) were 60 mmHg and 50 mmHg, respectively, above baseline.
Filling cystometry
Participant Demographics
AIS, American Spinal Injury Association Impairment Scale.
A summary of the maximum changes in SBP during CMG and ARM for all participants is provided in Figure 2. Analysis of the data from all 56 participants indicated that 90.9% experienced a maximum change in SBP above 20 mmHg during filling CMG (group mean of 45 mmHg), and 85.4% of individuals with a maximum change in SBP above 20 mmHg during ARM (group mean of 37 mmHg), including individuals with injuries below the T6 spinal level. One or two symptoms (S-1 and S-2), including goosebumps, sweating, flushing, chills, tingling, and headache, occurred in 43.6% of participants during CMG and 23.6% during ARM. No symptoms were reported in several individuals who exhibited maximum changes in SBP above 60 mmHg with a full bladder (28.6%). However, self-reported data collected from the LUT and bowel SCI questionnaires revealed a significantly higher percentage (p < 0.001) of individuals reporting AD-like symptoms related to bladder (47/56 vs. 30/56 during CMG) and bowel (33/56 vs. 13/56 during ARM) function. Of the 19 participants who reported AD-type symptoms (related to awareness of the need to empty the bladder) on the LUT questionnaire but did not show symptoms during CMG, only two cases had filling stopped due to reaching an SBP deemed high by the research nurse. For the others, filling CMG was stopped either because of a leak (n = 5), reaching a maximum tolerable amount (urgency; request to stop filling; n = 10), having a sustained high detrusor pressure (n = 1), or attaining the fill volume end-point of 600 mL (n = 1).
Maximum changes in systolic blood pressure (SBP) during filling cystometry
Cardiovascular outcomes were comparable for bladder versus bowel assessments, with observable higher BP’s during filling CMG (Fig. 3A–C). A significant negative correlation was found between SBP and HR (rise in SBP accompanied by slowing HR) during filling CMG (Fig. 3D). No significant differences were found based on sex, neurological level of injury, or AIS grade for either CMG or ARM assessments. The only exception was the maximum change in HR from baseline during CMG based upon the level of injury. Significant differences were found for all levels (upper cervical, lower cervical, and upper thoracic) relative to those participants having injuries T6 and below. Upon inspection of the data, there appears to be a lack of decrease in HR for those participants with levels of injury T6 and below, despite increased SBP. Plotting the changes in HR relative to baseline (Fig. 4) reveals less of a change in HR during filling when HR is low at baseline, which was the case on average for those grouped with levels of injury T6 and below.
Maximum changes in systolic blood pressure (SBP;
Heart rate (HR) prior to bladder filling
Maximum changes in SBP typically occurred at maximum vesical pressure and/or with bladder sensation during CMG (Fig. 5), and during balloon catheter insertion or withdrawal during the ARM procedure (Fig. 2B; orange portion of bars). The mean change in SBP was greater when symptoms were present during CMG, but not during ARM. Representative examples of data collected during CMG and ARM from five participants are provided in Figure 6.
A significant difference (*p < 0.01) is illustrated in
Representative participants (n = 5;
Discussion
Data collected from 56 research participants with clinically complete and incomplete SCIs, ranging from C2 to L3 spinal levels, indicate a very high prevalence of cardiovascular responses to distention of the bladder and anorectum, consistent with previous reports involving smaller sample sizes.22,39,40 The most common trigger during CMG was related to bladder fullness, based on high detrusor pressure (with or without sensation), and during ARM catheter insertion (mimicking digital stimulation, a commonly used bowel management technique) and/or removal (mimicking defecation). For potential variables including severity, level of injury, and sex, significant differences were found only based on level of injury for HR at high detrusor pressures. The prevalence of symptoms including goosebumps, chills, and headache was not always present with cardiovascular responses, even when the maximum change in SBP exceeded 60 mmHg, which is well above the 20-mmHg threshold that defines the occurrence of AD. 23 The CMG data are similar to those previously reported 41 in terms of type of symptoms and prevalence (50% of study participants had what was referred to as “silent AD”). However, in the current study, a much higher frequency of AD-type symptoms was self-reported in questionnaires for both bladder and bowel function.
Bladder- versus bowel-related outcomes
Each participant was tested for cardiovascular changes during standard procedures for assessing bladder and bowel functions. Testing, done on different days to avoid carry-over effects, revealed similar cardiovascular effects for stimuli applied to both systems. These below-level-of-injury stimuli lead to local vasoconstriction and a rise in BP. Baroreceptors increase parasympathetic signaling, leading to a compensatory slowing of the HR. Aside from the loss of sympathetic descending inhibitory neurons, reconfiguration of interneurons after SCI and the overexpression of α1 receptors due to lower circulating levels of catecholamines are known to be responsible for the hypersensitivity to stimuli. 42 Note that neurogenic detrusor overactivity can trigger serious AD episodes, 21 a reason why appropriate care of the LUT is a priority for these individuals. Current treatments are based upon the elimination of triggering factors and pharmacological interventions with vasodilators, 13 with potential future use of neuromodulation devices to modulate cardiovascular function,31,43–46 target the urogenital and bowel regions directly (e.g., relaxation of the bladder),30,47 or integrate these two approaches together.48,49 Botox is a therapeutic intervention that has been shown to decrease AD to bladder. 50
A decreased HR was found to correlate with the maximum change in SBP for bladder, but not for bowel assessments. The loss of bulbospinal pathways to modulate sympathetic pre-ganglionic neurons and the resulting unopposed parasympathetic-mediated vagal response to the SBP increases has been previously shown for individuals undergoing urodynamic studies, as well as for those going through penile vibrostimulation and sperm retrieval.40,51,52 Recommendations exist for cardiovascular monitoring during such procedures and for stopping assessments before SBP reaches dangerous levels, 40 which the current ARM studies extend to bowel-related functional assessments as well.
Comparisons of participant characteristics
No differences were found based on gender or severity of injury (based on the AIS). A significant difference was only found for HR related to the level of injury, and only during CMG testing (not ARM). There was a less reduction in HR in response to an increase in SBP during filling CMG in individuals with upper cervical injuries compared to those with lower cervical injuries, despite a similar magnitude of SBP increases. One potential explanation may be that upper cervical injuries result in more severe impairments in diaphragm function,53,54 and hand function, which may lead to less active lifestyle compared to individuals with lower cervical injuries. This, in turn, could contribute to more severe abnormalities in HR regulation, such as bradycardia and lower baroreflex sensitivity. 55 A further explanation could be from alterations in cortical level, which may affect HR regulation after SCI.56,57 Unexpectedly, changes in HR in response to SBP increases in individuals with lower thoracic and upper lumbar injuries were less than in other groups, partially due to low HR prior to bladder filling (Fig. 4C), indicating parasympathetic dominance. The HR in individuals with lower thoracic and upper lumbar injuries in this study was lower than those observed previously. 58 Possible reasons include the study sample size or individual variables such as types of medications taken.
Prevalence of symptoms
While symptoms varied from individual to individual, a striking finding was that more than half of the individuals showed no physical signs of any of the symptoms commonly associated with AD during testing, as seen by others for bladder, bowel, and sexual function and is referred to as silent AD.39,52,59 While the group having symptoms had overall significantly greater increases in SBP, 28% having the greatest increase (>60 mmHg) reported none of the typical symptoms. However, a higher prevalence was found through self-report questionnaires, contradicting the existence of a truly silent AD. This difference is likely due to experimental conditions, including end-points to stop filling the bladder during CMG and ARM balloon elasticity relative to firmer stool consistency. Upper limits set by the experimental protocol include filling of the bladder to the upper range of a normal-sized adult bladder (600 mL) and distention to the size of a large fecal bolus (200 mL balloon volume) during the ARM sensation portion for assessing bowel function. Anecdotal evidence from participants indicates regularity of going beyond 600 mL bladder volumes either from not waking up at night for catheterization, drinking a lot in a short period of time (e.g., alcohol consumption while socializing which inhibits release of vasopressin and facilitates diuresis), or from extending times between catheterizations to help maximize availability during daily activities. For the relatively small number of individuals who did not have physical symptoms of AD during testing or report signs of AD in questionnaires, it is possible that these individuals may experience symptoms that are non-physical in nature. These signs, such as feelings of uneasiness or anxiety, have been reported,17,60 but would not have been captured during the assessments or by the questionnaires used in the current study.
Conclusions
Taken together, the current results emphasize the importance of taking cardiovascular function into account when considering urogenital and bowel function post-SCI, especially but not only when higher lesion levels are involved. A better understanding of intersystem relationships will improve management when targeted with therapeutic interventions. One such therapy is neuromodulation with spinal cord stimulation. Our group has demonstrated how controlling one system (e.g., CV) with epidural stimulation influences other functions (bladder and bowel). 48 This may lead to the development of more effective treatments for dysfunction within the pelvic region (or other autonomic systems). Overall, the importance and ultimate impact of these data support the importance of educating both clinicians and SCI patients regarding AD signs and symptoms. 23
Transparency, Rigor, and Reproducibility Summary
The study was preregistered at Clinicaltrials.gov (NCT NCT04193709). Although the statistical analysis plan was not formally preregistered, the study biostatistician certifies that the statistical analysis plan was pre-specified in the grant proposal. A total sample size of 60 participants was planned based on an expected effect size of 50 for the primary outcome measure(s), calculated to yield 80% power to detect a Cohen’s h effect size of 1.2 (classified as very large61,62) using a two-sided chi-square test with a significance level of 0.05. Participants were blinded to the results throughout the study. Team members performing the analyses were blinded to relevant characteristics of the participants. Data were labeled using codes linked to participant identifying information. All international dataset questionnaires are referenced and available online. Deidentified data from this study are available in a FAIR-compliant data repository.
Ethics Statement and Informed Consent
The study was approved by the University of Louisville Institutional Review Board and conducted in accordance with the Declaration of Helsinki. The participant provided written informed consent. All study team members vouch for the completeness and accuracy of the data, the reporting of adverse events, and adherence to the study protocol (NCT04193709).
Data Availability
To request data for this study, contact Dr. Charles Hubscher at
Authors’ Contributions
C.H.H.: Conceptualization, funding acquisition, investigation, interpretation, writing—original draft, writing—review and editing, and final approval. S.W.: Analysis, visualization, writing—review and editing, and final approval. T.M.: Methodology, visualization, writing—review and editing, and final approval. K.J.: Methodology, writing—review and editing, and final approval. B.U. and D.M-.A.: Analysis, writing—review and editing and final approval. S.J.H.: Conceptualization, funding acquisition, investigation, interpretation, writing—review and editing, and final approval.
Footnotes
Acknowledgments
The authors are indebted to the research participant for his courage, dedication, and motivation, which made these research findings possible. The authors thank Dr. Sarah Wagers for providing medical oversight.
Author Disclosure Statement
No competing financial interests exist.
Funding Information
This work was supported by the