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Prediction of autonomic dysreflexia during urodynamics: a prospective cohort study Walter, Matthias; Knüpfer, Stephanie C; Cragg, Jacquelyn J; Leitner, Lorenz; Schneider, Marc P; Mehnert, Ulrich; Krassioukov, Andrei V; Schubert, Martin; Curt, Armin; Kessler, Thomas M Apr 13, 2018

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RESEARCH ARTICLE Open AccessPrediction of autonomic dysreflexia duringurodynamics: a prospective cohort studyMatthias Walter1,3† , Stephanie C. Knüpfer1†, Jacquelyn J. Cragg2,3, Lorenz Leitner1, Marc P. Schneider1,Ulrich Mehnert1, Andrei V. Krassioukov3, Martin Schubert2, Armin Curt2 and Thomas M. Kessler1*AbstractBackground: Autonomic dysreflexia is a severe and potentially life-threatening condition in patients with spinalcord injury, as it can lead to myocardial ischemia, brain hemorrhage, or even death. Urodynamic investigation is thegold standard to assess neurogenic lower urinary tract dysfunction due to spinal cord injury and reveal crucialpathological findings, such as neurogenic detrusor overactivity. However, neurogenic detrusor overactivity andurodynamic investigation are known to be leading triggers of autonomic dysreflexia. Therefore, we aimed todetermine predictors of autonomic dysreflexia in individuals with spinal cord injury during urodynamicinvestigation.Methods: This prospective cohort study included 300 patients with spinal cord injuries and complete datasets ofcontinuous non-invasive cardiovascular monitoring, recorded during same session repeat urodynamic investigation.We used logistic regression to reveal predictors of autonomic dysreflexia during urodynamic investigation.Results: We found that level of injury and presence of neurogenic detrusor overactivity were the only twoindependent significant predictors for autonomic dysreflexia during urodynamic investigation. A lesion atspinal segment T6 or above (odds ratio (OR) 5.5, 95% CI 3.2–9.4) compared to one at T7 or below, andpresence of neurogenic detrusor overactivity (OR 2.7, 95% confidence interval (CI) 1.4–4.9) were associatedwith a significant increased odds of autonomic dysreflexia during urodynamic investigation. Both oddspersisted after adjustment for age, sex, and completeness and stage of injury (adjusted OR (AOR) 6.6, 95% CI3.8–11.7, and AOR 2.2, 95% CI 1.1–4.5, respectively). Further stratification by lesion level showed level-dependent significantly increased adjusted odds of autonomic dysreflexia, i.e., from C1–C4 (AOR 16.2, 95% CI5.9–57.9) to T4–T6 (AOR 2.6, 95% CI 1.3–5.2), compared to lesions at T7 or below.Conclusions: In patients with neurogenic lower urinary tract dysfunction due to spinal cord injury, autonomicdysreflexia is independently predicted by lesion level and presence of neurogenic detrusor overactivity.Considering the health risks associated with autonomic dysreflexia, such as seizures, stroke, retinal bleeding, oreven death, we recommend both continuous cardiovascular monitoring during urodynamic investigation in allspinal cord-injured patients with emphasis on those with cervical lesions, and appropriate neurogenic detrusoroveractivity treatment to reduce the probability of potentially life-threatening complications.Trial registration: ClinicalTrials.gov, NCT01293110.Keywords: Autonomic dysreflexia, Neurogenic detrusor overactivity, Neurogenic lower urinary tractdysfunction, Prediction, Spinal cord injury, Urodynamic investigation* Correspondence: tkessler@gmx.ch†Equal contributors1Neuro-Urology, Spinal Cord Injury Center & Research, University of Zürich,Balgrist University Hospital, Zürich, SwitzerlandFull list of author information is available at the end of the article© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Walter et al. BMC Medicine  (2018) 16:53 https://doi.org/10.1186/s12916-018-1040-8BackgroundSpinal cord injury (SCI), a devastating event [1], is ac-quired by almost half a million people each year world-wide [2]. Besides motor recovery, i.e., the ability to walk orutilize the upper extremities, lower urinary tract (LUT) [3,4] and cardiovascular system (CVS) [5] function areamong the primary priorities for patients with SCI [6].Autonomic dysreflexia (AD) [7], a severe, potentially life-threatening condition affecting the CVS following SCIthat can occur more than 40 times a day [8], is elicited byeither noxious (e.g., pain) and innocuous stimuli (e.g.,bladder filling) from below the level of injury [9]. If mis-diagnosed or poorly managed, AD can result in disastrousconsequences [10], including myocardial ischemia [11],brain hemorrhage [12], seizures [13], and even death [14].Urodynamic investigation (UDI) is the gold standardto assess neurogenic lower urinary tract dysfunction(NLUTD) in patients with SCI [3, 4], but it may induceAD [15, 16]. Considering that it is currently not possibleto know in advance which patient will experience ADduring UDI and, of those with AD, to what extent thesystolic blood pressure (SBP) will increase, we aimed todetermine the overall incidence and predictors of ADduring UDI.MethodsParticipants and study designThis prospective cohort study was conducted at a singleuniversity SCI center between January 2011 and December2016. Inclusion criteria were patients with NLUTD due tosuprasacral SCI and age of at least 18 years. Exclusion cri-teria were symptomatic urinary tract infections (i.e., positiveurine culture and clinical symptoms including fever), pres-sure ulcers at the time of UDI, and incomplete data ofcardiovascular monitoring (CVM) during UDI. Overall, 300patients (41 females and 259 males, mean age 51 ± 16 years,mean duration since SCI 10 ± 12 years) with complete car-diovascular recordings were included for analysis. The pa-tients’ characteristics are shown in Table 1. This study wasapproved by the local ethics committee and is registered atClinicalTrials.gov (NCT01293110). All patients gave writteninformed consent according to the Helsinki II declaration.Predictor variables and outcomesThe neurological level and completeness of SCI, i.e.,sensorimotor impairment, were determined using theAmerican Spinal Injury Association Impairment Scale(AIS) according to the International Standards for Neuro-logical Classification of Spinal Cord Injury (ISNCSCI)[17]. The stage of injury was classified as acute (less than300 days since injury) and chronic (more than 300 dayssince injury), in accordance with the European MulticenterStudy about Spinal Cord Injury (EMSCI, www.emsci.org)definition.All methods, definitions, and units are in line with thestandards recommended by the International ContinenceSociety (ICS) [18, 19]. All patients were asked to emptytheir bladder and bowels prior to the UDI, which was per-formed according to Good Urodynamic Practice followingthe recommendations of the ICS [18].Individuals were investigated in a sitting position,whenever possible, which reflects the position of an indi-vidual with SCI when emptying the bladder, e.g., usingintermittent self-catheterization, while sitting in a wheel-chair or on a toilet. A 7 French transurethral latex-freesingle-use catheter and a common rectal catheter forsimultaneous measurements of vesical and abdominalpressure were used. Since rectal manipulation itself canelicit AD [20], UDI was only initiated in the absence ofAD. The bladder was filled retrograde with a 37°C mix-ture of 0.9% sodium chloride solution and contrastmedium.All patients underwent same session repeat UDI [21],i.e., two consecutive measurements, using a multichan-nel urodynamic system (Sedia®, Givisiez, Switzerland).Continuous cardiovascular monitoring (Finometer® PRO,Finapres Medical Systems (FMS), Amsterdam, TheNetherlands) [22] was applied to enable a non-stop“beat-to-beat” documentation of SBP, diastolic BP (DBP),and heart rate (HR) synchronous to the ongoing UDI.AD (the primary outcome) was defined according to theInternational Standards to document remaining Auto-nomic Function after SCI (ISAFSCI) as an increase inSBP ≥ 20 mmHg from baseline [23]. In case of clinicalsigns of AD such as headache, flushing, sweating, andpiloerection [24, 25], UDI was stopped immediately andthe bladder was emptied.Statistical analysisContinuous variables including age, time since injury,SBP, DBP, and HR were visually inspected for normaldistribution by using Q-Q plots. Normally distributeddata were analyzed using analysis of variance (ANOVA)or unpaired t tests to compare between groups. Resultsare presented as mean ± standard deviation (SD) or 95%confidence intervals (CIs), respectively. The k statisticwas used to investigate agreement of the presence or ab-sence of AD between the two UDI sessions. A chi-square test or Fisher’s exact test were used to assess therelationship between categorical variables.Logistic regression (bivariable and multivariable) wasused to investigate predictors of AD during UDI. Un-adjusted odds ratios (ORs) and adjusted odds ratios(AORs) are presented with corresponding 95% CI. Stat-istical significance was defined as a p value of less than0.05. Statistical analyses were performed using R Studioversion 1.0.136 (Integrated Development for R, RStudio,Inc., Boston, MA, USA).Walter et al. BMC Medicine  (2018) 16:53 Page 2 of 11ResultsOverall incidence and repeatability of autonomicdysreflexia during urodynamic investigationThe overall incidence of AD during UDI was 68%(204/300). AD was found in 176 (59%) vs. 162 (54%)of the 300 patients during the first and the secondUDI, respectively. In 66% (134/204) of patients withAD, an increase in SBP of at least 20 mmHg was elic-ited during both UDIs. Hence, in more than one thirdof all patients with AD (70/204), bladder filling elicitedAD in only one of two UDIs. The repeatability of de-tecting AD between the two same session UDIs wasmoderate (k = 0.53, 95% CI –0.4 to 1.5). Characteristics ofclinical symptoms presented by 37% (75/204) of pa-tients with AD during UDI are shown in Fig. 1. Wedid not observe any imminent complication as a re-sult of the increase in SBP associated with AD duringUDI. All patients were monitored until SBP returnedto baseline values and, whenever present, clinicalsymptoms disappeared.Table 1 Patients’ characteristics and cardiovascular changesCharacteristics All patients (n = 300) Female (n = 41) Male (n = 259) p valueMean (SD) age (years) 51 (16) 57 (18) 51 (16) 0.016Mean (SD) time after SCI (years) 10 (12) 6 (10) 11 (12) 0.019Stage of SCIaAcute vs. chronic, no. (%) 68 (23) vs. 232 (7) 16 (39) vs. 25 (61) 52 (20) vs. 207 (80) 0.007Type of plegiaTetraplegic vs. paraplegic, no. (%) 98 (33) vs. 202 (67) 11 (27) vs. 30 (73) 87 (45) vs. 172 (65) 0.391Completeness of lesion (AIS)Complete (AIS A) vs. incomplete (AIS B-D), no. (%) 120 (40) vs. 180 (60) 9 (22) vs. 32 (78) 111 (43) vs. 148 (57) 0.011Motor complete (AIS A–B) vs. incomplete(AIS C–D), no. (%)170 (57) vs. 130 (43) 15 (37) vs. 26 (63) 155 (60) vs. 104 (40) 0.005AIS A, no. (%) 120 (40) 9 (22) 111 (43)AIS B, no. (%) 50 (17) 6 (15) 44 (17)AIS C, no. (%) 45 (15) 9 (22) 36 (14)AIS D, no. (%) 85 (28) 17 (41) 68 (26)Lesion levelAt or above T6 vs. below T6, No. (%) 166 (55) vs. 134 (45) 16 (39) vs. 25 (61) 150 (58) vs. 109 (42) 0.024Cervical, no. (%) 98 (33) 11 (27) 87 (33)Thoracic, no. (%) 172 (57) 20 (49) 152 (59)Lumbar (L1–L2), no. (%) 30 (10) 10 (24) 20 (8)Start of UDIbBlood pressureMean (SD) systolic (mmHg) 127 (23) 123 (24) 127 (23) 0.237Mean (SD) diastolic (mmHg) 76 (13) 71 (15) 76 (13) 0.010Mean (SD) heart rate (bpm) 75 (15) 76 (14) 75 (16) 0.956Cardiovascular change (Δ) during UDIbBlood pressureMean (SD) systolic (mmHg) 42 (34) 38 (22) 43 (35) 0.384Mean (SD) diastolic (mmHg) 17 (14) 18 (12) 17 (14) 0.697Mean (SD) heart rate (bpm) –8 (14) –5 (10) –8 (15) 0.086Presence of NDObYes vs. No, no. (%) 249 (83) vs. 51 (17) 34 (83) vs. 7 (17) 215 (83) vs. 44 (17) 0.989Statistically significant differences (p<0.05) between female and male patients are highlighted in boldAll values are presented as mean (SD) or number of patients (%)aSCI defined as “acute” upon 300 days since injury and “chronic” after 300 days according to the European Multicenter Study about Spinal Cord Injury(EMSCI, www.emsci.org)bIndicating the worse of two same session UDIsAIS American Spinal Injury Association (ASIA) Impairment Scale, NDO neurogenic detrusor overactivity, SCI spinal cord injury, SD standard deviation,UDI urodynamic investigationWalter et al. BMC Medicine  (2018) 16:53 Page 3 of 11Prediction of autonomic dysreflexia during urodynamicinvestigationLogistic regression analyses (Table 2) revealed that the le-sion level, i.e., T6 or above vs. T7 or below, as well as thepresence of neurogenic detrusor overactivity (NDO) pre-dicted AD during UDI. Further stratification by lesionlevel showed a significantly increasing odds of AD withhigher lesion levels. When comparing patients with NDOand without NDO, statistically significant increases in SBPand DBP were observed, while changes in HR did not sig-nificantly differ between both groups (Fig. 2).Differences between patients with and withoutautonomic dysreflexiaWhen comparing patients with AD and without AD, sta-tistically significant differences in SBP, DBP, and HRwere observed (Table 3). Remarkably, almost one third(65/204, 32%) of the patients with AD had a lesionbelow T6.Characteristics of spinal cord injury affect cardiovascularchanges in patients with autonomic dysreflexiaExploring cardiovascular changes during UDI within thegroup of patients with AD, we found several significantdifferences related to SCI severity, i.e., the level and thecompleteness of the lesion, and the presence of clinicalsymptoms. Specifically, patients with cervical lesions ex-perienced a significantly higher increase in SBP duringUDI compared to those with a thoracic and lumbar le-sion (Additional file 1). Patients with lesions at T6 orabove showed a significantly higher increase in SBP anda greater decrease in HR compared to those with a le-sion at T7 or below (Fig. 3). When stratifying patientswith AD according to the AIS, significantly differentchanges in HR were discovered between AIS A and AISC, AIS A and AIS D, and AIS B and AIS D (Additionalfile 1). Patients suffering from a complete lesion (AIS A)compared to those with an incomplete lesion (AIS B–D) showed a significantly greater decrease in HR(Additional file 1). Patients with a motor completelesion (AIS A–B) compared to those with a motorincomplete lesion (AIS C–D) had a significantlyhigher increase in SBP and a greater decrease in HR(Additional file 1). Patients with symptomatic com-pared to asymptomatic AD demonstrated a signifi-cantly higher increase in SBP and DBP as well as agreater decrease in HR (Fig. 4). No significant cardio-vascular changes were found for AD patients withacute compared to those with chronic suprasacral SCI(Additional file 1).DiscussionIn this prospective cohort study including 300 pa-tients, we found a high incidence of AD in about twothirds of our patients with NLUTD due to suprasacralSCI. In addition, we identified the level of SCI as wellas the presence of NDO as independent significantpredictors to experience AD during UDI. Importantly,almost one third of our patients with AD had a lesionlevel below T6.A high number of physicians and other healthcare pro-fessionals may not be aware of AD, unless their patientpopulation includes individuals with SCI [26]. Thus, thelack of experience with AD-related SBP changes mightlead to misdiagnosed AD and even acceptance of the po-tential risk of life-threatening complications during UDI.Providing evidence on what constitutes an increased riskfor experiencing AD during UDI, i.e., predictors, couldlead to a safer way to perform UDI in this cohort. Mostimportantly, education regarding AD, i.e., knowledgetransfer to physicians, other health professionals, care-givers, and especially patients and family members iscrucial to raise awareness of AD so that AD-relatedcomplications during UDI and in everyday life (includingemergency room admissions for “not feeling right” orurinary tract symptoms) can be minimized or preventedat best.In contrast to episodic BP measurement, which hasoften been used to record AD during UDI [27–29], con-tinuous CVM provides a more accurate observation, asit allows one to detect short episodes of AD. The “beat-to-beat” technique allows the Finometer (via fingerphotoplethysmography) to monitor cardiovascularchanges of SBP, DBP, and HR continuously and accur-ately according to the Association for the Advancementof Medical Instrumentation. Furthermore, the BritishHypertension Society has recommended the Finometerfor measurements in the clinical set-up and for researchpurposes. In line with Liu et al. [9] and our previousstudy [16], we used continuous CVM to document SBP,DBP, and HR, i.e., “beat-to-beat” recordings, throughoutFig. 1 Characteristics of clinical symptoms related to autonomicdysreflexia (AD) during urodynamic investigation. In 75 patients withsymptomatic AD, 152 counts of clinical symptoms were recorded.Headache with 33 counts was the most frequent symptom. Theremaining 119 counts included feeling uncomfortable (31), spasticity(27), sweating (23), general pain (21), piloerection (9), flushing and/orfeeling warm/hot (5), chest pain or discomfort (2), and dyspnea (1)Walter et al. BMC Medicine  (2018) 16:53 Page 4 of 11the entire investigation to immediately reveal AD. Infact, AD was detected during UDI in more than twothirds (204/300) of our patients. In contrast, previous lit-erature measuring BP episodically reported incidence ofAD between 37 and 43%. This lower incidence of ADmight be attributed to intermittent instead of continuousCVM, as the former is likely to miss short-term episodesof AD [27–29]. Evidence for this hypothesis is given, aswe recently found a similarly high incidence of AD(73%) in women with NLUTD due to suprasacral SCI[16]. Thus, AD during UDI in individuals with SCIseems to be generally underestimated, and this mightput our patients at relevant risk if AD is not detectedand appropriately managed.Sympathetic pre-ganglionic neurons (SPNs) are regardedas the pivotal spinal neurons for central cardiovascular con-trol [30]. It is commonly believed that AD occurs in patientswith SCI at or above T6 [31, 32], and most studies have onlypresented data in this selected cohort [9, 27, 29, 33].However, AD can also occur in patients with a lesion levelTable 2 Odds ratios for autonomic dysreflexia during urodynamicsVariable Unadjusted OR (95% CI) p value Adjusted OR (95% CI) p valueSexMalea 1 1Female 2.1 (1.0–5.1) 0.070 2.0 (0.9–4.9) 0.101Stage of SCIbAcute 1.2 (0.7–2.1) 0.600 0.8 (0.4–1.7) 0.622Chronica 1 1AISA 0.9 (0.5–1.6) 0.719 1.4 (0.7–2.9) 0.700B 1.2 (0.6–2.6) 0.646 1.7 (0.7–4.3) 0.360C 1.0 (0.5–2.3) 0.939 1.2 (0.5–2.9) 0.850Da 1 1Complete vs. incomplete SCIAIS A–B 0.9 (0.5–1.4) 0.510 1.1 (0.7–2.0) 0.657AIS C–Da 1 1Motor complete vs. incomplete SCIAIS A 1.0 (0.6 – 1.6) 0.880 1.4 (0.8 – 2.6) 0.250AIS B-Da 1 1Lesion level, cutoff at T6At or above T6 5.5 (3.2–9.4) < 0.001 6.6 (3.8–11.7) < 0.001T7 and belowa 1 1Lesion level, distributions above T7C1–C4 13.9 (5.2–48.8) < 0.001 16.2 (5.9–57.9) < 0.001C5–C8 8.5 (3.5–23.8) < 0.001 12.2 (4.9–35.8) < 0.001T1–T3 4.3 (1.8–11.7) 0.002 5.2 (2.1–14.5) 0.001T4–T6 2.4 (1.3–4.7) 0.007 2.6 (1.3–5.2) 0.006T7 and belowa 1 1Presence of NDO during UDIcYes 2.7 (1.4–4.9) 0.002 2.2 (1.1–4.5) 0.030Noa 1 1Statistically significant differences (p<0.05) for the categorical variables against its own reference category are highlighted in boldAll values are presented as OR (95% CI)Bivariate logistic regression analysis between AD and each categorical variable resulted in crude OR. Multivariate logistic regression analysis between AD and allcategorical variables including age (as a continuous variable) in one model resulted in adjusted ORaReference categorybSCI defined as “acute” upon 300 days since injury and “chronic” after 300 days according to the European Multicenter Study about Spinal Cord Injury(EMSCI, www.emsci.org)cIndicating the worse of two same session UDIsAD autonomic dysreflexia, AIS American Spinal Injury Association (ASIA) Impairment Scale, C cervical, CI confidence interval, NDO neurogenic detrusor overactivity,OR odds ratio, SCI spinal cord injury, T thoracic, UDI urodynamic investigationWalter et al. BMC Medicine  (2018) 16:53 Page 5 of 11below T6, as the sympathetic outflow originates from T1 toL2 [34] and supplies various regions, such as the heart (T1–T5) and urinary bladder (L1–L2) [35]. Thus, similar toHuang et al. [28], we also included patients with SCI belowT6, and about one third of patients with AD in our studyhad a lesion below T6. The sympathetic postganglionic neu-rons, excited by SPNs, synapse with target organs, such asthe heart and blood vessels, and hence are responsible forthe innervation of the splanchnic vascular bed [32]. Thehigher the level of injury, the more SPNs are likely to be in-dependent of central inhibition. Therefore, a growing num-ber of independent SPNs receiving afferent input from belowthe level of injury could provide the critical mass of vasocon-striction needed to elevate the SBP accordingly [31]. To pro-vide further evidence on the impact of lesion level oncardiovascular changes, increase in SBP from baseline in pa-tients experiencing AD during UDI was highest in those witha cervical injury, followed by those with a thoracic and lum-bar injury, respectively. In patients with a lesion below T6, itis thought that either sympathetic innervation of vascularstructures remains sufficiently under supraspinal sympatheticcontrol [36], or the extent of disconnected vascular areas isreduced, leading to a normal inhibitory response tobaroreceptor-mediated reflexes to maintain homeostasis.AD can also be asymptomatic, known as silent AD[29, 33]. Remarkably, 63% (129/204) of our patients withAD were asymptomatic. This condition can be very haz-ardous, because the discrepancy between cardiovascularchanges and clinical symptoms might be misunderstoodby physicians and therefore assigned incorrectly to othercauses, which could lead to life-threatening situations.The group of 75 patients with symptomatic AD (37%)had significantly greater changes in all three cardiovas-cular domains, i.e., SPB, DBP, and HR, and consisted ofmore patients with a lesion level at or above T6 andcomplete lesions (AIS A) compared to those withasymptomatic AD.Considering the distribution of the lesion level, i.e., ator above T6 vs. below T6, more patients who wereasymptomatic had a lesion below T6. While preservedcentral control of SPNs allows inhibitory descending sig-nals to counterattack the vasoconstriction, individualswith a lesion above T6 are lacking central control ofSPNs that innervate the heart (T1–T5). The higher thelesion above T6, the more likely a patient will show aslowing down of the heartbeat, potentially result inbradycardia. This reflects the parasympathetic effort torespond to the sudden SBP increase in reducing theheart stroke volume through the vagal nerve. This mayultimately result in a deterioration of the patient’scondition.In line with the literature [37], our AD patients withan AIS A lesion demonstrated a significantly greater de-crease in HR than those with an AIS B–D lesion, indi-cating that the greater the extent of the injury, i.e., thefewer efferent fibers are spared to uphold centralFig. 2 Cardiovascular parameters during urodynamic investigation by presence of neurogenic detrusor overactivity. Cardiovascular changes in (a)SBP, (b) DBP, and (c) HR in SCI patients who have either presented NDO (right side in dark blue) or not (left side in Maya blue). At the start of UDI,cardiovascular parameters were not significantly different between both groups. In patients with NDO, cardiovascular changes in SBP (44, 95% CI40.2–48.6 vs. 30, 95% CI 21.1–39.6 mmHg, p = 0.007) and DBP (18, 95% CI 16.3–19.8 vs. 13, 95% CI 9.3–16.6 mmHg, p = 0.016) during UDI weresignificantly different compared to patients without NDO. Changes in HR (–8, 95% CI –10.0 to –6.4 vs. −4, 95% CI –7.7 to –0.4) did notsignificantly (p = 0.06) differ between both groups. Each circle represents one patient’s cardiovascular changes during UDI. Error bars representmean and the 95% CI of cardiovascular changes; i.e., the worse out of two same session UDIs was used. BPM beats per minute, CI confidenceinterval, DBP diastolic blood pressure, HR heart rate, NDO neurogenic detrusor overactivity, SBP systolic blood pressure, SCI spinal cord injury, UDIurodynamic investigationWalter et al. BMC Medicine  (2018) 16:53 Page 6 of 11sympathetic control of the heart, the greater the influ-ence on HR by the parasympathetic nervous system. Incontrast to our observation, Giannantoni et al. [27] re-ported that AD did not correlate with the completenessof a lesion. These discrepancies might be attributed todifferences in cardiovascular assessment, individualnumber, and characteristics of SCI, hampering a mean-ingful comparison but warranting further investigationof these issues. It should be acknowledged that the ex-tent of an SCI reaches beyond the sensorimotor impair-ment. Whether an SCI is autonomic complete, i.e.,supraspinal sympathetic control is entirely lost, or notseems to have a significant influence on blood pressureand heart rate. According to the review by West et al.[38] in patients with chronic SCI, the autonomiccompleteness of SCI is more strongly related toTable 3 Baseline characteristics and cardiovascular changes: differences between patients with and without ADCharacteristics No AD (n = 96) AD (n = 204) p valueSexMale vs. female, no. (%) 88 (92) vs. 8 (8) 171 (84) vs. 33 (16) 0.065Mean (SD) age (years) 49 (15) 53 (16) 0.044Mean (SD) time after SCI (years) 10 (10) 11 (12) 0.706Stage of SCIaAcute vs. chronic, no. (%) 20 (21) vs. 76 (79) 48 (23) vs. 156 (77) 0.603Type of plegiaTetraplegic vs. paraplegic, no. (%) 10 (10) vs. 86 (90) 88 (43) vs. 116 (57) < 0.001Completeness of lesion (AIS)Complete (AIS A) vs. incomplete (AIS B–D), no. (%) 41 (43) vs. 55 (57) 79 (39) vs. 125 (61) 0.511Motor complete (AIS A–B) vs. incomplete(AIS C–D), no. (%)55 (57) vs. 41 (43) 115 (56) vs. 89 (44) 0.881AIS A, no. (%) 41 (43) 79 (39)AIS B, no. (%) 14 (15) 36 (18)AIS C, no. (%) 14 (15) 31 (15)AIS D, no. (%) 27 (28) 58 (28)Lesion levelAt or above T6 vs. below T6, no. (%) 27 (28) vs. 69 (72) 139 (68) vs. 65 (32) < 0.001Cervical, no. (%) 10 (10) 88 (43)Thoracic, no. (%) 72 (75) 100 (49)Lumbar (L1–L2), no. (%) 14 (15) 16 (8)Start of UDIbBlood pressureMean (SD) systolic (mmHg) 133 (22) 124 (23) 0.001Mean (SD) diastolic (mmHg) 79 (15) 74 (12) 0.001Mean (SD) heart rate (bpm) 74 (15) 76 (16) 0.458Cardiovascular change (Δ) during UDIbBlood pressureMean (SD) systolic (mmHg) 7 (8) 58 (29) < 0.001Mean (SD) diastolic (mmHg) 5 (6) 23 (13) < 0.001Mean (SD) heart rate (bpm) 1 (8) –11 (15) < 0.001Presence of NDObYes vs. No, no. (%) 70 (73) vs. 26 (27) 179 (88) vs. 25 (12) 0.001Statistically significant differences (p<0.05) between patients with and without autonomic dysreflexia are highlighted in boldAll values are presented as mean (SD) or number of patients (%)aSCI defined as “acute” upon 300 days since injury and “chronic” after 300 days according to the European Multicenter Study about Spinal Cord Injury(EMSCI, www.emsci.org)bIndicating the worse of two same session UDIsAD autonomic dysreflexia, AIS American Spinal Injury Association (ASIA) Impairment Scale, NDO neurogenic detrusor overactivity, SCI spinal cord injury,SD standard deviation, UDI urodynamic investigationWalter et al. BMC Medicine  (2018) 16:53 Page 7 of 11Fig. 3 Cardiovascular changes during urodynamic investigation by lesion level (cutoff T6). Cardiovascular changes in (a) SBP, (b) DBP, and (c) HRin SCI patients with AD who have either sustained a SCI at T6 or above (left side in Maya blue) or at T7 or below (right side in dark blue). At thestart of UDI, cardiovascular parameters were not significantly different between both groups. In patients with a SCI at T6 or above, cardiovascularchanges in SBP (65, 95% CI 59.7–69.7 vs. 45, 95% CI 39.6–49.5 mmHg) and HR (−14, 95% CI –16.6 to –11.4 vs. −6, 95% CI –8.2 to –2.9 bpm) weresignificantly different (p < 0.001) compared to those of remaining patients. Each circle represents one patient’s cardiovascular changes during UDI.Error bars represent mean and the 95% CI of cardiovascular changes; i.e., the worse out of two same session UDIs were used. AD autonomicdysreflexia, BPM beats per minute, CI confidence interval, DBP diastolic blood pressure, HR heart rate, SBP systolic blood pressure, SCI spinal cordinjury, T thoracic, UDI urodynamic investigationFig. 4 Cardiovascular parameters during urodynamic investigation by symptomatic vs. asymptomatic AD. Cardiovascular changes in (a) SBP, (b)DBP, and (c) HR in SCI patients with AD who have either presented symptoms (right side in dark blue) or not (left side in Maya blue). At the start ofUDI, cardiovascular parameters were not significantly different between both groups. In patients with symptomatic AD, cardiovascular changes inSBP (72, 95% CI 67.6–76.7 vs. 50, 95% CI 45.8–54.8 mmHg), DBP (27, 95% CI 25.0–29.1 vs. 21, 95% CI 18.5–22.6 mmHg) and HR (−19, 95% CI –21.6to –16.7 vs. −7, 95% CI –9.0 to –4.3) during UDI were significantly different (p < 0.001) compared to those of remaining patients. Each circlerepresents one patient’s cardiovascular changes during UDI. Error bars represent mean and the 95% CI of cardiovascular changes; i.e., the worseout of two same session UDIs were used. AD autonomic dysreflexia, BPM beats per minute, CI confidence interval, DBP diastolic blood pressure,HR heart rate, SBP systolic blood pressure, SCI spinal cord injury, UDI urodynamic investigationWalter et al. BMC Medicine  (2018) 16:53 Page 8 of 11cardiovascular function than neurological completenessof injury. However, we do not have enough data from allof our patients to investigate the effect of autonomiccompleteness on the incidence of AD and cardiovascularchanges during UDI.In line with Liu et al. [15], we found significantly dif-ferent cardiovascular changes in patients with NDOcompared to those without. Being considered a majorcause to trigger AD [15] and leading to significant in-creases in arterial pressure [39], NDO seems to pose asignificant health risk to patients with SCI. This is clinic-ally relevant, as most patients with SCI suffer from NDO[40]. As a result of NDO, repeatedly increased intravesi-cal pressures can lead to morphological changes of theurinary tract and increased risk of upper urinary tractcomplications in the long term [4, 41]. The latter com-prise vesico-uretero-renal reflux, hydronephrosis, im-pairment of renal functions, or at worst renal failure [4].Treatment of NDO, i.e., with antimuscarinic drugs andintradetrusor onabotulinumtoxinA injections, results inreduction of intravesical pressure, improves quality oflife, and has been successfully implemented into clinicalpractice and guidelines [3]. Given the potential of NDOto elicit AD, successful treatment of NDO could alsohave a positive effect on AD incidence and extent of re-lated cardiovascular changes. In line with this hypoth-esis, Fougere et al. [42] provided evidence of effectivelyreducing the frequency and severity of AD after intrade-trusor onabotulinumtoxinA injections in patients withSCI. By improving LUT function and concurrently redu-cing cardiovascular responses to LUT stimuli, treatmentof NDO appears to have the capacity to lower the riskfor AD-related long-term complications.Although to the best of our knowledge this is the lar-gest prospective cohort study investigating AD usingcontinuous cardiovascular changes in patients withsuprasacral SCI suffering from NLUTD, some limita-tions should be addressed. Common conditions such asurinary tract infections, medications, and fluctuations ofthe neurological state can influence lower urinary tractfunction and consequently UDI and CVM parameters.Furthermore, as we only included those patients withSCI who are affected by NLUTD, which represents mostSCI patients, it is difficult to say whether our resultscould also be extrapolated to SCI patients withoutNLUTD. Moreover, demonstrating the impact of SCI le-sion level, completeness, and symptomatology of AD oncardiovascular changes during UDI, it would be of greatinterest to continuously monitor cardiovascular parame-ters during long-term ambulatory UDI to further assessthe cardiovascular risk profile in patients with SCI.Despite these limitations, our study is the first to pro-vide evidence that AD during UDI is predictable by le-sion level and presence of NDO. Our results clearlyunderline the importance of continuous CVM duringUDI in all patients with suprasacral SCI and emphasizethe relevance of proactive NDO treatment. In this way,AD can be detected earlier and more frequently, whichsubsequently could lead to fewer episodes of AD-relatedcomplications during diagnostic assessment or at bestnone. To further protect patients with SCI, continuousCVM should also be considered as standard surveillanceduring other diagnostic interventions such as cystoscopy[9] and sperm retrieval [43].ConclusionsConsidering all potential health risks associated withAD, such as seizures, stroke, retinal bleeding, or evendeath, we highly recommend continuous CVM duringUDI in all patients with suprasacral SCI, since focus-ing on lesions at T6 or above would result in missinga relevant percentage of patients with AD. However,particular emphasis should be given to individualswith cervical lesions, as they are at highest risk forAD during UDI.Given our previous experiences [16, 21], we proposeperforming same session repeat UDI with continuousCVM, which allows one to provide the treating urologistwith more precise information on the extent of NLUTDand cardiovascular changes during UDI.Moreover, we advise considering appropriate treat-ment of NDO, not only to protect the upper urinarytract from potential long-term damage, but also to im-prove quality of life and decrease the risk of AD. Follow-ing our recommendations will also allow for revealingfindings of cardiovascular risk factors in patients with si-lent AD and might subsequently reduce the risk of po-tentially life-threating complications related to suddenhypertension during AD.Additional fileAdditional file 1: Results. Table S1. Cardiovascular parameters by lesionlevel in patients with autonomic dysreflexia. Table S2. Cardiovascularparameters by completeness of injury according to the American SpinalInjury Association Impairment Scale. Table S3. Cardiovascular parametersby motor completeness of injury according to the American Spinal InjuryAssociation (ASIA) Impairment Scale (AIS). Table S4. Cardiovascularparameters by stage of injury. Figure S1. Cardiovascular parametersduring urodynamic investigation by American Spinal Injury Association(ASIA) Impairment Scale (AIS). (DOCX 260 kb)AbbreviationsAD: Autonomic dysreflexia; AIS: American Spinal Injury AssociationImpairment Scale; ANOVA: Analysis of variance; AOR: Adjusted odds ratio;CI: Confidence interval; CVS: Cardiovascular system; DBP: Diastolic bloodpressure; EMSCI: European Multicenter Study about Spinal Cord Injury;HR: Heart rate; ICS: International Continence Society; ISAFSCI: InternationalStandards to document remaining Autonomic Function after Spinal CordInjury; ISNCSCI: International Standards for Neurological Classification ofSpinal Cord Injury; LUT: Lower urinary tract; NDO: Neurogenic detrusoroveractivity; NLUTD: Neurogenic lower urinary tract dysfunction; OR: OddsWalter et al. BMC Medicine  (2018) 16:53 Page 9 of 11ratio; SBP: Systolic blood pressure; SCI: Spinal cord injury; SD: Standarddeviation; SPN: Sympathetic pre-ganglionic neuron; UDI: UrodynamicinvestigationAcknowledgementsWe thank the patients for their participation. We thank Catherine R. Jutzeler(International Collaboration On Repair Discoveries (ICORD), University ofBritish Columbia (UBC), Vancouver, Canada) for her assistance with thegraphical design.FundingThis work was funded by the Swiss National Science Foundation and theSwiss Continence Foundation. Matthias Walter is a 2017 Michael SmithFoundation for Health Research “Research Trainee Award” recipient, inpartnership with the Rick Hansen Foundation. The sponsors of the study hadno role in study design, data collection, data analysis, data interpretation, orwriting of the report. All authors had full access to all the data in the studyand responsibility for the decision to submit for publication.Availability of data and materialsThe datasets used and/or analyzed during the current study are availablefrom the corresponding author on request.Authors’ contributionsAccording to the guidelines of the International Committee of MedicalJournal Editors (ICMJE), all authors contributed to the four criteria. MW, SCK,JJC, LL, MPS, UM, MS, AC, AVK, and TMK conceived and designed the study.MW, SCK, LL, MPS, UM, and TMK acquired the data. MW, SCK, JJC, LL, MPS,UM, MS, AC, AVK, and TMK analyzed and interpreted the data. MW, SCK, andTMK drafted the manuscript. JJC, LL, MPS, UM, MS, AC, AVK, and TMKcritically revised the manuscript for important intellectual content. MW, SCK,JJC, and TMK performed the statistical analysis. All authors read andapproved the final manuscript.Ethics approval and consent to participateThe local ethics committee (Kantonale Ethikkommission Zürich) approvedthis study (KEK-2010-0207). All patients gave written informed consentaccording to the Helsinki II declaration.Competing interestsThe authors declare that they have no competing interests.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Author details1Neuro-Urology, Spinal Cord Injury Center & Research, University of Zürich,Balgrist University Hospital, Zürich, Switzerland. 2Neurology, Spinal CordInjury Center & Research, University of Zürich, Balgrist University Hospital,Zürich, Switzerland. 3International Collaboration On Repair Discoveries(ICORD), Faculty of Medicine, University of British Columbia, Vancouver,Canada.Received: 28 October 2017 Accepted: 20 March 2018References1. Pavese C, Schneider MP, Schubert M, Curt A, Scivoletto G, Finazzi-Agro E,Mehnert U, Maier D, Abel R, Rohrich F, et al. Prediction of bladder outcomesafter traumatic spinal cord injury: a longitudinal cohort study. PLoS Med.2016;13(6):e1002041.2. 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J Appl Physiol. 2005;99(1):53–8.•  We accept pre-submission inquiries •  Our selector tool helps you to find the most relevant journal•  We provide round the clock customer support •  Convenient online submission•  Thorough peer review•  Inclusion in PubMed and all major indexing services •  Maximum visibility for your researchSubmit your manuscript atwww.biomedcentral.com/submitSubmit your next manuscript to BioMed Central and we will help you at every step:Walter et al. BMC Medicine  (2018) 16:53 Page 11 of 11

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