Spontaneous Bladder Rupture: Demystifying the Condition – A Systematic Review Dr Deshin Reddy Student no. 303672 A Research Report submitted to the Faculty of Health Sciences of the University of the Witwatersrand, Johannesburg, in partial fulfilment of the requirements for the degree of Master of Medicine in Emergency Medicine Johannesburg, 2023 i DECLARATION I, Deshin Reddy, Student No. 303672, hereby declare that this research report is my own work and has not been submitted or presented for any other degree or professional qualification at this or any other institute. This research was undertaken in the Division of Emergency Medicine, University of the Witwatersrand, Johannesburg, South Africa. Signature of Student: Date: 04/08/2023 Supervisor 1: Prof. A. Laher Signature of Supervisor 1: ____________________ Date: 04/08/2023 Supervisor 2: Prof. A. Adam Signature of Supervisor 2:____________________ Date: 04/08/2023 ii ACKNOWLEDGEMENTS I would like to express my sincere gratitude to: My wife, Ilzè, for her unfailing support, kindness, and encouragement, and without whom this would not have been possible. I love you dearly. My son, Reece, for all the laughter and inspiration. My parents, Sathrugan and Nirmala, my deepest appreciation for your unparalleled support, sacrifice, and boundless encouragement throughout my life. My supervisors, Professors Abdullah Laher and Ahmed Adam, for all their unfailing guidance, support, ongoing encouragement, and assistance in all aspects of this research. The Head of the Health Sciences Library, Mr Devind Peter, for all his assistance and effort in retrieval of texts for this study. iii SUBMISSION FORMAT OF THIS RESEARCH REPORT As per University of the Witwatersrand, Faculty of Health Sciences guidelines, this research report is being submitted in the following format: “published online ahead of print.” One publication has emanated from this research: Reddy D, Laher AE, Lawrentschuk N, Adam A. Spontaneous (idiopathic) rupture of the urinary bladder: a systematic review of case series and reports. BJU Int. 2023 Jun;131(6):660-674. doi: 10.1111/bju.15974. Epub 2023 Feb 7. PMID: 36683400. BJU International is indexed in PubMed, Web of Science (Impact Factor 5.969) and Scopus (CiteScore 9) iv TABLE OF CONTENTS DECLARATION ..................................................................................................... i ACKNOWLEDGEMENTS .................................................................................... ii SUBMISSION FORMAT OF THIS RESEARCH REPORT ............................... iii PUBLISHED ARTICLE ........................................................................................ 1 ABSTRACT .......................................................................................................................... 2 INTRODUCTION ................................................................................................................. 3 METHODS ............................................................................................................................ 3 RESULTS .............................................................................................................................. 6 DISCUSSION ..................................................................................................................... 14 REFERENCES .................................................................................................................... 18 SUPPLEMENTARY MATERIAL ..................................................................................... 39 RESEARCH PROTOCOL ................................................................................... 47 ETHICS WAIVER ............................................................................................... 57 TURNITIN PLAIGARISM REPORT .................................................................. 58 1 PUBLISHED ARTICLE Spontaneous (Idiopathic) Rupture of the Urinary Bladder: A Systematic Review of Case Series and Reports Deshin Reddy1; Abdullah Ebrahim Laher1; Nathan Lawrentschuk2; Ahmed Adam3 1Division of Emergency Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 2Department of Urology, Royal Melbourne Hospital, Melbourne, Victoria, Australia 3Division of Urology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Correspondence: Deshin Reddy, Division of Emergency Medicine, Department of Family Medicine and Primary Care, School of Clinical Medicine, Faculty of Health Sciences, University of Witwatersrand, Private Bag X3, Johannesburg, 2050, South Africa. e-mail: deshinr@gmail.com 2 ABSTRACT Objectives: To perform a systematic review of all cases of spontaneous rupture of the urinary bladder (SRUB) and to describe the demographic data, associated co-morbidities, clinical presentation, diagnosis, relevant laboratory findings, associated factors, management, morbidity, and mortality associated with the presentation of SRUB. Methods: The study protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO). A search was carried out across the following electronic databases: PubMed, Web of Science, Scopus, Google Scholar, and the Cochrane Database of Systematic Reviews. Full texts of selected studies were analysed, and data extracted. The review was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Results: A total of 278 articles comprising 240 case reports and 38 case series, with a total of 351 patients were included. The median (IQR) age of all included patients was 47.5 (33-65) years. The median (IQR) time to presentation was 48 (24-96) hours, with the major presenting symptom being abdominal pain (76%). In patients in whom the diagnosis was made prior to any intervention, the condition was misdiagnosed in 64% of cases. The diagnosis was confirmed during explorative open surgery in 42% of cases. Pelvic radiation (13%) and alcohol intoxication (11%) were the most common associated factors. Intraperitoneal rupture (89%) was much more common with the dome of the bladder being most frequently involved (55%). The overall mortality was 15%. Conclusion: This review identified a number of key factors that appear to be associated with an increased incidence of SRUB. It also emphasised the high rate of misdiagnosis and challenges in confirming the diagnosis. Overall, it highlighted the importance of the need for increased awareness and maintaining a high index of suspicion for this condition. KEY WORDS spontaneous bladder rupture, idiopathic bladder rupture, atraumatic bladder rupture, uroperitoneum, urinary ascites, pseudo-renal failure, SRUB, #Urology, #UroTrauma 3 INTRODUCTION Rupture of the urinary bladder is a potentially life-threatening urological emergency requiring prompt diagnosis and treatment. The vast majority of cases of bladder rupture is secondary to bladder injury or trauma, however, in 3.4% of cases there is no prior history of trauma (1). In general, the diagnosis is rather challenging, placing this particular subset of patients at considerable risk due to time delays in definitive management (2). Much of the aetiology and risk factors associated with this condition appear to be poorly understood. Spontaneous rupture of the urinary bladder (SRUB) is defined as perforation or rupture of the bladder in the absence of trauma or direct stimulation (3,4). This term also excludes cases where the rupture has occurred as a direct result or complication of instrumentation or previous bladder surgery, e.g., cystoscopy, transurethral resection of bladder tumour (TURBT). Spontaneous rupture of the urinary bladder appears to be a relatively rare condition, with the incidence previously been described as 1:126 000 (5,6). Later studies have indicated that the actual incidence may be as high as 1:50 000 (7). Despite the relatively low reported incidence of SRUB, the mortality rate appears to be significant, ranging from 47-80% (6,8). It seems that the risk of mortality may be somewhat related to the underlying undiagnosed condition associated with the bladder rupture (9,10). This systematic review aims to determine and describe the potential risk factors, other associated factors, diagnosis, management, morbidity, and mortality of patients with SRUB METHODS Protocol and ethics The protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) in March 2021 (registration ID: CRD42021232134). An ethics waiver (W-CBP-210323-01) was received from the University of Witwatersrand Human Research Ethics Committee (Clinical) in March 2021. Search strategy A search was carried out in November 2021 across the following sources: PubMed, Web of Science, Scopus, Google Scholar, and the Cochrane Database of Systematic Reviews. 4 Additionally, a backwards citation search (pearl referencing) was also performed on articles that were retrieved, to identify articles that were missed during the search of the above databases. For the PubMed database search, the following Medical Subject Headings (MeSH) terms were verified and indexed in the search builder: “urinary bladder” and “rupture, spontaneous”. Once the search was executed, the following limits were applied: human species and English language. There was no time limit applied. Similarly, the search strategy for the Web of Science, Scopus and Google Scholar databases was conducted using the following terms: ‘urinary bladder’ AND ‘rupture’ AND ‘spontaneous’. The limits applied were the same as stated above for the PubMed database search. The Cochrane Library search strategy was carried out in the Systematic Review section. The all-text filter was used in conjunction with the above search terms and limits. Inclusion and exclusion criteria Studies were included if (i) they reported on SRUB, (ii) the full text was available in English and (iii) they were pertaining to human subjects. Studies were excluded if (i) there was any preceding history of trauma, (ii) there was a history of any known structural bladder abnormality or known bladder lesion (e.g., bladder malignancy or exstrophy), (iii) bladder rupture was secondary to a complication of a surgical procedure or a known medical condition, e.g. tubo-ovarian complex or appendicitis, (iv) there was a history of any instrumentation or bladder surgery that could have been directly linked to the rupture (e.g. augmentation, cystoscopy, neobladder, partial cystectomy, bladder stone removal or TURBT) (11,12), (v) intrapartum bladder rupture was a result of suspected traumatic vaginal delivery or as an iatrogenic complication during caesarean section, (vi) bladder rupture was diagnosed in the ante-natal period or presented during the neonatal period. Additionally, studies were also excluded in the event that an abstract did not contain all necessary information or the full-text was not available. Study selection Electronic search limits were first applied as part of the initial screening process. After removal of duplicates, an initial cursory abstract screening was thereafter carried out where irrelevant studies and studies where the full text was unavailable were removed. This was followed by a more thorough abstract screening where studies fulfilling exclusion criteria 5 were removed. Full text reports were thereafter reviewed. Exclusion criteria were again applied, thereafter resulting in the final number of studies included in the review (Figure 1). Figure 1: Study search strategy PRISMA flow diagram Data extraction and methodology evaluation The review was carried out using the framework outlined by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Two reviewers independently screened the articles using eligibility and exclusion criteria (DR & AL). Any disagreements or uncertainties related to whether a study should be included were resolved by a third reviewer (AA). Data was extracted from individual studies and collated in an Excel spreadsheet (Microsoft Corporation, Redmond, WA, USA). Data for individual variables (gender, age, co-morbidities, clinical presentation, examination findings, diagnostic data, authors’ assessment of exposure, serum laboratory parameters, management, and outcome) were tallied and represented as frequency and percentage. If data was not specified in the text, this was recorded as ‘not specified’. 6 Assessment of methodological quality of the included studies Since all studies meeting the inclusion criteria were case reports and case series, a modification to the tool proposed by Murad et al. (13) was used to assess the methodological quality of the included manuscripts. This modified tool has been utilised in several other systematic reviews of case reports (14,15) The original tool is comprised of four domains with eight questions in total. Since two of the questions pertain specifically to drug reactions, these were omitted. The included questions were as follows: 1) Does/do the patient(s) represent(s) the whole experience of the investigator or is the selection method unclear to the extent that other patients with similar presentation may not have been reported? 2) Was the condition adequately ascertained? 3) Was the outcome adequately ascertained? 4) Were other alternative causes that may explain the observation ruled out? 5) Was follow-up long enough for outcomes to occur? 6) Is/are the case(s) described with sufficient details to allow other investigators to replicate the research or to allow practitioners to make inferences related to their own practice? The overall methodological quality of each of the included articles was described as either low, intermediate, or high quality. High quality was defined as a “yes” answer to four or more of the included questions, while intermediate quality was defined as a “yes” answer to three of the included questions and low quality was defined as a “yes” answer to less than three of the included questions (Supplementary Table 1). Data synthesis The outcomes reported were summary data pertaining to the presentation of SRUB and included patient demographics, co-morbidities, clinical presentation, diagnosis, relevant laboratory findings, associated factors, site of bladder rupture, management, morbidity and mortality. Since all included studies were case reports, summative statistics and a narrative synthesis approach was primarily utilised to describe the findings. RESULTS The electronic search yielded a total of 1341 studies as follows: PubMed (301), Web of Science (102), Scopus (591), Google Scholar (339), Cochrane Database of Systematic Reviews (0) and, backwards citation search (pearl referencing) (8). Automatic search limits excluded 175 studies and a further 36 were removed as they were irrelevant. After duplicates were removed (665), a total of 465 abstracts were fully reviewed. Once exclusion criteria 7 were applied to the abstracts, 352 studies remained for full-text review. After again applying the exclusion criteria to the full-texts, a total of 278 manuscripts remained and were included in the final review (1–10,16–283). Details of the above are described in figure 1. Design of the included publications All included studies were either case reports (240) or case series (38) and comprised a total of 351 patients. Demographics The age range of all included patients was from 9 months to 91 years (Supplementary Figure 1), with a median (interquartile range – IQR) age of 47.5 (33-65) years. There was a bimodal age distribution with peaks at 21-40 years and ≥60 years (111/331; 34% for both). This was followed by the 41–60-year-old age group (88/331; 27%) and the under 20-year-old age group (21/331; 6.3%). Of the total number of cases that specified gender, the distribution had a slight female predominance (n=173/331; 52%) (Table 1). Co-morbidities A total of 153 (44%) patients had reported at least one co-morbid condition, with the most frequent co-morbidities being diabetes mellitus (n=21; 6.0%), cervical adenocarcinoma (n=21; 6.0%) and hypertension (n=15; 4.3%). The most common group of co-morbid conditions was cardiovascular-related disease (n=63; 18%), followed by malignancy (n=44; 13%). Most malignancies were pelvic in origin (n=40/44; 91%) (Table 1). Table 1: Demographic details, co-morbidities, time to presentation and diagnosis, laboratory variables, site of rupture, management and recurrence related to spontaneous rupture of the urinary bladder n (%) / median [IQR] Sex (n=351) Male 158 (45) Female 173 (49) Unspecified 20 (5.7) Age (n=331) Median age [IQR] (years) 47.5 [33-65] < 20 years old 21 (6.3) 21-40 years old 111 (34) 41-60 years old 88 (27) > 60 years old 111 (34) Major co-morbidities (n=351) Co-morbid disease present 153 (44) None 51 (15) 8 Not specified 147 (42) Cardiovascular 63 (18) Diabetes mellitus 21 (6.0) Hypertension 15 (4.3) Dyslipidaemia 7 (2.0) CVA 7 (2.0) Malignancy 44 (13) Cervical cancer 21 (6.0) Bladder cancer 5 (1.4) Prostate cancer 4 (1.2) Neurological 36 (10) Paraplegia 10 (2.9) Multiple sclerosis 7 (2.0) Quadriplegia 3 (0.9) Urological 35 (10) BPH 11 (3.2) Urolithiasis 9 (2.6) Vesicolith 6 (1.7) Psychiatric 12 (3.4) Schizophrenia 5 (1.4) Depression 3 (0.9) Renal 9 (2.6) Infection 8 (2.3) Pulmonary 6 (1.7) Genetic/autoimmune 7 (2.0) Gynaecological 7 (2.0) Rheumatological/orthopaedic 5 (1.4) Other 12 (3.4) Median time to presentation [IQR] (hours) 48 [24-96] Serum laboratory parameters Median urea [IQR] (mmol/L) 21.5 [13.0-35.0] Median creatinine [IQR] (µmol/L) 393.0 [199.8-590.8] Peritoneal site of rupture (n=351) Intraperitoneal 314 (89) Extraperitoneal 26 (7.4) Not specified 11 (3.1) Anatomical site of rupture (n=351) Dome 192 (55) Posterior wall 48 (14) Inferolateral wall 20 (5.7) Anterior wall 14 (4.0) Dome extending to posterior wall 5 (1.4) Dome extending to anterior wall 1 (0.3) Posterior wall extending to inferolateral wall 1 (0.3) Not specified 70 (20) Management (n=351) Open repair 249 (71) Conservative 47 (13) Laparoscopic repair 14 (4.0) HBO 4 (1.1) Cystectomy 2 (0.6) Open repair + HBO 1 (0.3) Demised prior to intervention (post-mortem) 12 (3.4) Not specified 22 (6.3) Management excluding cases diagnosed on laparotomy and post-mortem (n=195) Open repair 107 (55) Conservative 47 (24) Laparoscopic repair 14 (7.2) HBO 4 (2.1) 9 Open repair + HBO 1 (0.5) Not specified 22 (6.3) Recurrence (n=18) Open repair 10 (55) Conservative 7 (39) Laparoscopic repair 1 (0.6) IQR, interquartile range; ED, emergency department; CVA, cerebrovascular accident; HBO, hyperbaric oxygen. Clinical presentation The median (IQR) time to presentation was 48 (24-96) hours. The major presenting symptoms were abdominal pain (n=267; 76%), of which the majority was unspecified abdominal pain (n=128; 36%), followed by nausea and/or vomiting (n=79; 23%), abdominal distention (n=74; 21%), and acute urinary retention or difficulty voiding (n=63; 18%). Notably, urinary symptoms were present in almost three-quarters of patients (n=259; 74%). The most common examination findings were abdominal distention (n=131; 37%), abdominal tenderness (n=84; 24%) and fever (n=34; 9.7%). Of those in whom abdominal tenderness was reported, 34/84 (40%) had generalised peritonitis. Only one case study reported that abdominal examination was within normal limits (Supplementary Table 2). Diagnosis The median (IQR) time to diagnosis was 48 (24-96) hours. Of those cases that reported on the relevant data, the diagnosis was made in the emergency department (ED) in 28/253 (11%) cases. In patients in whom the diagnosis was made prior to any intervention, the condition was misdiagnosed in 119/185 (64%) cases, with the most common misdiagnosis being hollow viscus perforation (n=41/119; 34%) (Table 2). The diagnosis was confirmed during explorative open surgery in 147 (42%) cases, which excludes cases where the diagnosis was made at autopsy (n=11; 3.1%). This was followed by cases where the diagnosis was confirmed by plain-film x-ray cystography (n=72; 21%) and CT with cystography (n=47; 13%) (Table 2). Table 2: Diagnostic data and morbidity & mortality related to spontaneous rupture of the urinary bladder n (%) / median [IQR] Median time to diagnosis from presentation [IQR] (hours) 48 [24-96] Diagnosis made (n=351) 10 In emergency department 28 (8.0) Outside of ED 225 (64) Not specified 98 (28) A diagnosis made prior to intervention 185 (53) Incorrect 119/185 (64) Correct 66/185 (36) No diagnosis made prior to intervention 166 (47) Misdiagnoses (n=119) Gastrointestinal 102 (86) Hollow viscus perforation 41 (34) Bowel obstruction 13 (11) Acute peritonitis unspecified 10 (8.4) Urological 12 (10) Acute urinary retention 4 (3.4) Urosepsis 3 (2.5) Obstructive uropathy 2 (1.7) Renal 14 (12) Primary acute renal failure 12 (10) Pyelonephritis 1 (0.8) UTI not specified 1 (0.8) Gynaecological/obstetrics 7 (5.9) Recurrence of gynaecological malignancy 2 (1.7) Ruptured/torsion of ovarian cyst 2 (1.7) PV bleeding 1 (0.8) Diagnostic modalities used to confirm diagnosis (n=351) Exploratory laparotomy 147 (42) Plain-film cystography 72 (21) CT with cystography 47 (13) CT without cystography 26 (7.4) Cystoscopy 23 (6.6) Exploratory laparoscopy 11 (3.1) Autopsy 11 (3.1) Formal US 6 (1.7) Plain-film IV pyelography 1 (0.3) MRI pelvis 1 (0.3) Tc-99m DTPA renography 1 (0.3) Voiding cystourethrogram 1 (0.3) Bladder doppler US 1 (0.3) Data not available 3 (0.9) Use of bedside US in ED (n=351) Yes 11 (3.1) No 297 (85) Not specified 43 (12) Morbidity (n=351) No morbidity 124 (35) Not specified 132 (38) Total morbidities 95 (27) Respiratory 8 (2.3) Cardiac 2 (0.6) Bowel/intra-abdominal organ 9 (2.6) Gynaecological 3 (0.9) Urological 19 (5.4) Bladder-related complications (partial/ total cystectomy/ cystoplasty/ conduit) 8 (2.3) Non-bladder related 6 (1.7) Chronic catheterisation 5 (1.4) Sepsis and related complications 9 (2.6) Necrotising fasciitis 2 (0.6) Wound complications 3 (0.9) 11 Metabolic 1 (0.3) Recurrence 17 (4.8) Single episode of recurrence 13 (3.7) Multiple episodes of recurrence 4 (1.1) Missed during surgical intervention 3 (0.9) Failed conservative management 3 (0.9) Survival and mortality (n=351) Survival to hospital discharge 225 (64) Not specified 75 (21) Total deaths 51 (15) Time not specified 11 (3.1) <3 days 15 (4.3) 3-7 days 8 (2.3) 8-31 days 11 (3.1) 1-6 months 5 (1.4) >6 months 1 (0.3) UTI, urinary tract infection; PV, per vagina; CT, computed tomography; US, ultrasonography; IV, intravenous; Tc-99m, Technetium-99m; MRI, magnetic resonance imaging; DTPA, diethylenetriamine penta-acetate; IQR, interquartile range; ED, emergency department; HBO, hyperbaric oxygen. Median urea and creatinine The median (IQR) serum urea and creatinine levels were 21.5 (13-35) mmol/L and 393 (200- 591) µmol/L, respectively (Table 1). A total of 12 (3.4%) patients were misdiagnosed with primary acute renal failure and received renal replacement therapy (Table 2). Associated factors Rupture was considered idiopathic in 79 (23%) cases, where no exposure could be clearly identified. The most common associated factors related to SRUB were pelvic radiation (n=45; 13%) followed by alcohol intoxication (n=39; 11%) and post vaginal delivery (n=25; 7.1%). The most common associated factors in the two most prevalent age groups were alcohol intoxication (n=26/111; 23%) in the 21-40 years age group and pelvic radiation (n=23/111; 21%) in the older than 60-year-age group. Where the exposure was deemed to be infection or inflammation-related, Mycobacterium tuberculosis (TB) was the most prevalent causative agent (n=10/49; 20%) (Table 3). Table 3: Cumulative incidence of factors associated with spontaneous rupture of the urinary bladder† Factors associated with bladder rupture (n=351) n (%) Bladder outlet obstruction 44 (13) Intravesical 10 (2.8) Vesicolith 9 (2.6) 12 Bladder neck papilloma 1 (0.3) Extravesical 34 (9.7) Urological 27 (7.7) Prostatic enlargement 17 (4.8) BPH 16 (4.6) Prostate cancer 1 (0.3) Urethral catheterisation 6 (1.7) Urethral stricture 4 (1.1) Non-urological 7 (2.0) Uterine fibroids/adenomyosis 2 (0.6) Faecal impaction 2 (0.6) Pelvic organ prolapse 3 (0.9) Type not specified 5 (1.4) Pregnancy associated 32 (9.1) Post NVD 25 (7.1) Intrapartum 5 (1.4) Other 2 (0.6) Infection/inflammation 49 (14) Cystitis uncertain/unspecified origin 11 (3.1) TB 10 (2.8) Fungal 7 (2.0) Parasitic 6 (1.7) Bacterial (non-TB) 5 (1.4) Gangrenous/necrotising 4 (1.1) Eosinophilic 2 (0.6) Granulomatous (non-TB) 2 (0.6) Viral 1 (0.3) Interstitial 1 (0.3) Over-distention/delayed voiding 69 (20) Drug-associated 46 (13) Alcohol 39 (11) Anticholinergic 4 (1.1) Benzodiazepine 1 (0.3) Opioid 1 (0.3) Drug not specified 1 (0.3) Non-drug associated 23 (6.6) Neurogenic bladder 23 (6.6) Increased IAP 2 (0.6) Vomiting 1 (0.3) Seizures 1 (0.3) Bladder wall lesion 88 (24) Malignancy associated 67 (19) Radiation-associated fibrosis (pelvic malignancies of non-bladder origin) 45 (13) Bladder TCC 10 (2.8) Bladder SCC 7 (2.0) Bladder unspecified type 4 (1.1) Bladder leiomyosarcoma 1 (0.3) Non-malignancy associated 19 (5.4) Bladder diverticulum 17 (4.8) Bladder amyloidosis 1 (0.3) Fatty infiltration of bladder 1 (0.3) Other 2 (0.6) Warfarin toxicity 1 (0.3) Haemophilia 1 (0.3) Not identified (idiopathic) 79 (23) Top 5 associated factors stratified by age group <20-year age group (n=21) Bladder diverticulum 3 (14) 13 BOO (UO) 3 (14) Neurogenic bladder 3 (14) Alcohol intoxication 3 (14) Idiopathic 2 (9.5) 21–40-year age group (n=111) Alcohol intoxication 26 (23) Post NVD 21 (19) Idiopathic 13 (12) Cystitis (TB) 8 (7.2) Neurogenic bladder 7 (6.3) 41-60-year age group (n=88) Idiopathic 15 (17) Neurogenic bladder 14 (16) Alcohol intoxication 12 (14) Pelvic radiation 10 (11) Bladder diverticulum 7 (7.8) >60-year age group (n=111) Pelvic radiation 23 (21) BOO (BPH) 15 (14) Bladder diverticulum 14 (13) Idiopathic 10 (9.0) Neurogenic bladder 10 (9.0) BPH, benign prostatic hypertrophy; NVD, normal vaginal delivery; TB, tuberculosis; IAP, intra- abdominal pressure; TCC, transitional cell carcinoma; SCC, squamous cell carcinoma; BOO, bladder outlet obstruction; UO, unknown origin. †Not all authors reported on the presence or absence of all associated factors. Hence, it is possible that a patient may have had some associated factors that were not reported. Site of bladder rupture Intraperitoneal rupture (n=314; 89%) was much more common than extraperitoneal rupture (n=26; 7.4%), with the dome of the bladder being most frequently involved (n=192; 55%) (Table 1). Management Most patients were managed with open repair (n=249; 71%), followed by conservative management with catheterisation on free drainage (n=47; 13%). A total of 14 (4.0%) patients underwent laparoscopic repair. After excluding patients who were incidentally diagnosed with SRUB during exploratory laparotomy (n=156, 44%), 107/195 (55%) patients were managed with open repair and 47/195 (24%) were managed conservatively. Overall, the rate of recurrence was higher with conservative management (n=7/30; 23%) compared to open repair (n=10/147; 6.8%) (Table 1). Morbidity The overall number of reported morbidities was 95 (27%), with the most common morbidity 14 being rupture recurrence (17/351; 4.8%); most of which were single episodes. This was followed by sepsis or sepsis-related complications (n=9; 2.6%), intra-abdominal organ complications (n=9; 2.6%), respiratory tract complications (n=8, 2.3%) and other bladder- related (non-recurrence) complications (n=8, 2.3%) (Table 2). Mortality The overall number of reported deaths was 51 (15%). Most deaths occurred within 72 hours of presentation (n=15/51; 29%) (Table 2). A total of 13 (3.7%) patients demised prior to the correct diagnosis or intervention (i.e., the cause of death was determined at autopsy). A total of 38 (11%) patients demised despite intervention. DISCUSSION Spontaneous rupture of the urinary bladder appears to be a disease that predominantly affects young adults and the elderly (Table 1), with an almost equal incidence among males and females. The incidence of co- morbidities reflects the underlying factors related to SRUB. The major co-morbid disease found was diabetes mellitus which is likely associated with some degree of autonomic bladder neuropathy (284). There was also a high incidence of extra-vesical pelvic organ malignancy with all of these patients having received pelvic radiation. The major presenting symptoms were abdominal pain, which was predominantly localised to the lower abdomen followed by nausea and vomiting, abdominal distention, and difficulty in passing urine or acute urinary retention. Patients with ascites and abdominal distention in the setting of acute onset abdominal pain should have this diagnosis excluded, particularly those with concomitant urinary symptoms. The underlying pathogenesis of SRUB has previously been attributed to a predisposition of compromised bladder wall integrity in combination with increased intravesical pressure and/or increased intra-abdominal pressure (223). Radiation exposure was well noted as a cause of spontaneous bladder rupture in the literature (169,241). This is likely due to the effects of radiation cystitis where the initial mucosal insult of oedema and hyperaemia culminates in fibrosis and loss of bladder wall integrity (285). It is important to note that these patients can present with SRUB many years after treatment has been completed (169,241,259). Hence, the diagnosis of SRUB should always be considered in patients with a 15 past medical history of pelvic radiation. Alcohol intoxication was found to be the second most common exposure in this review (Table 3). The pathogenesis is thought to be secondary to alcohol-induced diuresis leading to increased intra-vesical pressure coupled with impaired awareness of bladder filling and the need to void (8). There may be significant overlap here between traumatic bladder rupture and SRUB, since intoxicated patients are less reliable historians and may not recall a history of trauma. Conversely, in patients presenting with abdominal pain and particularly those with urinary symptoms several days after an alcohol binge, consideration must be given to SRUB as part of the differential diagnosis. Having undergone normal vaginal delivery was the third most prevalent associated factor (Table 3). Again, this diagnosis may be easily missed and attributed to other more likely pathologies (250). It is important to note the risk of SRUB is increased when the bladder is not emptied prior to delivery and where there is perineal trauma leading to a degree of bladder outlet obstruction and urinary retention (38). A review of SRUB in pregnancy and the puerperium found that the majority (70%) occurred during normal vaginal delivery (250). Neurogenic bladder was found to be among the five most prevalent associated factors across all age groups (Table 3). Due to neurological dysfunction, these patients may not present with typical features of abdominal pain. Additionally, the bladder wall is often compromised in these patients, e.g. diverticulae or chronic inflammation, which places them at further risk of spontaneous rupture. Furthermore, many of these patients also harbour chronic indwelling urinary catheters which also contributes to bladder wall inflammation and rupture (33) as well as bowel erosion with resultant fistula formation (286). It is also important to consider the diagnosis of SRUB in cases where patients with chronic neurological conditions may not yet have been formally diagnosed with a neurogenic bladder, e.g. previous cerebrovascular event, diabetes mellitus, multiple sclerosis. The diagnosis of SRUB was largely made during explorative surgery (Table 2). To date, there have been no studies that have attempted to describe the gold-standard diagnostic modality, hence, evidence from the trauma literature has been used as a guide. Computed tomography (CT) without cystography has a low specificity in the diagnosis of traumatic bladder rupture (61%) compared to that of plain-film retrograde cystography (96%) (287). 16 Previously retrograde cystography was considered the gold-standard diagnostic modality for traumatic bladder rupture, but this has since shifted to CT cystography which has shown comparable specificity (288). CT has the distinct advantage of being less invasive than conventional cystography, easier to perform and is able to detect other intra-abdominal pathology while excluding bladder rupture (8). With the continued growth in use of point-of- care ultrasound in the emergency department, there appears to be some promise in its utility (47) and there is potential for further studies to investigate ultrasonographic signs and techniques to aid in making the diagnosis in the emergency department. A low index of suspicion and the non-specific clinical presentation are likely the major contributing factors to the high rate of misdiagnosis associated with SRUB. Another confounding issue contributing to the misdiagnosis of SRUB is the peritoneal reabsorption of urea and creatinine that has escaped through the bladder wall defect leading to elevated serum readings when laboratory investigations are performed. These results may easily be misinterpreted as renal failure (30,31,52,71,75,77,88,94,95,103,156,179,180,233) which is further confounded by presentation with oliguria or anuria (143,168,183), leading to the initiation of renal replacement therapy. When the diagnosis is made reasonably early and the defect repaired or bladder drained to allow sufficient healing to occur, the levels of urea and creatinine generally resolve spontaneously within 24 hours (179). It is important to note that although there is no initial insult to the kidneys, if the diagnosis is delayed this may lead to acute kidney injury and associated life-threatening complications including electrolyte abnormalities (144). The dome of the bladder is anatomically the most vulnerable region. As the bladder distends, the dome stretches resulting in a thinner wall, it also rises above the pelvis and away from the support offered by the bony pelvic structures, thereby making the bladder dome more prone to SRUB (175). In many cases where open repair was performed, the patient was taken for an exploratory laparotomy where SRUB was an incidental finding (272,274,279,280). After excluding patients who were incidentally diagnosed with SRUB at exploratory laparotomy, a higher proportion of patients were managed conservatively (47/195; 24% vs 47/351; 13%). This is likely a better reflection of the actual management related to this condition. Very few studies described successful management with laparoscopic surgery (49,122,263,270). Laparoscopic 17 repair in the hands of an experienced surgeon may be a better option but this remains to be validated by the evidence. There is a lack of literature related to the mortality associated with SRUB. In this review, the overall mortality rate, where reported, was 51/276 (18%), with the highest number of deaths (15/51; 29%) occurring within 72 hours of presentation. This underscores the need to make the diagnosis in a timely manner so definitive management may be implemented. A limitation of this study relates to the heterogenous nature of case reports in general. Case reports are often fraught with inconsistencies and bias, which may lead to inaccuracies when pooling data from multiples sources. For example, estimates of proportions reported in this paper are expected to be inaccurate due to publication bias or reporting inconsistencies, hence, these should be taken as a guide only. For example, case reports with death as an outcome may be more likely to be written-up and published, leading to an overestimate of the actual mortality of SRUB. Conversely, non-systematic reporting of associated features of SRUB such as pelvic radiation or alcohol intoxication may have resulted in an underestimation of these factors, e.g., some reports may not have mentioned these despite them being present. Comprehensive registration and reporting of cases would give a more accurate approximation, but this is challenging for such a rare presentation. In the past, there were few guidelines available to guide authors on the content of case reports to provide a measure of standardisation. This has since improved with the introduction of several widely accepted tools such as the tool by Murad et al. (13) and the CARE (CAse REport) guidelines (289). The hope is that as the use of such tools becomes more common practice, reporting on rare diseases will also become more standardised. There were missing data points in some of the included manuscripts. These were reported as “not specified” in the study summary results and were excluded from individual analyses, which is the reason for the smaller denominators for some variables. Possible examples of studies include prospective cohort studies to determine if certain exposures are indeed causally linked to development of this condition and clinical trials to determine what modalities are best in terms of diagnosis and treatment, as much of the current evidence related to bladder rupture originates from the trauma literature. 18 In conclusion, this review identified a number of key factors across different age groups that appear to be associated with an increased incidence of SRUB. It also emphasised the high rate of misdiagnosis and challenges encountered in confirming the diagnosis. Overall, this study highlights the importance of maintaining a high index of suspicion for SRUB in the appropriate patient. However, a number of important gaps were also identified as potential targets for future research. In light of these findings, healthcare professionals should be educated about the clinical manifestations and risk factors of SRUB. Developing enhanced diagnostic approaches, including imaging techniques and clinical algorithms, is crucial to improve accuracy and reduce misdiagnosis rates. ACKNOWLEDGMENTS We would like to thank Mr. Devind Peter and the staff at the Faculty of Health Sciences and Wartenweiler Libraries, University of Witwatersrand (Johannesburg, South Africa) for their valued assistance with retrieval of full-texts articles. FUNDING None. 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CARE guidelines for case reports: explanation and elaboration document. J Clin Epidemiol. 2017 Sep 1;89:218–35. 39 SUPPLEMENTARY MATERIAL SUPPLEMENTARY FIGURE Supplementary Figure 1: Histogram of ages of patients presenting with spontaneous rupture of the urinary bladder (SRUB) SUPPLEMENTARY TABLES Supplementary Table 1: Methodological quality assessment of the included reports and series Author Selection Ascertainment Causality Reporting Overall Quality* Question 1 Question 2 Question 3 Question 4 Question 5 Question 6 Ibrahimi et al. Yes Yes Yes Yes Yes Yes High Ouafidi et al. Yes Yes Yes Yes Yes Yes High Stabile et al. Yes Yes Yes Yes Yes Yes High Watanabe et al. Yes Yes Yes Yes Yes Yes High Zhang et al. Yes Yes Yes Yes Yes Yes High Raj et al. Yes Yes Yes Yes Yes Yes High Mukhtar et al. Yes No Yes Yes Yes Yes High Sholklapper et al. Yes No Yes Yes Yes Yes High Bergeron et al. Yes Yes Yes Yes Yes Yes High Ping Yes Yes Yes Yes Yes Yes High Modina et al. 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