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. 2021 Mar 19;13:17. doi: 10.1186/s13099-021-00414-8

Proton pump inhibitors use and risk of developing spontaneous bacterial peritonitis in cirrhotic patients: A systematic review and meta-analysis

Saad Alhumaid 1,✉, Abbas Al Mutair 2,3,4, Zainab Al Alawi 5, Abdul Rehman Zia Zaidi 6,7, Ali A Rabaan 8, Alyaa Elhazmi 6, Awad Al-Omari 6,7
PMCID: PMC7977161  PMID: 33741033

Abstract

Background

Spontaneous bacterial peritonitis (SBP) is one of the most common infectious diseases in patients with cirrhosis and is associated with serious prognosis. A prevailing dogma posits that SBP is exacerbated by the frequent use of proton pump inhibitors (PPIs).

Aims

To re-assess the association between PPIs use and SBP incidence with larger and better-quality data.

Method

The studies were identified by searching Proquest, Medline, and Embase for English language articles published between January 2008 and March 2020 using the following keywords alone or in combination: anti-ulcer agent, antacid, proton pump inhibitor, proton pumps, PPI, omeprazole, rabeprazole, lansoprazole, pantoprazole, esomeprazole, peritonitis, spontaneous bacterial peritonitis, SBP, ascites, cirrhosis, ascitic and cirrhotic. Three authors critically reviewed all of the studies retrieved and selected those judged to be the most relevant. Preferred

Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was followed. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Sub-group analyses were done to decrease the heterogeneity.

Results

A total of twenty-three studies: seven case–control, and sixteen cohorts, involving 10,386 patients were analyzed. The overall results showed a statistically significant association between SBP and PPIs use (pooled odds ratio (OR): 1.80, 95% CI of 1.41 to 2.31). Substantial heterogeneity was observed. On subgroup analysis involving cohort studies, the association was weaker (OR: 1.55 with 95% CI of 1.16 to 2.06 p < 0.00001) but still statistically significant and with high heterogeneity (Chi2p = 57.68; I2 = 74%). For case–control studies, the OR was 2.62 with a 95% CI of 1.94 to 3.54. The funnel plot was asymmetric and Egger’s test confirmed asymmetry suggesting publication bias (intercept = − 0.05, SE = 0.27, P = 0.850 two-tailed).

Conclusion

This meta-analysis sheds light on the conflicting results raised by previous studies regarding the association of SBP with PPIs use. Our meta-analysis showed that there is a weak association, although statistically significant, between SBP and PPIs use. However, the magnitude of the possible association diminished when analysis focused on higher quality data that were more robust. Thus, this updated meta-analysis suggests judicious use of PPIs among cirrhotic patients with ascites.

Keywords: Ascites, Cirrhosis, Meta-analysis, Proton pump inhibitors, Spontaneous bacterial peritonitis, Systematic review

Introduction

Spontaneous bacterial peritonitis (SBP) is defined as an ascitic fluid infection without an evident intra-abdominal surgically treatable source. Despite timely diagnosis and treatment its reported incidence in ascitic patients varies between 7 and 30% [1]. SBP should be suspected in a patient with ascites and any of the following: temperature greater than 37.8 °C (100°F), abdominal pain and/or tenderness, a change in mental status, or ascitic fluid polymorphonuclear leukocyte (PMN) count  ≥ 250 cells/mm3 [2]. SBP is one of the most common infectious diseases in patients with cirrhosis and is associated with a serious prognosis [3]. In-hospital mortality from SBP is estimated at 11–67% [4].

SBP is exacerbated by the frequent use of proton pump inhibitors (PPIs) in cirrhotic patients with ascites, leading to a reduction in gastric acidity and an increase in intestinal permeability which promotes bacterial translocation and colonization of mesenteric lymph nodes [5]. Subsequent infection of the fluid in the peritoneal cavity is also facilitated by the impairment of the body's defense mechanisms [6].

The use of PPIs has been widely reported to be associated with a higher incidence of SBP in hospitalized cirrhotic patients [7–11]. However, previous studies including case controls [7, 10], cohorts [8, 9, 11], and meta-analyses [12–14] provided conflicting conclusions. In light of newer studies that were done to re-evaluate the causality of PPI use and development of SBP, we aimed to re-assess the association between PPI use and SBP incidence with larger and better-quality data.

Methods

Design

We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA) in conducting this systematic review and meta-analysis [16]. The following electronic databases were searched: PROQUEST, MEDLINE, and EMBASE with Full Text. Search keywords included anti-ulcer agents, antacids, proton pump inhibitors, proton pumps, PPI, omeprazole, rabeprazole, lansoprazole, pantoprazole, esomeprazole, peritonitis, spontaneous bacterial peritonitis, SBP, ascites, cirrhosis, ascitic and cirrhotic. The search was limited to papers published in English, between 1 January 2008 and 31 March 2020. The title and abstract of each selected article were read, and the article was retained if it discussed the use of PPIs and the development of SBP. A manual search through the bibliographies of the retrieved publications (backward snowballing) was conducted to increase the yield of potentially relevant articles.

Inclusion–exclusion criteria

Articles were eligible for inclusion in this review and meta-analysis when they met all of these criteria: (1) observational study, including case control, and cohort study evaluating the risk of SBP associated with PPI therapy; (2) study population comprised adult patients (≥ 18 years); (3) SBP (defined as ≥ 250 polymorphonuclear leukocytes in the ascitic fluid) was a study endpoint; (4) hospital- or community-based study; and (5) date of publication between 2008 and 2020 in the English language. Articles were excluded if they met one of the following criteria: (1) editorials, commentaries, news analyses or reviews; (2) no control group of patients; (3) PPI therapy usage data (the type of therapy and who received the drug) was not available or could not be extracted, and (4) data were presented based on SBP episodes and not on the number of actual patients.

Data extraction

Three authors (S.A., A.A. and Z.A.) critically reviewed all of the studies retrieved and selected those judged to be the most relevant. The abstracts of all citations were examined thoroughly. Data were extracted from the relevant research studies using key headings, which are noted in Table 1, simplifying analysis, and review of the literature. Articles were categorized as a case–control or a cohort study. The following data were extracted from selected studies: authors; publication year; study location; study design and setting; sample size, age, gender, and follow-up; statistical adjustment for confounders; and Newcastle–Ottawa Scale (NOS) score.

Table 1.

General characteristics of included studies

Author, year [reference], study location Case/control or case/cohort Age (year), mean (SD) Study design and setting Male, n (%) Adjusted for Follow up (months) NOS score
Aditi et al. 2012 [21]; USA 307/682 Not reported

Retrospective;

cohort;

single center

 Not reported Bilirubin, albumin, creatinine, INR, and protein in ascitic fluid 38 (mean) 7
Bajaj et al. 2009 [22]; USA 70/70 54.5 (13.0) Retrospective; case–control; single center 79 (56.4) CTP class, age, and admission time period – 7
Campbell et al. 2008 [23]; USA 32/84 54.6 (10.7) Retrospective; case–control; single center 78 (67.2)

Age, bilirubin, INR, creatinine, MELD score, DM, gender, history of SBP,

etiology of liver disease, and race

 – 5
Choi et al. 2011 [24]; Korea 83/93 55.5 (10.7) Retrospective; case–control; single center 138 (78.4) CTP class, MELD score, and VB – 7
Cole et al. 2016 [25]; Scotland 114/92 20–74 (range)

Retrospective;

cohort;

single center

 135 (65.5) Age, MELD and UKELD scores, gender, etiology of liver disease, history of decompensate liver disease, and PPIs use 23.7 (median) 8
Dam et al. 2016 [26]; Denmark 340/525 57 (10.4)

Retrospective; cohort;

multicenter

 594 (68.8) Use of PPIs; sex; age; cirrhosis etiology; VB; MELD score; increase of sodium, albumin, and platelets; dose of lactulose, spironolactone, furosemide and potassium-sparing diuretic – 7
De Vos et al. 2013 [27]; Belgium 51/51 56 (8.9) Retrospective; case–control; single center 70 (68.6) None 1.5 (median) 7
Elzouki et al. 2019 [28]; Qatar 171/162 52.8 (12) Retrospective; case–control; single center 260 (78.1) Age, sex, DM, HTN, smoking, RF, and PPIs use – 7
Goel et al. 2012 [7]; USA 65/65 57.6 (11.1)

Retrospective;

case–control;

single center

 83 (63.8) CTP classification 1 (mean) 8
Huang et al. 2016 [29]; Taiwan 1,870/1,190 54.1 (12.5)

Retrospective; cohort;

multicenter

 3,535 (73.8)

Age, sex, CAD,

CHF, HTN,

DM, CKD, ascites, HE, and esophageal varices

 – 7
Janka et al. 2020 [30]; Hungary 74/39 50–64 (range)

Retrospective; cohort;

Single center

 69 (61.1) Compensated stage, age, gender, comorbidity, etiology, MELD score and PPIs use 38.5 (median) 8
Khan et al. 2020 [31]; Pakistan 190/190 46.9 (10.1)

Prospective; cohort;

Single center

 220 (61.1) Age, gender, etiology of liver disease, CTP score, albumin, bilirubin, and PT – 6
Kim et al. 2017 [32]; Korea 58/249 57.7 (10.4)

Retrospective; cohort;

single center

 239 (77.8) Age; sex; CTP score; SBP etiology; platelet count; ALT; GGT; BUN; creatinine; sodium; ascitic fluid protein; HC; H2RAs, PPIs, antibiotics, and Beta-blocker use 60 (mean) 7
Kwon et al. 2014 [33]; Korea 82/451 62.7 (9.5)

Retrospective; cohort;

multicenter

 410 (76.9) Age, MELD score, H2RAs, and PPIs use 1 (mean) 7
Mandorfer et al. 2014 [8]; Austria 520/87 57.5 (11.8)

Retrospective; cohort;

single center

 426 (70.2)

Age, HC, history of

variceal bleed, varices, and MELD score

 9.6 (mean) 8
Min et al. 2014 [34]; Korea 402/402 57.7 (9.8)

Retrospective; cohort;

single center

 609 (75.7) Age, gender, etiology of liver disease, CTP score, platelet count, GGT, BUN, creatinine, sodium, H2RAs, and PPIs use 25.1 (mean) 8
Miozzo et al. 2017 [35]; Brazil 151/107 54 (11.2)

Retrospective; cohort;

single center

 163 (63.4) PPIs use, CTP and MELD scores, and the presence of upper gastrointestinal bleeding 60 (median) 6
Miura et al. 2014 [36]; Japan 18/47 66.3 (9)

Retrospective; cohort;

single center

 44 (67.7) Age; gender; etiology of cirrhosis; DM; platelet count; creatinine; antibiotic, H2RAs and PPIs use; VB, HC, and HE; CTP and MELD scores and INR – 5
O'Leary et al. 2015 [9]; USA 46/142 56.8 (9.3)

Prospective; cohort;

multicenter

 102 (54.1) PPIs use, SBP prophylaxis, age, HR, MELD and CTP scores, platelet count, gender, sodium, albumin, MAP, index SBP infection, and number of infections – 8
Rajender et al. 2019 [37]; India 143/143 51.5 (11.5)

Retrospective; cohort;

single center

 188 (65.7) Age; gender; VB; HE; CTP and MELD scores; bilirubin; creatinine; cause of cirrhosis; ascitic fluid protein; PPIs, H2RAs and B blockers use – 7
Ratelle et al. 2014 [10]; Canada 51/102 60.6 (15.1)

Retrospective; case–control;

single center

 114 (74.5) PPIs use, gender, DM, sodium, and MELD score – 8
Schiavon et al. 2017 [38]; Brazil 93/98 54.3 (12.5)

Prospective; cohort;

Single center

 130 (68.1) Age, DM, previous hepatic encephalopathy and VB 32 (median) 7
Terg et al. 2015 [11]; Argentina 95/289 57.5 (11.5)

Retrospective; cohort;

multicenter

 265 (69) Age, gender, MELD and CTP scores, alcohol, HE, bilirubin, albumin, creatinine, sodium, INR, platelet and leucocytes counts, and PPIs use – 8
Open in a new tab

AKI: acute kidney injury, ALT: alanine aminotransferase, AST: aspartate transaminase, BUN: blood urea nitrogen, CAD: coronary artery disease, CHE: cholinesterase, CHF: congestive heart failure, CKD: chronic kidney disease, CRP: c-reactive protein, CTP: Child–Turcotte–Pugh class, DM: diabetes mellitus, H2RAs: H2 receptor antagonists, HC: hepatocellular carcinoma, HE: hepatic encephalopathy, HIV: human immunodeficiency virus, HR: heart rate, HTN: hypertension, INR: international normalized ratio, GGT: gamma-glutamyl transferase, MAP: mean arterial pressure, MELD: model for end-stage liver disease, NOS: Newcastle–Ottawa Scale, PPIs: proton pump inhibitors, PT: prothrombin time, RF: renal failure, UKELD: UK model for end-stage liver disease, VB: variceal bleeding

Quality assessment

Newcastle–Ottawa Scale (NOS) was used to assess the quality of the selected studies [15]. This assessment scale has two different tools for evaluating case–control and cohort studies. Each tool measures quality in the three parameters of selection, comparability, and exposure/outcome, and allocates a maximum of 4, 2, and 3 points, respectively. High-quality studies are scored greater than 7 on this scale, and moderate-quality studies, between 5 and 7. Quality assessment was performed by two authors (SA and AA) independently, with any disagreement to be resolved by consensus.

Data analysis

Meta-analyses were performed to calculate pooled odds ratios (ORs) with 95% confidence intervals (CIs). The similarity between the OR and other relative measures, such as RR, was assumed because SBP events and deaths were rare [17]. When both the crude and the adjusted OR/RR values were offered, only the adjusted value was adopted for the meta-analysis. If only the raw data was reported, we would calculate the unadjusted OR. Taking a conservative approach, a random effects model was used, which produces wider CIs than a fixed effect model.

Statistical heterogeneity was evaluated using the Cochran's chi-square (χ2) and the I2 statistic [18]. An I2 value of > 50% is suggestive of significant heterogeneity [19]. To detect the source of heterogeneity, subgroup analysis was performed based on study design (case–control or cohort), and quality of studies (high or moderate quality study). A sensitivity analysis was performed by excluding studies with relatively lower methodological quality. Publication bias was evaluated using funnel plots and the Egger’s correlation test, with P < 0.1 indicating statistical significance [20]. Review Manager (Version 5.3, Oxford, UK; The Cochrane Collaboration, 2014) and Stata (Version 13.0, Stata Corp, College Station, TX) were used to carry out all statistical analyses.

Results

Study characteristics and quality

A total of 178 publications were identified (Fig. 1). After scanning titles and abstracts, we discarded 86 duplicate articles. Another 18 irrelevant articles were excluded based on the titles and abstracts. The full texts of the 39 remaining articles were reviewed, and 16 irrelevant articles were excluded. As a result, we identified 23 studies that met our inclusion criteria [7–11, 21–38].

Fig. 1.

Fig. 1

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Flow diagram of studies included in the meta-analysis. SBP spontaneous bacterial peritonitis

The detailed characteristics of the included studies are shown in Table 1. A total of 10,386 patients were included in the meta-analysis, 88.9% (9,236) of whom were part of cohort studies. There were 7 case–control studies and 16 cohort studies. These studies were conducted in North America, South America, Europe, and Asia. All studies adjusted the impact of confounders when assessing the association between PPIs use and SBP development except one study made by de Vos et al. [27]. The potential confounders most often adjusted for were age, Child–Turcotte–Pugh class, and Model for End-stage Liver Disease score. Only eight studies were performed with a multi-center design. The median NOS score for these studies was 7 (range, 5–8). Among the 23 included studies, 15 studies were moderate-quality studies (i.e., NOS scores were between 5 and 7) and 8 studies demonstrated a relatively high quality (i.e., NOS scores > 7; Table 1).

Meta-analysis

The overall analysis of all 23 studies found that PPIs use was significantly associated with risk of SBP (OR = 1.80, 95% CI 1.41–2.31, p < 0.00001), with significant heterogeneity across studies (I2 = 72%, p < 0.00001). For the case–control studies, the pooled OR (95% CI) was 2.62 (1.94–3.54; p = 0.36; I2 = 10%). For the cohort studies, the pooled OR was 1.55 (95% CI 1.16–2.06, p < 0.00001; I2 = 74%; Fig. 2).

Fig. 2.

Fig. 2

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Forest plot for the association of SBP with PPIs use based on the design of the studies. CI confidence interval, PPIs proton pump inhibitors, SBP spontaneous bacterial peritonitis

Subgroup analysis was also carried out separately for high-quality and moderate-quality studies. The pooled OR for high-quality studies was 1.65 (95% CI 1.19–2.29, p = 0.10; I2 = 41%), and the pooled OR for moderate quality studies was 1.87 (95% CI 1.34–2.62, p < 0.00001; I2 = 79%; Fig. 3). The funnel plot for possible publication bias appeared asymmetrical on visual inspection, and Egger’s test confirmed asymmetry (intercept =—0.05, SE = 0.27, p = 0.850 two-tailed); Fig. 4.

Fig. 3.

Fig. 3

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Forest plot for the association of SBP with PPIs use based on the quality of the studies. CI confidence interval, PPIs proton pump inhibitors, SBP spontaneous bacterial peritonitis

Fig. 4.

Fig. 4

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Funnel plot to evaluate publication bias (PPIs use and development of SBP). OR odds ratio, PPI proton pump inhibitor, SBP spontaneous bacterial peritonitis

Discussion

This is the largest meta-analysis on the association between PPI use and risk of developing SBP in cirrhotic patients with/without ascites. This study involving 10,386 patients from 23 observational studies found statistically significant but quantitatively small associations between the development of SBP and the use of PPIs. The pooled data showed that PPIs use was associated with a 1.8-fold increased risk of developing SBP for cirrhotic patients. However, this harmful association was limited to cohort studies. The data from case–control studies demonstrated no causal relationships between the use of PPIs and SBP. The association was not statistically significant in the high-quality studies subgroup.

PPIs are used widely in clinical practice for a broad range of indications in patients. Indications for PPIs include the treatment of peptic ulcer disease, gastroesophageal reflux disease, Zollinger-Ellison syndrome, NSAID-associated ulcers, and eradication of Helicobacter pylori [39, 40]. They are also often used in patients with cirrhosis sometimes in the absence of a specific acid-related disease, with the aim of preventing peptic complications in patients with variceal or hypertensive gastropathic bleeding receiving multidrug treatment [41]. The use of this class of drugs seems more habit-related than evidence-based eventually leading to compromise patient safety and increase health costs [41]. Healthcare providers managing patients with cirrhosis should be aware of the fact that the use of PPIs is not justified in a majority of these patients and should make every effort to evaluate and reassess actively the existing PPI therapy. The use of PPIs by prescribers should be judicious and restricted for indications of proven benefit only.

Most studies involved in our systematic review showed that there was a risk between the use of PPIs and the development of SBP [7, 9, 10, 22, 24–26, 28–31, 33, 34, 36, 37], although few other included studies opposed this association [8, 21, 23, 27, 32, 35, 38]. The difference may be due to the patients with significant liver damage in the former fifteen studies. In addition, the mutant strains and its types, dosage of drugs may affect the results during treatment. The PPIs use and its association with the incidence of SBP in patients with cirrhosis is controversial, probably reflecting the heterogeneity of included patients across the studies and other methodological issues, such as retrospective design and insufficient follow-up. In addition, detrimental effects of PPIs may be restricted to specific subgroups, such as patients with decompensated cirrhosis, especially in the presence of ascites.

Although three latest previous systematic reviews have attempted to evaluate this association [12–14], our review is more current and more comprehensive. We included 21 published studies [7–11, 22–37] and 2 published abstracts [21, 38], with a higher patient population (n = 10,386); and the number of published studies in our analysis exceeds that in previous reviews. The inclusion of four studies published recently [28, 30, 31, 37] to our meta-analysis made a more precise estimate of the pooled OR effect size to evaluate PPI use and its association with incidence of SBP in cirrhotic patients.

Limitations

There are several limitations to our findings. First, the included studies are observational in nature and, therefore, have intrinsic shortcomings, including differences in populations and possible unidentified confounders. Although some of these studies have suggested an association between PPIs therapy and SBP, they cannot establish causality with certainty. Well-designed, multi-center trials are needed for this purpose. To date, there are no prospective clinical trials, randomizing cirrhotic patients with/without ascites to PPIs use or non-use, which could be difficult to justify on clinical, ethical, or economic bases. Second, adjustment for the duration of PPIs was not possible therapy because many of the included studies did not report on the relevant data. Both duration and dose of PPI treatment should be related to the risk for the outcome of interest to support a causal association. Last, the exclusion of studies published in languages other than English may have impacted the richness of the data included in this review.

Conclusion

Our meta-analysis of observational studies found that PPI use was associated with an increased risk of SBP in patients with cirrhosis with/without ascites. However, the magnitude of the possible association diminished when analysis focused on higher quality data that were more robust. PPIs can be used in the treatment of various therapeutic indications; nevertheless, PPIs therapy should be administered with caution in cirrhotic patients. Future studies maybe need to clarify the relationship between the occurrence of SBP and the type and dose of PPI in cirrhotic patients.

Acknowledgement

We would like to thank authors and their colleagues who contributed to the availability of evidence needed to compile this article.

Abbreviations

SBP

Spontaneous bacterial peritonitis

PPIs

Proton pump inhibitors

PRISMA

Preferred Reporting Items for systematic reviews and meta-Analyses

NOS

Newcastle–Ottawa scale

PMN

Polymorphonuclear leukocyte

Authors’ contributions

SA, AA, ZA, AAR and AAO contributed equally to this article. SA, AA and ZA.—Conception, proposal, data collection, data analysis, and manuscript preparation. All authors read and approved the final manuscript.

Funding

This research received no external funding.

Availability of data and materials

Data are available upon request, please contact author for data requests.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

All authors agreed to this publication.

Competing interest

The authors have no conflicts of interest to declare.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Contributor Information

Saad Alhumaid, Email: saalhumaid@moh.gov.sa.

Abbas Al Mutair, Email: abbas4080@hotmail.com.

Zainab Al Alawi, Email: dr_z.alawi@hotmail.com.

Abdul Rehman Zia Zaidi, Email: ar-zia@hotmail.com.

Ali A. Rabaan, Email: arabaan@gmail.com

Alyaa Elhazmi, Email: a.m.haz@live.com.

Awad Al-Omari, Email: awad.omari@drsulaimanalhabib.com.

References

  • 1.Koulaouzidis A, Bhat S, Karagiannidis A, Tan W, Linaker B. Spontaneous bacterial peritonitis. Postgrad Med J. 2007;83(980):379–383. doi: 10.1136/pgmj.2006.056168. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Runyon BA. The evolution of ascitic fluid analysis in the diagnosis of spontaneous bacterial peritonitis. Am J Gastroenterol. 2003;98(8):1675. doi: 10.1111/j.1572-0241.2003.07600.x. [DOI] [PubMed] [Google Scholar]
  • 3.Fernández J, Navasa M, Gómez J, Colmenero J, Vila J, Arroyo V, Rodés J. Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis. Hepatology. 2002;35(1):140–148. doi: 10.1053/jhep.2002.30082. [DOI] [PubMed] [Google Scholar]
  • 4.Tandon P, Garcia-Tsao G. Renal dysfunction is the most important independent predictor of mortality in cirrhotic patients with spontaneous bacterial peritonitis. Clin Gastroenterol Hepatol. 2011;9(3):260–265. doi: 10.1016/j.cgh.2010.11.038. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Guarner C, Runyon BA, Young S, Heck M, Sheikh MY. Intestinal bacterial overgrowth and bacterial translocation in cirrhotic rats with ascites. J Hepatol. 1997;26(6):1372–1378. doi: 10.1016/S0168-8278(97)80474-6. [DOI] [PubMed] [Google Scholar]
  • 6.Pardo A, Bartolí R, Lorenzo-Zúñiga V, Planas R, Viñado B, Riba J, Cabré E, Santos J, Luque T, Ausina V. Effect of cisapride on intestinal bacterial overgrowth and bacterial translocation in cirrhosis. Hepatology. 2000;31(4):858–863. doi: 10.1053/he.2000.5746. [DOI] [PubMed] [Google Scholar]
  • 7.Goel GA, Deshpande A, Lopez R, Hall GS, van Duin D, Carey WD. Increased rate of spontaneous bacterial peritonitis among cirrhotic patients receiving pharmacologic acid suppression. Clin Gastroenterol Hepatol. 2012;10(4):422–427. doi: 10.1016/j.cgh.2011.11.019. [DOI] [PubMed] [Google Scholar]
  • 8.Mandorfer M, Bota S, Schwabl P, Bucsics T, Pfisterer N, Summereder C, Hagmann M, Blacky A, Ferlitsch A, Sieghart W. Proton pump inhibitor intake neither predisposes to spontaneous bacterial peritonitis or other infections nor increases mortality in patients with cirrhosis and ascites. PLoS ONE. 2014;9(11). [DOI] [PMC free article] [PubMed]
  • 9.O'Leary JG, Reddy KR, Wong F, Kamath PS, Patton HM, Biggins SW, Fallon MB, Garcia-Tsao G, Subramanian RM, Malik R. Long-term use of antibiotics and proton pump inhibitors predict development of infections in patients with cirrhosis. Clinical Gastroenterol Hepatol. 2015;13(4):753–9.e2. doi: 10.1016/j.cgh.2014.07.060. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Ratelle M, Perreault S, Villeneuve J-P, Tremblay L. Association between proton pump inhibitor use and spontaneous bacterial peritonitis in cirrhotic patients with ascites. Canadian J Gastroenterol Hepatol. 2014;28(6):330–334. doi: 10.1155/2014/751921. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Terg R, Casciato P, Garbe C, Cartier M, Stieben T, Mendizabal M, Niveyro C, Benavides J, Marino M, Colombato L. Proton pump inhibitor therapy does not increase the incidence of spontaneous bacterial peritonitis in cirrhosis: a multicenter prospective study. J Hepatol. 2015;62(5):1056–1060. doi: 10.1016/j.jhep.2014.11.036. [DOI] [PubMed] [Google Scholar]
  • 12.Khan MA, Kamal S, Khan S, Lee WM, Howden CW. Systematic review and meta-analysis of the possible association between pharmacological gastric acid suppression and spontaneous bacterial peritonitis. Eur J Gastroenterol Hepatol. 2015;27(11):1327–1336. doi: 10.1097/MEG.0000000000000448. [DOI] [PubMed] [Google Scholar]
  • 13.Yu T, Tang Y, Jiang L, Zheng Y, Xiong W, Lin L. Proton pump inhibitor therapy and its association with spontaneous bacterial peritonitis incidence and mortality: a meta-analysis. Dig Liver Dis. 2016;48(4):353–359. doi: 10.1016/j.dld.2015.12.009. [DOI] [PubMed] [Google Scholar]
  • 14.Dong H, Luo S, Dong Y, Feng W, Wei Y. The use of PPI is associated with spontaneous bacterial peritonitis in cirrhotic patients of different ethnic groups: a meta-analysis. Int J Clin Exp Med. 2016;9(2):1227–1235. [Google Scholar]
  • 15.Wells GA, Tugwell P, O’Connell D, Welch V, Peterson J, Shea B, Losos M. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses. 2015.
  • 16.Moher D, Liberati A, Tetzlaff J, Altman DG, Group P Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097. doi: 10.1371/journal.pmed.1000097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Davies HTO, Crombie IK, Tavakoli M. When can odds ratios mislead? BMJ. 1998;316(7136):989–991. doi: 10.1136/bmj.316.7136.989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539–1558. doi: 10.1002/sim.1186. [DOI] [PubMed] [Google Scholar]
  • 19.Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–560. doi: 10.1136/bmj.327.7414.557. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629–634. doi: 10.1136/bmj.315.7109.629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Aditi A, Crippin JS, Abhishek A. Sa1014 Role of proton pump inhibitors in the development of spontaneous bacterial peritonitis amongst cirrhotics; a retrospective cohort study. Gastroenterol. 2012;142(5):S-946. doi: 10.1016/S0016-5085(12)63667-1. [DOI] [Google Scholar]
  • 22.Bajaj JS, Zadvornova Y, Heuman DM, Hafeezullah M, Hoffmann RG, Sanyal AJ, Saeian K. Association of proton pump inhibitor therapy with spontaneous bacterial peritonitis in cirrhotic patients with ascites. Am J Gastroenterol. 2009;104(5):1130–1134. doi: 10.1038/ajg.2009.80. [DOI] [PubMed] [Google Scholar]
  • 23.Campbell MS, Obstein K, Reddy KR, Yang Y-X. Association between proton pump inhibitor use and spontaneous bacterial peritonitis. Dig Dis Sci. 2008;53(2):394–398. doi: 10.1007/s10620-007-9899-9. [DOI] [PubMed] [Google Scholar]
  • 24.Choi EJ, Lee HJ, Kim KO, Lee SH, Eun JR, Jang BI, Kim TN. Association between acid suppressive therapy and spontaneous bacterial peritonitis in cirrhotic patients with ascites. Scand J Gastroenterol. 2011;46(5):616–620. doi: 10.3109/00365521.2011.551891. [DOI] [PubMed] [Google Scholar]
  • 25.Cole H, Pennycook S, Hayes P. The impact of proton pump inhibitor therapy on patients with liver disease. Aliment Pharmacol Ther. 2016;44(11–12):1213–1223. doi: 10.1111/apt.13827. [DOI] [PubMed] [Google Scholar]
  • 26.Dam G, Vilstrup H, Watson H, Jepsen P. Proton pump inhibitors as a risk factor for hepatic encephalopathy and spontaneous bacterial peritonitis in patients with cirrhosis with ascites. Hepatology. 2016;64(4):1265–1272. doi: 10.1002/hep.28737. [DOI] [PubMed] [Google Scholar]
  • 27.de Vos M, De Vroey B, Garcia BG, Roy C, Kidd F, Henrion J, Deltenre P. Role of proton pump inhibitors in the occurrence and the prognosis of spontaneous bacterial peritonitis in cirrhotic patients with ascites. Liver Int. 2013;33(9):1316–1323. doi: 10.1111/liv.12210. [DOI] [PubMed] [Google Scholar]
  • 28.Elzouki A-N, Neffati N, Rasoul FA, Abdallah A, Othman M, Waness A. Increased risk of Spontaneous bacterial peritonitis in cirrhotic patients using proton pump inhibitors GE-Portuguese. J Gastroenterol. 2019;26(2):83–89. doi: 10.1159/000487963. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Huang K-W, Kuan Y-C, Luo J-C, Lin C-L, Liang J-A, Kao C-H. Impact of long-term gastric acid suppression on spontaneous bacterial peritonitis in patients with advanced decompensated liver cirrhosis. Eur J Intern Med. 2016;32:91–95. doi: 10.1016/j.ejim.2016.04.016. [DOI] [PubMed] [Google Scholar]
  • 30.Janka T, Tornai T, Borbély B, Tornai D, Altorjay I, Papp M, Vitális Z. Deleterious effect of proton pump inhibitors on the disease course of cirrhosis. Eur J Gastroenterol Hepatol. 2020;32(2):257–264. doi: 10.1097/MEG.0000000000001499. [DOI] [PubMed] [Google Scholar]
  • 31.Khan TU, Khan W, Iqbal S. Frequency of spontaneous bacterial peritonintis in chronic liver disease patients using proton pump inhibitors. Professional Medical Journal. 2020;27(3).
  • 32.Kim JH, Lim KS, Min YW, Lee H, Min BH, Rhee PL, Kim JJ, Koh KC, Paik SW. Proton pump inhibitors do not increase the risk for recurrent spontaneous bacterial peritonitis in patients with cirrhosis. J Gastroenterol Hepatol. 2017;32(5):1064–1070. doi: 10.1111/jgh.13637. [DOI] [PubMed] [Google Scholar]
  • 33.Kwon JH, Koh SJ, Kim W, Jung YJ, Kim JW, Kim BG, Lee KL, Im JP, Kim YJ, Kim JS. Mortality associated with proton pump inhibitors in cirrhotic patients with spontaneous bacterial peritonitis. J Gastroenterol Hepatol. 2014;29(4):775–781. doi: 10.1111/jgh.12426. [DOI] [PubMed] [Google Scholar]
  • 34.Min Y, Lim K, Min BH, Gwak GY, Paik Y, Choi M, Lee J, Kim J, Koh K, Paik S. Proton pump inhibitor use significantly increases the risk of spontaneous bacterial peritonitis in 1965 patients with cirrhosis and ascites: a propensity score matched cohort study. Aliment Pharmacol Ther. 2014;40(6):695–704. doi: 10.1111/apt.12875. [DOI] [PubMed] [Google Scholar]
  • 35.Miozzo SA, John JA, Appel-da-Silva MC, Dossin IA, Tovo CV, Mattos AA. Influence of proton pump inhibitors in the development of spontaneous bacterial peritonitis. World J Hepatol. 2017;9(35):1278. doi: 10.4254/wjh.v9.i35.1278. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Miura K, Tanaka A, Yamamoto T, Adachi M, Takikawa H. Proton pump inhibitor use is associated with spontaneous bacterial peritonitis in patients with liver cirrhosis. Intern Med. 2014;53(10):1037–1042. doi: 10.2169/internalmedicine.53.2021. [DOI] [PubMed] [Google Scholar]
  • 37.Rajender A, Choudhary P, Mathur S, Bhargava R, Upadhyay S, Nepalia S. Proton pump inhibitor: a risk factor for spontaneous bacterial peritonitis in Indian cirrhotics decompensated with ascites. Int J Res Med Sci. 2019;7(2):378. doi: 10.18203/2320-6012.ijrms20190338. [DOI] [Google Scholar]
  • 38.Schiavon L, Silva T, Fischer J, Narciso-Schiavon J. proton pump inhibitors and prognosis of cirrhosis–searching for the balance point. Aliment Pharmacol Ther. 2017;45(2):378–379. doi: 10.1111/apt.13873. [DOI] [PubMed] [Google Scholar]
  • 39.Welage LS, Berardi RR. Evaluation of omeprazole, lansoprazole, pantoprazole, and rabeprazole in the treatment of acid-related diseases. Journal of the American Pharmaceutical Association (1996). 2000;40(1):52–62. [DOI] [PubMed]
  • 40.Savarino V, Dulbecco P, de Bortoli N, Ottonello A, Savarino E. The appropriate use of proton pump inhibitors (PPIs): need for a reappraisal. Eur J Intern Med. 2017;37:19–24. doi: 10.1016/j.ejim.2016.10.007. [DOI] [PubMed] [Google Scholar]
  • 41.Lodato F, Azzaroli F, Di Girolamo M, Feletti V, Cecinato P, Lisotti A, Festi D, Roda E, Mazzella G. Proton pump inhibitors in cirrhosis: tradition or evidence based practice? World J Gastroenterol. 2008;14(19):2980. doi: 10.3748/wjg.14.2980. [DOI] [PMC free article] [PubMed] [Google Scholar]

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