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24.01.2019 | Systematic Review

Stress ulcer prophylaxis with proton pump inhibitors or histamin-2 receptor antagonists in adult intensive care patients: a systematic review with meta-analysis and trial sequential analysis

verfasst von: Marija Barbateskovic, Søren Marker, Anders Granholm, Carl Thomas Anthon, Mette Krag, Janus Christian Jakobsen, Anders Perner, Jørn Wetterslev, Morten Hylander Møller

Erschienen in: Intensive Care Medicine | Ausgabe 2/2019

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Abstract

Purpose

Most intensive care unit (ICU) patients receive stress ulcer prophylaxis. We present updated evidence on the effects of prophylactic proton pump inhibitors (PPIs) or histamine 2 receptor antagonists (H2RAs) versus placebo/no prophylaxis on patient-important outcomes in adult ICU patients.

Methods

We conducted a systematic review with meta-analysis and trial sequential analysis (TSA) of randomised clinical trials assessing the effects of PPI/H2RA versus placebo/no prophylaxis on mortality, gastrointestinal (GI) bleeding, serious adverse events (SAEs), health-related quality of life (HRQoL), myocardial ischemia, pneumonia, and Clostridium (Cl.) difficile enteritis in ICU patients.

Results

We identified 42 trials randomising 6899 ICU patients; 3 had overall low risk of bias. We did not find an effect of stress ulcer prophylaxis on mortality [relative risk 1.03, 95% confidence interval (CI) 0.94–1.14; TSA-adjusted CI 0.94–1.14], but the occurrence of any GI bleeding was reduced as compared with placebo/no prophylaxis (0.60, 95% CI 0.47–0.77; TSA-adjusted CI 0.36–1.00). The conventional meta-analysis indicated that clinically important GI bleeding was reduced (RR 0.63, 95% CI 0.48–0.81), but the TSA-adjusted CI 0.35–1.13 indicated lack of firm evidence. The effects of stress ulcer prophylaxis on SAEs, HRQoL, pneumonia, myocardial ischemia and Cl. difficile enteritis are uncertain.

Conclusions

In this updated systematic review, we were able to refute a relative change of 20% of mortality. The occurrence of GI bleeding was reduced, but we lack firm evidence for a reduction in clinically important GI bleeding. The effects on SAEs, HRQoL, pneumonia, myocardial ischemia and Cl. difficile enteritis remain inconclusive.

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Marik PE, Vasu T, Hirani A, Pachinburavan M (2010) Stress ulcer prophylaxis in the new millennium: a systematic review and meta-analysis. Crit Care Med 38(11):2222–2228PubMedCrossRef

Krag M, Perner A, Wetterslev J, Wise M, Borthwick M, Bendel S et al (2015) Prevalence and outcome of gastrointestinal bleeding and use of acid suppressants in acutely ill adult intensive care patients. Intensive Care Med 41(5):833–845PubMedCrossRef

Krag M, Marker S, Perner A, Wetterslev J, Wise MP, Schefold JC et al (2018) Pantoprazole in patients at risk for gastrointestinal bleeding in the ICU. N Eng J Med. https://doi.org/10.1056/nejmoa1714919 CrossRef

Alhazzani W, Guyatt G, Alshahrani M, Deane AM, Marshall JC, Hall R et al (2017) Withholding pantoprazole for stress ulcer prophylaxis in critically ill patients: a pilot randomized clinical trial and meta-analysis. Crit Care Med 45(7):1121–1129PubMedCrossRef

Selvanderan SP, Summers MJ, Finnis ME, Plummer MP, Ali Abdelhamid Y, Anderson MB et al (2016) Pantoprazole or placebo for stress ulcer prophylaxis (pop-up): randomized double-blind exploratory study. Crit Care Med 44(10):1842–1850PubMedCrossRef

Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R et al (2017) Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med 43(3):304–377PubMedCrossRef

Madsen KR, Lorentzen K, Clausen N, Oberg E, Kirkegaard PR, Maymann-Holler N et al (2014) Guideline for stress ulcer prophylaxis in the intensive care unit. Dan Med J 61(3):C4811PubMed

Krag M, Perner A, Wetterslev J, Moller MH (2013) Stress ulcer prophylaxis in the intensive care unit: is it indicated? A topical systematic review. Acta Anaesthesiol Scand 57(7):835–847PubMedCrossRef

Marker S, Krag M, Moller MH (2017) What’s new with stress ulcer prophylaxis in the ICU? Intensive Care Med 43(8):1132–1134PubMedCrossRef

10.

Alhazzani W, Alenezi F, Jaeschke RZ, Moayyedi P, Cook DJ (2013) Proton pump inhibitors versus histamine 2 receptor antagonists for stress ulcer prophylaxis in critically ill patients: a systematic review and meta-analysis. Crit Care Med 41(3):693–705PubMedCrossRef

11.

Lin PC, Chang CH, Hsu PI, Tseng PL, Huang YB (2010) The efficacy and safety of proton pump inhibitors vs histamine-2 receptor antagonists for stress ulcer bleeding prophylaxis among critical care patients: a meta-analysis. Crit Care Med 38(4):1197–1205PubMedCrossRef

12.

Kantorova I, Svoboda P, Scheer P, Doubek J, Rehorkova D, Bosakova H et al (2004) Stress ulcer prophylaxis in critically ill patients: a randomized controlled trial. Hepatogastroenterology 51(57):757–761PubMed

13.

Pongprasobchai S, Kridkratoke S, Nopmaneejumruslers C (2009) Proton pump inhibitors for the prevention of stress-related mucosal disease in critically-ill patients: a meta-analysis. J Med Assoc Thai 92(5):632–637PubMed

14.

Barkun AN, Bardou M, Pham CQ, Martel M (2012) Proton pump inhibitors vs. histamine 2 receptor antagonists for stress-related mucosal bleeding prophylaxis in critically ill patients: a meta analysis. Am J Gastroenterol 107(4):507–520PubMedCrossRef

15.

Alshamsi F, Belley-Cote E, Cook D, Almenawer SA, Alqahtani Z, Perri D et al (2016) Efficacy and safety of proton pump inhibitors for stress ulcer prophylaxis in critically ill patients: a systematic review and meta-analysis of randomized trials. Crit Care 20(1):120PubMedPubMedCentralCrossRef

16.

Liu BL, Li B, Zhang X, Fei Z, Hu SJ, Lin W et al (2013) A randomized controlled study comparing omeprazole and cimetidine for the prophylaxis of stress-related upper gastrointestinal bleeding in patients with intracerebral hemorrhage. J Neurosurg 118(1):115–120PubMedCrossRef

17.

Lin CC, Hsu YL, Chung CS, Lee TH (2016) Stress ulcer prophylaxis in patients being weaned from the ventilator in a respiratory care center: a randomized control trial. J Formos Med Assoc 115(1):19–24PubMedCrossRef

18.

El-Kersh K, Jalil B, Mcclave SA, Cavallazzi R, Guardiola J, Guilkey K et al (2018) Enteral nutrition as stress ulcer prophylaxis in critically ill patients: a randomized controlled exploratory study. J Crit Care 43:108–113PubMedCrossRef

19.

Barbateskovic M, Marker S, Jakobsen JC, Krag M (2018) Stress ulcer prophylaxis in adult intensive care unit patients—a protocol for a systematic review. Acta Anaesthesiol Scand 62(6):744–755PubMedCrossRef

20.

Higgins JPT, Green S (eds) (2011) Cochrane handbook for systematic reviews of interventions version 5.1.0. Updated March 2011. The cochrane collaboration, 2011. Available from www.handbook.cochrane.org

21.

Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP et al (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 339:b2700PubMedPubMedCentralCrossRef

22.

Keus F, Wetterslev J, Gluud C, Van Laarhoven CJ (2010) Evidence at a glance: error matrix approach for overviewing available evidence. BMC Med Res Methodol 10:90PubMedPubMedCentralCrossRef

23.

Jakobsen JC, Wetterslev J, Winkel P, Lange T, Gluud C (2014) Thresholds for statistical and clinical significance in systematic reviews with meta-analytic methods. BMC Med Res Methodol 14:120PubMedPubMedCentralCrossRef

24.

Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S et al (2004) Grading quality of evidence and strength of recommendations. BMJ 328(7454):1490PubMedCrossRef

25.

International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use (1997). ICH harmonised tripartite guideline. Guideline for good clinical practice. Updated July 2002

26.

Savovic J, Turner RM, Mawdsley D, Jones HE, Beynon R, Higgins JPT et al (2018) Association between risk-of-bias assessments and results of randomized trials in cochrane reviews: the ROBES meta-epidemiologic study. Am J Epidemiol 187(5):1113–1122PubMedCrossRef

27.

Harbord RM, Egger M, Sterne JA (2006) A modified test for small-study effects in meta-analyses of controlled trials with binary endpoints. Stat Med 25(20):3443–3457PubMedCrossRef

28.

Thorlund K EJ, Wetterslev J, Brok J, Imberger G, Gluud C. User manual for trial sequential analysis (TSA). Www.Ctu.Dk/Tsa/Files/Tsa_Manual.Pdf. Accessed 15 Oct 2018

29.

Wetterslev J, Jakobsen JC, Gluud C (2017) Trial sequential analysis in systematic reviews with meta-analysis. BMC Med Res Methodol 17(1):39PubMedPubMedCentralCrossRef

30.

Revman (2014) Review manager (Revman) (computer program), version 5.3. The Nordic Cochrane Center, the Cochrane Collaboration, Copenhagen. https://Community.Cochrane.Org/Help/Tools-and-Software/Revman-5/Revman-5-Download. Accessed 15 Oct 2018

31.

Wetterslev J, Thorlund K, Brok J, Gluud C (2009) Estimating required information size by quantifying diversity in random-effects model meta-analyses. BMC Med Res Methodol 9:86PubMedPubMedCentralCrossRef

32.

Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22(4):719–748PubMed

33.

Demets DL (1987) Methods for combining randomized clinical trials: strengths and limitations. Stat Med 6(3):341–350PubMedCrossRef

34.

Dersimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188PubMedCrossRef

35.

Deeks JJ, Higgins JPT (2010) Statistical algorithms in review manager 5. 2010: RevMan 5.3

36.

Brok J, Thorlund K, Gluud C, Wetterslev J (2008) Trial sequential analysis reveals insufficient information size and potentially false positive results in many meta-analyses. J Clin Epidemiol 61(8):763–769PubMedCrossRef

37.

Brok J, Thorlund K, Wetterslev J, Gluud C (2009) Apparently conclusive meta-analyses may be inconclusive—trial sequential analysis adjustment of random error risk due to repetitive testing of accumulating data in apparently conclusive neonatal meta-analyses. Int J Epidemiol 38(1):287–298PubMedCrossRef

38.

Higgins JP, Whitehead A, Simmonds M (2011) Sequential methods for random-effects meta-analysis. Stat Med 30(9):903–921PubMedCrossRef

39.

Imberger G, Gluud C, Boylan J, Wetterslev J (2015) Systematic reviews of anesthesiologic interventions reported as statistically significant: problems with power, precision, and type 1 error protection. Anesth Analg 121(6):1611–1622PubMedCrossRef

40.

Mascha EJ (2015) Alpha, beta, meta: guidelines for assessing power and type i error in meta-analyses. Anesth Analg 121(6):1430–1433PubMedCrossRef

41.

Pogue JM, Yusuf S (1997) Cumulating evidence from randomized trials: utilizing sequential monitoring boundaries for cumulative meta-analysis. Control Clin Trials 18(6):580–593PubMedCrossRef

42.

Terkawi AS, Mavridis D, Flood P, Wetterslev J, Terkawi RS, Bin Abdulhak AA et al (2016) Does ondansetron modify sympathectomy due to subarachnoid anesthesia?: Meta-analysis, meta-regression, and trial sequential analysis. Anesthesiology 124(4):846–869PubMedCrossRef

43.

Thorlund K, Devereaux PJ, Wetterslev J, Guyatt G, Ioannidis JP, Thabane L et al (2009) Can trial sequential monitoring boundaries reduce spurious inferences from meta-analyses? Int J Epidemiol 38(1):276–286PubMedCrossRef

44.

Wetterslev J, Thorlund K, Brok J, Gluud C (2008) Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis. J Clin Epidemiol 61(1):64–75PubMedCrossRef

45.

Thorlund K, Imberger G, Johnston BC, Walsh M, Awad T, Thabane L et al (2012) Evolution of heterogeneity (I2) estimates and their 95% confidence intervals in large meta-analyses. PLoS ONE 7(7):e39471PubMedPubMedCentralCrossRef

46.

Apte NM, Karnad DR, Medhekar TP, Tilve GH, Morye S, Bhave GG (1992) Gastric colonization and pneumonia in intubated critically ill patients receiving stress ulcer prophylaxis: a randomized controlled trial. Crit Care Med 20(5):590–593PubMedCrossRef

47.

Basso N, Bagarani M, Materia A, Fiorani S, Lunardi P, Speranza V (1981) Cimetidine and antacid prophylaxis of acute upper gastrointestinal bleeding in high risk patients: controlled, randomized trial. Am J Surg 141(3):339–341PubMedCrossRef

48.

Ben-Menachem T, Fogel R, Patel RV, Touchette M, Zarowitz BJ, Hadzijahic N et al (1994) Prophylaxis for stress-related gastric hemorrhage in the medical intensive care unit: a randomized, controlled, single-blind study. Ann Intern Med 121(8):568–575PubMedCrossRef

49.

Van Den Berg B, Van Blankenstein M (1985) Prevention of stress-induced upper gastrointestinal bleeding by cimetidine in patients on assisted ventilation. Digestion 31(1):1–8PubMedCrossRef

50.

Burgess P, Larson GM, Davidson P, Brown J, Metz CA (1995) Effect of ranitidine on intragastric ph and stress-related upper gastrointestinal bleeding in patients with severe head injury. Dig Dis Sci 40(3):645–650PubMedCrossRef

51.

Cartier F, Gauthier-Lafaye P, Lareng L, Mottin J, Cara M, Passelecq J et al (1980) Cimetideine in patients at risk of stress ulcers: a multi-centre controlled trial. Intensive Care Med 6:54

52.

Chan KH, Lai EC, Tuen H, Ngan JH, Mok F, Fan YW et al (1995) Prospective double-blind placebo-controlled randomized trial on the use of ranitidine in preventing postoperative gastroduodenal complications in high-risk neurosurgical patients. J Neurosurg 82(3):413–417PubMedCrossRef

53.

Darlong V, Jayalakhsmi TS, Kaul HL, Tandon R (2003) Stress ulcer prophylaxis in patients on ventilator. Trop Gastroenterol 24(3):124–128PubMed

54.

Domingues SHS, Stoeber GH, Stoeber AC (1985) Ranitidina Injetável Em Pacientes De Alto Risco. Folha Med 91(3):225–228

55.

Friedman CJ, Oblinger MJ, Suratt PM, Bowers J, Goldberg SK, Sperling MH et al (1982) Prophylaxis of upper gastrointestinal hemorrhage in patients requiring mechanical ventilation. Crit Care Med 10(5):316–319PubMedCrossRef

56.

Groll A, Simon JB, Wigle RD, Taguchi K, Todd RJ, Depew WT (1986) Cimetidine prophylaxis for gastrointestinal bleeding in an intensive care unit. Gut 27(2):135–140PubMedPubMedCentralCrossRef

57.

Gundogan K, Karakoc E, Teke T, Zerman A, Coruh A, Sungur M (2017) Effects of enteral nutrition on stress ulcer hemorrhage in critically ill patients: multicenter randomized controlled trial. Intensive Care Med Exp 5(2):44

58.

Gursoy O, Memis D, Sut N (2008) Effect of proton pump inhibitors on gastric juice volume, gastric ph and gastric intramucosal pH in critically ill patients: a randomized, double-blind placebo-controlled study. Clin Drug Investig 28(12):777–782PubMedCrossRef

59.

Halloran LG, Zfass AM, Gayle WE, Wheeler CB, Miller JD (1980) Prevention of acute gastrointestinal complications after severe head injury: a controlled trial of cimetidine prophylaxis. Am J Surg 139(1):44–48PubMedCrossRef

60.

Hanisch EW, Encke A, Naujoks F, Windolf J (1998) A randomized, double-blind trial for stress ulcer prophylaxis shows no evidence of increased pneumonia. Am J Surg 176(5):453–457PubMedCrossRef

61.

Hummer-Sigiel M, Jacquier A, Girard A, Garric J, Laxenaire MC, Mandorla JY (1986) Ranitidine Pour La Prophylaxie De L’ulcére De Stress Chexz Les Traumatisés Crâniens Graves. Ann Med Nancy l’Est 25:101–103

62.

Jakob SM, Parviainen I, Ruokonen E, Uusaro A, Takala J (2005) Lack of effect of ranitidine on gastric luminal Ph and mucosal PCO2 during the first day in the ICU. Acta Anaesthesiol Scand 49(3):390–396PubMedCrossRef

63.

Kam J, Modi C, Doraiswamy V, Abdul-Jawad S, Dixit D, Spira T et al (2011) Role of gastrointestinal ulcer prophylaxis in critically ill patients. Am J Gastroenterol 106(suppl. 2):s420CrossRef

64.

Karlstadt RG, Iberti TJ, Silverstein J, Lindenberg L, Bright-Asare P, Rockhold F et al (1990) Comparison of cimetidine and placebo for the prophylaxis of upper gastrointestinal bleeding due to stress-related gastric mucosal damage in the intensive care unit. J Intensive Care Med 5:26–32CrossRef

65.

Koelz HR, Aeberhard P, Hassler H, Kunz H, Wagner HE, Roth F et al (1987) Prophylactic treatment of acute gastroduodenal stress ulceration: low-dose antacid treatment without and with additional ranitidine. Scand J Gastroenterol 22(9):1147–1152PubMedCrossRef

66.

Larson GM, Davidson P, Brown J, Wilson T, Bishop A (1989) Comparison of ranitidine versus placebo on 24-hour gastric Ph and upper gastrointestinal (UGI) bleeding in head injury patients. Abstr Am J Gastroenterol 84:1165

67.

Luk GD, Summer WR, Messersmith JF (1982) Cimetidine and antacid in prophylaxis of acute gastrointestinal bleeding: a randomized, double-blind, controlled study. Gastroenterology 82:1121

68.

Macdougall BR, Bailey RJ, Williams R (1977) H2-receptor antagonists and antacids in the prevention of acute gastrointestinal haemorrhage in fulminant hepatic failure: two controlled trials. Lancet 1(8012):617–619PubMedCrossRef

69.

Martin LF, Booth FV, Karlstadt RG, Silverstein JH, Jacobs DM, Hampsey J et al (1993) Continuous intravenous cimetidine decreases stress-related upper gastrointestinal hemorrhage without promoting pneumonia. Crit Care Med 21(1):19–30PubMedCrossRef

70.

Metz CA, Livingston DH, Smith JS, Larson GM, Wilson TH (1993) Impact of multiple risk factors and ranitidine prophylaxis on the development of stress-related upper gastrointestinal bleeding: a prospective, multicenter, double-blind, randomized trial. The Ranitidine Head Injury Study Group. Crit Care Med 21(12):1844–1849PubMedCrossRef

71.

Nielsen HJ, Witt K, Moesgaard F, Kehlet H (1989) Ranitidine for improvement of delayed hypersensitivity response in patients with sepsis. Acta Chir Scand 155(9):445–449PubMed

72.

Peura DA, Johnson LF (1985) Cimetidine for prevention and treatment of gastroduodenal mucosal lesions in patients in an intensive care unit. Ann Intern Med 103(2):173–177PubMedCrossRef

73.

Powell H, Morgan M, Li SK, Baron JH (1993) Inhibition of gastric acid secretion in the intensive care unit after coronary artery bypass graft. Theor Surg 8:125–130

74.

Rigaud D, Accary JP, Chastre J, Mignon M, Laigneau JP, Reinberg A et al (1988) Persistence of circadian rhythms in gastric acid, gastrin, and pancreatic polypeptide secretions despite loss of cortisol and body temperature rhythms in man under stress. Gastroenterol Clin Biol 12(1):12–18PubMed

75.

Rohde H, Lorenz W, Fischer M (1980) Eine Randomisierte Klinische Studie Zur Stressulkusprophylaxe Mit Cimetidin Beim Schweren Polytrauma. Z Gastroenterol 18(6):328–329PubMed

76.

Ruiz-Santana S, Ortiz E, Gonzalez B, Bolanos J, Ruiz-Santana AJ, Manzano JL (1991) Stress-induced gastroduodenal lesions and total parenteral nutrition in critically ill patients: frequency, complications, and the value of prophylactic treatment: a prospective, randomized study. Crit Care Med 19(7):887–891PubMedCrossRef

77.

Spapen H, Diltoer M, Nguyen DN, Ingels G, Ramet J, Huyghens L (1995) One week treatment with cimetidine does not attenuate the cortisol response to a short corticotropin test in stable intensive care patients: a prospective, randomized, and controlled study. Acta Anaesthesiol Belg 46(3–4):133–140PubMed

78.

Vlatten A, Wiedeck H, Reinelt H, Stanescu A, Georgieff M (1998) Stressulkus-Prophylaxe Bei Hoch-Risiko-Intensivpatienten. Vergleich Von Omeprazol, Pirenzepin Und Plazebo. Wien Klin Wochenschr Suppl 110(suppl. 1):38

79.

Zinner MJ, Zuidema GD, Smith P, Mignosa M (1981) The prevention of upper gastrointestinal tract bleeding in patients in an intensive care unit. Surg Gynecol Obstet 153(2):214–220PubMed

80.

Krag M, Perner A, Wetterslev J, Wise MP, Hylander Moller M (2014) Stress ulcer prophylaxis versus placebo or no prophylaxis in critically ill patients: a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis. Intensive Care Med 40(1):11–22PubMedCrossRef

81.

Toews I, George AT, Peter JV, Kirubakaran R, Fontes LES, Ezekiel JPB et al (2018) Interventions for preventing upper gastrointestinal bleeding in people admitted to intensive care units. Cochrane Database Syst Rev 6:Cd008687PubMed

82.

Huang HB, Jiang W, Wang CY, Qin HY, Du B (2018) Stress ulcer prophylaxis in intensive care unit patients receiving enteral nutrition: a systematic review and meta-analysis. Crit Care 22(1):20PubMedPubMedCentralCrossRef

83.

Alhazzani W, Alshamsi F, Belley-Cote E, Heels-Ansdell D, Brignardello-Petersen R, Alquraini M et al (2018) Efficacy and safety of stress ulcer prophylaxis in critically ill patients: a network meta-analysis of randomized trials. Intensive Care Med 44(1):1–11PubMedCrossRef

84.

Macias WL, Nelson DR, Williams M, Garg R, Janes J, Sashegyi A (2005) Lack of evidence for qualitative treatment by disease severity interactions in clinical studies of severe sepsis. Crit Care 9(6):R607–R622PubMedPubMedCentralCrossRef

Titel: Stress ulcer prophylaxis with proton pump inhibitors or histamin-2 receptor antagonists in adult intensive care patients: a systematic review with meta-analysis and trial sequential analysis
verfasst von: Marija Barbateskovic
Søren Marker
Anders Granholm
Carl Thomas Anthon
Mette Krag
Janus Christian Jakobsen
Anders Perner
Jørn Wetterslev
Morten Hylander Møller
Publikationsdatum: 24.01.2019
Verlag: Springer Berlin Heidelberg
Erschienen in: Intensive Care Medicine / Ausgabe 2/2019
Print ISSN: 0342-4642
Elektronische ISSN: 1432-1238
DOI: https://doi.org/10.1007/s00134-019-05526-z

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Stress ulcer prophylaxis with proton pump inhibitors or histamin-2 receptor antagonists in adult intensive care patients: a systematic review with meta-analysis and trial sequential analysis