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The effect of systemic corticosteroids on the incidence of gastrointestinal bleeding in critically ill adults: a systematic review with meta-analysis

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Abstract

Purpose

To assess the effect of systemic corticosteroids on the incidence of gastrointestinal bleeding in adult critically ill patients.

Methods

We systematically reviewed randomised clinical trials comparing systemic corticosteroids administered for more than 24 h with placebo/no treatment in adult critically ill patients. Trial selection, data abstraction and risk of bias assessments were performed in duplicate. We used trial sequential analysis (TSA) to assess the risk of random errors and the grading of recommendations, assessment, development, and evaluations (GRADE) approach to assess the quality of evidence. The primary outcome was the incidence of clinically important gastrointestinal bleeding within 90 days. The secondary outcome was the incidence of gastrointestinal bleeding of any severity within 90 days.

Results

Twenty-five trials (n = 14,615) reported data for the primary outcome and 55 trials (n = 21,792) for the secondary outcome. The pooled incidence of clinically important gastrointestinal bleeding was 2.3% in the corticosteroid group and 1.8% in the control group (RR, 1.26; 95% CI, 1.01–1.57; I2 = 0%, TSA-adjusted CI 0.51–3.14). We observed no difference in the risk of gastrointestinal bleeding of any severity (RR, 1.10; 95% CI, 0.92–1.32; I2 = 0%, TSA-adjusted CI 0.87–1.38). The GRADE quality of evidence was low (risk of bias and imprecision).

Conclusions

We observed an overall low incidence of clinically important gastrointestinal bleeding among adult critically ill patients. Corticosteroids may slightly increase the incidence of clinically important gastrointestinal bleeding, but not bleeding of any severity. Rarity of events, infrequent trial reporting and high risk of bias reduced the quality of evidence.

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Data availability

All data are freely available in the study and ESM.

References

  1. Krag M, Perner A, Wetterslev J, Wise MP, Borthwick M, Bendel S, McArthur C, Cook D, Nielsen N, Pelosi P, Keus F, Guttormsen AB, Moller AD, Moller MH (2015) Prevalence and outcome of gastrointestinal bleeding and use of acid suppressants in acutely ill adult intensive care patients. Intensive Care Med 41:833–845

    Article  CAS  PubMed  Google Scholar 

  2. Cook DJ, Fuller HD, Guyatt GH, Marshall JC, Leasa D, Hall R, Winton TL, Rutledge F, Todd TJ, Roy P et al (1994) Risk factors for gastrointestinal bleeding in critically ill patients. N Engl J Med 330:377–381

    Article  CAS  PubMed  Google Scholar 

  3. MacLaren R, Reynolds PM, Allen RR (2014) Histamine-2 receptor antagonists vs proton pump inhibitors on gastrointestinal tract hemorrhage and infectious complications in the intensive care unit. JAMA Intern Med 174:564–574

    Article  CAS  PubMed  Google Scholar 

  4. Cook D, Heyland D, Griffith L, Cook R, Marshall J, Pagliarello J (1999) Risk factors for clinically important upper gastrointestinal bleeding in patients requiring mechanical ventilation. Crit Care Med 27:2812–2817

    Article  CAS  PubMed  Google Scholar 

  5. Cook DJ, Griffith LE, Walter SD, Guyatt GH, Meade MO, Heyland DK, Kirby A, Tryba M (2001) The attributable mortality and length of intensive care unit stay of clinically important gastrointestinal bleeding in critically ill patients. Crit Care 5:368–375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Pastores SM, Annane D, Rochwerg B (2018) Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (part II): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017. Intensive Care Med 44:474–477

    Article  PubMed  Google Scholar 

  7. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, Rochwerg B, Rubenfeld GD, Angus DC, Annane D, Beale RJ, Bellinghan GJ, Bernard GR, Chiche JD, Coopersmith C, De Backer DP, French CJ, Fujishima S, Gerlach H, Hidalgo JL, Hollenberg SM, Jones AE, Karnad DR, Kleinpell RM, Koh Y, Lisboa TC, Machado FR, Marini JJ, Marshall JC, Mazuski JE, McIntyre LA, McLean AS, Mehta S, Moreno RP, Myburgh J, Navalesi P, Nishida O, Osborn TM, Perner A, Plunkett CM, Ranieri M, Schorr CA, Seckel MA, Seymour CW, Shieh L, Shukri KA, Simpson SQ, Singer M, Thompson BT, Townsend SR, Van der Poll T, Vincent JL, Wiersinga WJ, Zimmerman JL, Dellinger RP (2017) Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med 43:304–377

    Article  PubMed  Google Scholar 

  8. Annane D, Pastores SM, Rochwerg B, Arlt W, Balk RA, Beishuizen A, Briegel J, Carcillo J, Christ-Crain M, Cooper MS, Marik PE, Umberto Meduri G, Olsen KM, Rodgers SC, Russell JA, Van den Berghe G (2017) Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017. Crit Care Med 45:2078–2088

    Article  PubMed  Google Scholar 

  9. Kiser TH, Allen RR, Valuck RJ, Moss M, Vandivier RW (2014) Outcomes associated with corticosteroid dosage in critically ill patients with acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 189:1052–1064

    Article  CAS  PubMed  Google Scholar 

  10. Butler E, Moller MH, Cook O, Granholm A, Penketh J, Rygard SL, Aneman A, Perner A (2018) Corticosteroids and risk of gastrointestinal bleeding in critically ill adults: protocol for a systematic review. Acta Anaesthesiol Scand 62:1321–1326

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  12. Higgins J, Green S (2011) Cochrane handbook for systematic reviews of interventions version 5.1.0 [updated March 2011]. The Cochrane Collaboration. Available from http://handbook.cochrane.org

  13. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ (Clin Res Ed) 339:b2700

    Article  Google Scholar 

  14. Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, Shekelle P, Stewart LA (2015) Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ 349:g7647

    Article  Google Scholar 

  15. 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 14:120

    Article  PubMed  PubMed Central  Google Scholar 

  16. Friedrich JO, Adhikari NK, Beyene J (2007) Inclusion of zero total event trials in meta-analyses maintains analytic consistency and incorporates all available data. BMC Med Res Methodol 7:5

    Article  PubMed  PubMed Central  Google Scholar 

  17. Møller CH, Penninga L, Wetterslev J, Steinbrüchel DA, Gluud C (2008) Clinical outcomes in randomized trials of off- vs. on-pump coronary artery bypass surgery: systematic review with meta-analyses and trial sequential analyses. Eur Heart J 29:2601–2616

    Article  PubMed  Google Scholar 

  18. Sweeting MJ, Sutton AJ, Lambert PC (2004) What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of sparse data. Stat Med 23:1351–1375

    Article  PubMed  Google Scholar 

  19. Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S, Guyatt GH, Harbour RT, Haugh MC, Henry D, Hill S, Jaeschke R, Leng G, Liberati A, Magrini N, Mason J, Middleton P, Mrukowicz J, O’Connell D, Oxman AD, Phillips B, Schunemann HJ, Edejer T, Varonen H, Vist GE, Williams JW Jr, Zaza S, Group GW (2004) Grading quality of evidence and strength of recommendations. BMJ 328:1490

    Article  Google Scholar 

  20. El-Ghamrawy AH, Shokier MH, AA E (2006) Effects of low-dose hydrocortisone in ICU patients with severe community-acquired pneumonia. Egypt J Chest Dis Tuberc 55:91–99

    Google Scholar 

  21. Gaab MR, Trost HA, Alcantara A, Karimi-Nejad A, Moskopp D, Schultheiss R, Bock WJ, Piek J, Klinge H, Scheil F et al (1994) “Ultrahigh” dexamethasone in acute brain injury. Results from a prospective randomized double-blind multicenter trial (GUDHIS). German Ultrahigh Dexamethasone Head Injury Study Group. Zentralbl Neurochir 55:135–143

    CAS  PubMed  Google Scholar 

  22. Annane D, Renault A, Brun-Buisson C, Megarbane B, Quenot JP, Siami S, Cariou A, Forceville X, Schwebel C, Martin C, Timsit JF, Misset B, Ali Benali M, Colin G, Souweine B, Asehnoune K, Mercier E, Chimot L, Charpentier C, Francois B, Boulain T, Petitpas F, Constantin JM, Dhonneur G, Baudin F, Combes A, Bohe J, Loriferne JF, Amathieu R, Cook F, Slama M, Leroy O, Capellier G, Dargent A, Hissem T, Maxime V, Bellissant E (2018) Hydrocortisone plus fludrocortisone for adults with septic shock. N Engl J Med 378:809–818

    Article  CAS  PubMed  Google Scholar 

  23. Venkatesh B, Finfer S, Cohen J, Rajbhandari D, Arabi Y, Bellomo R, Billot L, Correa M, Glass P, Harward M, Joyce C, Li Q, McArthur C, Perner A, Rhodes A, Thompson K, Webb S, Myburgh J (2018) Adjunctive glucocorticoid therapy in patients with septic shock. N Engl J Med 378:797–808

    Article  CAS  PubMed  Google Scholar 

  24. Gordon AC, Mason AJ, Thirunavukkarasu N, Perkins GD, Cecconi M, Cepkova M, Pogson DG, Aya HD, Anjum A, Frazier GJ, Santhakumaran S, Ashby D, Brett SJ (2016) Effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock: the VANISH randomized clinical trialearly vasopressin vs norepinephrine on kidney failure in septic shock patientsearly vasopressin vs norepinephrine on kidney failure in septic shock patients. JAMA 316:509–518

    Article  CAS  PubMed  Google Scholar 

  25. Roquilly A, Mahe PJ, Seguin P, Guitton C, Floch H, Tellier AC, Merson L, Renard B, Malledant Y, Flet L, Sebille V, Volteau C, Masson D, Nguyen JM, Lejus C, Asehnoune K (2011) Hydrocortisone therapy for patients with multiple trauma: the randomized controlled HYPOLYTE study. JAMA 305:1201–1209

    Article  CAS  PubMed  Google Scholar 

  26. Tongyoo S, Permpikul C, Mongkolpun W, Vattanavanit V, Udompanturak S, Kocak M, Meduri GU (2016) Hydrocortisone treatment in early sepsis-associated acute respiratory distress syndrome: results of a randomized controlled trial. Crit Care 20:329

    Article  PubMed  PubMed Central  Google Scholar 

  27. Plummer MP, Blaser AR, Deane AM (2014) Stress ulceration: prevalence, pathology and association with adverse outcomes. Crit Care 18:213

    Article  PubMed  PubMed Central  Google Scholar 

  28. Narum S, Westergren T, Klemp M (2014) Corticosteroids and risk of gastrointestinal bleeding: a systematic review and meta-analysis. BMJ Open 4:e004587

    Article  PubMed  PubMed Central  Google Scholar 

  29. Beardsley J, Wolbers M, Kibengo FM, Ggayi A-BM, Kamali A, Cuc NTK, Binh TQ, Chau NVV, Farrar J, Merson L, Phuong L, Thwaites G, Van Kinh N, Thuy PT, Chierakul W, Siriboon S, Thiansukhon E, Onsanit S, Supphamongkholchaikul W, Chan AK, Heyderman R, Mwinjiwa E, van Oosterhout JJ, Imran D, Basri H, Mayxay M, Dance D, Phimmasone P, Rattanavong S, Lalloo DG, Day JN, CryptoDex I (2016) Adjunctive dexamethasone in HIV-associated cryptococcal meningitis. N Engl J Med 374:542–554

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Tongyoo S, Permpikul C, Mongkolpun W, Vattanavanit V, Udompanturak S, Kocak M, Meduri GU (2016) Hydrocortisone treatment in early sepsis-associated acute respiratory distress syndrome: results of a randomized controlled trial. Crit Care 20:329

    Article  PubMed  PubMed Central  Google Scholar 

  31. Keh D, Trips E, Marx G, Wirtz SP, Abduljawwad E, Bercker S, Bogatsch H, Briegel J, Engel C, Gerlach H, Goldmann A, Kuhn SO, Huter L, Meier-Hellmann A, Nierhaus A, Kluge S, Lehmke J, Loeffler M, Oppert M, Resener K, Schadler D, Schuerholz T, Simon P, Weiler N, Weyland A, Reinhart K, Brunkhorst FM (2016) Effect of hydrocortisone on development of shock among patients with severe sepsis: the HYPRESS randomized clinical trial. JAMA 316:1775–1785

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We are indebted to the numerous authors who have provided additional information and clarifications regarding their studies including Professors Ananne, Arabi, Ashenoune, Briegel, Christ-Crain, Chotmongkol, Cicarelli, Day, Edwards, Gordon, Hoffman, Keh, Kerr, Martin Jr, Meduri, Mirea, Paydas, Payen, Sawanyawisuth, Scarborough, Sorensen, Sprung, Thwaites, Venkatesh and Weigelt and Dr’s Alía, Blum, Fernandez-Serrano and Plassais. We are also grateful for the assistance with translations of non-English studies from Mr Chris Chui, Dr Peter Biesenbach and Dr Fernando Zampieri. We apologise if in the process of transcribing we have accidently left out authors who have aided this study and we offer our utmost gratitude. .

Funding

No funding was received for any aspect of this study.

Author information

Authors and Affiliations

  1. Royal North Shore Hospital, St Leonards, Australia

    Ethan Butler

  2. Intensive Care Unit, Liverpool Hospital, Sydney, Australia

    Oliver Cook, James Penketh & Anders Aneman

  3. South Western Sydney Clinical School, University of New South Wales, Sydney, Australia

    Ethan Butler & Anders Aneman

  4. Ingham Institute for Applied Medical Research, Sydney, Australia

    Anders Aneman

  5. Department of Intensive Care, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

    Morten Hylander Møller, Anders Granholm, Sofie Louise Rygård & Anders Perner

  6. Centre for Research in Intensive Care, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

    Morten Hylander Møller & Anders Perner

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  1. Ethan Butler
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  8. Anders Perner
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Corresponding author

Correspondence to Anders Perner.

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Conflicts of interest

EB, MHM, OC, AG, JP, SLR, AA: none to declare. AP: the ICU at Rigshospitalet, where AP chairs the Research Unit, receives funds for research from Ferring Pharmaceuticals and the Novo Nordisk Foundation.

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Butler, E., Møller, M.H., Cook, O. et al. The effect of systemic corticosteroids on the incidence of gastrointestinal bleeding in critically ill adults: a systematic review with meta-analysis. Intensive Care Med 45, 1540–1549 (2019). https://doi.org/10.1007/s00134-019-05754-3

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  • DOI: https://doi.org/10.1007/s00134-019-05754-3

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