Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Trials
Published in: Trials 1/2016

Open Access 01-12-2016 | Study protocol

Stress ulcer prophylaxis with a proton pump inhibitor versus placebo in critically ill patients (SUP-ICU trial): study protocol for a randomised controlled trial

Authors: Mette Krag, Anders Perner, Jørn Wetterslev, Matt P. Wise, Mark Borthwick, Stepani Bendel, Paolo Pelosi, Frederik Keus, Anne Berit Guttormsen, Joerg C. Schefold, Morten Hylander Møller, the SUP-ICU investigators

Published in: Trials | Issue 1/2016

Login to get access

Abstract

Background

Critically ill patients in the intensive care unit (ICU) are at risk of clinically important gastrointestinal bleeding, and acid suppressants are frequently used prophylactically. However, stress ulcer prophylaxis may increase the risk of serious adverse events and, additionally, the quantity and quality of evidence supporting the use of stress ulcer prophylaxis is low. The aim of the SUP-ICU trial is to assess the benefits and harms of stress ulcer prophylaxis with a proton pump inhibitor in adult patients in the ICU. We hypothesise that stress ulcer prophylaxis reduces the rate of gastrointestinal bleeding, but increases rates of nosocomial infections and myocardial ischaemia. The overall effect on mortality is unpredictable.

Methods/design

The SUP-ICU trial is an investigator-initiated, pragmatic, international, multicentre, randomised, blinded, parallel-group trial of stress ulcer prophylaxis with a proton pump inhibitor versus placebo (saline) in 3350 acutely ill ICU patients at risk of gastrointestinal bleeding. The primary outcome measure is 90-day mortality. Secondary outcomes include the proportion of patients with clinically important gastrointestinal bleeding, pneumonia, Clostridium difficile infection or myocardial ischaemia, days alive without life support in the 90-day period, serious adverse reactions, 1-year mortality, and health economic analyses.
The sample size will enable us to detect a 20 % relative risk difference (5 % absolute risk difference) in 90-day mortality assuming a 25 % event rate with a risk of type I error of 5 % and power of 90 %. The trial will be externally monitored according to Good Clinical Practice standards. Interim analyses will be performed after 1650 and 2500 patients.

Conclusion

The SUP-ICU trial will provide high-quality data on the benefits and harms of stress ulcer prophylaxis with a proton pump inhibitor in critically ill adult patients admitted in the ICU.

Trial registration

ClinicalTrials.gov Identifier: NCT02467621.
Appendix
Available only for authorised users
Literature
1.
Cook DJ, Griffith LE, Walter SD, Guyatt GH, Meade MO, Heyland DK, et al. The attributable mortality and length of intensive care unit stay of clinically important gastrointestinal bleeding in critically ill patients. Crit Care. 2001;5:368–75.CrossRefPubMedPubMedCentral
2.
Eddleston JM, Pearson RC, Holland J, Tooth JA, Vohra A, Doran BH. Prospective endoscopic study of stress erosions and ulcers in critically ill adult patients treated with either sucralfate or placebo. Crit Care Med. 1994;22:1949–54.CrossRefPubMed
3.
Martin LF. Stress ulcers are common after aortic surgery. Endoscopic evaluation of prophylactic therapy. Am Surg. 1994;60:169–74.PubMed
4.
Fennerty MB. Pathophysiology of the upper gastrointestinal tract in the critically ill patient: rationale for the therapeutic benefits of acid suppression. Crit Care Med. 2002;30:351–5.CrossRef
5.
Krag M, Perner A, Wetterslev J, Wise MP, Borthwick M, Bendel S, et al. Prevalence and outcome of gastrointestinal bleeding and use of acid suppressants in acutely ill adult intensive care patients. Intensive Care Med. 2015;41:833–45.CrossRefPubMed
6.
Alhazzani W, Alshahrani M, Moayyedi P, Jaeschke R. Stress ulcer prophylaxis in critically ill patients: review of the evidence. Pol Arch Med Wewnętrznej. 2012;122:107–14.
7.
Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013;39:165–228.CrossRefPubMed
8.
9.
ASHP Therapeutic Guidelines on Stress Ulcer Prophylaxis. ASHP Commission on Therapeutics and approved by the ASHP Board of Directors on 14 November 1998. Am J Health Syst Pharm. 1999;56:347–79.
10.
11.
Krag M, Perner A, Wetterslev J, Wise MP, Borthwick M, Bendel S, et al. Stress ulcer prophylaxis in the intensive care unit: an international survey of 97 units in 11 countries. Acta Anaesthesiol Scand. 2015;59:576–85.CrossRefPubMed
12.
Krag M, Perner A, Wetterslev J, Wise MP, Hylander MM. 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. 2014;40:11–22.CrossRefPubMed
13.
Wilhelm SM, Rjater RG, Kale-Pradhan PB. Perils and pitfalls of long-term effects of proton pump inhibitors. Expert Rev Clin Pharmacol. 2013;6:443–51.CrossRefPubMed
14.
Apte NM, Karnad DR, Medhekar TP, Tilve GH, Morye S, Bhave GG. Gastric colonization and pneumonia in intubated critically ill patients receiving stress ulcer prophylaxis: a randomized, controlled trial. Crit Care Med. 1992;20:590–3.CrossRefPubMed
15.
Howell M, Novack V, Grgurich P, Souillard D, Lena N, Pencina M, et al. Iatrogenic gastric acid suppression and the risk of nosocomial clostridium difficile infection. Arch Intern Med. 2010;170:784–90.CrossRefPubMed
16.
Wolfe M. Overview and comparison of the proton pump inhibitors for the treatment of acid-related disorders. UpToDate. 2015.
17.
Bavishi C, Dupont HL. Systematic review: the use of proton pump inhibitors and increased susceptibility to enteric infection. Aliment Pharmacol Ther. 2011;34:1269–81.CrossRefPubMed
18.
Marik PE, Vasu T, Hirani A, Pachinburavan M. Stress ulcer prophylaxis in the new millennium: a systematic review and meta-analysis. Crit Care Med. 2010;38:2222–8.CrossRefPubMed
19.
Maclaren R, Reynolds PM, Allen RR. Histamine-2 receptor antagonists vs proton pump inhibitors on gastrointestinal tract hemorrhage and infectious complications in the intensive care unit. JAMA Intern Med. 2014;174:564–74.CrossRefPubMed
20.
Leonard J, Marshall JK, Moayyedi P. Systematic review of the risk of enteric infection in patients taking acid suppression. Am J Gastroenterol. 2007;102:2047–56.CrossRefPubMed
21.
Kwok CS, Arthur AK, Anibueze CI, Singh S, Cavallazzi R, Loke YK. Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics: meta-analysis. Am J Gastroenterol. 2012;107:1011–9.CrossRefPubMed
22.
van Boxel OS, van Oijen MG, Hagenaars MP, Smout AJ, Siersema PD. Cardiovascular and gastrointestinal outcomes in clopidogrel users on proton pump inhibitors: results of a large Dutch cohort study. Am J Gastroenterol. 2010;105:2430–6. quiz 2437.CrossRefPubMed
23.
Charlot M, Ahlehoff O, Norgaard ML, Jørgensen CH, Sørensen R, Abildstrøm SZ, et al. Proton-pump inhibitors are associated with increased cardiovascular risk independent of clopidogrel use: a nationwide cohort study. Ann Intern Med. 2010;153:378–86.CrossRefPubMed
24.
Altman DG, Schulz KF, Moher D, Egger M, Davidoff F, Elbourne D, et al. The revised CONSORT statement for reporting randomized trials: explanation and elaboration. Ann Intern Med. 2001;134:663–94.CrossRefPubMed
25.
26.
27.
Schafer JL, Graham JW. Missing data: our view of the state of the art. Psychol Methods. 2002;7:147–77.CrossRefPubMed
28.
29.
30.
31.
32.
Basso N, Bagarani M, Materia A, Fiorani S, Lunardi P, Speranza V. Cimetidine and antacid prophylaxis of acute upper gastrointestinal bleeding in high risk patients. Controlled, randomized trial. Am J Surg. 1981;141:339–41.CrossRefPubMed
33.
Burgess P, Larson GM, Davidson P, Brown J, Metz CA. Effect of ranitidine on intragastric pH and stress-related upper gastrointestinal bleeding in patients with severe head injury. Dig Dis Sci. 1995;40:645–50.CrossRefPubMed
34.
Friedman CJ, Oblinger MJ, Suratt PM, Bowers J, Goldberg SK, Sperling MH, et al. Prophylaxis of upper gastrointestinal hemorrhage in patients requiring mechanical ventilation. Crit Care Med. 1982;10:316–9.PubMed
35.
Halloran LG, Zfass AM, Gayle WE, Wheeler CB, Miller JD. Prevention of acute gastrointestinal complications after severe head injury: a controlled trial of cimetidine prophylaxis. Am J Surg. 1980;139:44–8.CrossRefPubMed
36.
Karlstadt RG, Iberti TJ, Silverstein J, Lindenberg L, Rright-Asare P, Rockhold F, et al. 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. 1990;5:26–32.CrossRef
37.
MacDougall BR, Bailey RJ, Williams R. H2-receptor antagonists and antacids in the prevention of acute gastrointestinal haemorrhage in fulminant hepatic failure. Two controlled trials. Lancet. 1977;1:617–9.CrossRefPubMed
38.
Zinner MJ, Zuidema GD, Smith P, Mignosa M. The prevention of upper gastrointestinal tract bleeding in patients in an intensive care unit. Surg Gynecol Obs. 1981;153:214–20.
39.
Brett S. Science review: the use of proton pump inhibitors for gastric acid suppression in critical illness. Crit Care. 2005;9:45–50.CrossRefPubMed
40.
Alhazzani W, Alenezi F, Jaeschke RZ, Moayyedi P, Cook DJ. 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. 2013;41:693–705.CrossRefPubMed
41.
Savović J, Jones H, Altman D, Harris R, Jűni P, Pildal J, et al. Influence of reported study design characteristics on intervention effect estimates from randomised controlled trials: combined analysis of meta-epidemiological studies. Health Technol Assess. 2012;16:1–82.PubMed
42.
Perner A, Haase N, Guttormsen AB, Tenhunen J, Klemenzson G, Aneman A, et al. Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. N Engl J Med. 2012;367:124–34.CrossRefPubMed
43.
Haase N, Wetterslev J, Winkel P, Perner A. Bleeding and risk of death with hydroxyethyl starch in severe sepsis: post hoc analyses of a randomized clinical trial. Intensive Care Med. 2013;39:2126–34.CrossRefPubMed
44.
TSA. Trial sequential analysis (TSA). The Copenhagen Trial Unit, Center for Clinical Intervention Research, Rigshospitalet, Copenhagen, Denmark (2011) Software and manual. Available at www.​ctu.​dk/​tsa. Accessed 15 Jan 2016.
45.
Wetterslev J, Thorlund K, Brok J, Gluud C. Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis. J Clin Epidemiol. 2008;61:64–75.CrossRefPubMed
46.
Krag M, Perner A, Wetterslev J, Moller MH. Stress ulcer prophylaxis in the intensive care unit: is it indicated? A topical systematic review. Acta Anaesthesiol Scand. 2013;57:835–47.CrossRefPubMed
47.
Horan TC, Andrus M, Dudeck MA (2008) CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting. Am J Infect Control 36:309–32.
48.
Lan K, Demets D. Discrete sequential boundaries for clinical trials. Biometrika. 1983;70:659–63.CrossRef
49.
International Conference on Harmonisation; guidance on statistical principles for clinical trials; availability – FDA. Notice. Fed Regist. 1998; 63:49583–98.
Metadata
Title
Stress ulcer prophylaxis with a proton pump inhibitor versus placebo in critically ill patients (SUP-ICU trial): study protocol for a randomised controlled trial
Authors
Mette Krag
Anders Perner
Jørn Wetterslev
Matt P. Wise
Mark Borthwick
Stepani Bendel
Paolo Pelosi
Frederik Keus
Anne Berit Guttormsen
Joerg C. Schefold
Morten Hylander Møller
the SUP-ICU investigators
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Trials / Issue 1/2016
Electronic ISSN: 1745-6215
DOI
https://doi.org/10.1186/s13063-016-1331-3

Other articles of this Issue 1/2016

Trials 1/2016 Go to the issue

Study protocol

A patient decision aid for antidepressant use in pregnancy: study protocol for a randomized controlled trial

Study protocol

Effectiveness of an individualized program of muscular strength and endurance with aerobic training for improving germ cell cancer-related fatigue in men undergoing chemotherapy: EFICATEST study protocol for a randomized controlled trial

Study protocol

A parenting programme to prevent abuse of adolescents in South Africa: study protocol for a randomised controlled trial

Study protocol

Effectiveness of the WHO Safe Childbirth Checklist program in reducing severe maternal, fetal, and newborn harm in Uttar Pradesh, India: study protocol for a matched-pair, cluster-randomized controlled trial

Study protocol

Efficacy and safety of auricular point acupressure treatment for gastrointestinal dysfunction after laparoscopic cholecystectomy: study protocol for a randomized controlled trial

Study protocol

Study protocol for a multi-center, randomized controlled trial to develop Japanese denture adhesive guidelines for patients with complete dentures: the Denture Adhesive Guideline trial: study protocol for a randomized controlled trial