Reduction in gastrointestinal bleeding by development and implementation of a protocol for stress ulcer prophylaxis: a before-after study
© Ikemura et al. 2015
Received: 2 September 2015
Accepted: 22 November 2015
Published: 15 December 2015
The implementation of a protocol has been associated with improvements in the processes of care in clinical settings. Although stress ulcer prophylaxis is recommended for critically ill patients at high risk, there is currently no consensus on its use. Therefore, we herein developed a protocol for stress ulcer prophylaxis, and evaluated therapeutic outcomes in a before-after study.
The protocol was developed by considering the effectiveness, disadvantages (including adverse events) and cost of each agent based on previous findings. Patients who were admitted to the 8-bed emergency intensive care unit (ICU) of our hospital for more than 24 h during the year before and after implementation of the study were eligible. Each investigation item was evaluated retrospectively.
There were 211 and 238 study patients before and after implementation of the protocol, respectively. The baseline characteristics of patients on/during ICU admission were similar in the two groups. The proportion of medicated patients was 79.6 % before and 84.5 % after protocol implementation. Before implementation of the protocol, 4.3 % of patients developed clinically important gastrointestinal bleeding, and this incidence decreased significantly to 0.8 % after its implementation (P = 0.019). The frequency at which medication was discontinued due to adverse events was slightly lower after implementation of the protocol. No significant differences were observed in the costs of stress ulcer prophylactic agents or mortality in the ICU.
The results of the present study indicated that the development and implementation of a protocol for stress ulcer prophylaxis, for which there are currently no criteria, improved a main outcome, clinically important gastrointestinal bleeding.
KeywordsStress ulcer prophylaxis Intensive care unit Clinically important bleeding Protocol
Stress ulcers are superficial lesions generally, but not exclusively involving the mucosal layer of the stomach, and commonly occur in critically ill patients . Most critically ill patients have endoscopically detectable mucosal erosion and subepithelial hemorrhage within 24 h of admission to an intensive care unit (ICU) . The frequency of clinically important gastrointestinal (GI) bleeding in patients not receiving prophylaxis reportedly ranges from 0.1 to 39 % . The mortality rate is 48.5 % in ICU patients with clinically important bleeding, in contrast to 9.1 % in those without bleeding . Therefore, it has been recommended that stress ulcer prophylaxis should be implemented in patients at high risk.
Approaches to stress ulcer prophylaxis include medication with pharmacological agents and enteral nutrition [1, 2, 4–11]. Agents known to provide stress ulcer prophylaxis include antacids, prostanoids, sucralfate, histamine-2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs). The efficacy and safety of H2RAs and PPIs in particular have been investigated in recent studies [5–9]. In some studies, the effects of PPIs and H2RAs were found to be similar, whereas others indicated that PPIs decreased the risk of GI bleeding more than H2RAs [6–8]. A recent study suggested that PPIs were associated with a greater risk of GI hemorrhage, pneumonia and Clostridium difficile infection than H2RAs in mechanically ventilated patients . Therefore, both agents have advantages and disadvantages in clinical settings [5, 6].
Although various approaches to stress ulcer prophylaxis have been reported, there is limited evidence for and no consensus on their efficacy and safety. Few studies have proposed and examined criteria for selecting stress ulcer prophylactic agents. Since critically ill patients characteristically require various therapies, the absence of a therapeutic strategy potentially leads to inappropriate medication, which may have a negative impact on the process of care. An appropriate approach to stress ulcer prophylaxis based on the clinical characteristics of the patient, which are diverse and may vary from hour to hour, is considered necessary. The implementation of protocols has been associated with improvements in the processes of care in clinical settings . Therefore, the development of a protocol for stress ulcer prophylaxis may improve the process of care in critically ill patients. In the present study, we devised a protocol for stress ulcer prophylaxis, and evaluated therapeutic outcomes in the ICU before and after its implementation.
Development and implementation of a protocol for stress ulcer prophylaxis
The protocol was implemented from January 2013 for patients who fit the eligibility criteria. Intensive care physicians generally prescribed the agents specified by the protocol. In addition, pharmacists checked the patients’ conditions and medications nearly every day, and proposed changes to the physicians when the medications were not in accordance with the protocol.
Design, setting and participants
This was a retrospective observational before-after study. Patients who were admitted to the 8-bed emergency ICU in Kobe City Medical Center General Hospital, a 700-bed general hospital, between January and December 2012 (before implementation of the protocol) or between January and December 2013 (after its implementation), were enrolled. Patients were excluded if they were younger than 20 years, had GI bleeding on ICU admission, or were discharged within 24 h of admission. Although study patients admitted to the ICU for less than 24 h were ineligible for this study, the protocol was also used to select their treatment.
Baseline characteristics, including sex, age, the presence or absence of intubation, coagulopathy, trauma and burns on/during ICU admission, medication status and outcomes were evaluated. The medication status included medication or not, the types and number of agents used for stress ulcer prophylaxis, dosages, duration of administration, adverse events and costs during the ICU stay. Medicated patients were defined as those who received one or more of the following stress ulcer prophylactic agents: intravenous lansoprazole, omeprazole, cimetidine, famotidine and ranitidine; and oral esomeprazole, lansoprazole, omeprazole, rabeprazole, famotidine, ranitidine and sucralfate. Costs included those of the agents themselves, but not of the devices used to administer the medication, nutrition or treatment of adverse effects caused by the agents. Prices were calculated in Japanese yen. Adverse events caused by stress ulcer prophylactic agents were evaluated from the medical records. The studied outcomes of application of the protocol included the number of patients with GI bleeding and their baseline characteristics, duration of stay and mortality in the ICU. Clinically important bleeding was defined as reported by Krag et al. . Each investigation item was evaluated retrospectively using the electronic health record system.
Differences before and after implementation of the protocol were evaluated statistically by the two-sample χ 2 test of proportions (baseline characteristics including sex, number of intubated patients, patients with coagulopathy, trauma and burns, number of patients who received stress ulcer prophylactic agents, clinically important GI bleeding and mortality in the ICU), or the Mann-Whitney U test (age, medicated days, total cost of stress ulcer prophylactic agents, and duration of the ICU stay). Significance was set at P < 0.05.
This study was approved by the Institutional Review Board of Kobe City Medical Center General Hospital and the Board waived the need for patients’ consent (No. 1303-jn4).
Baseline characteristics on/during ICU admission
Before implementation of the protocol (n = 211)
After implementation of the protocol (n = 238)
Diagnosis and treatment department
Variables related to the use of stress ulcer prophylactic agents
Before implementation of the protocol (n = 211)
After implementation of the protocol (n = 238)
Duration of administration (days)a
Outcomes before and after implementation of the protocol
Before implementation of the protocol (N = 211)
After implementation of the protocol (N = 238)
Clinically important bleeding
Mortality in ICU
ICU stay (days)a
Previous studies demonstrated that protocols improved the processes of care . Although recent studies provided recommendations, few protocols for stress ulcer prophylaxis that detail agents and dosages have been published [9, 14]. Therefore, we developed the protocol presented herein to provide criteria for stress ulcer prophylaxis, including risk factors, agents, dosages and routes, based on previous findings (Fig. 1). Confirmation by clinicians and pharmacists prevented the use of unnecessary medication and omission of medication. As a result, more patients were medicated after implementation of the protocol despite similar baseline characteristics on/during ICU admission before and after implementation (Tables 1 and 2). This is because some patients did not receive necessary medication for stress ulcer prophylaxis because of the absence of a protocol. Therefore, implementation of the protocol was expected to augment the processes of care in critically ill patients.
The duration and cost of medications for stress ulcer prophylaxis were similar before and after introduction of the protocol (Table 2). In some circumstances the duration and cost decreased; for example, fewer patients received the agents as therapy for GI bleeding, not as prophylaxis, after implementation of the protocol. Other situations increased the duration and cost, such as when fewer patients at high risk of stress ulcers did not receive medication after implementation. Furthermore, the cost was decreased by earlier switching to oral administration. Conversely, standardization of the dosage of H2RAs based on renal function increased the average dosage.
Before introduction of the protocol, 4.3 % of patients had clinically important GI bleeding (Table 3), which was consistent with previously reported rates . This finding indicated that the medical care provided prior to protocol implementation was not substandard. After introduction of the protocol, significantly fewer patients had clinically important GI bleeding (0.8 %) (Table 3), an improvement we attributed to the implementation of the protocol. Before introduction of the protocol, some patients with GI bleeding had not received stress ulcer prophylaxis even though they were at high risk, partly because of adverse events and also because there were no clear criteria for selecting appropriate prophylactic agents. The protocol presented here includes multiple strategies to cover situations in which it is not possible to continue the administration of a particular agent. Furthermore, the protocol recommends minimum effective dosages, which may decrease the frequency of adverse events. Since adverse events occurred less frequently, medication was discontinued less often, a possible reason for the lower incidence of GI bleeding. Prior to introduction of the protocol, some patients with GI bleeding received agents that cannot be administered via a gastric tube, including omeprazole and rabeprazole. These medications may have been ineffective for stress ulcer prophylaxis. The protocol did not include these agents owing to risk management considerations; therefore, they were rarely selected after its introduction.
While the number of patients with clinically important GI bleeding was decreased after the implementation of the protocol, mortality in ICU was similar in two groups (Table 3). The mortality rate is known to be dramatically increased in patients with clinically important GI bleeding . Generally, a number of fatalities might be decreased, as a number of patients with clinically important GI bleeding are decreased. In this study, few patients with clinically important GI bleeding died in ICU. Therefore, mortality in ICU was not affected by the frequency of clinically important GI bleeding.
There were some limitations in our evaluation of the protocol. Although pneumonia is known to be one of the major adverse events associated with stress ulcer prophylactic agents, we did not evaluate its frequency because many patients had pulmonary disease on ICU admission. Previous studies suggested that acid-suppressive agents increased the risk of pneumonia [15, 16], and that this may be mediated by the growth of gastric flora with increasing pH . In the present study, mortality and the ICU stay were similar before and after introduction of the protocol, suggesting that there was no increase in the frequency of pneumonia.
The use of our protocol for stress ulcer prophylaxis, which was designed based on previous findings, resulted in a decrease in the frequency of clinically important GI bleeding in critically ill patients. These results indicated that the development and implementation of a protocol for stress ulcer prophylaxis, for which there are currently no criteria, might improve therapeutic outcomes.
histamine-2 receptor antagonist
intensive care unit
international normalized ratio
proton pump inhibitor
partial thromboplastin time
This study was supported in part by the Research on Regulatory Science of Pharmaceuticals and Medical Devices Study from the Ministry of Health, Labour and Welfare of Japan.
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- ASHP therapeutic guidelines on stress ulcer prophylaxis. Am J Health Syst Pharm. 1999;56:347–379.
- Mutlu GM, Mutlu EA, Factor P. GI complications in patients receiving mechanical ventilation. Chest. 2001;119:1222–41.View ArticlePubMedGoogle Scholar
- Cook DJ, Fuller HD, Guyatt GH, Marshall JC, Leasa D, Hall R, et al. Risk factors for gastrointestinal bleeding in critically ill patients. Canadian Critical Trials Group. N Engl J Med. 1994;330:377–81.View ArticlePubMedGoogle Scholar
- Tryba M, Cook D. Current guidelines on stress ulcer prophylaxis. Drugs. 1997;54:581–96.View ArticlePubMedGoogle Scholar
- 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.View ArticlePubMedGoogle Scholar
- Mohebbi L, Hesch K. Stress ulcer prophylaxis in the intensive care unit. Proc (Baylor Univ Med Cent). 2009;22:373–6.Google Scholar
- Lin PC, Chang CH, Hsu PI, Tseng PL, Huang YB. 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. 2010;38:1197–205.View ArticlePubMedGoogle Scholar
- 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.View ArticlePubMedGoogle Scholar
- Alhazzani W, Alshahrani M, Moayyedi P, Jaeschke R. Stress ulcer prophylaxis in critically ill patients: review of the evidence. Pol Arch Med Wewn. 2012;122:107–14.PubMedGoogle Scholar
- Cook D, Heyland D, Griffith L, Cook R, Marshall J, Pagliarello J. Risk factors for clinically important upper gastrointestinal bleeding in patients requiring mechanical ventilation. Canadian Critical Care Trials Group. Crit Care Med. 1999;27:2812–7.View ArticlePubMedGoogle Scholar
- Marik PE, Vasu T, Hirani A, Pachinburavan M. Stress ulcer prophylaxis in the new millennium: systematic review and meta-analysis. Crit Care Med. 2010;38:2222–8.View ArticlePubMedGoogle Scholar
- 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.View ArticlePubMedGoogle Scholar
- Sinuff T, Muscedere J, Adhikari NK, Stelfox HT, Dodek P, Heyland DK, et al. Knowledge translation interventions for critically ill patients: a systematic review. Crit Care Med. 2013;41:2627–40.View ArticlePubMedGoogle Scholar
- Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41:580–637.View ArticlePubMedGoogle Scholar
- Laheij RJ, Sturkenboom MC, Hassing RJ, Dieleman J, Stricker BH, Jansen JB. Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs. JAMA. 2004;292:1955–60.View ArticlePubMedGoogle Scholar
- Herzig SJ, Howell MD, Nqo LH, Marcantonio ER. Acid-suppressive medication use and the risk for hospital-acquired pneumonia. JAMA. 2009;301:2120–8.View ArticlePubMedGoogle Scholar
- Gray JD, Shiner M. Influence of gastric pH on gastric and jejunal flora. Gut. 1967;8:574–81.View ArticlePubMedGoogle Scholar