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Vol 56 Feb 15 1999 Am J Health-Syst Pharm 347

Stress ulcer prophylaxis ASHP Report

SHP EPORTRAASHP Therapeutic Guidelines on Stress UlcerProphylaxisDEVELOPED THROUGH THE ASHP COMMISSION ON THERAPEUTICS AND APPROVED BY THE ASHP BOARD OF DIRECTORS ONNOVEMBER 14, 1998

Am J Health-Syst Pharm. 1999; 56:347-79

Pharm.D.The bibliographic citation for this document is as follows:

American Society of Health-System Pharmacists. ASHP therapeu-tic guidelines on stress ulcer prophylaxis. Am J Health-Syst Pharm.1999; 56:347-79.

Index terms: American Society of Health-System Pharma-cists; Antacids; Economics; Gastrointestinal drugs; Health profes-sions; Organizations; Prostaglandin derivatives; Protocols; Ulcers

Copyright © 1999, American Society of Health-System Phar-macists, Inc. All rights reserved. 1079-2082/99/0202-0347$06.00.

The following professional organizations and persons submittedcomments on the draft document: the American Association ofCritical-Care Nurses; the American College of Chest Physicians;the American College of Clinical Pharmacy; the AmericanGastroenterological Association; Todd A. Armstrong, Pharm.D.,BCPS, BCNSP; Douglas B. Coursin, M.D.; John Devlin, Pharm.D.,BCPS; Jeanne Scott Duke; Douglas Fish, Pharm.D.; Edgar R.Gonzalez, Pharm.D., FASHP; Emily B. Hak, Pharm.D.; DarrellHeiselman, D.O.; Annie Herrington, Pharm.D.; Mary Hess,Pharm.D.; Robert J. Kuhn, Pharm.D.; Marc Lapointe, Pharm.D.;Robin L. Southwood, Pharm.D., BCPS; and Linda S. Welage,

espite the publication of more than 100 studiesof the frequency, risk factors, and prophylaxis ofstress ulcer bleeding, these subjects continue to

generate controversy. Several meta-analyses pertainingto stress ulcer bleeding have been published, includingone designed to resolve the discordant results of theothers. Given the sheer volume of published informa-tion, it is understandable that health care providersexperience frustration when confronting this topic.

Stress ulcers are superficial lesions commonly (butnot exclusively) involving the mucosal layer of thestomach that appear after major stressful events such assurgery and trauma.1 Endoscopic studies have foundgastroduodenal erosions (shallow ulcers) to be com-mon in patients who have had such stressful events,and these may lead to ulceration and bleeding.1 Micro-scopic bleeding associated with gastroduodenal lesionscan be detected by occult blood testing (e.g., guaiac test)in patients with gastric tubes.2 However, other factorsmay influence the results of occult testing. Simplyplacing tubes in the upper respiratory or GI tract mayinjure the mucosa and result in microscopic or macro-scopic (i.e., overt) bleeding. Because not all episodes ofmicroscopic bleeding are clinically relevant, studiesusing only microscopic bleeding as an endpoint artifi-cially inflate the reported frequency of GI bleeding.

D Making clinical use of these inflated estimates haspatient care implications and cost implications, be-cause stress ulcer prophylaxis adds to the number ofmedications given and increases the risk and cost ofadverse reactions.3,4

It is important to determine the frequency of clini-cally important bleeding due to stress-induced erosionsor ulcerations. Although endoscopy is a specific andsensitive test for GI bleeding, it is an invasive andexpensive procedure. For endoscopy to be used as adiagnostic tool, it would need to be repeated during theperiod the patient remains at risk for clinically impor-tant bleeding. Gastroduodenal bleeding associatedwith clinically important complications, such as hemo-dynamic compromise and the need for blood transfu-sions or surgery, has been suggested in the literature asa useful definition for clinically important bleeding.This definition was used to evaluate the clinical trials inorder to develop these guidelines.5 The reported fre-quency of clinically important bleeding has variedwidely, although the general perception is that thefrequency of stress-related bleeding has been decreas-ing in recent years.6 Whether this decrease is related tothe use of stress ulcer prophylaxis medications, im-provements in technology, or improvements in patientcare is not known, because a variety of factors (e.g., type

348 Am J Health-Syst Pharm Vol 56 Feb 15 1999

ASHP Report Stress ulcer prophylaxis

of resuscitative technique) may contribute to clinicallyimportant stress-related bleeding.7

The presence of patient risk factors for clinicallyimportant bleeding, not just admission to an intensivecare unit (ICU), should determine the need for stressulcer prophylaxis. The purpose of this document is tohelp health care professionals to identify appropriatecandidates for stress ulcer prophylaxis and select cost-effective modalities for prophylaxis when prophylaxisis indicated. An economic evaluation has been provid-ed that can be adapted to individual practice sites.

ScopeThese guidelines pertain to stress-induced bleeding

associated with events such as trauma, surgery, andacute organ failure. In general, they apply to the daysimmediately after the stressful event, when endoge-nous healing processes or exogenous manipulations byhealth care professionals have yet to substantially im-prove the underlying disease process. However, a pa-tient may have resolution of the initial problem butthen have reactivation or initiation of a stressful eventthat could precipitate stress-induced bleeding. Theseare not unexpected occurrences in patients with ICUstays of more than a few days and could lead to periodicinstitution of prophylaxis to prevent bleeding.

The guidelines focus on agents that are used forstress ulcer prophylaxis in the United States, whether ornot the agents have FDA-approved labeling for thisindication. A majority of studies have involved hista-mine H2-receptor antagonists, antacids, or sucralfate,and these agents are discussed in detail. Few controlled,comparative studies have been conducted to assess theefficacy of misoprostol or proton-pump inhibitors (e.g.,lansoprazole, omeprazole) in preventing clinically im-portant bleeding. The potential advantages and disad-vantages of the latter medications for stress ulcer pro-phylaxis are discussed.

The guidelines include information for patients inall age groups for which there is literature. When agegroups are not specifically cited, the discussion refers tothe adult patient population. Few prospective, random-ized studies in the pediatric population have beenpublished, particularly with regard to clinically impor-tant bleeding. Where appropriate, the lack of age-spe-cific data is specified. It is hoped that the guidelines willstimulate research in these areas.

The guidelines are not intended to apply to theprevention of bleeding associated with chronic diseasesor long-term medication use. However, the contribu-tion of pre-existing diseases and the use of ulcerogenicmedications as aggravating risk factors for stress-in-duced bleeding are considered appropriate issues forreview.

Guideline development and useThe ASHP Therapeutic Guidelines on Stress Ulcer

ASHP Therapeutic Guidelineson Stress Ulcer Prophylaxis

Project Coordinators

Brian L. Erstad, Pharm.D., FCCM, FASHP, BCPSAssociate Professor/Assistant Department HeadDepartment of Pharmacy Practice and ScienceCollege of PharmacyUniversity of ArizonaTucson, AZ 85721

Kathryn L. Grant, Pharm.D., FASHPAssistant ProfessorDepartment of Pharmacy Practice and ScienceCollege of PharmacyUniversity of ArizonaTucson, AZ 85721

Expert Panel

Bradley A. Boucher, Pharm.D., BCPSAssociate Professor and Director of ResearchDepartment of Clinical PharmacyThe University of TennesseeMemphis, TN 38163

Jimmi Hatton, Pharm.D., BCNSPAssociate Professor of Pharmacy and SurgeryUniversity of Kentucky Medical CenterLexington, KY 40536

Judith Jacobi, Pharm.D., BCPSCritical Care Clinical PharmacistDepartment of Pharmacy ServicesMethodist Hospital of IndianaIndianapolis, IN 46206

Rick Jones, Jr.Manager, Strategic DevelopmentPharmacy DepartmentOrlando Regional Healthcare SystemOrlando, FL 32806

Keith M. Olsen, Pharm.D., FCCPAssociate Professor of PharmacyCollege of PharmacyUniversity of Nebraska Medical CenterOmaha, NE 68198

H. David Reines, M.D.Professor of SurgeryTufts University School of MedicineNewton, MA 02162

Andrea Quinn Wilson, APRN, CETN, CSClinical Nurse SpecialistYale New Haven HospitalNew Haven, CT 06504

ASHP Staff Liaison

Leslie Dotson Jaggers, Pharm.D., BCPSClinical Affairs AssociateASHPBethesda, MD 20814

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Prophylaxis were prepared by the University of Arizonaunder contract to ASHP. The project was coordinated bytwo pharmacy specialists, one with expertise in criticalcare and the other with expertise in drug information,who consulted with two physicians and a nurse special-ist from the Arizona Health Sciences Center. Theproject coordinators worked in conjunction with anindependent multidisciplinary panel of seven clinicalspecialists (a surgeon, a nurse, and five pharmacists)representing adult or pediatric critical care. The panelwas appointed by ASHP. Panel members and contrac-tors were required to disclose any possible conflicts ofinterest before their appointment. The guidelines un-derwent multidisciplinary field review in order to eval-uate their validity, reliability, and utility in clinicalpractice. The final document was approved by theASHP Commission on Therapeutics and the ASHPBoard of Directors.

The recommendations in this document may not beappropriate for use in all clinical situations.8 Decisionsto follow these recommendations must be based on theprofessional judgment of the clinician and must takeinto account individual patient circumstances andavailable resources. These guidelines reflect currentknowledge (at the time of publication) on the use ofstress ulcer prophylaxis in critically ill patients. Giventhe dynamic nature of scientific information and tech-nology, periodic review, updating, and revision are tobe expected.

Literature searchDetailed and exhaustive literature searches of MED-

LINE from 1966 to 1997 and International Pharmaceu-tical Abstracts (IPA) from 1970 to 1997 were performed.The searches of the two databases were compared tocheck for duplicates and were subsequently comparedwith the references listed in a recent meta-analysis byCook et al.5 for completeness.

Ten key articles pertinent to stress ulcer prophylaxiswere identified and entered into MEDLINE to captureappropriate MeSH headings. Applicable MeSH head-ings were combined with relevant text words into fivesets. Set A1 combined terms for the condition to beavoided in broad terms (e.g., peptic ulcer) by using thesubheadings prevention and control and complications. SetA2 covered terms more specific to the condition beingtreated (e.g., peptic ulcer hemorrhage) by using thesame subheadings. Set B included terms describingpatient location (e.g., intensive care) or condition (e.g.,critical illness). Set C covered terms related to thetreatments to be considered (e.g., H2-receptor antago-nists) with the subheadings adverse effects and therapeu-tic use, and set D was the free-text term stress ulcerprophylaxis. The sets were combined as [(A1 and B) or(A2 and C) or D]. The search was limited to reports onhumans published in the English language. The searchin IPA differed in that combining set A2 and C de-

ASHP Commission on TherapeuticsIn late 1990, the ASHP Board of Directors created an advi-sory body called the Commission on Therapeutics to beconcerned with societal drug use and therapeutic issues.This is consistent with the ASHP governing documents,which state that one purpose of ASHP is “to foster rationaldrug use in society such as through advocating publicpolicies toward that end.” The Commission is chargedwith the following:

• Identifying new and emerging therapeutic modali-ties for ASHP consideration,

• Developing documents on issues related to rationaland cost-effective drug use in society,

• Reviewing and responding to selected therapeutic ordrug-use initiatives of other organizations and agen-cies, and

• Consulting with ASHP on drug-use and therapeuticissues.

Members of the 1998–1999 ASHP Commission on Thera-peutics are Austin J. Lee, Pharm.D., BCPS, FASHP, Chair; C.Wayne Weart, Pharm.D., FASHP, Vice Chair; G. DennisClifton, Pharm.D.; Matthew A. Fuller, Pharm.D., BCPS,BCPP; Kent M. Nelson, Pharm.D., BCPS; William L. Green,Pharm.D., BCPS, FASHP; Mary Beth Gross, Pharm.D.;Michael D. Katz, Pharm.D.; Shirley J. Reitz, Pharm.D.; JaneE. DeWitt, Student Member; Donald T. Kishi, Pharm.D.,Board Liaison; and Leslie Dotson Jaggers, Pharm.D., BCPS,Secretary.

creased the retrieval. The sets were combined in IPA as{[(A1 or A2) and B] or D}. All relevant citations wereprinted and reviewed for pertinent articles, which weresubsequently retrieved and copied. The reference listsof the retrieved articles were studied for investigationsthat may have been missed through the computerizedsearch.

Periodic literature searches using the same methodwere conducted during the compilation of the guide-lines. The reference lists of review articles were exam-ined for potentially pertinent references. Unpublishedabstracts (e.g., those presented at meetings) and ab-stracts in foreign languages were not included in theevaluation.

Although all relevant articles were reviewed, they arenot necessarily referenced in this document. In partic-ular, isolated case reports or case series involving fewerthan 25 patients were not routinely included unlessthey provided unique information that would substan-tially affect the recommendations. Similarly, pharma-cokinetic and pharmacodynamic studies of medica-tions were not included unless there was some applica-bility to stress ulcer prophylaxis.

Level of evidence for recommendationsThere are several methods for assessing the literature

by using evidence tables.9-12 The methods of Guyatt etal.9 and the American College of Chest Physicians (1995revision)10 were determined to be the most applicable to



the literature to be reviewed because they involvedmeta-analysis and distinctions based on confidenceintervals, homogeneity, and heterogeneity. Thesemethods were modified slightly and expanded to in-clude a category D that represents a panel consensusbased on the clinical experience of the panel membersand a paucity of quality supporting literature. Beforereviewing the literature, the panel of experts agreedthat a meta-analysis carried more weight than a ran-domized, controlled trial (RCT) in determining a rec-ommendation unless at least two RCTs had similarresults or one RCT was designed with a sample largeenough to detect a difference of 50% or less in bleedingrates (considered the primary outcome) between thetreatment and control groups with a power of ≥80%and an α of ≤0.05.

The recommendations in this document were catego-rized according to the strength of the evidence. CategoryA corresponds to levels of evidence I+, I, and I–; categoryB to levels II+, II, and II–; and category C to levels III+, III,IV+, IV, and V. Table 1 includes definitions for each levelof evidence. The level of evidence was evaluated for eachtrial. When there were multiple RCTs of comparablepower pertaining to a particular recommendation andtheir levels of evidence differed, the level of evidence forthe least stringent trial was used in determining thestrength of evidence for a recommendation. Recommen-dations were assigned to category D if they representedthe expert opinion of panel members. For a recommen-dation based on RCTs to be assigned to category A, therehad to be at least two RCTs or one RCT with a sample sizesufficient for detecting a difference of 50% or less in ratesof clinically important bleeding with a power of ≥0.8 andan α of ≤0.05.

Table 1.System Used for Defining Levels of Evidence in Stress Ulcer Prophylaxis Guidelinesa

Level ofEvidence Definition

Meta-analysis of randomized, controlled trials (RCTs) with homogeneityb of results and a 95% confidence interval (CI)that lies entirely on one side of the numerical threshold for clinically important benefit

Meta-analysis of RCTs with homogeneity of results but with a 95% CI that includes the threshold for clinicallyimportant benefit

RCT in which the entire 95% CI lies on one side of the threshold for clinically important benefitMeta-analysis of RCTs with heterogeneity of results and a 95% CI that lies entirely on one side of the threshold for

clinically important benefitMeta-analysis of RCTs with heterogeneity of results and a 95% CI that includes the threshold for clinically important

benefitRCT in which the 95% CI includes the threshold for clinically important benefitNonrandomized concurrent cohort study in which the entire 95% CI lies on one side of the threshold for clinically

important benefitc

Nonrandomized concurrent cohort study in which the 95% CI includes the threshold for clinically important benefitNonrandomized historic cohort study in which the entire 95% CI lies on one side of the threshold for clinically

important benefitNonrandomized historic cohort study in which the 95% CI includes the threshold for clinically important benefitCase series suggesting clinically important benefit

I+

I

I–II+

II

II–III+

IIIIV+

IVV

aAdapted from references 9 and 10.bVarious definitions of homogeneity were used in the literature (e.g., the difference between the risk reductions or odds ratios between the two most

disparate trials is less than 20% and the difference between 95% confidence intervals for the two most disparate trials is less than 5%); the fact thathomogeneity was tested for is more important than the precise method used.

cThis assumes the availability of comparative data for calculating 95% CIs.

One problem with both the grading systems9,10 onwhich this system was based is the relative inability todistinguish the quality of individual investigations.Two RCTs may each be ranked similarly, but one mayhave been better designed and reported than the other.Therefore, in addition to listing levels of evidence forthe various trials, the superscript wd was used to signifya well-designed and well-reported trial when the guide-lines were sent to the panel of experts and other review-ers to aid them in evaluating the literature presented.More than 30 criteria, some of which have been pub-lished, were used in the analysis of the investiga-tions.13,14 The criteria represented a nonnumerical as-sessment and were not used as a scoring system for theformal statistical analysis.15

The levels of evidence were used to evaluate thosestudies that assessed the frequency of clinically impor-tant bleeding (i.e., gastroduodenal bleeding associatedwith hemodynamic compromise or the need for bloodtransfusion or surgery) and nosocomial pneumonia.Analysis of the number and type of risk factors associat-ed with bleeding by a rigid evidence-based evaluationmay be misleading for a number of reasons, includingthe following: studies used various definitions of bleed-ing and risk factors associated with bleeding, variousrisk factors were studied, various risk factors were usedas inclusion criteria, the analysis of risk factors oftenwas not a study objective, and, in many studies, multi-variate analysis was not used to determine which riskfactors might be independent predictors of bleeding.Observational trials with large numbers of patients areoften used appropriately to assess risk factors for bleed-ing, although the strength of evidence would never behigher than C.



Pathophysiology of stress-induced lesionsStress ulceration is a form of hemorrhagic gastritis

that may occur in patients who have had a majorstressful event such as trauma, surgery, organ failure,sepsis, or thermal injury. In general, the histologicaland macroscopic appearance of stress-induced fundallesions are similar to those associated with nonsteroidalanti-inflammatory drugs (NSAIDs) seen in the antrumand the body of the stomach. However, in contrast toNSAID-induced lesions, stress-induced lesions oftencause more congestion and bleeding, and they eventu-ally involve multiple sites in the upper GI tract.16 Cush-ing’s ulcer, which is associated with CNS injury, oftenpresents as a single deep lesion in the duodenum or inthe stomach.16 Curling’s ulcer, which is associated withthermal injury, is morphologically similar to otherstress-induced lesions but may appear in the esopha-gus, the stomach, the small intestine, or the colon.16

The pathogenesis of stress-induced lesions is proba-bly multifactorial.17 Acid hypersecretion is often statedas being particularly important in the formation ofulcers associated with head and thermal injuries.18

However, acid hypersecretion is not a universal findingin such patients, and higher pH values (>4.5) do notensure avoidance of lesions.19-21 During stressful events,normal protective mechanisms are altered, includingepithelial turnover in the gastric mucosa and secretionsof mucus and bicarbonate. These events, combinedwith the release of various mediators (e.g., arachidonicacid metabolites, cytokines, oxygen free radicals), resultin erosions that may progress to ulceration and bleed-ing.22 Reductions in mucosal blood flow may also beimportant in ulcer formation. Alterations in blood flowat the microcirculatory level may initiate a series ofchanges resulting in erosions that could progress toulceration and bleeding. Necrosis and erosions of thegastric membrane have occurred within 45 minutes ofhemorrhagic shock in experiments in rats.23 In adulthumans, erosions may occur very quickly (i.e., duringthe first 24 hours of hospital admission) in associationwith a stressful event, although the time from theinciting event to the diagnosis of bleeding may bemuch longer (e.g., >10–14 days).

Other less well-studied factors may be involved in thepathogenesis of stress-related lesions. For example, ele-vated concentrations of anti-Helicobacter pylori immuno-globulin A have been found in the serum of critically illpatients.24 Although the association between H. pyloriand chronic ulceration has been established, few studieshave been performed in acute care settings.

It is not known whether differences in basal ormaximal gastric acid production seen in various agegroups affect the frequency of ulceration and clinicallyimportant bleeding. For example, premature infantstypically produce less gastric acid than full-term in-fants, albeit with substantial interinfant variability.25,26

Newborns often have slightly acidic gastric pH values

that become more acidic within a few hours of birth.27

Gastric pH values in infants begin to approach those ofhealthy adults during the first six months of life. How-ever, stress ulcer lesions may occur at any age, includingin preterm infants, lending additional support to amultifactorial process.28

The frequency of ulceration, the number of ulcers, andthe sites of ulceration may be different between childrenand adults, depending on the stress-related event. In oneretrospective study involving 93 children less than 10years of age and 178 adults who died of burn-relatedinjuries, 13 (14.0%) of the children had duodenal ulcer-ation on postmortem examination compared with 13(7.3%) of the adults. In addition, 21 (22.6%) of thechildren had gastric ulceration compared with 20(11.2%) of the adults.29 No relationship between sex andulceration was found. Another review of infants less thanone year of age with stress ulceration found that singleduodenal ulcers were common, in contrast to the multi-ple gastric erosions usually found in adults.30

Frequency of bleeding, efficacyof prophylaxis, and risk factors for bleedingin general (medical, surgical, respiratory,pediatric) ICU populations

Acute bleeding in critically ill patients has beendescribed in the medical literature since the 1800s. Todetermine the true frequency of, and risk factors associ-ated with, stress-induced bleeding in general ICU pop-ulations, studies that contained at least one definedgroup of patients who did not receive prophylaxis wereevaluated.31-63 As will be seen in the following discus-sion, determining a true frequency of clinically impor-tant bleeding is complicated by the difficulty in mea-suring endpoints, the variability in endpoints used, thevariability in definitions of endpoints, and the hetero-geneity of the patient populations.

In general, the studies included in this section of thedocument on general ICU populations determined thefrequency of stress ulcer lesions and the risk factorsassociated with clinically important bleeding in pa-tients in medical, surgical, or respiratory ICUs. Onlytwo of the studies involved a relatively homogeneoussample of patients with a single-system disease or sur-gery. One study was conducted in patients with respira-tory disease, and the other involved patients undergo-ing abdominal surgery.36,44 These studies were includedbecause the patient populations were similar to thoseenrolled in other investigations. Studies enrolling pa-tients with single-system injuries (e.g., head or spinalcord surgery), patients with thermal injuries, or pa-tients undergoing transplantation were not included(see the section on special populations) because ofpresumed differences in the pathophysiology or fre-quency of stress-induced bleeding.

Frequency of bleeding. In all studies conductedbefore 1978, the frequency of clinically important



bleeding and related complications ranged from 5.3%to 33%. From 1978 on, substantial differences in thefrequency of stress-induced bleeding have been record-ed among trials. For example, in an RCT published byPinilla et al.42 in 1985, the frequency of bleeding was1.6% (1 of 61 patients), and it was not clear whether thispatient had clinically important bleeding. In contrast,an RCT published by Peura and Johnson43 in the sameyear, involving adult patients in a medical ICU, founda 39% frequency (7 of 18 patients) of endoscopicallyconfirmed, clinically important, stress-induced bleed-ing in patients not receiving prophylaxis. Articles pub-lished from 1984 to 1994 on the frequency of clinicallyimportant bleeding in patients not receiving prophy-laxis indicate that the average frequency of bleeding is6% (0.1–39%).64

With regard to the pediatric population, it is difficultto estimate the frequency of clinically important bleed-ing because of the small numbers of patients enrolled inpublished investigations and the use of endpoints oth-er than clinically important bleeding (e.g., endoscopicevidence of bleeding or overt bleeding). There are im-portant exceptions, albeit with differing results. In onestudy involving 140 children from birth to 20 years ofage, the frequency of clinically important bleeding was20% in a control group and 5.7% in a combined treat-ment group.65 In contrast, the frequency of clinicallyimportant bleeding (not defined in the published ab-stract) was 1.6% in a study of 1006 admissions to apediatric ICU, although it was not stated whether thechildren received any form of stress ulcer prophylaxis.66

Efficacy. Prophylaxis versus no prophylaxis. Twostudies conducted in the 1990s can be used to illustratethe disparate results of the more than 20 RCTs ofprophylaxis conducted in general ICU populations.The first trial, conducted in 1993 by Martin et al.,58 wasa multicenter, double-blind, placebo-controlled studyinvolving general medical and surgical ICU patientswith an expected length of stay of at least 36 hours andat least one risk factor (of eight studied) for bleeding.The study had 90% power to detect a 75% difference inbleeding between placebo and pH-adjusted cimetidinetherapy. The study was terminated early when an inter-im analysis revealed a significant difference in bleedingrates between the control and cimetidine groups. In thecontrol group, 16 (24.2%) of 66 patients had overt andclinically important bleeding (some bleeding was notcleared by lavage, but the patients did not requiretransfusion), compared with 5 (7.7%) of 65 patients inthe treatment group (p = 0.009). Six (10.0%) of 66patients in the control group and 4 (6.2%) of 65 in thetreatment group had clinically important bleeding. Sta-tistical testing of this endpoint was not performed.

The second study, a single-blind RCT, was conduct-ed in 1994 by Ben-Menachem et al.59 In that trial, onlymedical ICU patients who were expected to have alength of ICU stay of at least 24 hours were enrolled.

The study was designed to have 80% power to detect a75% treatment-related reduction in bleeding. Patientscould be randomly assigned to a control (no placebo)group, a pH-adjusted cimetidine group, or a sucralfategroup. There were no significant differences betweengroups with respect to clinically important bleedingepisodes (including some patients whose bleeding didnot clear by lavage): 6 of 100 patients in the controlgroup, 5 of 100 patients in the cimetidine group, and 5of 100 patients in the sucralfate group. In addition,there were no significant differences between groupswhen respiratory failure and coagulopathy were stud-ied as risk factors. If the different findings between thistrial and that of Martin et al. can be attributed todifferences in the populations being studied, it mightbe reasonable to consider withholding prophylaxis ingeneral medical ICU patients. However, it should bestressed that the trial by Ben-Menachem et al. was notdesigned to detect a difference of less than 75% inbleeding between groups, even though a smaller differ-ence might be clinically important.

Another study enrolled 90 intensive care patientswith septic shock, severe head injury, and trauma.67 Thepatients were randomly assigned to receive pirenzepine30 mg/day, omeprazole 80 mg/day, or no prophylaxis.A rating scale of zero (normal mucosa) to four (>25hemorrhages, erosions, or invasive ulcers) was used toevaluate all patients at baseline and after five days ofprophylaxis. Although all patients were at high risk forstress ulcer hemorrhage, no patients developed severebleeding from stress lesions, and no difference in endo-scopic evaluations was noted at baseline or at five daysamong the three groups.

Because individual trials have demonstrated con-flicting results with respect to the frequency of bleedingwith or without prophylaxis, several meta-analyseshave sought to resolve this issue (Table 2).5,68-71 Ab-stracts and non-English-language articles were fre-quently included in the data sets of these analyses, aswere reports of studies involving populations that otherstudies specifically excluded (e.g., patients with head orthermal injuries). One meta-analysis was published in1989, and three were published in 1991, so the numberof trials combined for each analysis was limited.68-71

Despite this difference in time frame, there was definiteoverlap among the meta-analyses in the studies thatwere included. Only one of the meta-analyses investi-gated the difference in bleeding rates with sucralfatecompared with no prophylaxis.5

The meta-analysis conducted by Lacroix et al.68 in-cluded randomized studies only. The frequency ofbleeding in patients receiving no prophylaxis (or place-bo) ranged from 3.4% to 52.7%. Use of cimetidine andantacids was associated with a significantly lower fre-quency of bleeding compared with no prophylaxis.Among the limitations of this meta-analysis were thatthe evaluated studies had methodological problems,



demonstrated heterogeneous effects, and investigatedthe frequency of occult or overt—but not necessarilyclinically important—bleeding, defined as hemody-namic instability or the need for blood transfusion.

In a meta-analysis published by Tryba69 in 1991,overt and clinically important bleeding (i.e., need forblood transfusion) were combined in the definition ofupper GI bleeding. Randomized and nonrandomizedstudies were included. The odds ratios (ORs) and 95%confidence intervals (CIs) calculated for H2-receptorantagonists or antacids compared with no prophylaxiswere all less than one (i.e., treatment was effective inpreventing bleeding). The data were presented only inthe form of figures, so the exact ORs and CIs are notavailable. However, the frequency of bleeding was 5.3%in the group receiving H2-receptor antagonists versus16.1% with no prophylaxis and 5.6% in the group

receiving antacids versus 14.9% with no prophylaxis. Asecond meta-analysis by Tryba71 in 1991 included onlystudies with clinically important bleeding. The resultswere similar to those of Tryba’s previous meta-analysis.

Two meta-analyses published by Cook et al.5,70 in1991 and 1996 included only randomized, controlledtrials. The investigations looked at clinically importantbleeding, defined as overt bleeding with hemodynamicchanges (a 20-mm Hg decrease in blood pressure within24 hours or a 10-mm Hg decrease plus a 20-beat/minincrease in heart rate on standing) or the need fortransfusion (a decrease in hemoglobin of 2 g/dL plustransfusion of two units of blood in 24 hours). In the1991 analysis, H2-receptor antagonists were found to bemore efficacious in preventing clinically importantbleeding than no prophylaxis.

The 1996 meta-analysis was performed to resolve

Table 2.Meta-analyses Investigating the Risk of Bleeding with and without Stress Ulcer Prophylaxis

Reference

68

69

71

70

5

Cimetidine versuscontrol

Antacids versuscontrol

Cimetidine versusantacids


H2-RAs versuscontrol

H2-RAs versusantacids

Sucralfate versusH2-RAs

Sucralfate versusantacids






Antacids versussucralfate

H2-RAs versussucralfate




Sucralfate versuscontrol



No. TrialsComparisona

7

9

10

6

14

14

6

10

9

10

3

6

9

5

1

3

10

10

1

5

4

Overt bleeding

Overt bleeding

Overt bleeding

Overt or clinically importantbleeding





Clinically important bleeding













OR = 0.32, CI = 0.21–0.49 (lower rate ofbleeding with cimetidine)

OR = 0.12, CI = 0.08–0.19 (lower rate ofbleeding with antacids)

OR = 1.61, CI = 0.97–2.65

OR and CI < 1 (lower rate of bleeding withantacids)

OR and CI < 1 (lower rate of bleeding with H2-RAs)

CI included 1

OR and CI < 1 (lower rate of bleeding withsucralfate)

CI included 1

OR = 0.532, CI = 0.303–0.933 (lower rate ofbleeding with sucralfate)

OR = 0.868, CI = 0.452–1.667

OR = 0.35, CI = 0.08–1.33

OR = 0.35, CI = 0.15–0.76 (lower rate ofbleeding with H2-RAs)

OR = 0.84, CI = 0.45–1.56

OR = 0.65, CI = 0.16–2.49

OR = 0.95, CI = 0.06–15.40

OR = 0.35, CI = 0.09–1.41

OR = 0.44, CI = 0.22–0.88 (lower rate ofbleeding with H2-RAs)

OR = 0.86, CI = 0.46–1.59

OR = 1.26, CI = 0.12–12.87

OR = 1.49, CI = 0.43–5.27

OR = 1.28, CI = 0.27–6.11

Endpoint Resultsb

aH2-RAs = histamine H2-receptor antagonists.bOR = odds ratio, CI = 95% confidence interval. Exact values provided when available; some values were extrapolated from figures.



some of the inconsistencies associated with the previ-ously conducted meta-analyses and to incorporatemore recent studies.5 The methodology was similar tothat of the earlier meta-analysis. Only H2-receptor an-tagonists were found to have a 95% CI of <1 for prevent-ing clinically important bleeding compared with noprophylaxis. However, only three trials with an antacidgroup and one with a sucralfate group were available forcomparison with no prophylaxis. Because the 1996meta-analysis was the most recent and comprehensive,its results are used in this document whenever thefindings from previous meta-analyses are conflicting.

To date, the study with the largest number of pro-spectively enrolled patients was published by Cook etal. in 1994.61 This multicenter follow-up trial enrolled2252 patients older than 16 years of age who wereadmitted to medical and surgical ICUs. Approximatelyhalf of the enrolled patients were admitted for cardio-vascular surgery. Some subgroups (head or spinal cordinjuries, multiple trauma or thermal injuries, and trans-plantation) had few patients. This limits the generaliz-ability of the results to these populations. Lack ofresources at three of the four hospitals prohibited en-rollment of consecutive patients as intended, and phy-sicians were not required to withhold prophylaxis.Various prophylactic medications were used, and thedosage and duration of prophylaxis were not con-trolled. Clinically important bleeding occurred in 10(0.6%) of 1578 patients not receiving prophylaxis and23 (3.4%) of 674 patients receiving prophylaxis (22 ofthe 33 bleeding episodes were confirmed). This suggeststhat, in this observational design, physicians wereprobably able to predict who was at risk for bleedingand administer prophylaxis; it does not necessarilyrepresent failure of prophylaxis.

Prophylaxis in pediatric patients. The number of stress-induced lesions progressing to clinically importantbleeding with or without prophylaxis is not well stud-ied in pediatric patients. Lacroix et al.48 compared pro-phylaxis with no prophylaxis in 40 patients from birthto 18 years of age. When the results were reported, overtbleeding was not distinguished from clinically impor-tant bleeding, and no differences in upper GI bleedingwere noted between the cimetidine group (9 of 19patients) and the placebo group (8 of 21 patients). Sixpatients had massive bleeding, defined as the presenceof nasogastric blood with changes in blood pressure orhemoglobin levels. It was not stated which groups thesepatients were in, and it was noted that five of thesepatients had bleeding at other sites due to disseminatedintravascular coagulation. The researchers concludedthat routine prophylaxis in medical pediatric patients isnot warranted.

In another study, 165 pediatric patients admitted toan ICU were randomly assigned to one of three active-treatment groups or a no-treatment group.65 The inves-tigators used clinically important bleeding as an out-

come. A significant (p < 0.05) difference between theactive-treatment groups and the no-treatment groupwas achieved only if the results for the three active-treatment groups were combined. Two studies focusedon a neonatal population but did not use clinicallyimportant bleeding as an endpoint.49,63 In one of thesestudies that had a control group, the risk of endoscop-ically diagnosed gastric lesions in mechanically venti-lated infants was found to be lower with ranitidineprophylaxis (OR = 0.03; 95% CI, 0.003–0.178). Surfac-tant therapy, which was used to treat infants withrespiratory distress syndrome, was also associated witha lower rate of formation of lesions (OR = 0.083; 95% CI,0.009–0.788).63 The mechanism for the apparent pro-tective effect of surfactant on the GI tract remains to beelucidated. No RCT conducted to date in pediatric pa-tients has conclusively demonstrated a significant dif-ference in clinically important bleeding when prophy-laxis was compared with no prophylaxis.

Risk factors. In Cook’s prospective observationalstudy, two risk factors were found to be significantpredictors of stress-induced bleeding: respiratory fail-ure, as defined by mechanical ventilation for at least 48hours (OR = 15.6; CI not reported, p < 0.001), andcoagulopathy, defined as a platelet count of <50,000mm3, an International Normalized Ratio of >1.5, or apartial thromboplastin time of >2 times the controlvalue (OR = 4.3; CI not reported, p < 0.001).61 Thefrequency of bleeding was 3.7% (95% CI, 2.5–5.2%) ifone or both of these risk factors were present and 0.1%(95% CI, 0.02–0.5%) if neither factor was present. Pa-tients who had received prophylaxis and those whohad not were included. Simple regression analysisshowed that sepsis, renal insufficiency, hepatic failure,enteral feeding, and the use of glucocorticoids, heparin,and warfarin were risk factors for bleeding; multipleregression analysis showed that only mechanical venti-lation and coagulopathy were independently predic-tive of clinically important bleeding.

The finding that enteral feeding was a risk factor forbleeding (OR = 3.8, p < 0.001) is of interest becauseprevious retrospective studies in adults have foundvarious effects of enteral feedings on pH and the fre-quency of bleeding.72-75 These differences may be due todifferences in location of the enteral feeding tubes. Forexample, feedings placed into the stomach may alkalin-ize stomach contents, and jejunal feedings may stimu-late gastric acid secretion. The fact that patients are ableto tolerate tube feedings may mean they are less ill thanpatients who cannot tolerate such feedings, and thismay determine the differences noted. Other factorsmay be specific to certain types of injury, such as thedevelopment of GI edema after thermal injury.

Conflicting associations with total parenteral nutri-tion (TPN) and bleeding have been noted. Ben-Men-achem et al.59 found that the frequency of bleeding wasnot related to the use of TPN. Ruiz-Santana et al.52



concluded that TPN was protective, but their samplesize was small, and their findings require confirmationin larger randomized trials.

The most recently published large-sample retrospec-tive study of risk factors in ICU trauma patients involved2574 patients.76 The only patients receiving prophylaxis(antacids) were those with a history of gastroduodenalulcerations. The published abstract does not reveal howmany of the 2574 patients received antacids. Clinicallyimportant bleeding was not analyzed separately from GIbleeding. GI bleeding was noted in 60 (2.3%) of thepatients. The risk factors associated with a higher risk ofbleeding included male sex, spinal cord injury, respirato-ry failure, acute renal failure, and severe sepsis.

Of the other trials in which risk factors were studied,a majority of those conducted in adults showed ahigher risk of bleeding as the number of risk factorsincreased.37-39,42,45-47,54,55,58 The results of most trials areconsistent with those of the 1994 study by Cook et al.61

in that mechanical ventilation (as a measure for respira-tory failure)36,41,59 and coagulopathy36,41,53 are the prima-ry risk factors for bleeding. Other risk factors associatedwith bleeding in adult patients in some studies includesepsis,35 length of ICU stay greater than one week,41

presence of occult bleeding for at least six days,53 andadministration of high doses of corticosteroids (>250mg/day of hydrocortisone or equivalent).54,59 However,the studies by Cook et al. did not find use of corticoster-oids, heparin, warfarin, or NSAIDs to be independentrisk factors for bleeding when respiratory failure andcoagulopathy were considered.53,61

Prophylaxis does not necessarily prevent bleeding inpatients with documented risk factors, and the effec-tiveness of prophylaxis varies in different popula-tions.59 Some potential risk factors for bleeding havenot been adequately studied, and it is unclear whetherthey are independent predictors of bleeding. A majorityof investigations excluded patients with a history of GIdisease, particularly ulcers and bleeding. It is unknownwhether a history of ulceration or bleeding increasesthe risk of acute, stress-induced bleeding. Similarly,ulcerogenic medications with well-documented associ-ations with bleeding problems, such as long-term use ofNSAIDs, have not been adequately studied as risk fac-tors for stress-induced bleeding. Typically, patients re-ceiving such medications either were not discussed inthe methods section of study reports or were prohibitedfrom enrolling in the studies.

In pediatric patients (birth to 19 years of age), coag-ulopathy,48,57 shock,56 surgery lasting for longer thanthree hours,56 trauma,56,57 and pneumonia57 were associ-ated with an increased risk of bleeding, while the use ofenteral nutrition reduced the risk of bleeding.57 Theresults were not stratified by age. One study in pediatricpatients (median age, 34.9 months) found that a Pedi-atric Risk of Mortality Score greater than 10 was associ-ated with a greater risk of bleeding.57 Another study in

mechanically ventilated preterm and full-term infantsfound that 20 (80%) of 25 patients had stress-inducedlesions as determined by endoscopic evaluation whenno prophylaxis was administered.63 That study andothers demonstrated that gastric lesions due to stressmay occur in the very young despite their possiblephysiological differences from adults.29,63

The rate of progression of these lesions to clinicallyimportant bleeding is not known. In a study in 881pediatric ICU patients (1006 admissions), 16 (1.6%)clinically important bleeding episodes occurred.66 Be-cause this was an observational investigation, physi-cians were not hindered from prescribing medicationsfor stress ulcer prophylaxis. Among the 110 patientswho received prophylaxis, there were 10 clinically im-portant bleeding episodes. The authors noted that thethree strongest independent risk factors for clinicallyimportant bleeding were respiratory failure (OR = 10.2),coagulopathy (OR = 9.3), and a Pediatric Risk of Mortal-ity Score of ≥10 (OR = 4.0). Of the 16 patients withclinically significant bleeding, 9 (56%) had all three riskfactors and 14 (88%) had at least two.

Summary. The reported frequency of stress-in-duced bleeding has varied substantially since approxi-mately 1978 and depends on the number and type ofrisk factors. Data from large prospective, observationalinvestigations in children and adults have found thatgeneral medical and surgical ICU patients who haveeither coagulopathy or respiratory failure requiring me-chanical ventilation have a substantially higher risk ofclinically important bleeding. The studies often exclud-ed neurosurgery, burn, and transplant patients. Anoth-er risk factor for children is a Pediatric Risk of MortalityScore of ≥10. A number of other risk factors have beenassociated with overt bleeding in isolated studies (pro-longed ICU stay or occult bleeding and administrationof high-dose corticosteroids in adults; prolonged shockor surgery and trauma in children), but it is unknownwhether these are independent predictors of clinicallyimportant bleeding, except in the case of coagulopathyor respiratory failure. Several studies that included bothmedical and surgical ICU patients suggest that, as thenumber of risk factors increases, the frequency of clin-ically important bleeding increases. It has been pro-posed that adult medical ICU patients may not neces-sarily need stress ulcer prophylaxis, even if they haverespiratory failure or coagulopathy. However, there areconcerns related to inadequate sample sizes in thestudies that resulted in this conclusion. Overall, accord-ing to RCTs, about 6% (range, 0.1–39%) of adult medi-cal and surgical patients at risk for stress ulcers who donot receive prophylaxis have clinically importantbleeding.64 Observational studies involving large num-bers of pediatric or adult patients suggest that the riskmay be substantially lower.61,66

Recommendation (adults): Risk factors for ICU patients havebeen delineated in trials comparing prophylaxis with no



prophylaxis by using clinically important bleeding as anendpoint. Prophylaxis is recommended in patients withcoagulopathy or patients requiring mechanical ventilationfor more than 48 hours. (Strength of evidence = C) Prophy-laxis is also recommended in patients with a history of GIulceration or bleeding within one year before admission andin patients with at least two of the following risk factors:sepsis, ICU stay of more than one week, occult bleedinglasting six days or more, and use of high-dose corticosteroids(>250 mg per day of hydrocortisone or the equivalent).(Strength of evidence = D) (Table 3) Recommendations forspecific prophylactic medications can be found in the Medi-cations used for prophylaxis section.

Recommendation (pediatrics): Although various risk factorshave been associated with bleeding in pediatric patients,published RCTs have either not used clinically importantbleeding as an outcome or had insufficient power to enable adefinitive conclusion that prophylaxis provides protection.Risk factors that have been associated with clinically impor-tant bleeding include respiratory failure, coagulopathy, anda Pediatric Risk of Mortality Score of ≥10. (Strength ofevidence = C)

Frequency of bleeding, efficacyof prophylaxis, and risk factors for bleedingin special populations (single-systeminjuries, thermal injuries, transplantation,miscellaneous)

Patients with head or spinal cord injuries or patientsundergoing surgical exploration for suspected diseasehave usually been studied as defined groups rather thanas part of general ICU populations.77-84 A majority ofthese studies in special populations were conducted inadults, although two studies included younger patients(mean age, 28 years, range, 2–74; mean age, 35 years,range 13–76) who were not discussed separately whenthe results were reported.77,79 Five of the trials wereRCTs.78,81-84 Three of these trials found significantlylower rates of clinically important bleeding with H2-receptor antagonist prophylaxis than with no prophy-laxis.78,83,84 However, in the RCT with the largest num-ber of patients (n = 167), the number of patients withclinically important bleeding was not reported.82 Onlytwo of the studies looked at a possible associationbetween the number of risk factors and the frequency ofbleeding. In both studies, the frequency of bleedingincreased with the number of risk factors.82,84

In general, the studies demonstrate an increasingfrequency of bleeding as the severity of injury increases.Two RCTs demonstrated substantial increases in clinical-ly important bleeding (27.8–45.8%) with severe headinjury (inability to obey simple commands in one trialand Glasgow Coma Score of ≤10 in the other), irrespec-tive of corticosteroid administration.78,84 In another RCTinvolving patients with head injuries, no association wasfound among 12 specific risk factors and bleeding, al-though bleeding rates were significantly higher whenmore than five risk factors were present.82 In patientsundergoing surgery for nontraumatic cerebral disease,cimetidine prophylaxis was more likely to fail when the

Table 3.Strength of Evidence for Prophylaxis for Adult ICUPatients According to Risk Factora

Risk Factor

General (medical, surgical,respiratory) ICU populationsb

Head injury with GlasgowComa Score of ≤10 orinability to obey simplecommands

Thermal injury involving>35% of body surface area

Partial hepatectomy

Hepatic or renal transplantation

Multiple trauma with InjurySeverity Score of ≥16

Spinal cord injury

Hepatic failure

History of gastric ulceration orbleeding during year beforeadmission

Presence of at least two of thefollowing: sepsis, ICU stay of>1 wk, occult or overtbleeding for ≥6 days,corticosteroid therapy(>250 mg of hydrocortisoneor equivalent daily)

A (for H2-RAs, antacids),B (for sucralfate)

B (for H2-RAs), D (forantacids, sucralfate)

B (for antacids), D (forH2-RAs, sucralfate)

C (for H2-RAs), D (forantacids, sucralfate)

D (for H2-RAs, antacids,sucralfate)






aH2-RAs = histamine H2-receptor antagonists, INR = International Nor-malized Ratio, PTT = partial thromboplastin time. Refer to the text fordiscussion of the risk factors and the economic analysis behind therecommendation.

bThere is evidence to suggest that patients in general ICU populationswho have respiratory failure or coagulopathies (as defined in the text) areat higher risk for clinically important bleeding.

Strength of Evidence

preoperative Glasgow Coma Score was <15 (impairedconsciousness) or when the syndrome of inappropriateantidiuretic hormone secretion was present.80

Patients with thermal injuries represent anotherpopulation that has usually been studied separatelywith regard to stress ulcer prophylaxis and bleeding.85-91

In the only trial that appeared to be randomized (48patients), the frequency of clinically important bleed-ing was 29.2% in patients who received no prophylaxisand 4.2% in patients given antacids (p < 0.02).90 Onlypatients with thermal injury to >35% of their bodysurface area (BSA) were included in this trial. In otherpublished investigations, the number and types of riskfactors (other than the thermal injury that may havecontributed to bleeding) were not studied, except for apossible association between sepsis and ulceration. Theretrospective study by Solem et al.91 was one of the firstto suggest that enteral feedings might be effective pro-phylaxis for stress-induced bleeding, but the feedingswere administered only if ulcers were unlikely to devel-op, a situation that was not defined. In addition, somepatients received both antacids and enteral feedings.

While many of the thermal injury studies includedinjuries in children (35 days to 13 years of age), only

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one study investigated the effect of no prophylaxis inpediatric patients only.88 All 477 children had thermalinjuries involving 13% or more of their BSA. Thirty-six(7.5%) of the children had clinically important bleed-ing when no prophylaxis was given (or at least was notmentioned). Some 32 of the 36 children (89%) withclinically important bleeding required blood transfu-sions, and 5 patients (14%) required surgery; 1 death(2.8%) was associated with GI bleeding.

Another defined population studied for stress ulcerprophylaxis includes patients (at least 14 years of agein published studies) undergoing renal or hepatictransplantation or hepatic surgery.92-97 Cimetidine orantacids were used for prophylaxis in all the trialsexcept one investigation that used ranitidine.97 Of thestudies evaluated, one was randomized. In all theinvestigations, both randomized and nonrandomized,overt and clinically important bleeding were com-bined. The frequency of bleeding was lower with ci-metidine prophylaxis in one study involving renaltransplant patients but not in the other.93,94

Prophylaxis with ranitidine was associated with asignificantly lower frequency of endoscopically con-firmed stress ulceration in the one available study ofhepatic transplant patients, but the frequency of clini-cally important bleeding was not delineated.97 One RCTinvolved patients with hepatic failure,95 and one pro-spective trial enrolled patients undergoing partial hepa-tectomy.96 The frequency of bleeding was lower withprophylaxis in both studies, but only the hepatectomystudy contained adequate information about clinicallyimportant bleeding to be able to conclude that it wassignificantly lower with prophylaxis. None of the stud-ies looking at renal or hepatic surgery or disease inves-tigated the number or type of other risk factors poten-tially associated with bleeding. Thus, direct evidencethat concomitant organ disease or surgery increases therisk of clinically important bleeding is lacking.

Several studies have included defined patient popu-lations other than those previously mentioned.98-102

Only one of these investigations was randomized.That study involved patients with tetanus who hadtracheostomies, a majority of whom were not mechan-ically ventilated.100 The frequency of overt bleedingwas similar between the patients who did and did notreceive prophylaxis, and there were no episodes ofclinically important bleeding. The frequency of bleed-ing and risk factors associated with bleeding wereevaluated in one retrospective study of 33,637 traumapatients, most of them adults.101 It is unknown howmany of these patients received prophylaxis, and overtand clinically important bleeding episodes were com-bined (18 of 33,367 patients bled). Risk factors associ-ated with bleeding included an Injury Severity Score of≥16, a Glasgow Coma Score of <8, and spinal cordinjury. Elderly patients and patients with infectionsand organ failure were also more likely to bleed.

The frequency of, and risk factors for, clinicallyimportant bleeding in patients with single-system inju-ries such as head trauma, spinal cord injury, and ther-mal injuries; patients undergoing transplantation; andpatients with multiple trauma have not been well stud-ied. These populations were usually excluded fromstudies in which patients might be randomly assignedto receive no prophylaxis. It is not known whetherrespiratory failure or coagulopathy would serve as inde-pendent predictors of bleeding in these populations.

Recommendation (adults): Prophylaxis is recommended forICU patients with a Glasgow Coma Score of ≤10 (or theinability to obey simple commands) or thermal injuries to>35% of their BSA. (Strength of evidence = B) ICU patientswith partial hepatectomy may also benefit from prophylaxis.(Strength of evidence = C) Prophylaxis may also be indicatedin ICU patients with multiple trauma (e.g., Injury SeverityScore of ≥16), transplantation patients in the ICU perioper-atively, ICU patients with hepatic failure, and ICU patientswith spinal cord injuries. (Strength of evidence = D) (Table 3)

Recommendation (pediatrics): For pediatric patients (onemonth of age or older) with thermal injuries, prophylaxis isrecommended, but there is insufficient evidence to recom-mend prophylaxis based on any given percentage of BSA.(Strength of evidence = D) For other pediatric surgery ortrauma patients, insufficient evidence is available to allowrecommendations about prophylaxis to be made.

Medications used for prophylaxisIn general, medications used for preventing stress-

induced bleeding exert their pharmacologic effectthrough one of the following mechanisms: inhibitionof gastric acid secretion, neutralization of gastric acidsecretions, and protective mechanisms unrelated toacid secretion or neutralization.103 The H2-receptor an-tagonists, prostaglandin analogues, and proton-pumpinhibitors act primarily as antisecretory agents by in-hibiting gastric acid secretion. But, other explanationsfor the beneficial actions of these agents have beenproposed. For example, H2-receptor antagonists haveimmunomodulatory actions at the cellular and media-tor levels.104 However, mediation of cytokine concen-trations is a complex process, and the cytokine concen-trations fluctuate widely in critically ill patients, oftennot correlating with more global physiological de-rangements.105 Similarly, the prostaglandin analoguemisoprostol prevents gastric mucosal damage by irri-tants that do not appear to depend on acid or acidsecretion and is sometimes referred to as a cytoprotec-tive agent.106 There is no convincing evidence to estab-lish that “cytoprotection” with misoprostol plays animportant role in preventing stress-induced lesions.107

Although alternative explanations for the effectivenessof antacids in preventing stress-induced bleeding havebeen proposed (e.g., stimulation of prostaglandin re-lease), neutralization of gastric acid is the primarymechanism of action.108 In contrast, sucralfate has mul-tiple actions on the GI tract besides providing a directprotective barrier, including modulation of pepsin and



mucus activity, arachidonic acid metabolism, bicarbon-ate secretion, and tissue growth or repair.109 Which, ifany, of these mechanisms is of primary importance forstress ulcer prophylaxis is not clear.

The H2-receptor antagonists that are available com-mercially in the United States are cimetidine, famoti-dine, nizatidine, and ranitidine. Only cimetidine ad-ministered as a continuous intravenous infusion hasFDA-approved labeling for the prevention of bleedingin critically ill patients, although there is no reason tosuspect any substantial difference in prophylactic effi-cacy when other H2-receptor antagonists are given inequipotent doses.110 However, other reasons may pre-clude their use, such as the lack of an i.v. dosage form(as with nizatidine). No RCTs of adequate sample sizehave compared dosage regimens (e.g., intermittent ver-sus continuous i.v. administration) or routes (e.g., i.v.versus oral) of H2-receptor antagonists by using clinical-ly important bleeding as a study endpoint.

One concern with using oral H2-receptor antagonistsand proton-pump inhibitors in critically ill patients isthe potential for malabsorption. Because these agentsmust be absorbed to exert their effects, the patient musthave a functioning GI tract. A functioning GI tract isusually presumed when tube feedings are toleratedwithout nausea, vomiting, abdominal distention, ordiarrhea. In patients with nasogastric tubes, the clini-cian may monitor the gastric residual volume whenfeeding formulas are administered into the stomach.Residuals refer to the feedings and gastric secretionsthat accumulate with GI dysfunction. A volume ofmore than 200 mL or an amount greater than thevolume infused over a two-hour period is usually indic-ative of dysfunction.111

Although widely used for stress ulcer prophylaxis,sucralfate is not labeled for this indication. Because su-cralfate appears to exert its predominant effects locally, itmust be administered either orally or by a nasogastric,orogastric, or gastrostomy tube. Sucralfate should not beadministered with nasogastric tube feedings (see Adverseeffects of prophylactic agents). Neither should it be ad-ministered by feeding duodenal or jejunostomy tubesbecause the medication will miss the site of action.

Similar to sucralfate, antacids have local actions andmust be administered directly into the stomach. Anumber of antacid products have been routinely usedfor stress ulcer prophylaxis. Several formulations carryFDA-approved labeling for this indication.

Misoprostol is available in tablet form, while proton-pump inhibitors such as omeprazole and lansoprazoleare available in delayed-release capsules. These medica-tions have not been well studied for stress ulcer prophy-laxis and are not labeled for this indication. The de-layed-release dosage forms of the proton-pump inhibi-tors create administration problems when oral intake isnot possible, although some interesting compoundingtechniques for omeprazole have been reported.112-115 In

addition, lansoprazole has FDA-approved labeling foradministration by nasogastric tube with some fruitjuices.116 One open-label study involving 75 mechani-cally ventilated surgery patients found a compoundedomeprazole suspension effective in preventing stress-induced bleeding.114 Larger comparative studies areneeded to determine efficacy and assess the potentialfor adverse effects such as pneumonia (from increasedgastric pH, as postulated for the H2-receptor antago-nists) and other unanticipated problems.

Although medications may have different mecha-nisms for their protective effects, there is no evidencethat combination therapy is more effective than asingle agent for initial prophylaxis, but the potentialrisk of adverse effects would increase with combinationtherapy. Therefore, combination therapy for initialprophylaxis cannot be recommended. Combinationtherapy for the prevention of recurrent bleeding isdiscussed further in this document (see Prevention ofrecurrent bleeding).

Efficacy of prophylactic agents: Preventionof bleeding

A substantial number of clinical trials, a majority ofwhich were randomized, have involved comparisons ofmedications used for stress ulcer prophylaxis.117-174 Ingeneral, no significant differences between medica-tions used for the prophylaxis of clinically importantbleeding have been found. However, in a majority ofstudies, the sample size needed to detect a differencebetween treatment groups in clinically importantbleeding was not calculated. Therefore, the number ofpatients enrolled in any given study was often insuffi-cient to preclude a Type II statistical error. Other studieshave found substantial differences in bleeding betweengroups, but the frequency of bleeding was unexpectedlyhigh for one of the groups. For example, Phillips et al.175

reported clinically important bleeding (the definitionof clinically important was different than the definitionused in these guidelines) in 4 (16%) of 25 patientsreceiving ranitidine by continuous i.v. infusion and 1(3%) of 33 patients receiving omeprazole suspension.Compared with the results of other studies, 16% is ahigh rate of bleeding with ranitidine.64,176

In the largest RCT published to date, 1200 patientswho required mechanical ventilation for at least 48hours were assigned to receive either nasogastric sucral-fate slurry (1 g every 6 hours) and i.v. placebo or i.v.ranitidine (50 mg every 8 hours) and nasogastric place-bo.176 The patients in this multicenter study were ad-mitted to medical and surgical services (approximately60% and 40%, respectively). There were relatively fewpatients from special populations: CNS surgery, 49patients; trauma, 158; burns, 12; and transplantation,19. These special populations were not discussed sepa-rately. Although the estimated sample size was basedon the power to detect differences in rates of pneumo-



nia (power, or 1–β = 75%), the rates of clinically impor-tant bleeding and mortality were additional study ob-jectives, and the trial’s power to detect a difference inbleeding rate was 90%. A significant difference in favorof the H2-receptor antagonist (ranitidine) comparedwith sucralfate was noted. Ten (1.7%) of the 596 pa-tients in the ranitidine group and 23 (3.8%) of 604patients in the sucralfate group had clinically impor-tant bleeding (relative risk, 0.44; 95% CI, 0.21–0.92; p =0.02). Endoscopic confirmation of an upper GI sourceof bleeding was obtained for 3 patients in the ranitidinegroup and 10 in the sucralfate group. An additionalpatient in the ranitidine group had an upper GI sourceof bleeding confirmed by angiography and red bloodcell scanning. Because invasive diagnostic testing wasleft to the discretion of participating physicians, thesource of bleeding was not found for 19 patients. Inaddition, no differences were noted in the overalllength of stay or mortality. Therefore, the largest RCTconducted to date has not definitively determined theagent of choice for the prevention of clinically impor-tant GI bleeding.

Five meta-analyses have been conducted to resolvesome of the discrepancies noted between RCTs, includ-ing the issue of inadequate sample size.5,68-71 None ofthese meta-analyses included the recently publishedRCT by Cook et al. (1998) and the Canadian CriticalCare Trials Group (Table 2).176 The other major limita-tions of these analyses have been discussed previously.In general, the meta-analyses found H2-receptor antag-onists and antacids to be more effective than no pro-phylaxis, but in some cases the 95% CIs were wide,indicating substantial variation in the data. Only onetrial compared sucralfate with no prophylaxis, and thistrial was included in the 1996 meta-analysis by Cook etal.5 The results of these meta-analyses were conflictingwhen medications were compared. In the meta-analy-ses by Lacroix et al.68 and Tryba,69 H2-receptor antago-nists were compared with antacids, but the 95% CIsincluded 1, indicating that the two regimens did notdiffer significantly. In the 1991 meta-analysis by Cooket al.,70 H2-receptor antagonists were significantly moreeffective than antacids for preventing overt bleeding,but the therapies were similar in preventing clinicallyimportant bleeding.

Tryba71 found sucralfate to be significantly moreeffective than H2-receptor antagonists and similar inefficacy to antacids (OR = 0.532; 95% CI, 0.303–0.933).Cook et al.70 (1991) found sucralfate to be similar to H2-receptor antagonists or antacids for preventing overtand clinically important bleeding.

Given the disparities noted in the previous meta-analyses, Cook et al.5 (1996) conducted a meta-analysisto resolve the apparent discrepancies. This meta-analy-sis included studies that were not available when theinitial meta-analyses were completed. In addition tobeing significantly more effective than no prophylaxis,

H2-receptor antagonists were found to be significantlymore effective than antacids in preventing overt bleed-ing but not clinically important bleeding. Sucralfatewas similar to antacids or H2-receptor antagonists forprophylaxis of both overt bleeding and clinically im-portant bleeding.

While useful, this meta-analysis raises some impor-tant questions.5 For example, the definitions for overtand clinically important bleeding are very explicit,which contrasts to the definitions used in many of therandomized investigations that were analyzed. It is notpossible to derive rates of clinically important bleedingfrom many of the trials, particularly if a rigid definitionis used. The meta-analysis also included RCTs from avariety of populations that have usually been studied asdistinct populations (e.g., patients with head and ther-mal injuries). Even if one assumes that the pathogenesisof bleeding is similar, there may be differences in thefrequencies of bleeding compared with populationsstudied more frequently (e.g., general medical and sur-gical ICU patients). If the frequency of bleeding hasdecreased over time as a result of improvements in thecare of the ICU patient (which is difficult to verifybecause many recent studies have not included a no-treatment group), this could have also influenced theresults of the meta-analysis. Finally, the results of thismeta-analysis are somewhat inconsistent with the find-ings of the large RCT recently published by the samelead authors with regard to possible differences in med-ication efficacy.176

Recommendation (adults): Given the conflicting results ofseveral meta-analyses and a recent RCT (both with strengthsof evidence = A), the choice among antacids, H2-receptorantagonists, and sucralfate for use as prophylactic agents toprevent clinically important bleeding associated with stressin adult patients admitted to general medical and surgicalICUs should be made on an institution-specific basis. Thischoice should take into account concerns regarding adminis-tration (e.g., functioning GI tract), adverse-effect profile, andtotal costs. (Strength of evidence = D) Insufficient data onmisoprostol or the proton-pump inhibitors are available toallow any recommendation about these agents to be made.

Recommendation (pediatrics and special populations): Thelack of comparative trials of these agents in pediatric andspecial populations (e.g., patients with burns, trauma pa-tients, patients undergoing neurosurgical procedures or withneurologic disorders, and transplantation patients) precludesdefinitive recommendations as to the agent of choice in thesesituations. The choice of agent should be made on an institu-tion-specific basis and should take into account concernsabout administration (e.g., functioning GI tract), adverse-effect profile, and total costs.

Efficacy of prophylactic agents: MortalityMany of the available studies did not include mortal-

ity outcomes, and still fewer specifically associatedmortality with bleeding. In the largest RCT to date,there was not a significant difference in mortality be-tween ranitidine recipients and sucralfate recipients



Table 4.Meta-analyses Investigating the Risk of Mortalitywith and without Stress Ulcer Prophylaxis

No.Trials ResultsbComparisonaReference

69

70

177

5

H2-RAs orantacids(combinedgroup) versuscontrol

Sucralfate versusH2-RAs orantacids(combinedgroup)




Antacids versussucralfate

H2-RAs versussucralfate












11

9

6

9

14

8

3

5

11

15

11

7

3

15

14

4

11

11

CI included 1

OR and CI < 1 (lowerrate of mortalitywith sucralfate)

OR = 1.06,CI = 0.67–1.66

OR = 0.80,CI = 0.54–1.18

OR = 1.16,CI = 0.83–1.61

OR = 1.22,CI = 0.83–1.79

OR = 1.25,CI = 0.61–2.58

OR = 1.36,CI = 0.83–2.24

OR = 1.03,CI = 0.73–1.48

OR = 1.06,CI = 0.78–1.46

OR = 0.70,CI = 0.52–0.94(lower rate ofmortality withsucralfate)

OR = 0.71,CI = 0.49–1.04

OR = 1.42,CI = 0.82–2.47

OR = 1.15,CI = 0.86–1.53

OR = 0.89,CI = 0.66–1.21

OR = 1.06,CI = 0.67–1.67

OR = 0.73,CI = 0.54–0.97(lower rate ofmortality withsucralfate)

OR = 0.83,CI = 0.62–1.09

aH2-RAs = histamine H2-receptor antagonists.bOR = odds ratio, CI = 95% confidence interval. Exact values provided

when available; some values were extrapolated from figures.

despite the finding of a lower frequency of clinicallyimportant bleeding with ranitidine.176 This may bepartially explained by the relatively low frequency ofbleeding in both groups. Any attempt to attribute dif-ferences in mortality to any single intervention in ICUpatients must be interpreted with caution given theproblems with controlling multiple confounding vari-ables. Furthermore, the limitations associated with theextraction and interpretation of this information fromthe original trials must be appreciated during consider-ation of the results of published meta-analyses thathave investigated the mortality associated with variousforms of prophylaxis.

In a meta-analysis by Tryba69 in 1991, sucralfate wasassociated with a lower mortality rate than use of eithera H2-receptor antagonist or an antacid. No significantdifferences in mortality were found between any of thegroups in the 1991 meta-analysis by Cook et al.70 (Table4). In contrast to the finding of the 1991 meta-analysis,sucralfate was associated with a lower rate of mortalitythan antacids in two other meta-analyses conducted byCook et al.5,177 (1994 and 1996). When medicationswere compared with no prophylaxis, all the CIs in thepublished meta-analyses included 1, the threshold ofimportance, suggesting no substantial differences inmortality.

Adverse effects of prophylactic agentsMost adverse effects attributable to antacids, H2-

receptor antagonists, and sucralfate are uncommonand occur in less than 1% of adult patients, particularlywhen given on a short-term basis (e.g., for less than twoweeks).178 The frequency of adverse effects may increaseif certain diseases are present, such as renal failure,when electrolyte accumulation secondary to antacidadministration or CNS disturbances secondary to ad-ministration of H2-receptor antagonists may occur. Su-cralfate may cause substantial elevations in serum alu-minum concentrations in adult patients with chronicrenal insufficiency or in the elderly,179 although thisdoes not appear to be a problem when the drug is usedfor less than two weeks in critically ill patients.180,181

Elevated aluminum concentrations and resultant toxic-ity are more of a concern in children with renal dys-function, particularly given that well-defined dosageguidelines have not been established.182 Although alu-minum hydroxide-containing antacids and sucralfatemay be used to lower phosphate levels in patients withuremia, they may cause unwanted hypophosphatemiain patients with normal renal function.183

Some products given by oral, nasogastric, or enteraladministration may result in local adverse effects. Forexample, constipation may occur with aluminum-con-taining antacids and sucralfate and diarrhea may occurwith magnesium-containing antacids at frequencieshigher than 1%.184 Sucralfate and antacids may occludefeeding tubes. If the occlusion cannot be removed, the

tube may have to be replaced, potentially causing pa-tient discomfort and resulting in complications fromplacement of a new tube (e.g., esophageal perforation,aspiration, inappropriate placement in the trachea).185

Although not well studied, there are potential inter-actions between enteral feeding products and medica-tions administered enterally for prophylaxis. Such in-teractions could result in clogged feeding tubes or di-minished medication efficacy (e.g., by inhibiting thelocal actions of sucralfate or interfering with the ab-



sorption of other medications). When intermittentfeedings are used, interactions can be minimized bygiving the feedings and medications at different times.When continuous feedings are used in conjunctionwith any medications, the feedings should be tempo-rarily stopped. The tube should be flushed with waterbefore the medication is administered. After the medi-cation is administered, the tube should again be flushedwith water to ensure passage through the tube. It isprobably unnecessary to discontinue postpyloric (jeju-nal) feedings for administration of sucralfate, becausesucralfate binds to the stomach mucosa. For more de-tails about enteral feeding–medication interactions andmethods to prevent them, the reader is referred topublished reviews.111,186

Case reports suggest that sucralfate may contributeto esophageal and GI bezoar formation, especiallywhen given in conjunction with enteral feedings inpatients with motility disorders.187-190 In addition totechnical problems related to the removal of bezoars,complications such as intestinal obstruction and perfo-ration have been reported in pediatric patients. Forexample, intestinal obstruction and perforation werereported with sucralfate in a low-birth-weight infantwho was given 250 mg every eight hours by nasogastrictube.191 Also, bezoars, hypermagnesemia, and intestinalperforation have been reported with liquid antacidsused in premature infants and newborns.192,193 There-fore, sucralfate and antacids should be used with cau-tion, particularly in premature infants.

The H2-receptor antagonists are associated with anumber of adverse effects that occur infrequently butmay lead to a consultation with a specialist, a diagnos-tic test, a new medication to treat the adverse effect, ora switch to another medication for prophylaxis. Poten-tial adverse effects include hepatitis, cytopenia, andcardiovascular and CNS toxicities. The exact frequencyof each of these problems is difficult to determine, butestimates range from 0.0023% for cytopenia to 1.9% forCNS toxicity.194-199 The low rate of these adverse effectsin adults and limitations associated with postmarketingsurveillance studies prohibit accurate comparisons ofthe frequencies of such effects among medications inthis class. The lack of studies in the pediatric populationprecludes an accurate assessment of the frequency ofparticular adverse effects. There is a possibility thatpediatric patients may be more susceptible to someadverse effects (e.g., thrombocytopenia associated withcimetidine49) than adults. Similarly, the lack of infor-mation related to pediatric dosing could result in eitherunderdosing with diminished efficacy or overdosingwith increased adverse effects.

H2-receptor antagonists and proton-pump inhibitorshave the potential for drug–drug, drug–nutrient, anddrug–test interactions through a variety of mechanisms.For example, some drug–drug interactions are mediatedthrough effects on the cytochrome P-450 systems in the

liver. Although a number of interactions with some ofthese acid-suppressing agents are of potential concern(e.g., warfarin, ketoconazole, phenytoin, theophylline),few are clinically important when patients are adequate-ly monitored.200 However, there may be other reasons foravoiding particular medications. For example, cimeti-dine may increase serum creatinine concentrations with-out affecting the glomerular filtration rate by competi-tion for tubular secretion in the kidneys.201 This could beinterpreted as renal dysfunction in patients receivingnephrotoxic medications, leading to inappropriate re-ductions in the dosage of the suspected medication.Other interactions may occur as a result of the acid-suppressing properties of these two classes of agents.

Sucralfate and antacids can affect the absorption ofother medications. Although most problems can beavoided if doses of sucralfate and antacids are separatedfrom doses of potentially interacting substances, thispractice is often not used.202 Potentially interacting med-ications should be administered one to two hours beforethe sucralfate dose. Furthermore, medications may inter-act with sucralfate and antacids despite separation (e.g.,the bioavailability of quinolone antimicrobials has beensubstantially reduced by sucralfate even when the twoproducts were separated by two or more hours).203,204

Test interference is a cause for concern with allmedications used for stress ulcer prophylaxis. This con-cern also applies to agents that do not alter pH (e.g.,sucralfate interferes with at least one method of occultblood testing).205

A full discussion of all potential drug–drug interac-tions with these agents is beyond the scope of theseguidelines; however, comprehensive reviews have beenpublished.206

The proton-pump inhibitors have few clinically im-portant adverse effects. The most common concerns aremild GI or CNS toxicities.207 The prostaglandin ana-logue misoprostol is rarely used clinically for prophy-laxis and is associated with substantial adverse effectscompared with placebo (nausea, abdominal pain, diar-rhea).208

Lansoprazole (pregnancy risk category B) and ome-prazole (FDA pregnancy risk category C) should be usedin pregnant or nursing mothers only when the poten-tial benefits exceed the potential risks.116,209 Similarcaution is advised for the H2-receptor antagonists (preg-nancy risk category B for cimetidine, famotidine, andranitidine; pregnancy risk category C for nizatidine)and sucralfate (pregnancy risk category B).110,210-213 Mis-oprostol is an abortifacient, may result in miscarriage(pregnancy risk category X), and is generally contrain-dicated in pregnant women, women of childbearingage, and nursing mothers.214

Pneumonia. The frequency of nosocomial pneu-monia associated with stress ulcer prophylaxis has beenwidely debated. In addition to patient morbidity andeconomic concerns, mortality rates associated with



pneumonia may be as high as 70%.215 There are multi-ple mechanisms by which bacteria may enter the lungs,including inhalation, hematogenous spread, contigu-ous spread, direct inoculation, aspiration of secretions,and translocation from the GI tract.216 The vast majorityof studies investigating a possible connection betweenpneumonia and stress ulcer prophylaxis have beenconducted in adults. In the few studies involving pedi-atric patients receiving stress ulcer prophylaxis, pneu-monia was usually not studied. When pneumonia wasreported, it was typically not a primary endpoint.65

Early reports of adult patients receiving antacids andcimetidine demonstrated that the stomach and upperairways had similar bacterial flora, suggesting retro-grade transmission from the stomach.217 Gastric coloni-zation was uniformly seen in patients with alkalinizedstomach contents.218 However, a positive correlationbetween increased gastric pH and colonization withbacteria does not mean there is a linear relationshipbetween acid-suppressing drugs and pneumonia.

It is also important to keep in mind that the tech-niques used to diagnose pneumonia have continued toevolve. Bronchoscopy, which is now a widely used andaccepted diagnostic tool in research, was not performedin older studies of medication-associated pneumonia.Although the sensitivity and specificity of bronchosco-py for diagnosis of infection have been improved bynewer techniques such as use of a protected-specimenbrush, morbidity and economic concerns have beenexpressed about its widespread clinical use.219 Othermethods are less invasive but often have lower sensitiv-ity and specificity, particularly when not performedappropriately.

Agents that do not alter gastric pH, such as sucralfate,may be less likely to result in pneumonia through retro-grade transmission or translocation of bacteria.220,221

When protected specimens, bronchoalveolar lavage, orboth were used, one prospective randomized, double-blind study involving 141 patients showed no differ-ence in the effect of antacids or sucralfate on gastricacidity or rates of bacterial colonization or ventilator-associated pneumonia.145 Decreased gastric acidity wasobserved in conjunction with greater colonization ofthe stomach but not of the upper respiratory tract. Inanother prospective investigation in which sampleswere obtained by bronchoscopy, mechanically venti-lated patients were randomly assigned to receive eitherantacids or sucralfate and then studied for risk factorsassociated with colonization and pneumonia.222 As inthe previous study, gastric colonization was not associ-ated with the development of pneumonia, but durationof mechanical ventilation and upper-respiratory-tractcolonization were found to be risk factors. A morerecent study on this issue had a double-blind, double-dummy design and compared the growth of gastricpathogens in 140 patients undergoing elective surgerywho were randomly assigned to receive either sucralfate

or antacids.223 Patients’ gastric and respiratory tractcontents were cultured for routine aerobic bacteria andfungi before surgery and daily throughout the hospital-ization until the patient was discharged or died. Clini-cal endpoints included upper GI tract bleeding (grosslybloody fluid in nasogastric aspirate that failed to clearwith saline lavage), pneumonia, wound infection, andurinary tract infection. New gastric microorganismsappeared in 24% of the patients receiving sucralfate and51% of the patients receiving antacids. The rates ofgastric bleeding, pneumonia, and nosocomial infectionwere not significantly different.

Other risk factors for nosocomial pneumonia havebeen identified and ranked according to supporting evi-dence.224 In addition to host factors (e.g., gastric hypoa-cidity) and environmental factors, the use of a nasogas-tric tube to administer medications (with the attendantrisks of aspiration and guaiac-positive stools from naso-gastric manipulation), along with the volume and pH ofmedications and feedings administered, determines thefrequency of pneumonia. However, despite these otherrisk factors, a committee associated with the Centers forDisease Control and Prevention has recommended thatnon-pH-altering medications (e.g., sucralfate) be used forprophylaxis in mechanically ventilated patients (agesnot specified).225 The recommendation was “suggestedfor implementation in many hospitals.” While sucralfatemay not contribute to translocation or colonization ofthe airways by bacteria, animal models of aspirationpneumonia have demonstrated that the volume of fluidadministered with sucralfate and the drug’s minimalbuffering activity may increase the risk of acid aspirationand pulmonary edema.226

In the RCT by Cook et al.176 that involved 1200patients, the determination of ventilator-associatedpneumonia was based on criteria modified from theCenters for Disease Control and Prevention. The studyhad sufficient power to detect a 25% difference in ratesof pneumonia (power = 75%). Bronchoalveolar lavageor protected specimen brush sampling was used fordiagnostic confirmation in patients with pneumoniasuspected by clinical criteria. One potentially con-founding variable was the use of enteral feedings by amajority (approximately 70%) of patients in eachgroup. Pneumonia was diagnosed in 114 (19.1%) of 596patients in the ranitidine group and 98 (16.3%) of 604patients in the sucralfate group, a difference that wasnot significant (relative risk, 1.18; 95% CI, 0.92–1.51; p= 0.19). It is possible that a significant, albeit small,difference in favor of sucralfate would be found if alarger trial were conducted. There were five patientswith “definite” pneumonia in the ranitidine group(0.8%) but none in the sucralfate group (95% CI, 0.1–1.6; p = 0.03).

Five meta-analyses of the frequency of nosocomialpneumonia associated with stress ulcer prophylaxishave also been conducted (Table 5). Two of the investi-



had a lower rate of pneumonia than patients whoreceived an antacid or an H2-receptor antagonist. How-ever, in the other two meta-analyses, no significantdifferences among any of the treatments werefound.5,227 However, these findings should be interpret-ed with caution given the methodological differences(e.g., diagnostic criteria for pneumonia) among thetrials being evaluated, the trials not included in themeta-analyses, and the tendency to combine the resultsfor acid-suppressive therapies together (i.e., H2-receptorantagonists and antacids).228

Summary. Antacids, H2-receptor antagonists, andsucralfate have been used for many years and have well-delineated adverse-effect profiles, with the one notableexception of nosocomial pneumonia associated withpH-altering agents in critically ill patients. Althoughdata from RCTs or large surveillance studies are lackingfor pediatric patients, all these agents have been used invarious age groups for multiple GI disorders with rela-tively few adverse effects. Experience with the proton-pump inhibitors for stress ulcer prophylaxis is limited,but experience treating peptic ulcers suggests that theseagents have a low rate of serious adverse effects in adultswhen used on a short-term basis. When compared withthat of other agents, the adverse-effect profile of miso-prostol, as well as the fact that there are limited studiesof efficacy, precludes its use for stress ulcer prophylaxis.

Recommendation (adults and pediatrics): It is recommend-ed that patients with a history of serious reactions toantacids, H2-receptor antagonists, proton-pump inhibitors,or sucralfate avoid future use of the offending agent. Thereare no other absolute contraindications that would precludethe short-term use of any of these medications for stressulcer prophylaxis. However, unless the benefits clearly ex-ceed the risks, it is recommended that sucralfate and antac-ids be avoided in neonates (particularly premature neonates)because of the possibility of adverse effects (e.g., bezoarformation, accumulation of aluminum and magnesium).Also, it is recommended that aluminum-containing prod-ucts such as sucralfate be avoided in children with renalfailure because dosing information has not been well estab-lished. Whether acid-suppressing agents are associatedwith a higher rate of pneumonia than sucralfate is unre-solved, although any difference between these medicationswould appear to be small. It is recommended that potentialadverse effects be considered as part of the economic anal-ysis when an agent is chosen (see Economic analysis).(Strength of evidence = D)

Initial dosageSome of the dosages listed in Table 6 had to be

extracted from the literature because stress ulcer pro-phylaxis is not an FDA-approved indication for most ofthe medications used for this purpose.110,209-211,213 Thedosages included in Table 6 have been commonly usedfor initiating prophylaxis against stress-induced bleed-ing in adults. In some of the studies, dosages weresubsequently adjusted according to gastric pH measure-ments. Dosages for patients with renal dysfunction

gations published in 1991 were conducted by Tryba andincluded many of the studies previously mentioned.One meta-analysis found a lower rate of pneumoniawith sucralfate use than with use of either an H2-receptor antagonist or an antacid.69 The second meta-analysis showed a lower rate of pneumonia with sucral-fate than with H2-receptor antagonists and for sucral-fate than with antacids.71 The other three meta-analyseswere conducted by Cook et al. and were published inthe 1990s. In the 1994 meta-analysis by Cook et al.177

involving six investigations, sucralfate-treated patients

Table 5.Meta-analyses Investigating the Risk of Pneumoniawith Medications Used for Stress Ulcer Prophylaxis

No.Trials ResultsbComparisonaReference

69

71

227

177

5

Sucralfate versusH2-RAs orantacids(combinedgroup)



Prophylaxisadjustedaccording togastic pHversus noadjustment

Antacids or H2-RAs versusplacebo versuscontrol(combinedgroup)

Sucralfate versusantacids or H2-RAs (combinedgroup)

Sucralfate versusantacids or H2-RAs (combinedgroup)






6

5

4

3

4

4

6

8

3

2

6

11

OR and CI < 1 (lowerrate of pneumoniawith sucralfate)

OR = 0.498,CI = 0.316–0.783(lower rate ofpneumonia withsucralfate)


OR = 0.63,CI = 0.24–1.62

OR = 0.42,CI = 0.61–1.10

OR = 0.55,CI = 0.28–1.06


OR = 1.25,CI = 0.78–2.00

OR = 1.01,CI = 0.65–1.57

OR = 2.11,CI = 0.82–5.44

OR = 0.80,CI = 0.56–1.15

OR = 0.78,CI = 0.62–1.09

aH2-RAs = histamine H2-receptor antagonists.bOR = odds ratio, CI = 95% confidence interval. Exact values provided

when available; some values were extrapolated from figures.



were mostly taken from published guidelines.110,209-211,213

No well-documented maximum dosage for each agenthas been reported, although studies involving pH de-terminations often set an arbitrary upper limit. Antac-ids were not included in Table 6 because of the largenumber of commercially available products with differ-ing acid-neutralizing capacities and the large number ofregimens used in the literature (many adjusted on thebasis of gastric pH determinations); the reader is en-couraged to consult available studies.36-40,42,54,90-92 Thedosage guidelines in Table 6 are based on limited clini-cal data and may need to be adjusted according toadverse effects or clinical response.229

Dosages for pediatric patients can be estimated fromthe few studies that have been published on stress ulcerprophylaxis (Table 7), extrapolated from pediatrichandbooks that describe dosing for related conditions(e.g., GI bleeding), or extrapolated from pharmacoki-netic studies.48,49,56,57,63,65,88,168,230-235 In published studies,i.v. ranitidine was given in dosages of 2–6 mg/kg/day(in three or four divided doses) to preterm newbornsand children up to 18 years of age.63,65,232,233,235 Cimeti-dine was given i.v. in dosages of 15–24 mg/kg/day (infour divided doses) in two studies involving newborns

Table 6.Initial Adult Dosage Regimens for Agents Usedfor Prophylaxis of Stress-Induced Bleedinga

NormalRenal

Function

ReducedRenal

FunctionMedication

Cimetidine110,178

Famotidine178,210

Ranitidine178,211

Omeprazole112-115,209

Sucralfate178,213

300 mg fourtimes a dayp.o., NG, or i.v.or 50 mg/hr bycontinuous i.v.infusion

20 mg twicedaily p.o., NG,or i.v. or 1.7mg/hr bycontinuous i.v.infusion

150 mg twicedaily p.o. orNG, 50 mgevery 6–8 hri.v., or 6.25mg/hr bycontinuous i.v.infusion

40-mg loadingdose, then 20–40 mg dailyp.o. or NG

1 g four timesdaily p.o. orNG

If CLcr <30 mL/min: 300 mgtwice a dayp.o., NG, or i.v.or 25 mg/hr bycontinuous i.v.infusion

If CLcr < 30 mL/min: 20 mgonce daily p.o.,NG, or i.v. or0.85 mg/hr bycontinuous i.v.infusion

If CLcr < 50 mL/min: 150 mgonce or twicedaily p.o. orNG, 50 mgevery 12–24 hri.v., or 2–4 mg/hr by continu-ous i.v. infusion

No adjustmentnecessary

No adjustmentnecessary

aNG = by nasogastric tube, CLcr = creatinine clearance. Dosages canbe modified on the basis of response or adverse effects.

and another study involving patients from birth to 18years of age (maximum dosage, 1000 mg/day).48,49,231

Pharmacokinetic or dosage studies in pediatric pa-tients have been published, but these are not necessar-ily related to the prevention of stress-induced bleeding.For example, Martyn et al.236 determined the pharmaco-kinetics of cimetidine in children with burn injuries.Twenty-one children ranging in age from 0.3 to 17.5years were administered cimetidine in doses of 10–15mg/kg. These children had higher cimetidine clearanc-es and shorter elimination half-lives than healthy orburned adults (primarily because of greater renal clear-ance). The authors suggested that in order to maintaina gastric pH of ≥4, continuous infusions of cimetidinewould be required.

Another study looked at the pharmacokinetics ofcimetidine in 30 critically ill children age 4.5 to 15years.237 The patients received a mean dosage of 26 mg/kg/day administered in four doses infused over 15minutes. Patients receiving ≥20 mg/kg/day maintainedplasma cimetidine concentrations at ≥0.5 µg/mL forlonger periods. The investigators found a significant (p< 0.001) inverse correlation between age and total bodyclearance (r = 0.75, p < 0.001) and age and apparentvolume of distribution (r = 0.76, p < 0.001). Theyconcluded that a dosage of cimetidine of 20–30 mg/kg/day given in six divided doses would provide moreoptimal steady-state plasma cimetidine concentra-tions.

Ranitidine was studied in 12 children ranging in agefrom 3.5 to 16 years with peptic ulcer disease.238 Eachchild received ranitidine by continuous i.v. infusion,with the rate adjusted to achieve at least 90% inhibitionof gastric acid secretion. The dosage and response datawere used to design intermittent dosage regimens, con-sisting of i.v. bolus doses given every 6 hours and thenoral doses given every 12 hours. The i.v. dose rangedfrom 0.13 to 0.8 mg/kg. Another study involving ranit-idine for neonates with documented gastric bleedingused a loading dose of 0.6 mg/kg followed by a contin-uous infusion of 0.15 mg/kg/hr.239 No adverse effectsfrom the ranitidine were noted.

Treem and colleagues240 studied i.v. famotidine in 18children ranging in age from 0.16 to 5.7 years who wereadmitted to a pediatric ICU after major elective ortho-pedic or cardiac surgery. Doses required to keep thegastric pH above 4 for at least six hours ranged from 0.4to 0.8 mg/kg. Famotidine was pharmacokineticallyevaluated in 14 children ranging in age from 1.25 to15.5 years who were diagnosed with gastric or duodenalulcers.241 Although famotidine effectively treated theulcers, 0.5 mg/kg i.v. or orally twice daily failed to keepthe pH above 5 for the dosage interval. These twostudies suggest that, for children, famotidine should begiven every six hours or, at least, every eight hours.

In summary, pharmacokinetic studies suggest thatchildren clear H2-receptor antagonists faster and have



Table 7.Studies of Stress Ulcer Prophylaxis in Pediatric Populationsa

MedicationStudy Design and Population(No. Patients or Admissions)Reference Age

No. with ClinicallyImportant Bleeding

larger volumes of distribution than adults and thatdoses should be given either by continuous infusion ormore frequently than those recommended for adults.Studies addressing the proper dosing of agents for stressulcer prophylaxis in pediatrics are needed.

In general, there is little dosing information for theneonatal population, in particular, premature neo-nates. Dosing in premature neonates is further compli-cated by decreased renal function secondary to diseaseor lack of maturation. Caution should be exercisedwhen H2-receptor antagonists are used in combinationwith tolazoline. Tolazoline may still be used in someinstitutions to treat pulmonary hypertension in neo-nates and has been associated with gastric bleeding. Casereports have implicated both cimetidine and ranitidinewith reversal of tolazoline’s histamine-mediated effects

on pulmonary vasculature.242 In general, the use of ant-acids and sucralfate should be avoided in prematureinfants because of the possibility of complications (seeAdverse effects of prophylactic agents).

Doses of H2-receptor antagonists are often reduced(or the intervals extended) for patients with renal dys-function, because all these medications have slowerclearances and longer half-lives in this population.243

These alterations in dose or interval have been based onexpected serum drug concentrations, because well-con-trolled studies have not investigated various dosageregimens in preventing stress-induced bleeding.Whether doses or intervals of H2-receptor antagonistsneed to be adjusted in patients with severe hepaticdysfunction or other diseases that might affect thepharmacokinetic properties of the agents is not known.

88

230

48

231

232

49

65

56

57

168

63

233

66

Retrospective; thermal injuryto 13–93% (mean, 29%)BSA; (477)

Retrospective; thermal injuryto 5–92% BSA (582)

Prospective, randomized;general ICU (40)





Prospective, observational;general ICU (208)


Prospective, randomized;cardiac surgery (79)




35 days to 13 yr;mean, 4.3 yr

4 wk to 15 yr

Birth to 18 yr; mean,1.85 yr

30–41.5 wk

Birth to 18 yr; mean,2.6–4.3 yr (varied bygroup)

Full-term neonates

Birth to 20 yr; mean,4.6 yr

Mean ± S.D.,38 ± 53.5 mo

Mean ± S.E.,62.6 ± 2.1 mo

35 days to 9.85 yr;mean, 2.62 yr

Neonates, mostlypreterm; mean,32 wk gestation

2 wk to 264 mo;median, 36 mo

3 days to 18 yr; mean,61.5 mo

None stated

Milk or feeding formula plusdiazepam

Cimetidine 5 mg/kg i.v.every 6 hr (1 g/daymaximum)

Cimetidine 6 mg/kg i.v.every 6 hr

Ranitidine 2–4 mg/kg NGevery 12 hr or 0.75–1.5mg/kg i.v. every 6 hr

Cimetidine 3.75–5 mg/kgi.v. every 6 hr

Ranitidine 1.5 mg/kg i.v.every 6 hr, sucralfate 0.5g (<10 kg) or 1 g (>10kg) every 6 hr, antacid(almagate) 0.25–0.5 mL/kg every 2 hr

None

Various (per discretion ofphysician)

Famotidine or pirenzepine1 mg/kg/day i.v. (3 dosesif <10 kg), 0.5 mg/kg/dayif serum creatinine > 3mg/dL

Ranitidine 1.67 mg/kg i.v.every 8 hr

Ranitidine 2–6 mg/kg/dayi.v. (mean, 3.3 mg/kg/day) given at intervals of6, 8, or 12 hrb

Various (per discretion ofphysician)

36

2

NA

NA

NA

NA

7/35 in control groupversus 6/105 incombined medica-tion groups (p <0.05); no significantdifferences for anysingle medicationversus control group

None

2/698 with no prophy-laxis versus 2/286with prophylaxis

NA

NA

None

6/990 with no prophy-laxis versus 10/110with prophylaxis

aOnly studies with at least 25 patients were included. BSA = body surface area, ICU = intensive care unit, NA = not available, NG = by nasogastric tube.bAdministered every eight hours in 89% of patients.



There are no adequate dosage guidelines for childrenwith renal dysfunction. Many practitioners recom-mend estimation of renal function by establishedmethods for children. Most methods yield creatinineclearances normalized to an average BSA (mL/min/1.73m2). Adjustments are then made by using adult guide-lines for impaired renal function. Still other practitio-ners may not make adjustments, believing that the risksof excessive dosing would not outweigh the risk ofunderdosing in children.

Gastric pH monitoring may help in developingdosage regimens, especially in patients with renal dys-function or immaturity (preterm infants). On days apatient is being dialyzed, it is advisable to administerthe medications after dialysis to avoid rapid clearanceduring the dialysis procedure.

Table 6 lists dosage regimens for commonly usedagents in adult patients. Some of the oral dosage regi-mens are equivalent to the i.v. regimens in terms oftotal daily dosage (e.g., cimetidine, famotidine), al-though an argument could be made for larger oraldosages on the basis of bioavailability differences be-tween the two routes of administration. Table 8 pro-vides pediatric doses for the H2-receptor antagonistsand sucralfate. The recommendations were derivedfrom limited data from published studies and werebased on toxicity as well as efficacy considerations.

Table 8.Pediatric Dosage Recommendations for H2-Receptor Antagonists and Sucralfate

Dosagea

ChildrenInfantsNeonatesMedication

30–40 mg/kg/day i.v.(1200 mg/day maximum)in 6 divided doses

1.6 (1–2) mg/kg/day i.v.(40 mg/day maximum)in 3 divided doses

6 (3–6) mg/kg/day i.v.(200 mg/day maximum)in 4 divided doses

40–80 mg/kg/day p.o. or NG(lower end of range foryounger children, 4000mg/day maximum)in 4 divided dosesd

20–40 mg/kg/day i.v.in 3 or 4 divided doses

1.2 (1–2) mg/kg/day i.v.in 2 or 3 divided doses

4.5 (3–6) mg/kg/day i.v.in 3 divided doses

40 mg/kg/day p.o. or NGin 4 divided dosesd

10 (5–20) mg/kg/day i.v. in2 or 3 divided dosesb

Inadequate informationavailable to make dosagerecommendations

Continuous i.v. infusion:0.0625–0.2 mg/kg/hrIntermittent i.v. doses: If fullterm, 1.5–3 mg/kg/day in 3divided doses; if premature,0.5 mg/kg/day in 2 divideddoses

Not recommendedc

Cimetidine48,49,231,236,237

Famotidine168,240,241

Ranitidine63,65,232,233,235,238,239,244,245

Sucralfate65,234

aDosages are for patients with normal renal function. NG = by nasogastric tube. There is a lack of data to make definitive dosage adjustments in pediatricpatients for renal dysfunction, but decreases in the total daily dosage of cimetidine, famotidine, and ranitidine would be logical. This could be done either bydecreasing individual doses while keeping the dosage interval the same as for patients with normal renal function or by extending the dosage interval andkeeping individual doses the same as for patients with normal renal function. No adjustment in the dosage of sucralfate is required for patients with renaldysfunction.

bIn general, half-lives were longer in neonates (2–3.4 hours), more than likely because of immature renal function. There is inadequate dosage informationon premature neonates with respect to stratification by birth weight or gestational age. Thus, a wide range of dosages have been reported in the literature.Many dosage handbooks and institutions use 5–10 mg/kg/day divided every 12 hours in premature neonates.

cInadequate information is available. Not recommended because of reports of bezoar formation in neonates (particularly premature neonates). Amount ofaluminum in adult doses of sucralfate may contribute to hypophosphatemia in neonates.

dDosage not well established. Bezoar formation with obstruction has been reported. Caution is advised when sucralfate is administered to any pediatricpatient, especially in cases of impaired gastric motility and dehydration.

MonitoringFor agents that do not affect gastric pH, such as

sucralfate, monitoring is limited to potential adverseevents and GI bleeding. However, for agents that neutral-ize gastric acid, particularly antacids, monitoring hasfrequently included pH determinations. No large, con-trolled studies have been published that document abenefit to pH monitoring in association with stress ulcerprophylaxis. The issue is further complicated by differ-ences in the validity and reliability of methods used tomeasure gastric pH. Although monitoring with pH paperis simple and is considered by many clinicians to be astandard of practice for agents that raise gastric pH, thismethod lacks accuracy.246 One study found that 33% ofgastric pH determinations were not ≥4, despite pH papertesting demonstrating evidence to the contrary.247

A number of studies have concluded from gastric pHdeterminations that continuous infusions of H2-recep-tor antagonists are more effective than intermittentdosage schedules.248-253 Many factors must be consid-ered in the interpretation of these studies, beginningwith the role of gastric acidity in the pathogenesis ofstress ulceration. Although gastric acidity may have arole in stress-induced damage, gastric acid is unlikely tobe the main cause of bleeding.254 Not only do many ICUpatients have hyposecretion of gastric acid,255 but gas-tric pH fluctuates rapidly and may not be controlled



even if dosages of antisecretory agents are individual-ized.256,257 Gastric pH can also be increased by the pres-ence of blood and bile in the GI tract. Although newermethods of pH monitoring, such as noninvasive, intra-mucosal pH measurements, may prove useful for pre-dicting stress-induced bleeding, such measurementshave been studied primarily as indicators of systemictissue oxygenation and hence of overall mortality ratesin critically ill patients.258

Checking for microscopic bleeding by occult bloodtesting techniques has similar limitations. Most impor-tant, there is no proven relationship between micro-scopic bleeding and outcomes such as clinically impor-tant bleeding, although the results of one prospectivestudy suggest that occult bleeding for at least six daysincreases the risk for overt bleeding.53 Overt bleeding isdefined as the presence of blood or “coffee-ground”material in nasogastric aspirates, hematemesis, hema-tochezia, or melena. Overt bleeding that results inhemodynamic compromise or the need for blood trans-fusions or surgery is clinically important. Therefore,patients at risk for stress-related complications shouldbe routinely followed for overt bleeding.

When overt bleeding occurs, the patient should beclosely monitored for decreases in blood pressure (e.g.,a decrease of 20 mm Hg or more in the diastolic pressureduring a 24-hour period), hemoglobin (e.g., ≥3 g/dLduring a 24-hour period), and hematocrit (e.g., ≥9%during a 24-hour period), all of which suggest clinicallyimportant GI bleeding in the absence of other causes.When overt bleeding, with or without hemodynamiccompromise, continues despite conservative therapiessuch as saline lavage, endoscopy is usually indicated.Endoscopy can be used to confirm a GI source ofbleeding.

Recommendation (adults and pediatrics): It is recommendedthat all patients receiving medications for stress ulcer pro-phylaxis be monitored for bleeding and adverse drug effects(see Adverse effects of prophylactic agents). Paper techniquesfor measuring gastric pH have questionable validity andreliability, and there is no evidence that adjusting the dosageof pH-altering medications (antacids, H2-receptor antago-nists, proton-pump inhibitors) on the basis of these measure-ments influences patient morbidity or mortality. Despite thelack of supporting data, pH monitoring for antacids may beappropriate (goal pH of >3.5–4). Such monitoring may alsobe useful for H2-receptor antagonists when standard dosageregimens might not be appropriate (e.g., in cases of renaldysfunction, for increased dosages due to perceived failure oftherapy, in pediatric patients). (Strength of evidence = D)

Other options for prophylaxisSimilar to the principles involved in preventing

global ischemia, a primary intervention for reducingthe frequency of stress-induced bleeding should be theprevention of GI hypoperfusion and attendant ischem-ic complications.259,260 If ischemia is prevented duringthe early stages of injury, stress ulcer prophylaxis maybe unnecessary. In fact, acid inhibitors or neutralizers

may be harmful. In the case of acid neutralizers, increas-ing gastric pH allows for bacterial overgrowth, withsubsequent spread to other organs.261

As discussed previously, the effect of enteral feedingson the frequency of stress-induced bleeding and pneu-monia has not been established through controlledtrials. Although gastric acid appears to play a role instress-induced bleeding, and while it is clear that micro-bial growth is inhibited at low gastric pH, it has notbeen conclusively demonstrated that continuous orintermittent enteral feedings consistently raise gastricpH.262 The site of enteral feeding administration (stom-ach or sites distal to the pylorus) varied in publishedstudies, and potential site-specific effects remain to beelucidated. The possibility that enteral feedings offerprotection against bleeding and pneumonia throughother mechanisms (e.g., maintenance of a positive ni-trogen balance that is important for normal reparativefunctions of the gastric mucosa) should be explored.

Appropriate supportive care, such as administrationof fluids and blood products, nutritional support, ven-tilatory support, and timely definitive surgery, maypreclude the need for stress ulcer prophylaxis in manypatients.263,264 Before the widespread use of H2-receptorantagonists for stress ulcer prophylaxis, a number ofregimens were used to prevent acute upper GI bleedingin burn patients, including milk and diazepam given tochildren and vitamin A injection given to adults.230,264

Although corticosteroids have been studied as incitingfactors for GI bleeding, other evidence suggests thatcorticosteroids may protect against bleeding in somepopulations, including patients with shock.265

Combinations of allopurinol and dimethyl sulfox-ide have been studied in two RCTs in patients with legor pelvic fractures who had clinical evidence ofshock.166,266 These agents were studied because of theirability to decrease free-radical formation and, there-fore, potentially prevent gastric mucosal injury. Bothtrials showed significant (p < 0.01) decreases in endo-scopically confirmed lesions. Both of these studies arepromising but require confirmation in different popu-lations. Comparisons with existing agents that includeeconomic evaluations of the options are also needed.

Recommendation (adults and pediatrics): It is premature torecommend the use of novel therapies (e.g., free-radicalscavengers) in place of conventional agents for stress ulcerprophylaxis, although the limited number of studies havehad promising results. (Strength of evidence = D)

Prevention of recurrent bleedingThe efficacy of nonsurgical therapies such as antac-

ids and H2-receptor antagonists in preventing recurrentbleeding has varied considerably from study tostudy.267-269 The number of patients requiring surgeryfor continued or recurring stress-induced bleeding hassteadily decreased since approximately 1978. In a num-ber of published studies, bleeding stopped spontane-



ously without intervention. In others, the patients’bleeding often stopped and did not recur when conser-vative measures were instituted, usually an increase inthe dosage of the current medication, a switch to adifferent medication, or the addition of another agent,plus gastric lavage. No large controlled trials have com-pared the various medication options for preventing arecurrence of stress-induced bleeding. However, whencombination therapy for prophylaxis is being consid-ered in a patient who bled while receiving single-agentprophylaxis, use of drugs with different mechanisms ofaction would seem logical. Potential interactions be-tween prophylactic agents from different classes havenot been well studied but could occur (e.g., reducedactivity of sucralfate with neutral or alkaline gastric pH,binding of agents by sucralfate). Providing any defini-tive recommendation regarding this issue is difficult.The assumption is, of course, that any medication is ofbenefit in preventing recurrent bleeding.

Recommendation (adults and pediatrics): The lack of avail-able trials prohibits definitive recommendations for pre-venting recurrent bleeding after an episode of stress-inducedGI bleeding, although consideration could be given to in-creasing the dosage of the prophylactic agent, adding an-other medication, or switching to a different agent. (Strengthof evidence = D)

Prophylaxis in non-ICU settingsIt is possible that patients in non-ICU settings could

have coagulopathy or other conditions that have beenidentified as risk factors for bleeding (e.g., transplanta-tion). Only one RCT has addressed stress ulcer prophy-laxis in non-ICU settings.54 The study involved 100adults and was conducted on a general medical andsurgical hospital ward in Spain. Bleeding was signifi-cantly (p < 0.001) less frequent with antacid prophylax-is than with placebo. However, bleeding was definedbroadly to include patients who had a decrease inhematocrit, regardless of whether they required trans-fusion. Three patients required transfusion in the place-bo group and none in the antacid group. Upon institu-tion of antacid and H2-receptor antagonist therapy, thebleeding stopped in the three patients in the placebogroup without subsequent complications. The frequen-cy of all types of bleeding (e.g., overt, clinically impor-tant) was significantly lower with prophylaxis only iftwo or more risk factors for bleeding were present beforeprophylaxis was initiated.

Discontinuation of prophylaxisAn increase in the number of risk factors has been

associated with a higher risk of bleeding in multiplestudies conducted in the ICU setting and one studyconducted on a hospital ward. The risk of clinicallyimportant bleeding would probably diminish as thenumber of risk factors is reduced. In most clinical trials,prophylaxis was discontinued without evidence of clin-

ically important bleeding upon extubation or the pa-tient’s discharge from the ICU. Thus, it is reasonable toassume that prophylaxis can be stopped once risk fac-tors have resolved.

Recommendation (adults): Stress ulcer prophylaxis is notrecommended for adult patients in non-ICU settings. (Strengthof evidence = B for general medical and surgical patients withfewer than two risk factors for clinically important bleeding;strength of evidence = D for patients with two or more riskfactors) (Table 3)

Recommendation (pediatrics): Stress ulcer prophylaxis is notrecommended for pediatric general medical and surgicalpatients or special populations (e.g., transplantation) in non-ICU settings if fewer than two risk factors for bleeding arepresent. (Strength of evidence = D). Data are insufficient toallow recommendations to be made about the use of prophy-laxis in pediatric patients with two or more risk factors. Ifprophylaxis is given, it should be discontinued once riskfactors have resolved. (Strength of evidence = D)

Economic analysisInappropriate stress ulcer prophylaxis can be costly,

but implementing guidelines may decrease the inap-propriateness and the expense.270,271 Published econom-ic analyses can be useful for developing institution-specific guidelines for prophylaxis. Two cost-effective-ness analyses have been completed concerning prophy-laxis for stress-induced bleeding. In the first investiga-tion, by Schumock et al.,272 an antacid regimen of 30 mLgiven every 4 hours was compared with sucralfate 1 ggiven four times daily and three H2-receptor antago-nists (ranitidine 50 mg i.v. every 8 hours, cimetidine300 mg i.v. every 6 hours, and famotidine 20 mg i.v.every 12 hours), all of which were based on a seven-daycourse of therapy. The study was conducted from theviewpoint of the payer, with hospital charges measuredin 1994 dollars. The authors assumed that the frequen-cy of bleeding would be approximately 70%, 80%, and36% lower with the use of sucralfate, antacids, and H2-receptor antagonists, respectively, and that it cost$6128 to treat an episode of bleeding. The frequency ofpneumonia was assumed to be unchanged with sucral-fate but increased by approximately 7% with antacidsand 13% with H2-receptor antagonists. The net savingassociated with prevention of one case of acute upperGI bleeding was $7373 for sucralfate and $4321 forantacids. In contrast, therapy with an H2-receptor an-tagonist would cost between $6655 and $7986 to pre-vent one episode of acute upper GI bleeding. Thedifference in costs between sucralfate or antacids andH2-receptor antagonists was related to the assumedhigher rates of bleeding and nosocomial pneumoniawith H2-receptor antagonists. One-way sensitivity anal-ysis showed that sucralfate remained the preferredagent regardless of the cost of prophylaxis, the cost oftreatment for pneumonia or bleeding, or the presumedfrequency of bleeding or nosocomial pneumonia.

The second cost-effectiveness study, by Ben-Men-



achem et al.,64 was based on the perspective of thehealth care provider. Cimetidine (300 mg i.v. every sixhours) was compared with sucralfate (1 g every sixhours), both given for seven days. One notable differ-ence from the previous analysis was the assumptionthat it would cost $595 to treat a GI bleed. It waspresumed that both therapies would decrease the fre-quency of bleeding by 50%; in the sensitivity analysis,the percent reduction was varied over the range of 10–90%. Despite different assumptions from the investiga-tion by Schumock et al., the results were similar in thatsucralfate (cost of $1144 per bleeding event averted)was more cost-effective than cimetidine ($7538 perbleeding event averted), even when rates of pneumoniawere presumed to be equal.

In one study involving a small number of patients,the costs of enteral and i.v. ranitidine administrationwere compared, although only enteral administrationwas used.273 Ten patients were assigned to receive raniti-dine 150 mg every 12 hours and eight patients to receive300 mg every 12 hours; both dosages were given bynasogastric tube. Both therapies reduced stimulatedacid secretion by at least 50%. Drug costs were calculat-ed to be at least 48% less with the enteral administra-tion than with i.v. administration.

A formal economic analysis from an institutionalperspective was conducted as part of the guidelinedevelopment process. The general steps of acceptablecost-effectiveness analysis were followed: identificationof clinical choices, determination of costs and benefits,statement of time frame, determination of cost-effective-ness ratio, and performance of a sensitivity analysis.274

Readers are encouraged to make institution-specific deci-sions and to use the template to construct their owninstitution-specific economic analysis.

The medications were assumed to have equal pro-phylactic efficacy on the basis of the most recent meta-analysis.5 Although both the meta-analysis and therecent large RCT met our criteria for a grade of A, themeta-analysis had a level of evidence of I and the RCTa level of evidence of I– (see Table 1 for definitions).

Drug and administration costs9,64 and adverse eventcosts9,185,275,276 and frequency61,64,176,194-199,277,278 were ex-trapolated from the literature (Table 9). Ranitidine waschosen as the representative H2-receptor antagonist;i.v. administration was assumed. Because of the cost ofcommercial sucralfate suspension, the cost analysis wasdone under the assumption that nursing staff wouldadminister sucralfate tablets as a slurry through a naso-gastric tube. The medication cost figures were based ona five-day course of prophylaxis. Costs and benefitswere assumed to occur within the same period, makingdiscounting unnecessary. Any estimates not based onthe literature were mentioned. The cost estimates formany of the adverse effects were small (e.g., $500),because it was assumed that the effects would be readilyreversible or found to have a different cause. The costs

reflect laboratory or consultation estimates that wouldbe incurred even if the problem were eventually foundto be unrelated to the medication. One hundred pa-tients were assumed to be in each treatment group inour decision model because of the small probabilities ofsome of the events. It was assumed that the number ofevents would not vary with the number of patients.

Figure 1 is the decision tree used for the economicanalysis associated with these guidelines. The overallresults are consistent with those of other publishedcost-effectiveness analyses that concluded that sucral-fate is the most cost-effective agent for prophylaxis,with a saving of $4913 for each episode of bleedingaverted. The cost-effectiveness ratio for ranitidine waslower, with a cost saving of $1766. Antacids were nearlycost neutral. The differences are particularly notable ifthe pH-altering medications are assumed to cause ahigher rate of nosocomial pneumonia (0.8% for acidsuppressants and 0 for sucralfate); this is true regardlessof the route of administration for the H2-receptor antag-onists. If it is assumed that none of the medicationscause adverse effects (including pneumonia) and thatthey are similar in efficacy, sucralfate and orally admin-istered H2-receptor antagonists would have similarcosts.

The following is a template for evaluating the cost-effectiveness of stress ulcer prophylaxis regimens onthe basis of institution-specific data.

Step 1. Estimate the risk of clinically important bleed-ing events without prophylaxis (baseline rate stated as apercentage).Step 2. Estimate the reduction in clinically importantbleeding events associated with prophylaxis.Step 3. Estimate the cost per patient of treating GIbleeding at the institution.Step 4. Estimate the cost of using sucralfate prophylaxisin 100 patients.Step 5. Estimate the cost of adverse events per 100patients if all 100 are given prophylaxis.Step 6. Estimate the cost of treating bleeding per 100

Table 9.Cost Assumptions 9,64,185,275,276

Cost Assumptions perEpisode or Course

of Therapy ($)aVariable

PneumoniaBleedingHepatitisCNS toxicityCytopeniaCardiovascular toxicityClogged tubesAntacids every two hoursHistamine H2-receptor antagonist

three times dailyb

Sucralfate four times daily

10,062 7,000 500 500 500 500 160 78.00

61.50 33.80

aA course of therapy was assumed to be five days. Drug acquisitioncosts are average wholesale costs.

bRanitidine used as the example.



Pneumonia 0.8%

Hepatitis 0.6%

CNS toxicity 1.8%

Cytopenia 0.0023%

CV toxicity 0.6%

Pneumonia 0.8%

Hepatitis 0.6%

CNS toxicity 1.8%

Cytopenia 0.0023%

CV toxicity 0.6%

Pneumonia 0.8%

Clogged tubes 18%

Pneumonia 0.8%

Clogged tubes 18%

No bleeding

97%

Bleeding

3%$7000 perepisode

No bleeding97%

3%$7000 perepisode

Bleeding

No bleeding

97%

3%$7000 perepisode

Bleeding

$160 per episode

$10,062 per episode

$500 per episode

$500 per episode

$500 per episode

$500 per episode

$10,062 per episode

$500 per episode

$500 per episode

$500 per episode

$500 per episode

$10,062 per episode

$160 per episode

$10,062 per episode

$160 per episode

$160 per episode

Adversedrug

reactions

No adverse drug reactions 97.3%

Adversedrug

reactions


Adverse drug reactions, clogged tubes 18%

No adverse drug reactions 82%



Adverse drug reactions, clogged tubes 18%

No adverse drug reactions 82%

Adversedrug

reactions

Adversedrug

reactions

Sucralfate

n = 100$33.80 percourse oftherapy

Antacids

n = 100$78 per

course oftherapy

n = 100$61.50 percourse oftherapy

H2-RAs

Bleeding 6% $7000 per episode

No bleeding 94%

n = 300

Yes

n = 400patients at

risk

Stress ulcerprophylaxis

No

5,804

7,856

327

980

1

327

20,613

Cost per 100patients ($)

411

136

408

1

136

2,688

3,384

17,303

3,885

6,144

7,869

4,156

17,242

411

3,909

0

42,000

TOTAL(H2-RAs)

$37,000 per100 patients

TOTAL(sucralfate)$27,260 per100 patients

TOTAL(antacids)

$39,731 per100 patients

TOTAL(no prophylaxis)$42,000 per 100

patientsn = 100

Figure 1. Decision tree for stress ulcer prophylaxis. H2-RAs = histamine H2-receptor antagonists, CV = cardiovascular.

patients treated [(risk of bleeding without prophylaxis)× (estimated cost of treating GI bleed per patient)].Step 7. Estimate the savings with stress ulcer prophy-laxis per 100 patients treated {[(risk of bleeding withoutprophylaxis) (risk reduction with prophylaxis expressedas a decimal)] × (cost of treating GI bleed per patient)}.Step 8. Determine the marginal cost of prophylaxis per100 patients treated {[(cost of medication per 100 pa-tients) + (cost of adverse drug events per 100 patients)]– (savings with stress ulcer prophylaxis in 100 patients)}.Note that positive numbers represent a cost liability,negative numbers a cost saving.

Step 9. Determine the cost-effectiveness ratio [(margin-al cost of prophylaxis in 100 patients)/(risk ofbleeding)(risk reduction with prophylaxis expressed as adecimal)]. A negative value indicates a saving.

Table 10 provides an example of how the cost-effectiveness calculation for sucralfate was performed.The cost-effectiveness ratios for the various therapiescan be compared in order to choose the appropriateagent. As with any guidelines, patient-specific informa-tion should always be used for determining prophylaxisfor the individual patient. To perform a sensitivity

admin

高亮

admin

高亮



analysis for various rates of bleeding and reductions inbleeding associated with prophylaxis, simply vary thevalues in step 9. Table 11 shows the results of thesensitivity analysis for sucralfate.

Figure 2 is an algorithm for stress ulcer prophylaxisin adult patients that is based on the recommendationscontained in this document. The lack of pediatric RCTsinvolving medications and the age stratification inthose studies that did include pediatric patients pre-clude development of a separate pediatric algorithm.Because the number (≥2) and type (coagulopathy, respi-ratory failure, and Pediatric Risk of Mortality Score of≥10) of risk factors for clinically important bleedinghave been elucidated,66 the reader is referred to thediscussion in the section titled “Adverse effects of pro-phylactic agents” for help in deciding which medica-tion, if any, should be used for prophylaxis.

The adult algorithm is intended to serve as a templatethat can be modified according to institution-specific

data. The strength of the evidence for prophylaxis variessubstantially from one risk factor to the next (Table 3).ICU patients with a history of recent GI pathology aredeemed appropriate candidates for prophylaxis, but therecommendation must be graded D because patientswith recent histories of GI pathology were often excludedfrom the published investigations, and thus it is un-known whether these patients are at increased risk forclinically important bleeding. The recommendation foruse of oral H2-receptor antagonists in patients with func-tioning GI tracts (Figure 2) is based on presumptiveefficacy, because no RCTs are available that have com-pared i.v. with oral H2-receptor antagonists administra-tion for preventing clinically important bleeding.

Recommendation (adults): Given some of the unresolvedissues regarding stress ulcer prophylaxis, it is recommendedthat institution-specific guidelines be developed on thebasis of economic models such as the one included in thisdocument. For institutions willing to accept the assumptionthat H2-receptor antagonists and sucralfate have equalefficacy, the accompanying economic analysis found su-cralfate to be the most cost-effective agent. Exceptions tothe use of sucralfate include lack of oral or other gastricaccess for administration and, potentially, documentedfailure of prophylaxis with sucralfate. If ranitidine is as-sumed to be more effective than sucralfate without increas-ing the risk of pneumonia, ranitidine (and presumablyother H2-receptor antagonists) would be the drug of choiceand would also result in a cost saving, although less thanthat achieved with sucralfate.

Recommendation (pediatrics): There are also unresolvedissues for pediatric patients. Institution-specific guidelinescan be developed by using the economic models included inthis document, but the percentages and costs need to betailored to this population on the basis of institution-specific data. There is supporting evidence in the literaturethat the risk of stress-induced bleeding is greater in pediatricpatients with respiratory failure, coagulopathy, a PediatricRisk of Mortality Score of ≥10, and thermal injuries. Whetherprophylaxis will reduce the risk of bleeding is yet to beproven in this population, so there is no clear agent of choiceat this time.

ConclusionAlthough medications such as antacids have been

used for at least two decades to prevent stress-inducedbleeding, many issues remain unresolved. While pro-

Table 11.Cost-effectiveness Ratio for Sucralfate Prophylaxis: Results of Sensitivity Analysisa

aAssumptions about the risk of bleeding and the effectiveness of prophylaxis were varied from 0.1% to 39% and from 10% to 90%, respectively. Thevalues represent the cost or saving (in parentheses) for each bleeding episode averted. Costs and benefits were presumed to occur within a similar period,making discounting unnecessary.

Risk of Bleeding (%)

0.1

(5,395)(6,465)(6,679)(6,771)(6,822)

(3,870)(5,957)(6,374)(6,553)(6,652)

(740)(4,913)(5,748)(6,106)(6,304)

3,433(3,522)(4,913)(5,509)(5,841)

8,650(1,783)(3,870)(4,764)(5,261)

24,3003,433(740)

(2,528)(3,522)

55,60013,8675,5201,943

(44)

619,000201,667118,20082,42962,556

3920106421% Reduction in Risk

with Prophylaxis

1030507090

Table 10.Cost-effectiveness Calculations for Sucralfate

Variable Value

Risk of bleeding withoutprophylaxis (%)

Risk reduction withprophylaxis (%)

Cost of treating episode of GIbleeding per patient ($)

Cost of sucralfate per 100patients ($)

Cost of adverse drug eventsper 100 patients treated ($)

Cost of treating GI bleeding in100 patients ($)[(Six episodes of bleeding) ×($7000 cost of treatment)]

Savings with stress ulcerprophylaxis in 100 patients ($)[(Three episodes ofbleeding) × ($7000 cost oftreatment)]

Marginal cost of prophylaxisin 100 patients ($)[($3380 + $2880) – ($21,000)]

Cost-effectiveness ratio

6.0 (0.1–39)61,64

50 (10–90)64

7000

3380

2880

42,000

21,000

–14,740

4913 for eachbleeding episodeaverted



Figure 2. Algorithm for stress ulcer prophylaxis in adult patients.

Continue periodic assessment

Is stress ulcer prophylaxis needed?(Prophylaxis is appropriate for patientsadmitted to the ICU with one or moreof the risk factors listed in Table 3.)

Yes No

Does patient have gastric access via oral route,nasogastric tube, or gastrostomy?

Sucralfate (ifcontinuous

nasogastric suction,stop suction for two hours after

giving sucralfate)

Does patient haveenteral access

(via nasoenteral tubeor ostomy)

and adequateGI function

(i.e., absorption offeedings)?

Yes No

Yes No

I.V. H2-blocker

Enteral H2-blocker

Continue periodic assessments

phylactic agents have demonstrated efficacy in pre-venting clinically important bleeding in randomized,controlled trials (and meta-analyses), the frequency ofstress-induced bleeding has varied substantially fromstudy to study since approximately 1978. This has ledsome experts to suggest that prophylactic agents arevery effective if used appropriately; other experts con-clude that the frequency of clinically important stress-induced bleeding has been decreasing as a result ofadvances in technology and patient care, not medica-tion prophylaxis. The collection of institution-specificdata should help clinicians to resolve this issue, at leastfor their particular patient populations.

When institution-specific rates of stress-inducedbleeding are not available, the recommendations con-tained in these guidelines can serve as a model foradaptation by the institution. Although the recom-mendations were made on the basis of data publishedup to the final guideline review process, changes maybe needed as information evolves. The reader is encour-aged to consider such changes as they occur rather thanwait for revised guidelines.

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3. Halpern NA, Bettes L, Greenstein R. Federal and nationwideintensive care units and healthcare costs: 1986-1992. CritCare Med. 1994; 22:2001-7.

4. Dasta JF. Drug prescribing issues in the intensive care unit:finding answers to common questions. Crit Care Med. 1994;22:909-12.

5. Cook DJ, Reeve BK, Guyatt GH et al. Stress ulcer prophylaxisin critically ill patients: resolving discordant meta-analyses.JAMA. 1996; 275:308-14.

6. Peura DA. Prophylactic therapy of stress-related mucosaldamage: why, which, who, and so what? Am J Gastroenterol.1990; 85:935-7.

7. Tryba M. Stress ulcer prophylaxis—quo vadis? Intensive CareMed. 1994; 20:311-3.

8. Berger JT, Rosner F. The ethics of practice guidelines. ArchIntern Med. 1996; 156:2051-6.

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Stress ulcer prophylaxis ASHP ReportRecommendationsIndications for prophylaxisFor adults: Risk factors for ICU patients have been delineated intrials comparing prophylaxis with no prophylaxis by usingclinically important bleeding as an endpoint. Prophylaxis isrecommended in patients with coagulopathy or patients re-quiring mechanical ventilation for more than 48 hours.(Strength of evidence = C) Prophylaxis is also recommended inpatients with a history of GI ulceration or bleeding within oneyear before admission and in patients with at least two of thefollowing risk factors: sepsis, ICU stay of more than one week,occult bleeding lasting six days or more, and use of high-dosecorticosteroids (>250 mg per day of hydrocortisone or theequivalent). (Strength of evidence = D) (Table 3) Recommenda-tions for specific prophylactic medications can be found in theMedications used for prophylaxis section.For pediatrics: Although various risk factors have been associat-ed with bleeding in pediatric patients, published randomized,controlled trials (RCTs) have either not used clinically impor-tant bleeding as an outcome or had insufficient power to en-able a definitive conclusion that prophylaxis providesprotection. Risk factors that have been associated with clinical-ly important bleeding include respiratory failure, coagulopa-thy, and a Pediatric Risk of Mortality Score of ≥10. (Strength ofevidence = C)Indications in special populationsFor adults: Prophylaxis is recommended for ICU patients with aGlasgow Coma Score of ≤10 (or the inability to obey simplecommands) or thermal injuries to >35% of their body surfacearea (BSA). (Strength of evidence = B) ICU patients with partialhepatectomy may also benefit from prophylaxis. (Strength ofevidence = C) Prophylaxis may also be indicated in ICU pa-tients with multiple trauma (e.g., Injury Severity Score of ≥16),transplantation patients in the ICU perioperatively, ICU pa-tients with hepatic failure, and ICU patients with spinal cordinjuries. (Strength of evidence = D) (Table 3)For pediatrics: For pediatric patients (one month of age or older)with thermal injuries, prophylaxis is recommended, but thereis insufficient evidence to recommend prophylaxis based onany given percentage of BSA. (Strength of evidence = D) Forother pediatric surgery or trauma patients, insufficient evi-dence is available to allow recommendations about prophylaxisto be made.Agent of choiceFor adults: Given the conflicting results of several meta-analysesand a recent RCT (both with strengths of evidence = A), thechoice among antacids, H2-receptor antagonists, and sucralfatefor use as prophylactic agents to prevent clinically importantbleeding associated with stress in adult patients admitted togeneral medical and surgical ICUs should be made on an insti-tution-specific basis. This choice should take into account con-cerns regarding administration (e.g., functioning GI tract),adverse-effect profile, and total costs. (Strength of evidence = D)Insufficient data on misoprostol or the proton-pump inhibitorsare available to allow any recommendation about these agentsto be made.For pediatrics and special populations: The lack of comparativetrials of these agents in pediatric and special populations (e.g.,patients with burns, trauma patients, patients undergoing neu-rosurgical procedures or with neurologic disorders, and trans-plantation patients) precludes definitive recommendations asto the agent of choice in these situations. The choice of agentshould be made on an institution-specific basis and should takeinto account concerns about administration (e.g., functioningGI tract), adverse-effect profile, and total costs.Adverse effectsFor adults and pediatrics: It is recommended that patients with ahistory of serious reactions to antacids, H2-receptor antagonists,proton-pump inhibitors, or sucralfate avoid future use of theoffending agent. There are no other absolute contraindicationsthat would preclude the short-term use of any of these medica-tions for stress ulcer prophylaxis. However, unless the benefitsclearly exceed the risks, it is recommended that sucralfate andantacids be avoided in neonates (particularly premature neo-nates) because of the possibility of adverse effects (e.g., bezoar

formation, accumulation of aluminum and magnesium). Also, it isrecommended that aluminum-containing products such as sucralfatebe avoided in children with renal failure because dosing informationhas not been well established. Whether acid-suppressing agents areassociated with a higher rate of pneumonia than sucralfate is unre-solved, although any difference between these medications wouldappear to be small. It is recommended that potential adverse effectsbe considered as part of the economic analysis when an agent ischosen (see Economic analysis). (Strength of evidence = D)MonitoringFor adults and pediatrics: It is recommended that all patients receivingmedications for stress ulcer prophylaxis be monitored for bleedingand adverse drug effects (see Adverse effects of prophylactic agents).Paper techniques for measuring gastric pH have questionable validityand reliability, and there is no evidence that adjusting the dosage ofpH-altering medications (antacids, H2-receptor antagonists, proton-pump inhibitors) on the basis of these measurements influencespatient morbidity or mortality. Despite the lack of supporting data,pH monitoring for antacids may be appropriate (goal pH of >3.5–4).Such monitoring may also be useful for H2-receptor antagonists whenstandard dosage regimens might not be appropriate (e.g., in cases ofrenal dysfunction, for increased dosages due to perceived failure oftherapy, in pediatric patients). (Strength of evidence = D)Other optionsFor adults and pediatrics: It is premature to recommend the use ofnovel therapies (e.g., free-radical scavengers) in place of conventionalagents for stress ulcer prophylaxis, although the limited number ofstudies have had promising results. (Strength of evidence = D)Prevention of recurrent bleedingFor adults and pediatrics: The lack of available trials prohibits definitiverecommendations for preventing recurrent bleeding after an episodeof stress-induced GI bleeding, although consideration could be givento increasing the dosage of the prophylactic agent, adding anothermedication, or switching to a different agent. (Strength of evidence =D)Non-ICU patientsFor adults: Stress ulcer prophylaxis is not recommended for adultpatients in non-ICU settings. (Strength of evidence = B for generalmedical and surgical patients with fewer than two risk factors forclinically important bleeding; strength of evidence = D for patientswith two or more risk factors) (Table 3)For pediatrics: Stress ulcer prophylaxis is not recommended forpediatric general medical and surgical patients or special popula-tions (e.g., transplantation) in non-ICU settings if fewer than tworisk factors for bleeding are present. (Strength of evidence = D)Data are insufficient to allow recommendations to be made aboutthe use of prophylaxis in pediatric patients with two or more riskfactors. If prophylaxis is given, it should be discontinued once riskfactors have resolved. (Strength of evidence = D)Institution-specific guidelinesFor adults: Given some of the unresolved issues regarding stressulcer prophylaxis, it is recommended that institution-specificguidelines be developed on the basis of economic models such asthe one included in this document. For institutions willing toaccept the assumption that H2-receptor antagonists and sucralfatehave equal efficacy, the accompanying economic analysis foundsucralfate to be the most cost-effective agent. Exceptions to the useof sucralfate include lack of oral or other gastric access for adminis-tration and, potentially, documented failure of prophylaxis withsucralfate. If ranitidine is assumed to be more effective than sucral-fate without increasing the risk of pneumonia, ranitidine (andpresumably other H2-receptor antagonists) would be the drug ofchoice and would also result in a cost saving, although less thanthat achieved with sucralfate.For pediatrics: There are also unresolved issues for pediatric pa-tients. Institution-specific guidelines can be developed by usingthe economic models included in this document, but the percent-ages and costs need to be tailored to this population on the basis ofinstitution-specific data. There is supporting evidence in the litera-ture that the risk of stress-induced bleeding is greater in pediatricpatients with respiratory failure, coagulopathy, a Pediatric Risk ofMortality Score of ≥10, and thermal injuries. Whether prophylaxiswill reduce the risk of bleeding is yet to be proven in this popula-tion, so there is no clear agent of choice at this time.



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