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Stress ulcer prophylaxis ASHP Report

A SHP REPORT

ASHP Therapeutic Guidelines on Stress Ulcer
Prophylaxis
DEVELOPED THROUGH THE ASHP COMMISSION ON THERAPEUTICS AND APPROVED BY THE ASHP BOARD OF DIRECTORS ON
NOVEMBER 14, 1998

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

D espite the publication of more than 100 studies
of the frequency, risk factors, and prophylaxis of
stress ulcer bleeding, these subjects continue to
generate controversy. Several meta-analyses pertaining
to stress ulcer bleeding have been published, including
Making clinical use of these inflated estimates has
patient care implications and cost implications, be-
cause stress ulcer prophylaxis adds to the number of
medications given and increases the risk and cost of
adverse reactions.3,4
one designed to resolve the discordant results of the It is important to determine the frequency of clini-
others. Given the sheer volume of published informa- cally important bleeding due to stress-induced erosions
tion, it is understandable that health care providers or ulcerations. Although endoscopy is a specific and
experience frustration when confronting this topic. sensitive test for GI bleeding, it is an invasive and
Stress ulcers are superficial lesions commonly (but expensive procedure. For endoscopy to be used as a
not exclusively) involving the mucosal layer of the diagnostic tool, it would need to be repeated during the
stomach that appear after major stressful events such as period the patient remains at risk for clinically impor-
surgery and trauma.1 Endoscopic studies have found tant bleeding. Gastroduodenal bleeding associated
gastroduodenal erosions (shallow ulcers) to be com- with clinically important complications, such as hemo-
mon in patients who have had such stressful events, dynamic compromise and the need for blood transfu-
and these may lead to ulceration and bleeding.1 Micro- sions or surgery, has been suggested in the literature as
scopic bleeding associated with gastroduodenal lesions a useful definition for clinically important bleeding.
can be detected by occult blood testing (e.g., guaiac test) This definition was used to evaluate the clinical trials in
in patients with gastric tubes.2 However, other factors order to develop these guidelines.5 The reported fre-
may influence the results of occult testing. Simply quency of clinically important bleeding has varied
placing tubes in the upper respiratory or GI tract may widely, although the general perception is that the
injure the mucosa and result in microscopic or macro- frequency of stress-related bleeding has been decreas-
scopic (i.e., overt) bleeding. Because not all episodes of ing in recent years.6 Whether this decrease is related to
microscopic bleeding are clinically relevant, studies the use of stress ulcer prophylaxis medications, im-
using only microscopic bleeding as an endpoint artifi- provements in technology, or improvements in patient
cially inflate the reported frequency of GI bleeding. care is not known, because a variety of factors (e.g., type

The following professional organizations and persons submitted Pharm.D.
comments on the draft document: the American Association of The bibliographic citation for this document is as follows:
Critical-Care Nurses; the American College of Chest Physicians; American Society of Health-System Pharmacists. ASHP therapeu-
the American College of Clinical Pharmacy; the American tic guidelines on stress ulcer prophylaxis. Am J Health-Syst Pharm.
Gastroenterological Association; Todd A. Armstrong, Pharm.D., 1999; 56:347-79.
BCPS, BCNSP; Douglas B. Coursin, M.D.; John Devlin, Pharm.D., Index terms: American Society of Health-System Pharma-
BCPS; Jeanne Scott Duke; Douglas Fish, Pharm.D.; Edgar R. cists; Antacids; Economics; Gastrointestinal drugs; Health profes-
Gonzalez, Pharm.D., FASHP; Emily B. Hak, Pharm.D.; Darrell sions; Organizations; Prostaglandin derivatives; Protocols; Ulcers
Heiselman, D.O.; Annie Herrington, Pharm.D.; Mary Hess,
Pharm.D.; Robert J. Kuhn, Pharm.D.; Marc Lapointe, Pharm.D.; Copyright © 1999, American Society of Health-System Phar-
Robin L. Southwood, Pharm.D., BCPS; and Linda S. Welage, macists, Inc. All rights reserved. 1079-2082/99/0202-0347$06.00.

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

ASHP Report Stress ulcer prophylaxis

of resuscitative technique) may contribute to clinically
ASHP Therapeutic Guidelines important stress-related bleeding.7
The presence of patient risk factors for clinically
on Stress Ulcer Prophylaxis important bleeding, not just admission to an intensive
care unit (ICU), should determine the need for stress
Project Coordinators ulcer prophylaxis. The purpose of this document is to
Brian L. Erstad, Pharm.D., FCCM, FASHP, BCPS
help health care professionals to identify appropriate
Associate Professor/Assistant Department Head candidates for stress ulcer prophylaxis and select cost-
Department of Pharmacy Practice and Science effective modalities for prophylaxis when prophylaxis
College of Pharmacy is indicated. An economic evaluation has been provid-
University of Arizona
Tucson, AZ 85721 ed that can be adapted to individual practice sites.

Kathryn L. Grant, Pharm.D., FASHP Scope
Assistant Professor
These guidelines pertain to stress-induced bleeding
Department of Pharmacy Practice and Science
College of Pharmacy associated with events such as trauma, surgery, and
University of Arizona acute organ failure. In general, they apply to the days
Tucson, AZ 85721 immediately after the stressful event, when endoge-
Expert Panel
nous healing processes or exogenous manipulations by
health care professionals have yet to substantially im-
Bradley A. Boucher, Pharm.D., BCPS prove the underlying disease process. However, a pa-
Associate Professor and Director of Research tient may have resolution of the initial problem but
Department of Clinical Pharmacy
The University of Tennessee then have reactivation or initiation of a stressful event
Memphis, TN 38163 that could precipitate stress-induced bleeding. These
are not unexpected occurrences in patients with ICU
Jimmi Hatton, Pharm.D., BCNSP
Associate Professor of Pharmacy and Surgery
stays of more than a few days and could lead to periodic
University of Kentucky Medical Center institution of prophylaxis to prevent bleeding.
Lexington, KY 40536 The guidelines focus on agents that are used for
stress ulcer prophylaxis in the United States, whether or
Judith Jacobi, Pharm.D., BCPS
Critical Care Clinical Pharmacist not the agents have FDA-approved labeling for this
Department of Pharmacy Services indication. A majority of studies have involved hista-
Methodist Hospital of Indiana mine H2-receptor antagonists, antacids, or sucralfate,
Indianapolis, IN 46206
and these agents are discussed in detail. Few controlled,
Rick Jones, Jr. comparative studies have been conducted to assess the
Manager, Strategic Development efficacy of misoprostol or proton-pump inhibitors (e.g.,
Pharmacy Department lansoprazole, omeprazole) in preventing clinically im-
Orlando Regional Healthcare System
Orlando, FL 32806
portant bleeding. The potential advantages and disad-
vantages of the latter medications for stress ulcer pro-
Keith M. Olsen, Pharm.D., FCCP phylaxis are discussed.
Associate Professor of Pharmacy The guidelines include information for patients in
College of Pharmacy
University of Nebraska Medical Center all age groups for which there is literature. When age
Omaha, NE 68198 groups are not specifically cited, the discussion refers to
the adult patient population. Few prospective, random-
H. David Reines, M.D.
Professor of Surgery
ized studies in the pediatric population have been
Tufts University School of Medicine published, particularly with regard to clinically impor-
Newton, MA 02162 tant bleeding. Where appropriate, the lack of age-spe-
cific data is specified. It is hoped that the guidelines will
Andrea Quinn Wilson, APRN, CETN, CS
Clinical Nurse Specialist stimulate research in these areas.
Yale New Haven Hospital The guidelines are not intended to apply to the
New Haven, CT 06504 prevention of bleeding associated with chronic diseases
or long-term medication use. However, the contribu-
ASHP Staff Liaison
tion of pre-existing diseases and the use of ulcerogenic
Leslie Dotson Jaggers, Pharm.D., BCPS medications as aggravating risk factors for stress-in-
Clinical Affairs Associate duced bleeding are considered appropriate issues for
ASHP
Bethesda, MD 20814
review.

Guideline development and use
The ASHP Therapeutic Guidelines on Stress Ulcer

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

Stress ulcer prophylaxis ASHP Report

Prophylaxis were prepared by the University of Arizona
under contract to ASHP. The project was coordinated by ASHP Commission on Therapeutics
two pharmacy specialists, one with expertise in critical
In late 1990, the ASHP Board of Directors created an advi-
care and the other with expertise in drug information, sory body called the Commission on Therapeutics to be
who consulted with two physicians and a nurse special- concerned with societal drug use and therapeutic issues.
ist from the Arizona Health Sciences Center. The This is consistent with the ASHP governing documents,
project coordinators worked in conjunction with an which state that one purpose of ASHP is “to foster rational
drug use in society such as through advocating public
independent multidisciplinary panel of seven clinical policies toward that end.” The Commission is charged
specialists (a surgeon, a nurse, and five pharmacists) with the following:
representing adult or pediatric critical care. The panel • Identifying new and emerging therapeutic modali-
was appointed by ASHP. Panel members and contrac- ties for ASHP consideration,
tors were required to disclose any possible conflicts of • Developing documents on issues related to rational
and cost-effective drug use in society,
interest before their appointment. The guidelines un- • Reviewing and responding to selected therapeutic or
derwent multidisciplinary field review in order to eval- drug-use initiatives of other organizations and agen-
uate their validity, reliability, and utility in clinical cies, and
• Consulting with ASHP on drug-use and therapeutic
practice. The final document was approved by the
issues.
ASHP Commission on Therapeutics and the ASHP
Members of the 1998–1999 ASHP Commission on Thera-
Board of Directors. peutics are Austin J. Lee, Pharm.D., BCPS, FASHP, Chair; C.
The recommendations in this document may not be Wayne Weart, Pharm.D., FASHP, Vice Chair; G. Dennis
appropriate for use in all clinical situations.8 Decisions Clifton, Pharm.D.; Matthew A. Fuller, Pharm.D., BCPS,
BCPP; Kent M. Nelson, Pharm.D., BCPS; William L. Green,
to follow these recommendations must be based on the
Pharm.D., BCPS, FASHP; Mary Beth Gross, Pharm.D.;
professional judgment of the clinician and must take Michael D. Katz, Pharm.D.; Shirley J. Reitz, Pharm.D.; Jane
into account individual patient circumstances and E. DeWitt, Student Member; Donald T. Kishi, Pharm.D.,
available resources. These guidelines reflect current Board Liaison; and Leslie Dotson Jaggers, Pharm.D., BCPS,
Secretary.
knowledge (at the time of publication) on the use of
stress ulcer prophylaxis in critically ill patients. Given
the dynamic nature of scientific information and tech-
nology, periodic review, updating, and revision are to
be expected. creased the retrieval. The sets were combined in IPA as
{[(A1 or A2) and B] or D}. All relevant citations were
Literature search printed and reviewed for pertinent articles, which were
Detailed and exhaustive literature searches of MED- subsequently retrieved and copied. The reference lists
LINE from 1966 to 1997 and International Pharmaceu- of the retrieved articles were studied for investigations
tical Abstracts (IPA) from 1970 to 1997 were performed. that may have been missed through the computerized
The searches of the two databases were compared to search.
check for duplicates and were subsequently compared Periodic literature searches using the same method
with the references listed in a recent meta-analysis by were conducted during the compilation of the guide-
Cook et al.5 for completeness. lines. The reference lists of review articles were exam-
Ten key articles pertinent to stress ulcer prophylaxis ined for potentially pertinent references. Unpublished
were identified and entered into MEDLINE to capture abstracts (e.g., those presented at meetings) and ab-
appropriate MeSH headings. Applicable MeSH head- stracts in foreign languages were not included in the
ings were combined with relevant text words into five evaluation.
sets. Set A1 combined terms for the condition to be Although all relevant articles were reviewed, they are
avoided in broad terms (e.g., peptic ulcer) by using the not necessarily referenced in this document. In partic-
subheadings prevention and control and complications. Set ular, isolated case reports or case series involving fewer
A2 covered terms more specific to the condition being than 25 patients were not routinely included unless
treated (e.g., peptic ulcer hemorrhage) by using the they provided unique information that would substan-
same subheadings. Set B included terms describing tially affect the recommendations. Similarly, pharma-
patient location (e.g., intensive care) or condition (e.g., cokinetic and pharmacodynamic studies of medica-
critical illness). Set C covered terms related to the tions were not included unless there was some applica-
treatments to be considered (e.g., H2-receptor antago- bility to stress ulcer prophylaxis.
nists) with the subheadings adverse effects and therapeu-
tic use, and set D was the free-text term stress ulcer Level of evidence for recommendations
prophylaxis. The sets were combined as [(A1 and B) or There are several methods for assessing the literature
(A2 and C) or D]. The search was limited to reports on by using evidence tables.9-12 The methods of Guyatt et
humans published in the English language. The search al.9 and the American College of Chest Physicians (1995
in IPA differed in that combining set A2 and C de- revision)10 were determined to be the most applicable to

Vol 56 Feb 15 1999 Am J Health-Syst Pharm 349

based on the clinical experience of the panel members Therefore. and II–. there factors might be independent predictors of bleeding. some of which have been pub- results or one RCT was designed with a sample large lished. higher than C.15 and an α of ≤0. various risk factors were used strength of evidence for a recommendation. c This assumes the availability of comparative data for calculating 95% CIs. System Used for Defining Levels of Evidence in Stress Ulcer Prophylaxis Guidelinesa Level of Evidence Definition I+ Meta-analysis of randomized.. the superscript wd was used to signify reviewing the literature. 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%). Table 1. b Various definitions of homogeneity were used in the literature (e. The levels of evidence were used to evaluate those The recommendations in this document were catego.05. ers to aid them in evaluating the literature presented. The level of evidence was evaluated for each ed with bleeding by a rigid evidence-based evaluation trial. gastroduodenal bleeding associated A corresponds to levels of evidence I+.g.ASHP Report Stress ulcer prophylaxis the literature to be reviewed because they involved One problem with both the grading systems9. although the strength of evidence would never be an α of ≤0. in addition to listing levels of evidence for and a paucity of quality supporting literature. ommendation unless at least two RCTs had similar More than 30 criteria. the level of evidence for ing and risk factors associated with bleeding. and heterogeneity. When there were multiple RCTs of comparable may be misleading for a number of reasons. various the least stringent trial was used in determining the risk factors were studied. including power pertaining to a particular recommendation and the following: studies used various definitions of bleed- their levels of evidence differed. Before the various trials. the analysis of risk factors often dations were assigned to category D if they represented was not a study objective. 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 I Meta-analysis of RCTs with homogeneity of results but with a 95% CI that includes the threshold for clinically important benefit I– RCT in which the entire 95% CI lies on one side of the threshold for clinically important benefit II+ Meta-analysis of RCTs with heterogeneity of results and a 95% CI that lies entirely on one side of the threshold for clinically important benefit II Meta-analysis of RCTs with heterogeneity of results and a 95% CI that includes the threshold for clinically important benefit II– RCT in which the 95% CI includes the threshold for clinically important benefit III+ Nonrandomized concurrent cohort study in which the entire 95% CI lies on one side of the threshold for clinically important benefitc III Nonrandomized concurrent cohort study in which the 95% CI includes the threshold for clinically important benefit IV+ Nonrandomized historic cohort study in which the entire 95% CI lies on one side of the threshold for clinically important benefit IV Nonrandomized historic cohort study in which the 95% CI includes the threshold for clinically important benefit V Case series suggesting clinically important benefit a Adapted from references 9 and 10. controlled trial (RCT) in determining a rec. Category tant bleeding (i. and V. lines were sent to the panel of experts and other review- domized. IV. studies that assessed the frequency of clinically impor- rized according to the strength of the evidence. methods were modified slightly and expanded to in. homogeneity. Two RCTs may each be ranked similarly.10 on meta-analysis and distinctions based on confidence which this system was based is the relative inability to intervals.e. I. but one may clude a category D that represents a panel consensus have been better designed and reported than the other. Table 1 includes definitions for each level Analysis of the number and type of risk factors associat- of evidence. and.05. the fact that homogeneity was tested for is more important than the precise method used. and category C to levels III+.8 and ing. had to be at least two RCTs or one RCT with a sample size Observational trials with large numbers of patients are sufficient for detecting a difference of 50% or less in rates often used appropriately to assess risk factors for bleed- of clinically important bleeding with a power of ≥0. 350 Am J Health-Syst Pharm Vol 56 Feb 15 1999 . transfusion or surgery) and nosocomial pneumonia. multi- the expert opinion of panel members. IV+. as inclusion criteria. II. in many studies. III.14 The criteria represented a nonnumerical as- rates (considered the primary outcome) between the sessment and were not used as a scoring system for the treatment and control groups with a power of ≥80% formal statistical analysis. category with hemodynamic compromise or the need for blood B to levels II+. variate analysis was not used to determine which risk dation based on RCTs to be assigned to category A.. For a recommen. Recommen. and I–. the panel of experts agreed a well-designed and well-reported trial when the guide- that a meta-analysis carried more weight than a ran.13. were used in the analysis of the investiga- enough to detect a difference of 50% or less in bleeding tions. These distinguish the quality of individual investigations.

gery. For example. or thermal injury. the histological in preterm infants. stress-induced bleeding in general ICU pop- acid metabolites. which is associated with children had gastric ulceration compared with 20 thermal injury.. tients with single-system injuries (e. during document on general ICU populations determined the the first 24 hours of hospital admission) in association frequency of stress ulcer lesions and the risk factors with a stressful event. and the other involved patients undergo- globulin A have been found in the serum of critically ill ing abdominal surgery. In all studies conducted Newborns often have slightly acidic gastric pH values before 1978. In general. the studies included in this section of the humans. ensure avoidance of lesions. One study was conducted in patients with respira- vated concentrations of anti-Helicobacter pylori immuno.26 Frequency of bleeding. the number of ulcers. injuries. respiratory. surgical.23 In adult In general. ulceration was found.28 lesions are similar to those associated with nonsteroidal The frequency of ulceration. group of patients who did not receive prophylaxis were ing. lending additional support to a and macroscopic appearance of stress-induced fundal multifactorial process.36. surgery. or respiratory ICUs. erosions may occur very quickly (i.25. 13 (14. pediatric) ICU populations normal protective mechanisms are altered. result ulations. ele. arachidonic ated with. >10–14 days). These events. surgical. although the time from the associated with clinically important bleeding in pa- inciting event to the diagnosis of bleeding may be tients in medical. and they eventu. Only much longer (e.5) do not in general (medical. pylori because the patient populations were similar to those and chronic ulceration has been established. head or spinal It is not known whether differences in basal or cord surgery). duodenal ulcers were common. acid hypersecretion is not a universal finding of prophylaxis. years of age and 178 adults who died of burn-related ally involve multiple sites in the upper GI tract.g.27 Stress ulceration is a form of hemorrhagic gastritis Gastric pH values in infants begin to approach those of that may occur in patients who have had a major healthy adults during the first six months of life. cytokines.2%) of the adults. few studies enrolled in other investigations. or the colon. However.6%) of the the stomach.g.17 Acid hypersecretion is often stated ple gastric erosions usually found in adults.18 Frequency of bleeding. in contrast to the multi- bly multifactorial. determining a true frequency of clinically impor- at the microcirculatory level may initiate a series of tant bleeding is complicated by the difficulty in mea- changes resulting in erosions that could progress to suring endpoints. the ulceration and bleeding. in contrast to and adults.31-63 As will be seen in the following discus- important in ulcer formation. and anti-inflammatory drugs (NSAIDs) seen in the antrum the sites of ulceration may be different between children and the body of the stomach. How- stressful event such as trauma. which is associated with CNS injury. depending on the stress-related event.22 Reductions in mucosal blood flow may also be evaluated. stress-induced lesions often retrospective study involving 93 children less than 10 cause more congestion and bleeding. Stress ulcer prophylaxis ASHP Report Pathophysiology of stress-induced lesions that become more acidic within a few hours of birth. the stomach.30 as being particularly important in the formation of ulcers associated with head and thermal injuries.24 Although the association between H. combined determine the true frequency of. the variability in endpoints used. or pa- maximal gastric acid production seen in various age tients undergoing transplantation were not included groups affect the frequency of ulceration and clinically (see the section on special populations) because of important bleeding. hemorrhagic shock in experiments in rats. Necrosis and erosions of the variability in definitions of endpoints.29 No relationship between sex and stress-induced lesions but may appear in the esopha.0%) of the children had duodenal ulcer- ing’s ulcer.16 Curling’s ulcer.19-21 During stressful events. the small intestine.e. studies that contained at least one defined in erosions that may progress to ulceration and bleed. In one NSAID-induced lesions. and risk factors associ- with the release of various mediators (e. 21 (22. efficacy However. including sepsis. oxygen free radicals). including Acute bleeding in critically ill patients has been epithelial turnover in the gastric mucosa and secretions described in the medical literature since the 1800s. two of the studies involved a relatively homogeneous Other less well-studied factors may be involved in the sample of patients with a single-system disease or sur- pathogenesis of stress-related lesions. often ation on postmortem examination compared with 13 presents as a single deep lesion in the duodenum or in (7. organ failure.g. Studies enrolling pa- have been performed in acute care settings. Alterations in blood flow sion. quency of stress-induced bleeding.44 These studies were included patients. In addition. ever. and higher pH values (>4. patients with thermal injuries. tory disease.16 Cush. and the hetero- gastric membrane have occurred within 45 minutes of geneity of the patient populations.. premature infants presumed differences in the pathophysiology or fre- typically produce less gastric acid than full-term in. To of mucus and bicarbonate. fants. is morphologically similar to other (11. the frequency of clinically important Vol 56 Feb 15 1999 Am J Health-Syst Pharm 351 . albeit with substantial interinfant variability.. and risk factors for bleeding in such patients..3%) of the adults. For example. stress ulcer lesions may occur at any age.16 one year of age with stress ulceration found that single The pathogenesis of stress-induced lesions is proba. Another review of infants less than gus.

the disparate results of the more than 20 RCTs of Because individual trials have demonstrated con- prophylaxis conducted in general ICU populations. There are im. episodes (including some patients whose bleeding did an RCT published by Peura and Johnson43 in the same not clear by lavage): 6 of 100 patients in the control year. flicting results with respect to the frequency of bleeding The first trial. In contrast. severe head injury.68-71 Ab- involving general medical and surgical ICU patients stracts and non-English-language articles were fre- with an expected length of stay of at least 36 hours and quently included in the data sets of these analyses. Patients frequency of stress-induced bleeding have been record.59 In that trial. can be attributed to laxis indicate that the average frequency of bleeding is differences in the populations being studied. Prophylaxis versus no prophylaxis. The frequency of treatment group had clinically important bleeding. bleeding in patients receiving no prophylaxis (or place- tistical testing of this endpoint was not performed. patients with head or bleeding between placebo and pH-adjusted cimetidine thermal injuries). 1989. 16 (24. it should be to estimate the frequency of clinically important bleed. was not ing because of the small numbers of patients enrolled in designed to detect a difference of less than 75% in published investigations and the use of endpoints oth.1–39%). substantial differences in the 75% treatment-related reduction in bleeding. A rating scale of zero (normal mucosa) to four (>25 ment group. 20% in a control group and 5. In the Despite this difference in time frame. and no difference in endo- Efficacy.. confirmed. so the number im analysis revealed a significant difference in bleeding of trials combined for each analysis was limited. placebo-controlled study have sought to resolve this issue (Table 2). 352 Am J Health-Syst Pharm Vol 56 Feb 15 1999 .7%. In one with septic shock. Although all patients were at high risk for pediatric ICU.g.68-71 rates between the control and cimetidine groups. There were no significant differences between 1.65 In contrast.7%) of 65 patients in compared with no prophylaxis. antacids was associated with a significantly lower fre- ed in 1994 by Ben-Menachem et al.g.64 be reasonable to consider withholding prophylaxis in With regard to the pediatric population.6% (1 of 61 patients). a single-blind RCT. were reports of studies involving populations that other The study had 90% power to detect a 75% difference in studies specifically excluded (e. However. there was definite control group. although it was not stated whether the stress ulcer hemorrhage. it is difficult general medical ICU patients. in an RCT published by group. stressed that the trial by Ben-Menachem et al.58 was with or without prophylaxis. bo) ranged from 3.6% in a study of 1006 admissions to a prophylaxis. found group.5. endoscopic ence might be clinically important.0%) of 66 The meta-analysis conducted by Lacroix et al. was conduct. The study was terminated early when an inter.66 bleeding from stress lesions. there were no significant differences between groups ing in patients not receiving prophylaxis. the frequency of bleeding was group. and trauma. or no prophylaxis.2%) of 65 in the cluded randomized studies only. a pH-adjusted cimetidine group. could be randomly assigned to a control (no placebo) ed among trials. several meta-analyses a multicenter. or a sucralfate Pinilla et al. double-blind. From 1978 on. and three were published in 1991. Articles pub. If the different findings between this important bleeding in patients not receiving prophy. the frequency of clinically hemorrhages. Sta. evaluate all patients at baseline and after five days of stract) was 1. and 5 a 39% frequency (7 of 18 patients) of endoscopically of 100 patients in the sucralfate group.ASHP Report Stress ulcer prophylaxis bleeding and related complications ranged from 5. Six (10.. only quency of bleeding compared with no prophylaxis. medical ICU patients who were expected to have a Among the limitations of this meta-analysis were that length of ICU stay of at least 24 hours were enrolled. the frequency of clinically important bleeding was 30 mg/day. trial and that of Martin et al. or invasive ulcers) was used to important bleeding (not defined in the published ab.2%) of 66 patients had overt and overlap among the meta-analyses in the studies that clinically important bleeding (some bleeding was not were included. In addition. the evaluated studies had methodological problems.5 the treatment group (p = 0.7% in a combined treat.67 The study involving 140 children from birth to 20 years of patients were randomly assigned to receive pirenzepine age. Two scopic evaluations was noted at baseline or at five days studies conducted in the 1990s can be used to illustrate among the three groups.009). Another study enrolled 90 intensive care patients portant exceptions. it might 6% (0. Use of cimetidine and The second study. bleeding between groups. no patients developed severe children received any form of stress ulcer prophylaxis. and it was not clear whether this groups with respect to clinically important bleeding patient had clinically important bleeding. conducted in 1993 by Martin et al.4% to 52. when respiratory failure and coagulopathy were stud- lished from 1984 to 1994 on the frequency of clinically ied as risk factors. 5 of 100 patients in the cimetidine group.3% The study was designed to have 80% power to detect a to 33%. clinically important. One meta-analysis was published in therapy. as at least one risk factor (of eight studied) for bleeding.42 in 1985. compared with 5 (7. even though a smaller differ- er than clinically important bleeding (e. Only one of the meta-analyses investi- cleared by lavage.68 in- patients in the control group and 4 (6. erosions. omeprazole 80 mg/day. For example. but the patients did not require gated the difference in bleeding rates with sucralfate transfusion).. stress-induced bleed. albeit with differing results. evidence of bleeding or overt bleeding). involving adult patients in a medical ICU.

45–1.12. CI = 95% confidence interval. treatment was effective in transfusion (a decrease in hemoglobin of 2 g/dL plus preventing bleeding). A the frequency of occult or overt—but not necessarily second meta-analysis by Tryba71 in 1991 included only clinically important—bleeding. In a meta-analysis published by Tryba69 in 1991. Stress ulcer prophylaxis ASHP Report demonstrated heterogeneous effects.95.44. The odds ratios (ORs) and 95% changes (a 20-mm Hg decrease in blood pressure within confidence intervals (CIs) calculated for H2-receptor 24 hours or a 10-mm Hg decrease plus a 20-beat/min antagonists or antacids compared with no prophylaxis increase in heart rate on standing) or the need for were all less than one (i. CI = 0.452–1.33 control H2-RAs versus 6 Clinically important bleeding OR = 0. some values were extrapolated from figures.09–1.49 sucralfate H2-RAs versus 1 Clinically important bleeding OR = 0. CI = 0. CI = 0. CI = 0. Vol 56 Feb 15 1999 Am J Health-Syst Pharm 353 .97–2. defined as hemody.12–12.08–1. were similar to those of Tryba’s previous meta-analysis.27–6.e. b OR = odds ratio.6% in the group The 1996 meta-analysis was performed to resolve Table 2. CI = 0. Meta-analyses Investigating the Risk of Bleeding with and without Stress Ulcer Prophylaxis Reference Comparisona No. controlled blood transfusion) were combined in the definition of trials. In the the form of figures.43–5.667 antacids 70 Antacids versus 3 Clinically important bleeding OR = 0.56 antacids Antacids versus 5 Clinically important bleeding OR = 0. CI = 0.5.e.32. The results namic instability or the need for blood transfusion.16–2..9% with no prophylaxis.65 antacids 69 Antacids versus 6 Overt or clinically important OR and CI < 1 (lower rate of bleeding with control bleeding antacids) H2-RAs versus 14 Overt or clinically important OR and CI < 1 (lower rate of bleeding with H2- control bleeding RAs) H2-RAs versus 14 Overt or clinically important CI included 1 antacids bleeding Sucralfate versus 6 Overt or clinically important OR and CI < 1 (lower rate of bleeding with H2-RAs bleeding sucralfate) Sucralfate versus 10 Overt or clinically important CI included 1 antacids bleeding 71 Sucralfate versus 9 Clinically important bleeding OR = 0.41 control H2-RAs versus 10 Clinically important bleeding OR = 0.. defined as overt bleeding with hemodynamic studies were included. The data were presented only in transfusion of two units of blood in 24 hours).35.88 (lower rate of control bleeding with H2-RAs) H2-RAs versus 10 Clinically important bleeding OR = 0.933 (lower rate of H2-RAs bleeding with sucralfate) Sucralfate versus 10 Clinically important bleeding OR = 0.59 antacids Sucralfate versus 1 Clinically important bleeding OR = 1. CI = 0. CI = 0. Two meta-analyses published by Cook et al. and investigated receiving antacids versus 14.06–15.11 H2-RAs a H2-RAs = histamine H2-receptor antagonists. CI = 0.532.1% with no prophylaxis and 5. Exact values provided when available.3% more efficacious in preventing clinically important in the group receiving H2-receptor antagonists versus bleeding than no prophylaxis.40 sucralfate 5 Antacids versus 3 Clinically important bleeding OR = 0.70 in overt and clinically important bleeding (i. Trials Endpoint Resultsb 68 Cimetidine versus 7 Overt bleeding OR = 0.303–0.84. The investigations looked at clinically important upper GI bleeding.49 (lower rate of control bleeding with cimetidine) Antacids versus 9 Overt bleeding OR = 0.08–0.27 antacids Sucralfate versus 4 Clinically important bleeding OR = 1. 16.49.87 control Sucralfate versus 5 Clinically important bleeding OR = 1. CI = 0.26.22–0.65.35. studies with clinically important bleeding.28. H2-receptor antagonists were found to be available.15–0. so the exact ORs and CIs are not 1991 analysis. CI = 0.86. Randomized and nonrandomized bleeding. CI = 0. CI = 0.46–1.19 (lower rate of control bleeding with antacids) Cimetidine versus 10 Overt bleeding OR = 1. CI = 0.76 (lower rate of control bleeding with H2-RAs) H2-RAs versus 9 Clinically important bleeding OR = 0. need for 1991 and 1996 included only randomized. the frequency of bleeding was 5. CI = 0. However.35.868.21–0. CI = 0.61.

represent failure of prophylaxis. 165 pediatric patients admitted to Conflicting associations with total parenteral nutri- an ICU were randomly assigned to one of three active. study. defined as a platelet count of <50. two risk factors were found to be significant ability of the results to these populations.000 Various prophylactic medications were used. 95% CI. Lack of predictors of stress-induced bleeding: respiratory fail- resources at three of the four hospitals prohibited en. tion (TPN) and bleeding have been noted.6%) of 1578 patients not receiving prophylaxis and frequency of bleeding was 3.48 compared pro. multiple induced lesions progressing to clinically important regression analysis showed that only mechanical venti- bleeding with or without prophylaxis is not well stud.001).5%) if neither factor was present.61 This multicenter follow-up trial enrolled tective effect of surfactant on the GI tract remains to be 2252 patients older than 16 years of age who were elucidated. partial thromboplastin time of >2 times the control trolled. The researchers concluded may determine the differences noted.65 The inves. in this observational design. ure. only three trials with an antacid studies that had a control group. Clinically important bleeding occurred in 10 value (OR = 4. physicians were tients who had received prophylaxis and those who probably able to predict who was at risk for bleeding had not were included.788). Pa- that. p < 0.009–0. In Cook’s prospective observational plantation) had few patients.63 In one of these prophylaxis. achem et al. 0.001). This limits the generaliz. or a dosage and duration of prophylaxis were not con. The fact that patients are able patients were in. 0. renal insufficiency. respiratory distress syndrome. Surfac- its results are used in this document whenever the tant therapy. injuries. Six differences in location of the enteral feeding tubes. 95% CI.72-75 These differences may be due to patients) and the placebo group (8 of 21 patients). the risk of endoscop- group and one with a sucralfate group were available for ically diagnosed gastric lesions in mechanically venti- comparison with no prophylaxis.02–0.001) is of interest because bleeding was not distinguished from clinically impor. CI not reported. p < 0.61 The (0.5 The methodology was similar to was achieved only if the results for the three active- that of the earlier meta-analysis.5–5. 2. Simple regression analysis and administer prophylaxis. on a neonatal population but did not use clinically ing clinically important bleeding compared with no important bleeding as an endpoint. When the results were reported. and the mm3. and this intravascular coagulation. Risk factors. Because the 1996 lated infants was found to be lower with ranitidine meta-analysis was the most recent and comprehensive.59 found that the frequency of bleeding was tigators used clinically important bleeding as an out. tive of clinically important bleeding. it does not necessarily showed that sepsis. p < 0. In another study. an International Normalized Ratio of >1. hours (OR = 15. However. Approximately tients has conclusively demonstrated a significant dif- half of the enrolled patients were admitted for cardio. and phy. CI not reported. Ruiz-Santana et al. hepatic failure. such as the not warranted. Ben-Men- treatment groups or a no-treatment group. not related to the use of TPN.083. Only H2-receptor an.05) difference between the ously conducted meta-analyses and to incorporate active-treatment groups and the no-treatment group more recent studies. Two studies focused tagonists were found to have a 95% CI of <1 for prevent. previous retrospective studies in adults have found tant bleeding. No RCT conducted to date in pediatric pa- admitted to medical and surgical ICUs.178).6. feedings placed into the stomach may alkalin- of nasogastric blood with changes in blood pressure or ize stomach contents. as defined by mechanical ventilation for at least 48 rollment of consecutive patients as intended. come. Other factors that routine prophylaxis in medical pediatric patients is may be specific to certain types of injury.8. phylaxis with no prophylaxis in 40 patients from birth The finding that enteral feeding was a risk factor for to 18 years of age. treatment groups were combined. the study with the largest number of pro.ASHP Report Stress ulcer prophylaxis some of the inconsistencies associated with the previ.49. coagulopathy. enteral feeding. ference in clinically important bleeding when prophy- vascular surgery.4%) of 674 patients receiving prophylaxis (22 of one or both of these risk factors were present and 0. and warfarin were risk factors for bleeding. and it was noted that five of these to tolerate tube feedings may mean they are less ill than patients had bleeding at other sites due to disseminated patients who cannot tolerate such feedings. and no differences in upper GI bleeding various effects of enteral feedings on pH and the fre- were noted between the cimetidine group (9 of 19 quency of bleeding.03. in 1994. This suggests (95% CI. and jejunal feedings may stimu- hemoglobin levels. and the use of glucocorticoids.63 The mechanism for the apparent pro- al. Lacroix et al.2%) if 23 (3. which was used to treat infants with findings from previous meta-analyses are conflicting.5.1% the 33 bleeding episodes were confirmed). overt bleeding (OR = 3. heparin. Some subgroups (head or spinal cord laxis was compared with no prophylaxis. defined as the presence example.52 354 Am J Health-Syst Pharm Vol 56 Feb 15 1999 . lation and coagulopathy were independently predic- ied in pediatric patients. A significant (p < 0.003–0.7% (95% CI. and trans.3. The number of stress. prophylaxis (OR = 0. Prophylaxis in pediatric patients. and sicians were not required to withhold prophylaxis. was also associated with To date. development of GI edema after thermal injury. spectively enrolled patients was published by Cook et 0. multiple trauma or thermal injuries. It was not stated which groups these late gastric acid secretion. a lower rate of formation of lesions (OR = 0. For patients had massive bleeding.

3%) of the clinically important bleeding episodes occurred. The studies often exclud- Prophylaxis does not necessarily prevent bleeding in ed neurosurgery. observational mg/day of hydrocortisone or equivalent). and a Pediatric Risk of Mortal- in that mechanical ventilation (as a measure for respira. as the ations with bleeding problems. A majority of high-dose corticosteroids in adults. burn.59 However. and it is unclear whether longed ICU stay or occult bleeding and administration they are independent predictors of bleeding. accord- ulopathy.53 are the prima. Other risk factors associated factors and 14 (88%) had at least two.56. physi- bleeding included male sex. spinal cord injury.54. However.29. and transplant patients. cal and surgical patients at risk for stress ulcers who do ated with an increased risk of bleeding. or respiratory failure. Clinically important bleeding is not known. ity Score of ≥10 (OR = 4.61 clinically important bleeding.1–39%) of adult medi- three hours. The reported frequency of stress-in- sepsis.53. Score of ≥10. for stress ulcer prophylaxis. Typically.76 The only patients receiving prophylaxis may occur in the very young despite their possible (antacids) were those with a history of gastroduodenal physiological differences from adults.64 Observational studies involving large num- results were not stratified by age. prolonged shock of investigations excluded patients with a history of GI or surgery and trauma in children).3).57 shock.56 surgery lasting for longer than ing to RCTs. acute renal failure. may be substantially lower. who received prophylaxis.53 and mately 1978 and depends on the number and type of administration of high doses of corticosteroids (>250 risk factors. ically important bleeding increases. but it is unknown disease. and their findings require confirmation found that 20 (80%) of 25 patients had stress-induced in larger randomized trials.2). One study in pediatric bers of pediatric or adult patients suggest that the risk patients (median age.41. 34. The risk factors associated with a higher risk of cause this was an observational investigation. coag.61 coagulopathy (OR = 9.37-39. the frequency of clin- NSAIDs. Several studies that included both ulcerogenic medications with well-documented associ. medical and surgical ICU patients suggest that. such as long-term use of number of risk factors increases. general medical and surgical ICU patients who have oids.56 trauma.61. 16 (1.58 The results of most trials are important bleeding were respiratory failure (OR = 10. particularly ulcers and bleeding.66 atric Risk of Mortality Score greater than 10 was associ.59 Some potential risk factors for bleeding have associated with overt bleeding in isolated studies (pro- not been adequately studied.41. no prophylaxis was administered. there are from enrolling in the studies. 0. and the effec.54.42. concerns related to inadequate sample sizes in the In pediatric patients (birth to 19 years of age). Stress ulcer prophylaxis ASHP Report concluded that TPN was protective.45-47. 9 (56%) had all three risk ry risk factors for bleeding. The authors noted that the higher risk of bleeding as the number of risk factors three strongest independent risk factors for clinically increased.57 Another study in been delineated in trials comparing prophylaxis with no Vol 56 Feb 15 1999 Am J Health-Syst Pharm 355 .41 duced bleeding has varied substantially since approxi- presence of occult bleeding for at least six days. while the use of not receive prophylaxis have clinically important enteral nutrition reduced the risk of bleeding. posed that adult medical ICU patients may not neces- ceiving such medications either were not discussed in sarily need stress ulcer prophylaxis. Data from large prospective. heparin. and severe sepsis. It has been pro- tors for stress-induced bleeding.63 ulcerations.9 months) found that a Pedi. Anoth- patients with documented risk factors. or NSAIDs to be independent either coagulopathy or respiratory failure requiring me- risk factors for bleeding when respiratory failure and chanical ventilation have a substantially higher risk of coagulopathy were considered. respirato. investigations in children and adults have found that the studies by Cook et al. lesions as determined by endoscopic evaluation when The most recently published large-sample retrospec. with bleeding in adult patients in some studies include Summary.59 and coagulopathy36. Recommendation (adults): Risk factors for ICU patients have ated with a greater risk of bleeding. Similarly. did not find use of corticoster.55. Of the 16 patients with tory failure)36. about 6% (range. cians were not hindered from prescribing medications ry failure. er risk factor for children is a Pediatric Risk of Mortality tiveness of prophylaxis varies in different popula. warfarin. Among the 110 patients Of the other trials in which risk factors were studied. A number of other risk factors have been tions.57 and pneumonia57 were associ. but their sample mechanically ventilated preterm and full-term infants size was small.63 That study and tive study of risk factors in ICU trauma patients involved others demonstrated that gastric lesions due to stress 2574 patients.6%) bleeding.66 Be- patients. consistent with those of the 1994 study by Cook et al.0). patients re. even if they have the methods section of study reports or were prohibited respiratory failure or coagulopathy. have not been adequately studied as risk fac. clinically significant bleeding. there were 10 clinically im- a majority of those conducted in adults showed a portant bleeding episodes.48. studies that resulted in this conclusion. The published abstract does not reveal how The rate of progression of these lesions to clinically many of the 2574 patients received antacids. stress-induced bleeding. Overall. It is unknown whether these are independent predictors of clinically whether a history of ulceration or bleeding increases important bleeding.57 The bleeding. except in the case of coagulopathy the risk of acute. GI bleeding was noted in 60 (2.35 length of ICU stay greater than one week. In a study in 881 important bleeding was not analyzed separately from GI pediatric ICU patients (1006 admissions).

antacids. respiratory) ICU populationsb B (for sucralfate) in patients with at least two of the following risk factors: Head injury with Glasgow B (for H2-RAs). ICU stay of sucralfate) in special populations (single-system >1 wk. Prophylaxis is recommended in patients with Strength of Evidence for Prophylaxis for Adult ICU coagulopathy or patients requiring mechanical ventilation Patients According to Risk Factora for more than 48 hours. 28 years. 2–74. of prophylaxis. and risk factors for bleeding following: sepsis.78. antacids. sucralfate) Recommendation (pediatrics): Although various risk factors Hepatic or renal transplantation D (for H2-RAs. sucralfate) cations used for prophylaxis section. sucralfate) tant bleeding include respiratory failure. D (for antacids. population that has usually been studied separately ber of patients (n = 167). (Strength of sucralfate) History of gastric ulceration or D (for H2-RAs. although two studies included younger patients at higher risk for clinically important bleeding.82 In patients patients received both antacids and enteral feedings.82. sucralfate) lasting six days or more. some more than five risk factors were present.80 receptor antagonist prophylaxis than with no prophy.81-84 Three of these trials found significantly consciousness) or when the syndrome of inappropriate lower rates of clinically important bleeding with H2. >35% of body surface area H2-RAs. undergoing surgery for nontraumatic cerebral disease. In both studies. mean age. b There is evidence to suggest that patients in general ICU populations these studies in special populations were conducted in who have respiratory failure or coagulopathies (as defined in the text) are adults. the frequency of bleeding and 4.79 Five of the trials were preoperative Glasgow Coma Score was <15 (impaired RCTs. no association was phylaxis for stress-induced bleeding. published investigations. (mean age. antacids.91 was one of the first tive of corticosteroid administration. Spinal cord injury D (for H2-RAs. evidence = C) bleeding during year before sucralfate) admission Frequency of bleeding. D (for specific prophylactic medications can be found in the Medi. but the feedings found among 12 specific risk factors and bleeding. a situation that was not defined. in the RCT with the largest num. occult bleeding Coma Score of ≤10 or antacids. D (for sepsis. While many of the thermal injury studies included cimetidine prophylaxis was more likely to fail when the injuries in children (35 days to 13 years of age).77-84 A majority of recommendation. PTT = partial thromboplastin time. endpoint. the number of patients with with regard to stress ulcer prophylaxis and bleeding. transplantation. range. irrespec. ICU stay of more than one week. (Strength of evidence = C) Prophy- Risk Factor Strength of Evidence laxis is also recommended in patients with a history of GI ulceration or bleeding within one year before admission and General (medical. antidiuretic hormone secretion was present. the number and types of risk Two RCTs demonstrated substantial increases in clinical.8–45. INR = International Nor- malized Ratio. antacids).78. coagulopathy. 35 years.ASHP Report Stress ulcer prophylaxis prophylaxis by using clinically important bleeding as an Table 3. Patients with thermal injuries represent another laxis. Partial hepatectomy C (for H2-RAs). antacids. corticosteroid therapy miscellaneous) (>250 mg of hydrocortisone Patients with head or spinal cord injuries or patients or equivalent daily) a undergoing surgical exploration for suspected disease H2-RAs = histamine H2-receptor antagonists. a Pediatric Risk of Mortality Score of ≥10. have been associated with bleeding in pediatric patients. were administered only if ulcers were unlikely to devel- though bleeding rates were significantly higher when op. The and Glasgow Coma Score of ≤10 in the other). retrospective study by Solem et al. and Hepatic failure D (for H2-RAs.83.84 In another RCT to suggest that enteral feedings might be effective pro- involving patients with head injuries.02). al.2% in patients given antacids (p < 0. and use of high-dose corticosteroids inability to obey simple (>250 mg per day of hydrocortisone or the equivalent). In other frequency of bleeding as the severity of injury increases.82 Only In the only trial that appeared to be randomized (48 two of the studies looked at a possible association patients). injuries. factors (other than the thermal injury that may have ly important bleeding (27. antacids. antacids.77.8%) with severe head contributed to bleeding) were not studied.84 patients with thermal injury to >35% of their body In general. except for a injury (inability to obey simple commands in one trial possible association between sepsis and ulceration. the studies demonstrate an increasing surface area (BSA) were included in this trial. Refer to the text for have usually been studied as defined groups rather than discussion of the risk factors and the economic analysis behind the as part of general ICU populations. thermal injuries. only 356 Am J Health-Syst Pharm Vol 56 Feb 15 1999 . efficacy Presence of at least two of the D (for H2-RAs.78. A (for H2-RAs.84 However. surgical.85-91 clinically important bleeding was not reported. occult or overt bleeding for ≥6 days. In addition. bleeding as an outcome or had insufficient power to enable a Severity Score of ≥16 sucralfate) definitive conclusion that prophylaxis provides protection. the frequency of clinically important bleed- between the number of risk factors and the frequency of ing was 29. commands (Strength of evidence = D) (Table 3) Recommendations for Thermal injury involving B (for antacids). Risk factors that have been associated with clinically impor. sucralfate) published RCTs have either not used clinically important Multiple trauma with Injury D (for H2-RAs. range 13–76) who were not discussed separately when the results were reported.90 Only increased with the number of risk factors.2% in patients who received no prophylaxis bleeding.

with spinal cord injuries. but the frequency of clini. medications used for preventing stress- tectomy.98-102 tor levels. These populations were usually excluded from clinically important bleeding required blood transfu. other explanations that concomitant organ disease or surgery increases the for the beneficial actions of these agents have been risk of clinically important bleeding is lacking. and overt Although alternative explanations for the effectiveness and clinically important bleeding episodes were com.88 All 477 children had thermal important bleeding in patients with single-system inju- injuries involving 13% or more of their BSA. direct evidence hibiting gastric acid secretion. (Strength of evidence = C) Prophylaxis may also be indicated studies evaluated. and the cytokine concen- That study involved patients with tetanus who had trations fluctuate widely in critically ill patients. Injury Severity investigations. and there were no episodes of tants that do not appear to depend on acid or acid clinically important bleeding. studies in which patients might be randomly assigned sions.104 However. atively.94 month of age or older) with thermal injuries.637 trauma lish that “cytoprotection” with misoprostol plays an patients. Stress ulcer prophylaxis ASHP Report one study investigated the effect of no prophylaxis in The frequency of.g. The frequency of bleeding was lower with ci. secretion and is sometimes referred to as a cytoprotec- ing and risk factors associated with bleeding were tive agent. insufficient evidence is available to allow hepatic transplant patients. transplantation patients in the ICU perioper- overt and clinically important bleeding were com. protective barrier. but there is insufficient evidence to recom- significantly lower frequency of endoscopically con. (Strength of evidence = D) (Table 3) metidine prophylaxis in one study involving renal Recommendation (pediatrics): For pediatric patients (one transplant patients but not in the other. not correlating with more global physiological de- ically ventilated. a Glasgow Coma Score of <8. Some 32 of the 36 children (89%) with ied. In all the in ICU patients with multiple trauma (e.101 It is unknown how important role in preventing stress-induced lesions.93. Medications used for prophylaxis spective trial enrolled patients undergoing partial hepa. and ing when no prophylaxis was given (or at least was not patients with multiple trauma have not been well stud- mentioned).107 many of these patients received prophylaxis.108 In contrast. neutralization of gastric acid important bleeding to be able to conclude that it was secretions. including modulation of pepsin and Vol 56 Feb 15 1999 Am J Health-Syst Pharm 357 . 1 death to receive no prophylaxis. one was randomized. Thus. immunomodulatory actions at the cellular and media- lations other than those previously mentioned. clinically pediatric patients only. Risk factors associ. of antacids in preventing stress-induced bleeding have bined (18 of 33. stimulation of prostaglandin re- ated with bleeding included an Injury Severity Score of lease). None of the stud. prophylaxis includes patients (at least 14 years of age Recommendation (adults): Prophylaxis is recommended for in published studies) undergoing renal or hepatic ICU patients with a Glasgow Coma Score of ≤10 (or the transplantation or hepatic surgery. spinal cord injury.105 Similarly. often tracheostomies.97 One RCT involved patients with hepatic failure.. It is not known whether (2. and risk factors for. prophylaxis is Prophylaxis with ranitidine was associated with a recommended. and protective mechanisms unrelated to significantly lower with prophylaxis. Elderly patients and patients with infections tiple actions on the GI tract besides providing a direct and organ failure were also more likely to bleed. most of them adults. (Strength of evidence = B) ICU patients except one investigation that used ranitidine. Score of ≥16).92-97 Cimetidine or inability to obey simple commands) or thermal injuries to antacids were used for prophylaxis in all the trials >35% of their BSA. and ICU patients bined. proposed. mend prophylaxis based on any given percentage of BSA. patients undergoing transplantation.367 patients bled).8%) was associated with GI bleeding.97 Of the with partial hepatectomy may also benefit from prophylaxis. but only the hepatectomy through one of the following mechanisms: inhibition study contained adequate information about clinically of gastric acid secretion.96 The frequency of bleeding was lower with induced bleeding exert their pharmacologic effect prophylaxis in both studies. inhibitors act primarily as antisecretory agents by in- tially associated with bleeding. mal injuries. neutralization of gastric acid is the primary ≥16. respiratory failure or coagulopathy would serve as inde- Another defined population studied for stress ulcer pendent predictors of bleeding in these populations. mediation of cytokine concen- Only one of these investigations was randomized. and proton-pump tigated the number or type of other risk factors poten. trations is a complex process. tagonists. In general. recommendations about prophylaxis to be made.103 The H2-receptor an- ies looking at renal or hepatic surgery or disease inves.100 The frequency of overt bleeding rangements. ICU patients with hepatic failure. and spinal cord mechanism of action. acid secretion or neutralization. the prostaglandin analogue was similar between the patients who did and did not misoprostol prevents gastric mucosal damage by irri- receive prophylaxis. been proposed (e. For example.. a majority of whom were not mechan.95 and one pro. and ther- (7. both randomized and nonrandomized. Thirty-six ries such as head trauma. and 5 patients (14%) required surgery. cally important bleeding was not delineated. (Strength of evidence = D) For other pediatric surgery or firmed stress ulceration in the one available study of trauma patients. But.g.106 There is no convincing evidence to estab- evaluated in one retrospective study of 33.5%) of the children had clinically important bleed. H2-receptor antagonists have Several studies have included defined patient popu. The frequency of bleed. prostaglandin analogues. sucralfate has mul- injury.

there is no evidence equipotent doses.114 Larger comparative studies are dine. A In the largest RCT published to date. no significant differences between medica- cian may monitor the gastric residual volume when tions used for the prophylaxis of clinically important feeding formulas are administered into the stomach. or gastrostomy tube. receiving ranitidine by continuous i. of these mechanisms is of primary importance for juices. and transplantation. a majority of usually presumed when tube feedings are tolerated which were randomized. induced bleeding. patients. abdominal distention. respectively).ASHP Report Stress ulcer prophylaxis mucus activity. Neither should it be ad. burns. groups.g. lansoprazole has FDA-approved labeling for ate secretion. such as the lack of an i. prophylaxis cannot be recommended. suspect any substantial difference in prophylactic effi. although some interesting compounding rately.v.110 However. Although medications may have different mecha- cacy when other H2-receptor antagonists are given in nisms for their protective effects.112-115 In on the power to detect differences in rates of pneumo- 358 Am J Health-Syst Pharm Vol 56 Feb 15 1999 . and proton-pump inhibitors in critically ill patients is the potential for malabsorption. tors create administration problems when oral intake is 19. and ranitidine.176 must be administered directly into the stomach. other reasons may pre.. Therefore.116 One open-label study involving 75 mechani- stress ulcer prophylaxis is not clear. although there is no reason to nists) and other unanticipated problems. or medications used for stress ulcer prophylaxis. A functioning GI tract is A substantial number of clinical trials. because the medication will miss the site of action. the number of volume infused over a two-hour period is usually indic. and tissue growth or repair. Misoprostol is available in tablet form. infusion and 1 ministered by feeding duodenal or jejunostomy tubes (3%) of 33 patients receiving omeprazole suspension.109 Which.111 cient to preclude a Type II statistical error. in a majority of Residuals refer to the feedings and gastric secretions studies.175 must be administered either orally or by a nasogastric.. Although the estimated sample size was based techniques for omeprazole have been reported. Combination versus oral) of H2-receptor antagonists by using clinical. ranitidine (50 mg every 8 hours) and nasogastric place- pump inhibitors such as omeprazole and lansoprazole bo. nizatidine. trauma. the patient must of bleeding have a functioning GI tract. 12. combination therapy for initial sus continuous i. Only cimetidine ad. reported clinically important bleeding (the definition orogastric.g. In patients with nasogastric tubes. 16% is a Similar to sucralfate. For example. 60% and 40%. cally ventilated surgery patients found a compounded The H2-receptor antagonists that are available com. as postulated for the H2-receptor antago- in critically ill patients. 158. it high for one of the groups. bleeding have been found. Because these agents Efficacy of prophylactic agents: Prevention must be absorbed to exert their effects. Sucralfate should not be of clinically important was different than the definition administered with nasogastric tube feedings (see Adverse used in these guidelines) in 4 (16%) of 25 patients effects of prophylactic agents). No RCTs of adequate sample size risk of adverse effects would increase with combination have compared dosage regimens (e. i. Phillips et al.v. therapy.117-174 In diarrhea. general. arachidonic acid metabolism. but the potential (as with nizatidine). therapy for the prevention of recurrent bleeding is ly important bleeding as a study endpoint. the sample size needed to detect a difference that accumulate with GI dysfunction. placebo or i. However.v. but the frequency of bleeding was unexpectedly cralfate appears to exert its predominant effects locally. The de. fate slurry (1 g every 6 hours) and i.64.v. patients from special populations: CNS surgery. administration) or routes (e.v. omeprazole suspension effective in preventing stress- mercially in the United States are cimetidine. mitted to medical and surgical services (approximately tions have not been well studied for stress ulcer prophy. discussed further in this document (see Prevention of One concern with using oral H2-receptor antagonists recurrent bleeding). addition. if administration by nasogastric tube with some fruit any. the clini. that combination therapy is more effective than a clude their use. have involved comparisons of without nausea. Several formulations carry hours were assigned to receive either nasogastric sucral- FDA-approved labeling for this indication. Other studies Although widely used for stress ulcer prophylaxis. antacids have local actions and high rate of bleeding with ranitidine. These medica. vomiting. A volume of between treatment groups in clinically important more than 200 mL or an amount greater than the bleeding was not calculated. 49 layed-release dosage forms of the proton-pump inhibi. while proton. Therefore. There were relatively few laxis and are not labeled for this indication. These special populations were not discussed sepa- not possible.v. intermittent ver. have found substantial differences in bleeding between sucralfate is not labeled for this indication. famoti. dosage form single agent for initial prophylaxis. needed to determine efficacy and assess the potential ministered as a continuous intravenous infusion has for adverse effects such as pneumonia (from increased FDA-approved labeling for the prevention of bleeding gastric pH.176 The patients in this multicenter study were ad- are available in delayed-release capsules. Compared with the results of other studies. patients enrolled in any given study was often insuffi- ative of dysfunction. Because su. 1200 patients number of antacid products have been routinely used who required mechanical ventilation for at least 48 for stress ulcer prophylaxis. bicarbon.

176 The other major limita.02). In mal injuries). the distinct populations (e. particularly if a rigid definition of bleeding confirmed by angiography and red blood is used.g. Ten (1. functioning GI tract). 0. and this antagonists. H2-receptor trial compared sucralfate with no prophylaxis.44. The meta-analysis also included RCTs from a cell scanning. but the 95% CIs total costs. the definitions for overt tant bleeding (relative risk. If the frequency of bleeding has tant GI bleeding.69 H2-receptor antago. In the 1991 meta-analysis by Cook allow any recommendation about these agents to be made.5 For example. tration (e. Stress ulcer prophylaxis ASHP Report nia (power. This when medications were compared. functioning GI tract).303–0.5. Recommendation (adults): Given the conflicting results of phylaxis.. Finally. there may be differences in the length of stay or mortality.92. portant bleeding. several meta-analyses and a recent RCT (both with strengths indicating substantial variation in the data. ication efficacy. 95% CI. trauma pa- but the therapies were similar in preventing clinically tients.5 (1996) conducted a meta-analysis Many of the available studies did not include mortal- to resolve the apparent discrepancies.. patients with head and ther- source of bleeding was not found for 19 patients. the choice among antacids. patients with burns. tion-specific basis and should take into account concerns Cook et al. about administration (e. tients in the ranitidine group and 23 (3.7%) of the 596 pa. lack of comparative trials of these agents in pediatric and special populations (e. but in some cases the 95% CIs were wide.8%) of 604 While useful. and clinically important bleeding. this could have also influenced the these meta-analyses included the recently published results of the meta-analysis. tant questions. Because invasive diagnostic testing was variety of populations that have usually been studied as left to the discretion of participating physicians..68 and Tryba. patients undergoing neurosurgical procedures or with important bleeding.176 onists and antacids to be more effective than no pro. This meta-analy. and the trial’s power to detect a difference in ing but not clinically important bleeding. the meta-analyses found H2-receptor antag. initial meta-analyses were completed. gical ICU patients).68-71 None of treatment group). Endoscopic confirmation of an upper GI source which contrasts to the definitions used in many of the of bleeding was obtained for 3 patients in the ranitidine randomized investigations that were analyzed.5 The results of these meta-analyses were conflicting ICUs should be made on an institution-specific basis. and sucralfate for use as prophylactic agents to trial was included in the 1996 meta-analysis by Cook et prevent clinically important bleeding associated with stress in adult patients admitted to general medical and surgical al. The choice of agent should be made on an institu- efficacy to antacids (OR = 0. and still fewer specifically associated sis included studies that were not available when the mortality with bleeding. It is not group and 10 in the sucralfate group. the largest RCT frequencies of bleeding compared with populations conducted to date has not definitively determined the studied more frequently (e. includ. adverse- receptor antagonists or antacids for preventing overt effect profile. A significant difference in favor was similar to antacids or H2-receptor antagonists for of the H2-receptor antagonist (ranitidine) compared prophylaxis of both overt bleeding and clinically im- with sucralfate was noted.g. (Strength of evidence = D) Insufficient data on included 1. decreased over time as a result of improvements in the Five meta-analyses have been conducted to resolve care of the ICU patient (which is difficult to verify some of the discrepancies noted between RCTs. 95% CI..g.g. Even if one assumes that the pathogenesis addition. Sucralfate bleeding rate was 90%.933). An additional possible to derive rates of clinically important bleeding patient in the ranitidine group had an upper GI source from many of the trials.. because many recent studies have not included a no- ing the issue of inadequate sample size.g. ity outcomes. and transplantation patients) precludes Tryba71 found sucralfate to be significantly more definitive recommendations as to the agent of choice in these effective than H2-receptor antagonists and similar in situations. 0. the results of this RCT by Cook et al. (1998) and the Canadian Critical meta-analysis are somewhat inconsistent with the find- Care Trials Group (Table 2). p = and clinically important bleeding are very explicit. ings of the large RCT recently published by the same tions of these analyses have been discussed previously.70 H2-receptor antagonists were significantly more Recommendation (pediatrics and special populations): The effective than antacids for preventing overt bleeding. 0. Only one of evidence = A). Efficacy of prophylactic agents: Mortality analyses. In the meta-analy. In the largest RCT to date. Given the disparities noted in the previous meta. adverse-effect profile. H2-receptor antagonists were found to be significantly tant bleeding and mortality were additional study ob.. the rates of clinically impor.70 (1991) found sucralfate to be similar to H2. lead authors with regard to possible differences in med- In general. 0. Therefore. tween ranitidine recipients and sucralfate recipients Vol 56 Feb 15 1999 Am J Health-Syst Pharm 359 . indicating that the two regimens did not misoprostol or the proton-pump inhibitors are available to differ significantly. et al. Cook et al. In addition to there was not a significant difference in mortality be- being significantly more effective than no prophylaxis. no differences were noted in the overall of bleeding is similar. general medical and sur- agent of choice for the prevention of clinically impor. this meta-analysis raises some impor- patients in the sucralfate group had clinically impor. more effective than antacids in preventing overt bleed- jectives. neurologic disorders. or 1–β = 75%). and nists were compared with antacids.532. and total costs.21–0. choice should take into account concerns regarding adminis- ses by Lacroix et al.

16.67 cralfate may cause substantial elevations in serum alu. sucralfate) receptor antagonists. group) 70 Antacids versus 6 OR = 1. particularly given that well-defined dosage when available. (combined ables. importance.ASHP Report Stress ulcer prophylaxis despite the finding of a lower frequency of clinically Table 4. In a meta-analysis by Tryba69 in 1991.70 (Table Antacids versus 8 OR = 1.178 The frequency of adverse effects may increase H2-RAs versus 15 OR = 1. ferences in mortality to any single intervention in ICU Reference Comparisona Trials Resultsb patients must be interpreted with caution given the 69 H2-RAs or 11 CI included 1 antacids problems with controlling multiple confounding vari. Exact values provided function.06.g. by inhibiting the feeding tubes. such as renal failure. sucralfate was control CI = 0. b OR = odds ratio.06.97 minum concentrations in adult patients with chronic (lower rate of renal insufficiency or in the elderly.80.83. control CI = 0. antacids CI = 0. important bleeding with ranitidine. suggesting no substantial differences in antacids CI = 0. a H2-receptor antagonist or an antacid.54–1.04 5 Antacids versus 3 OR = 1.61–2.48 H2-RAs versus 15 OR = 1. particularly H2-RAs CI = 0.09 Elevated aluminum concentrations and resultant toxic- a ity are more of a concern in children with renal dys.g. published meta-analyses included 1. or enteral aspiration.70.180. No. for less than two control CI = 0. Sucralfate versus 4 OR = 1.71. When medications control CI = 0.46 mortality. potentially causing pa- uremia.52–0.66–1. they may cause unwanted hypophosphatemia tient discomfort and resulting in complications from in patients with normal renal function.89.54–0. sucralfate CI = 0. H2-RAs CI = 0. Sucralfate versus 11 OR = 0. and sucralfate are uncommon Sucralfate versus 7 OR = 0. ministration of H2-receptor antagonists may occur. actions between enteral feeding products and medica- taining antacids and sucralfate and diarrhea may occur tions administered enterally for prophylaxis.73–1.g.177 (1994 and 1996). inappropriate placement in the trachea). constipation may occur with aluminum-con.24 were compared with no prophylaxis. Some products given by oral. antacids CI = 0. the local actions of sucralfate or interfering with the ab- 360 Am J Health-Syst Pharm Vol 56 Feb 15 1999 .183 placement of a new tube (e. Furthermore. Cook et al.49–1.21 administration or CNS disturbances secondary to ad. Such in- with magnesium-containing antacids at frequencies teractions could result in clogged feeding tubes or di- higher than 1%.42.18 differences in mortality were found between any of the H2-RAs versus 14 OR = 1.79 sucralfate was associated with a lower rate of mortality H2-RAs versus 3 OR = 1.83–1. some values were extrapolated from figures.86–1.83–2. If the occlusion cannot be removed. H2. Su.36. sucralfate CI = 0. In contrast to the finding of the 1991 meta-analysis.53 when electrolyte accumulation secondary to antacid H2-RAs versus 14 OR = 0. there are potential inter- example. Any attempt to attribute dif. CI = 95% confidence interval. Sucralfate versus 11 OR = 0.15. nasogastric.82–2.94 Adverse effects of prophylactic agents (lower rate of mortality with Most adverse effects attributable to antacids. when given on a short-term basis (e. antacids CI = 0.184 Sucralfate and antacids may occlude minished medication efficacy (e.185 administration may result in local adverse effects.62–1. all the CIs in the H2-RAs versus 11 OR = 1.58 than antacids in two other meta-analyses conducted by 177 Antacids versus 5 OR = 1.. and occur in less than 1% of adult patients.83–1.61 groups in the 1991 meta-analysis by Cook et al.176 This may be Meta-analyses Investigating the Risk of Mortality partially explained by the relatively low frequency of with and without Stress Ulcer Prophylaxis bleeding in both groups. No significant control CI = 0. antacids CI = 0.181 Sucralfate versus 11 OR = 0..03.179 although this mortality with does not appear to be a problem when the drug is used sucralfate) for less than two weeks in critically ill patients. 4). the limitations associated with the group) versus extraction and interpretation of this information from control Sucralfate versus 9 OR and CI < 1 (lower the original trials must be appreciated during consider- H2-RAs or rate of mortality ation of the results of published meta-analyses that antacids with sucralfate) have investigated the mortality associated with various (combined forms of prophylaxis..67–1.66 associated with a lower mortality rate than use of either H2-RAs versus 9 OR = 0.06.78–1.25.67–1. H2-RAs = histamine H2-receptor antagonists. if certain diseases are present.47 weeks).73.5. the threshold of control CI = 0. esophageal perforation.22. For Although not well studied.182 Although alu- minum hydroxide-containing antacids and sucralfate may be used to lower phosphate levels in patients with tube may have to be replaced. control CI = 0. guidelines have not been established.

hypermagnesemia. fore. and sucralfate (pregnancy risk category B). For example.209 Similar particular adverse effects.210-213 Mis- mation related to pediatric dosing could result in either oprostol is an abortifacient.187-190 In addition to practice is often not used. drug–nutrient. bezoars.186 Sucralfate and antacids can affect the absorption of Case reports suggest that sucralfate may contribute other medications. sucralfate interferes with at least one method of occult tion. For act with sucralfate and antacids despite separation (e. warfarin. dicated in pregnant women. the sucralfate dose. blood testing). There is a possibility that caution is advised for the H2-receptor antagonists (preg- pediatric patients may be more susceptible to some nancy risk category B for cimetidine. and is generally contrain- with increased adverse effects.202 Potentially interacting med- technical problems related to the removal of bezoars. published reviews. sucralfate and antacids should be used with cau. and Pneumonia. Poten. The most common concerns are cardiovascular and CNS toxicities. may result in miscarriage underdosing with diminished efficacy or overdosing (pregnancy risk category X).. famotidine. the lack of infor. this patients with motility disorders. The proton-pump inhibitors have few clinically im- tial adverse effects include hepatitis.g.208 surveillance studies prohibit accurate comparisons of Lansoprazole (pregnancy risk category B) and ome- the frequencies of such effects among medications in prazole (FDA pregnancy risk category C) should be used this class. cern also applies to agents that do not alter pH (e.. ductions in the dosage of the suspected medication. especially avoided if doses of sucralfate and antacids are separated when given in conjunction with enteral feedings in from doses of potentially interacting substances. the feedings should be tempo. The frequency of nosocomial pneu- drug–test interactions through a variety of mechanisms. theophylline).201 This could be probably unnecessary to discontinue postpyloric (jeju. Stress ulcer prophylaxis ASHP Report sorption of other medications). cimeti- before the medication is administered.110. particularly in premature infants. When intermittent liver. and intestinal Test interference is a cause for concern with all perforation have been reported with liquid antacids medications used for stress ulcer prophylaxis. interpreted as renal dysfunction in patients receiving nal) feedings for administration of sucralfate.214 have the potential for drug–drug. or published. This con- used in premature infants and newborns. intestinal obstruction and perforation were the bioavailability of quinolone antimicrobials has been reported with sucralfate in a low-birth-weight infant substantially reduced by sucralfate even when the two who was given 250 mg every eight hours by nasogastric products were separated by two or more hours). interactions can be minimized by these acid-suppressing agents are of potential concern giving the feedings and medications at different times. monia associated with stress ulcer prophylaxis has been For example. comprehensive reviews have been tic test. and portant adverse effects.g.g. and nursing mothers. tails about enteral feeding–medication interactions and Other interactions may occur as a result of the acid- methods to prevent them.207 The prostaglandin ana- of each of these problems is difficult to determine. but logue misoprostol is rarely used clinically for prophy- estimates range from 0. ications should be administered one to two hours before complications such as intestinal obstruction and perfo. and adverse effects (e.193 There. example.194-199 The low rate of these adverse effects compared with placebo (nausea. cytopenia. Although most problems can be to esophageal and GI bezoar formation. pregnancy risk category C for nizatidine) cimetidine49) than adults. leading to inappropriate re- sucralfate binds to the stomach mucosa.111. The tube should be flushed with water avoiding particular medications.204 tube. The lack of studies in the pediatric population in pregnant or nursing mothers only when the poten- precludes an accurate assessment of the frequency of tial benefits exceed the potential risks.205 The H2-receptor antagonists are associated with a A full discussion of all potential drug–drug interac- number of adverse effects that occur infrequently but tions with these agents is beyond the scope of these may lead to a consultation with a specialist. however.200 However. Although a number of interactions with some of feedings are used. In addition to patient morbidity and through effects on the cytochrome P-450 systems in the economic concerns.g. When continuous feedings are used in conjunction few are clinically important when patients are adequate- with any medications. diar- in adults and limitations associated with postmarketing rhea). the tube should again be flushed out affecting the glomerular filtration rate by competi- with water to ensure passage through the tube. medications may inter- ration have been reported in pediatric patients. Similarly. the reader is referred to suppressing properties of these two classes of agents. there may be other reasons for rarily stopped. (e.9% for laxis and is associated with substantial adverse effects CNS toxicity. a diagnos. It is tion for tubular secretion in the kidneys. mortality rates associated with Vol 56 Feb 15 1999 Am J Health-Syst Pharm 361 . some drug–drug interactions are mediated widely debated.0023% for cytopenia to 1.191 Also. guidelines. women of childbearing H2-receptor antagonists and proton-pump inhibitors age...192. thrombocytopenia associated with ranitidine. After the medi. ly monitored. Furthermore. phenytoin. abdominal pain.203. dine may increase serum creatinine concentrations with- cation is administered. a new medication to treat the adverse effect. ketoconazole. The exact frequency mild GI or CNS toxicities.116.206 a switch to another medication for prophylaxis. because nephrotoxic medications. For more de.

Pneumonia was diagnosed in 114 (19. 95% CI. medications and feedings administered. 0. been identified and ranked according to supporting evi- grade transmission from the stomach.176 that involved 1200 may be less likely to result in pneumonia through retro. particularly when not performed buffering activity may increase the risk of acid aspiration appropriately. wound infection.ASHP Report Stress ulcer prophylaxis pneumonia may be as high as 70%.224 In addition to host factors (e. When pneumonia was 51% of the patients receiving antacids.92–1. 1. double. a positive correlation tric tube to administer medications (with the attendant between increased gastric pH and colonization with risks of aspiration and guaiac-positive stools from naso- bacteria does not mean there is a linear relationship gastric manipulation). of pneumonia (power = 75%). animal models of aspiration expressed about its widespread clinical use. urinary tract infection. aspiration of secretions.” While sucralfate newer techniques such as use of a protected-specimen may not contribute to translocation or colonization of brush. patients.51. one prospective randomized. albeit small. dummy design and compared the growth of gastric Five meta-analyses of the frequency of nosocomial pathogens in 140 patients undergoing elective surgery pneumonia associated with stress ulcer prophylaxis who were randomly assigned to receive either sucralfate have also been conducted (Table 5). or antacids. New gastric microorganisms atric patients receiving stress ulcer prophylaxis. p associated with colonization and pneumonia. 1. Two of the investi- 362 Am J Health-Syst Pharm Vol 56 Feb 15 1999 . The study both were used. along with the volume and pH of between acid-suppressing drugs and pneumonia. mechanically venti. Clini- and translocation from the GI tract. suggesting retro. such as sucralfate.221 pneumonia was based on criteria modified from the When protected specimens.215 There are multi. which is now a widely used and Disease Control and Prevention has recommended that accepted diagnostic tool in research. and nosocomial infection Early reports of adult patients receiving antacids and were not significantly different. morbidity and economic concerns have been the airways by bacteria. dence.217 Gastric coloni. gastric colonization was not associ.65 gastric bleeding. 0. administered with sucralfate and the drug’s minimal ity and specificity. was not performed non-pH-altering medications (e. In the RCT by Cook et al. gastric hypoa- zation was uniformly seen in patients with alkalinized cidity) and environmental factors.216 The vast majority cal endpoints included upper GI tract bleeding (grossly of studies investigating a possible connection between bloody fluid in nasogastric aspirate that failed to clear pneumonia and stress ulcer prophylaxis have been with saline lavage)..218 However.226 Agents that do not alter gastric pH..03).3%) of 604 lated patients were randomly assigned to receive either patients in the sucralfate group. contents were cultured for routine aerobic bacteria and including inhalation. In the few studies involving pedi. There were five patients of mechanical ventilation and upper-respiratory-tract with “definite” pneumonia in the ranitidine group colonization were found to be risk factors. bronchoalveolar lavage. and pulmonary edema. Bronchoalveolar lavage ence in the effect of antacids or sucralfate on gastric or protected specimen brush sampling was used for acidity or rates of bacterial colonization or ventilator. pneu. despite these other niques used to diagnose pneumonia have continued to risk factors.18. p = 0. difference in favor of sucralfate would be found if a ated with the development of pneumonia.222 As in = 0. a difference that was antacids or sucralfate and then studied for risk factors not significant (relative risk. double. pneumonia. and conducted in adults. diagnostic confirmation in patients with pneumonia associated pneumonia. had sufficient power to detect a 25% difference in rates blind study involving 141 patients showed no differ.225 The recommendation was “suggested py for diagnosis of infection have been improved by for implementation in many hospitals. the determination of ventilator-associated grade transmission or translocation of bacteria. frequency of pneumonia.1%) of 596 were obtained by bronchoscopy. A more (0.g.6. contigu.145 Decreased gastric acidity was suspected by clinical criteria.219 Other pneumonia have demonstrated that the volume of fluid methods are less invasive but often have lower sensitiv. appeared in 24% of the patients receiving sucralfate and monia was usually not studied.g. the use of a nasogas- stomach contents.223 Patients’ gastric and respiratory tract ple mechanisms by which bacteria may enter the lungs. pneumonia. direct inoculation. a committee associated with the Centers for evolve. However. fungi before surgery and daily throughout the hospital- ous spread.19). cimetidine demonstrated that the stomach and upper Other risk factors for nosocomial pneumonia have airways had similar bacterial flora. the previous study. prophylaxis in mechanically ventilated patients (ages Although the sensitivity and specificity of bronchosco. Bronchoscopy. hematogenous spread.220. determines the It is also important to keep in mind that the tech. it was typically not a primary endpoint. One potentially con- observed in conjunction with greater colonization of founding variable was the use of enteral feedings by a the stomach but not of the upper respiratory tract.8%) but none in the sucralfate group (95% CI. In majority (approximately 70%) of patients in each another prospective investigation in which samples group. sucralfate) be used for in older studies of medication-associated pneumonia. ization until the patient was discharged or died. It is possible that a significant. but duration larger trial were conducted.1– recent study on this issue had a double-blind. not specified). The rates of reported. patients in the ranitidine group and 98 (16. or Centers for Disease Control and Prevention.

these findings should be interpret- 69 Sucralfate versus 6 OR and CI < 1 (lower H2-RAs or rate of pneumonia ed with caution given the methodological differences antacids with sucralfate) (e.28–1. However. Dosages for patients with renal dysfunction Vol 56 Feb 15 1999 Am J Health-Syst Pharm 363 .227 However. control CI = 0.44 Also. sucralfate-treated patients ments.24–1.e. formation. In the 1994 meta-analysis by Cook et al. the medications used for this purpose. it is recommended that aluminum-containing prod- Sucralfate versus 6 OR = 0.79 or sucralfate avoid future use of the offending agent. How- with Medications Used for Stress Ulcer Prophylaxis ever. H2-RAs CI = 0. and the tendency to combine the results 71 Sucralfate versus 5 OR = 0. bezoar Sucralfate versus 2 OR = 2. ids be avoided in neonates (particularly premature neonates) antacids CI = 0. It is recommended that potential adverse effects be considered as part of the economic anal- ysis when an agent is chosen (see Economic analysis). In some of the studies. CI = 95% confidence interval.78–2. and were published in ing in adults. proton-pump inhibitors. the adverse-effect profile of miso- group) prostol.61–1. differences among any of the treatments were Reference Comparisona Trials Resultsb found. with the one notable (lower rate of exception of nosocomial pneumonia associated with pneumonia with pH-altering agents in critically ill patients.235–0. dosages were the 1990s. CI = 0.21–0. Antacids or H2. phylaxis is not an FDA-approved indication for most of analysis showed a lower rate of pneumonia with sucral. would appear to be small.55. 4 OR = 0. control CI = 0.42.g. data from RCTs or large surveillance studies are lacking adjusted CI = 0. Experience with the proton- versus no adjustment pump inhibitors for stress ulcer prophylaxis is limited. diagnostic criteria for pneumonia) among the (combined trials being evaluated.78. of efficacy. antacids or H2. Initial dosage One meta-analysis found a lower rate of pneumonia Some of the dosages listed in Table 6 had to be with sucralfate use than with use of either an H2. Stress ulcer prophylaxis ASHP Report Table 5.687 delineated adverse-effect profiles. ucts such as sucralfate be avoided in children with renal antacids CI = 0.50..783 for acid-suppressive therapies together (i.498. Whether acid-suppressing agents are associated H2-RAs CI = 0. H2-receptor antagonists.402.69 The second meta.15 failure because dosing information has not been well estab- Sucralfate versus 11 OR = 0.80. H2-receptor antagonists.63.57 because of the possibility of adverse effects (e.. CI = 0.09 with a higher rate of pneumonia than sucralfate is unre- a H2-RAs = histamine H2-receptor antagonists. antacids or H2. (Strength of evidence = D) gations published in 1991 were conducted by Tryba and included many of the studies previously mentioned. When compared with (combined that of other agents. lished.00 ceed the risks.62 for pediatric patients.01. but experience treating peptic ulcers suggests that these RAs versus CI = 0. although any difference between these medications b OR = odds ratio. There RAs (combined (lower rate of are no other absolute contraindications that would preclude group) pneumonia with the short-term use of any of these medications for stress sucralfate) 8 ulcer prophylaxis.g.209-211. antacids CI = 0. antacids.110.213 The fate than with H2-receptor antagonists and for sucral. solved.316–0.62–1..71 The other three meta-analyses for initiating prophylaxis against stress-induced bleed- were conducted by Cook et al. Antacids. Although sucralfate) 227 Prophylaxis 3 OR = 0. unless the benefits clearly ex- 5 H2-RAs versus OR = 1. the trials not included in the group) meta-analyses. it is recommended that sucralfate and antac- H2-RAs versus 3 OR = 1. all these agents have been used in according to various age groups for multiple GI disorders with rela- gastic pH tively few adverse effects.06 RAs (combined Recommendation (adults and pediatrics): It is recommend- group) ed that patients with a history of serious reactions to 177 Sucralfate versus 6 OR = 0.11. some values were extrapolated from figures.177 subsequently adjusted according to gastric pH measure- involving six investigations.5. in the other two meta-analyses. extracted from the literature because stress ulcer pro- receptor antagonist or an antacid. Exact values provided when available. dosages included in Table 6 have been commonly used fate than with antacids.56–1. had a lower rate of pneumonia than patients who Meta-analyses Investigating the Risk of Pneumonia received an antacid or an H2-receptor antagonist.25. H2-receptor (lower rate of antagonists and antacids). as well as the fact that there are limited studies Sucralfate versus 4 OR = 0. precludes its use for stress ulcer prophylaxis.10 agents have a low rate of serious adverse effects in adults placebo versus control when used on a short-term basis.228 pneumonia with Summary. accumulation of aluminum and magnesium).65–1. and sucralfate) 4 sucralfate have been used for many years and have well- Sucralfate versus OR = 0.82–5. no significant No.

241 Although famotidine effectively treated the netic studies. twice a day or 50 mg/hr by p.. These two (in three or four divided doses) to preterm newborns studies suggest that. from the ranitidine were noted.v.230-235 In published studies. famotidine in 18 dosage guidelines in Table 6 are based on limited clini.v. child received ranitidine by continuous i. ulcers.232. 0. continuous infusions of cimetidine mg/hr by NG. given every six hours or. Antac. at least. or would be required. years were administered cimetidine in doses of 10–15 continuous i. 50 mg plasma cimetidine concentrations at ≥0.001) and age and apparent Omeprazole112-115.5 µg/mL for mg/hr by every 12–24 hr longer periods. couraged to consult available studies.v. NG. or min: 150 mg kg/day administered in four doses infused over 15 NG.238 Each be modified on the basis of response or adverse effects.v.v. es and shorter elimination half-lives than healthy or infusion burned adults (primarily because of greater renal clear- Famotidine178. the reader is en. or 25 mg/hr by mg/kg.o..o. The dosage and response data No well-documented maximum dosage for each agent were used to design intermittent dosage regimens. or i.209 40-mg loading No adjustment volume of distribution (r = 0.209-211.16 to 5.42.v.213 1 g four times No adjustment optimal steady-state plasma cimetidine concentra- daily p. p < 0. or necessary tions.168.210 20 mg twice If CLcr < 30 mL/ daily p.v.76. Another study involving ranit- number of commercially available products with differ. They dose.v.001) inverse correlation between age and total body ous i.36-40. Martyn et al.o. p < 0. or 2–4 mg/ infusion hr by continu- < 0.o.65.88. idine for neonates with documented gastric bleeding ing acid-neutralizing capacities and the large number of used a loading dose of 0.178 300 mg four If CLcr <30 mL/ kinetics of cimetidine in children with burn injuries. Doses required to keep the Dosages for pediatric patients can be estimated from gastric pH above 4 for at least six hours ranged from 0.231 for Prophylaxis of Stress-Induced Bleedinga Pharmacokinetic or dosage studies in pediatric pa- Normal Reduced tients have been published. or orally twice daily failed to keep i.5 to 16 years with peptic ulcer disease.v.o. 50 mg once or twice every 6–8 hr daily p.8 mg/kg.v.5 to 15 Ranitidine178. children ranging in age from 0.65. or NG day given in six divided doses would provide more Sucralfate178.229 pedic or cardiac surgery. Famotidine was pharmacokinetically prophylaxis (Table 7). dose ranged ids were not included in Table 6 because of the large from 0. min: 20 mg ance). sisting of i.63.v. for children.49..o. or i.235 Cimeti. Patients receiving ≥20 mg/kg/day maintained i. GI bleeding). or 1. These children had higher cimetidine clearanc- infusion continuous i. famotidine should be and children up to 18 years of age. infusion clearance (r = 0. NG Ranitidine was studied in 12 children ranging in age a NG = by nasogastric tube. ranitidine was given in dosages of 2–6 mg/kg/day the pH above 5 for the dosage interval.3 to 17.54. i. extrapolated from pediatric evaluated in 14 children ranging in age from 1.o.13 to 0. a gastric pH of ≥4.25 NG. every eight hours.. Another study looked at the pharmacokinetics of infusion cimetidine in 30 critically ill children age 4.25 to handbooks that describe dosing for related conditions 15. dine was given i. Dosages can from 3.211 150 mg twice If CLcr < 50 mL/ years..15 mg/kg/hr.v. and another study involving patients from birth to 18 Initial Adult Dosage Regimens for Agents Used years of age (maximum dosage.213 of gastric acid secretion.239 No adverse effects basis of gastric pH determinations).5 mg/kg i.7 years who were cal data and may need to be adjusted according to admitted to a pediatric ICU after major elective ortho- adverse effects or clinical response. or 6.110.g. or extrapolated from pharmacoki. oral doses given every 12 hours. or minutes.236 determined the pharmaco- Cimetidine110.v. con- has been reported.56.ASHP Report Stress ulcer prophylaxis Table 6. The authors suggested that in order to maintain or i.4 the few studies that have been published on stress ulcer to 0. or i.49.90-92 The Treem and colleagues240 studied i. bolus doses given every 6 hours and then terminations often set an arbitrary upper limit.233. but these are not necessar- Renal Renal ily related to the prevention of stress-induced bleeding. The investigators found a significant (p continuous i. times a day min: 300 mg Twenty-one children ranging in age from 0. with the rate adjusted to achieve at least 90% inhibition were mostly taken from published guidelines. pharmacokinetic studies suggest that four divided doses) in two studies involving newborns children clear H2-receptor antagonists faster and have 364 Am J Health-Syst Pharm Vol 56 Feb 15 1999 . although studies involving pH de. NG.5 years who were diagnosed with gastric or duodenal (e. ulcers.v.75. 1000 mg/day).7 once daily p.o. Medication Function Function For example. The i.001).48.. infusion.85 mg/hr by infusion continuous i.5 p. CLcr = creatinine clearance.v.8 mg/kg.v.v. continuous i. then 20– necessary concluded that a dosage of cimetidine of 20–30 mg/kg/ 40 mg daily p.6 mg/kg followed by a contin- regimens used in the literature (many adjusted on the uous infusion of 0.57. in dosages of 15–24 mg/kg/day (in In summary.v.63.237 The patients received a mean dosage of 26 mg/ daily p. 0.48.. NG.v.

randomized.6 yr every 6 hr. None None general ICU (208) 38 ± 53. mean. 2 wk to 264 mo. Doses of H2-receptor antagonists are often reduced In general. because all these medications have slower nates. 3. randomized.67 mg/kg i. function. BSA = body surface area. Various (per discretion of 6/990 with no prophy- general ICU (1006) 61.75–1. every 8 hr 32 wk gestation 233 Prospective. Whether doses or intervals of H2-receptor antagonists nates and has been associated with gastric bleeding. thermal injury 35 days to 13 yr. mean.v. 3 days to 18 yr. observational. observational. (3 doses if <10 kg). NA = not available. or 12 hrb 66 Prospective.5 mL/ 0. None stated 36 to 13–93% (mean. Studies of Stress Ulcer Prophylaxis in Pediatric Populationsa Study Design and Population No. every 6 hr 65 Prospective.. Various (per discretion of 2/698 with no prophy- general ICU (984) 62. Stress ulcer prophylaxis ASHP Report Table 7. NG = by nasogastric tube. with Clinically Reference (No.v.5 wk Cimetidine 6 mg/kg i. no significant kg every 2 hr differences for any single medication versus control group 56 Prospective.v.1 mo physician) laxis versus 2/286 with prophylaxis 168 Prospective. Patients or Admissions) Age Medication Important Bleeding 88 Retrospective. mean. infants because of the possibility of complications (see Studies addressing the proper dosing of agents for stress Adverse effects of prophylactic agents). randomized.05). Vol 56 Feb 15 1999 Am J Health-Syst Pharm 365 . thermal injury 4 wk to 15 yr Milk or feeding formula plus 2 to 5–92% BSA (582) diazepam 48 Prospective. Birth to 20 yr.v. randomized.E.5 mg/kg i.5 mo 57 Prospective. 0. Mean ± S.v.85 yr. 7/35 in control group general ICU (140) 4.85 yr every 6 hr (1 g/day maximum) 231 Prospective.25–0. Full-term neonates Cimetidine 3. mean. Cimetidine 5 mg/kg i. clearances and longer half-lives in this population. observational.v. mean. observational. b Administered every eight hours in 89% of patients.242 In general. Famotidine or pirenzepine NA cardiac surgery (79) mean. mostly Ranitidine 1. Dosing in premature neonates is further compli. Neonates. NA general ICU (53) preterm. because well-con- when H2-receptor antagonists are used in combination trolled studies have not investigated various dosage with tolazoline.5 mo physician) laxis versus 10/110 with prophylaxis a Only studies with at least 25 patients were included.243 cated by decreased renal function secondary to disease These alterations in dose or interval have been based on or lack of maturation.5 group) mg/kg i. 36 mo i.6 ± 2.3 yr (varied by every 12 hr or 0. NA general ICU (33) every 6 hr 232 Prospective. larger volumes of distribution than adults and that on pulmonary vasculature. 30–41. ICU = intensive care unit. Case need to be adjusted in patients with severe hepatic reports have implicated both cimetidine and ranitidine dysfunction or other diseases that might affect the with reversal of tolazoline’s histamine-mediated effects pharmacokinetic properties of the agents is not known. 35 days to 9. 4. Birth to 18 yr.v.3 mg/kg/ day) given at intervals of 6. Mean ± S. randomized. randomized. (477) 230 Retrospective. Ranitidine 2–6 mg/kg/day None general ICU (45) median. sucralfate 0. there is little dosing information for the (or the intervals extended) for patients with renal dys- neonatal population.75–5 mg/kg NA general ICU (100) i.5 mg/kg/day if serum creatinine > 3 mg/dL 63 Prospective.. Caution should be exercised expected serum drug concentrations.6–4. institutions to treat pulmonary hypertension in neo. Ranitidine 1. 29%) mean.D. every 6 hr 49 Prospective. antacid tion groups (p < (almagate) 0.62 yr 1 mg/kg/day i.5 versus 6/105 in g (<10 kg) or 1 g (>10 combined medica- kg) every 6 hr. 8. randomized.3 yr BSA.v. (mean. premature neo. Tolazoline may still be used in some regimens in preventing stress-induced bleeding. 2. in particular. Birth to 18 yr. ulcer prophylaxis in pediatrics are needed. Ranitidine 2–4 mg/kg NG NA general ICU (40) 2. NA general ICU (40) 1. the use of ant- doses should be given either by continuous infusion or acids and sucralfate should be avoided in premature more frequently than those recommended for adults.

it is advisable to administer method lacks accuracy. The issue is further complicated by differ- underdosing in children. 4000 mg/day maximum) in 4 divided dosesd a Dosages are for patients with normal renal function.49.v. Although gastric acidity may have a vides pediatric doses for the H2-receptor antagonists role in stress-induced damage. infusion: 4. Thus. particularly antacids. Amount of aluminum in adult doses of sucralfate may contribute to hypophosphatemia in neonates. There is a lack of data to make definitive dosage adjustments in pediatric patients for renal dysfunction. al.o. 1.237 10 (5–20) mg/kg/day i.o.v. gastric acid is unlikely to and sucralfate. However. famotidine). and ranitidine would be logical. is simple and is considered by many clinicians to be a function or immaturity (preterm infants).238. dosage schedules. Caution is advised when sucralfate is administered to any pediatric patient. cimetidine. especially in patients with renal dys. trolled studies have been published that document a ners may not make adjustments. c Inadequate information is available. There is inadequate dosage information on premature neonates with respect to stratification by birth weight or gestational age.v.v. doses: If full in 4 divided doses term.236.g.231.0625–0.4 hours).254 Not only do many ICU from limited data from published studies and were patients have hyposecretion of gastric acid. 1. or NG in 4 divided dosesd (lower end of range for younger children. but decreases in the total daily dosage of cimetidine. Pediatric Dosage Recommendations for H2-Receptor Antagonists and Sucralfate Dosagea Medication Neonates Infants Children Cimetidine48. this patient is being dialyzed. Some of the oral dosage regi. beginning dosages on the basis of bioavailability differences be. for agents that neutral- clearances normalized to an average BSA (mL/min/1. famotidine. 0. available to make dosage in 2 or 3 divided doses (40 mg/day maximum) recommendations in 3 divided doses Ranitidine63. Table 8 pro.240. or NG 40–80 mg/kg/day p. ences in the validity and reliability of methods used to Gastric pH monitoring may help in developing measure gastric pH.v. 366 Am J Health-Syst Pharm Vol 56 Feb 15 1999 . Many practitioners recom. in 20–40 mg/kg/day i. The recommendations were derived be the main cause of bleeding.65.ASHP Report Stress ulcer prophylaxis There are no adequate dosage guidelines for children Monitoring with renal dysfunction. monitoring is limited to potential adverse methods for children.255 but gas- based on toxicity as well as efficacy considerations. with the role of gastric acidity in the pathogenesis of tween the two routes of administration. despite pH paper during the dialysis procedure.5 mg/kg/day in 2 divided doses Sucralfate65. This could be done either by decreasing individual doses while keeping the dosage interval the same as for patients with normal renal function or by extending the dosage interval and keeping individual doses the same as for patients with normal renal function. No adjustment in the dosage of sucralfate is required for patients with renal dysfunction. stress ulceration. Most methods yield creatinine events and GI bleeding.v.2 (1–2) mg/kg/day i. regimens in terms of tor antagonists are more effective than intermittent total daily dosage (e.73 ize gastric acid.6 (1–2) mg/kg/day i. 30–40 mg/kg/day i.5 (3–6) mg/kg/day i.v. On days a standard of practice for agents that raise gastric pH. No large. b In general. d Dosage not well established.2 mg/kg/hr in 3 divided doses (200 mg/day maximum) Intermittent i.v. Still other practitio. monitoring has m2). Not recommended because of reports of bezoar formation in neonates (particularly premature neonates). if premature.239. Many dosage handbooks and institutions use 5–10 mg/kg/day divided every 12 hours in premature neonates. determinations that continuous infusions of H2-recep- mens are equivalent to the i.234 Not recommendedc 40 mg/kg/day p.246 One study found that 33% of the medications after dialysis to avoid rapid clearance gastric pH determinations were not ≥4.245 Continuous i. a wide range of dosages have been reported in the literature.233.232. Bezoar formation with obstruction has been reported. NG = by nasogastric tube. con- lines for impaired renal function. half-lives were longer in neonates (2–3. more than likely because of immature renal function.248-253 Many factors must be consid- though an argument could be made for larger oral ered in the interpretation of these studies. frequently included pH determinations. such as mend estimation of renal function by established sucralfate.. tric pH fluctuates rapidly and may not be controlled Table 8.244. Although monitoring with pH paper dosage regimens. For agents that do not affect gastric pH.235.5–3 mg/kg/day in 3 divided doses.v. 6 (3–6) mg/kg/day i.247 Table 6 lists dosage regimens for commonly used A number of studies have concluded from gastric pH agents in adult patients. believing that the risks benefit to pH monitoring in association with stress ulcer of excessive dosing would not outweigh the risk of prophylaxis.v. especially in cases of impaired gastric motility and dehydration. Adjustments are then made by using adult guide. 0.241 Inadequate information 1. testing demonstrating evidence to the contrary. 2 or 3 divided dosesb in 3 or 4 divided doses (1200 mg/day maximum) in 6 divided doses Famotidine168.

.166. Stress ulcer prophylaxis ASHP Report even if dosages of antisecretory agents are individual. for increased dosages due to perceived failure of had promising results. pH. Both of these studies are reliability. Although newer subsequent spread to other organs. trogen balance that is important for normal reparative tochezia. Therefore.. there- phylaxis be monitored for bleeding and adverse drug effects fore. Most impor. nutritional support. acid inhibitors or neutralizers ber of published studies. or pelvic fractures who had clinical evidence of Recommendation (adults and pediatrics): It is recommended shock. including patients with shock.g.256. increas- ized. although the results of one prospective studies. ≥9% children and vitamin A injection given to adults. ≥3 g/dL in burn patients.267-269 The number of patients requiring surgery ic complications.263. in cases of renal prophylaxis. all of which suggest clinically Although corticosteroids have been studied as inciting important GI bleeding in the absence of other causes. there is no proven relationship between micro. (Strength of evidence = D) Other options for prophylaxis Prevention of recurrent bleeding Similar to the principles involved in preventing The efficacy of nonsurgical therapies such as antac- global ischemia.. such measurements monia has not been established through controlled have been studied primarily as indicators of systemic trials. on the frequency of stress-induced bleeding and pneu- dicting stress-induced bleeding. and there is no evidence that adjusting the dosage of pH-altering medications (antacids. pH monitoring for antacids may be Recommendation (adults and pediatrics): It is premature to appropriate (goal pH of >3. continues despite conservative therapies populations. lack of supporting data. intermittent enteral feedings consistently raise gastric tant. in pediatric patients). stress ulcer prophylaxis may steadily decreased since approximately 1978.259. hema. and potential site-specific effects remain to be study suggest that occult bleeding for at least six days elucidated. may prove useful for pre.260 If ischemia is prevented during for continued or recurring stress-induced bleeding has the early stages of injury. Appropriate supportive care. potentially prevent gastric mucosal injury. with ence of blood and bile in the GI tract. and hematocrit (e. including milk and diazepam given to during a 24-hour period).264 Before the widespread use of H2-receptor closely monitored for decreases in blood pressure (e. and timely definitive surgery. the effect of enteral feedings mucosal pH measurements. endoscopy is usually indicated.261 methods of pH monitoring. As discussed previously. other evidence suggests that When overt bleeding.5–4). proton-pump inhibitors) on the basis of these measure. or melena.53 Overt bleeding is protection against bleeding and pneumonia through defined as the presence of blood or “coffee-ground” other mechanisms (e. free-radical be useful for H2-receptor antagonists when standard dosage scavengers) in place of conventional agents for stress ulcer regimens might not be appropriate (e.230. Comparisons with existing agents that include ments influences patient morbidity or mortality. ability to decrease free-radical formation and. Combinations of allopurinol and dimethyl sulfox- Endoscopy can be used to confirm a GI source of ide have been studied in two RCTs in patients with leg bleeding. the patient should be patients.. ing gastric pH allows for bacterial overgrowth. with or without hemodynamic corticosteroids may protect against bleeding in some compromise. H2-receptor antago- promising but require confirmation in different popu- nists.. preclude the need for stress ulcer prophylaxis in many When overt bleeding occurs. Despite the economic evaluations of the options are also needed. and while it is clear that micro- in critically ill patients. In the case of acid neutralizers. hemoglobin (e. ven- patients at risk for stress-related complications should tilatory support. Such monitoring may also recommend the use of novel therapies (e. although the limited number of studies have dysfunction.262 The site of enteral feeding administration (stom- scopic bleeding and outcomes such as clinically impor.266 These agents were studied because of their that all patients receiving medications for stress ulcer pro. Paper techniques trials showed significant (p < 0. ach or sites distal to the pylorus) varied in published tant bleeding.01) decreases in endo- for measuring gastric pH have questionable validity and scopically confirmed lesions. such as administration fusions or surgery is clinically important.g. such as noninvasive.264 during a 24-hour period). bleeding stopped spontane- Vol 56 Feb 15 1999 Am J Health-Syst Pharm 367 . study. In a num- be unnecessary. maintenance of a positive ni- material in nasogastric aspirates.g. may be harmful.g.258 bial growth is inhibited at low gastric pH. a number of a decrease of 20 mm Hg or more in the diastolic pressure regimens were used to prevent acute upper GI bleeding during a 24-hour period). (Strength of evidence = D) therapy.265 such as saline lavage.g. of fluids and blood products. hematemesis. hemodynamic compromise or the need for blood trans. Although gastric acid appears to play a role in tissue oxygenation and hence of overall mortality rates stress-induced bleeding. Both (see Adverse effects of prophylactic agents). intra.257 Gastric pH can also be increased by the pres. The possibility that enteral feedings offer increases the risk for overt bleeding. a primary intervention for reducing ids and H2-receptor antagonists in preventing recurrent the frequency of stress-induced bleeding should be the bleeding has varied considerably from study to prevention of GI hypoperfusion and attendant ischem. factors for GI bleeding. it has not Checking for microscopic bleeding by occult blood been conclusively demonstrated that continuous or testing techniques has similar limitations. antagonists for stress ulcer prophylaxis.g. In fact. lations.. may be routinely followed for overt bleeding. Overt bleeding that results in functions of the gastric mucosa) should be explored.

associated with prevention of one case of acute upper cy of all types of bleeding (e. clinically impor. Only one RCT has addressed stress ulcer prophy. The authors assumed that the frequen- is than with placebo. Economic analysis Recommendation (adults and pediatrics): The lack of avail- Inappropriate stress ulcer prophylaxis can be costly. tient’s discharge from the ICU. recommended for adult patients in non-ICU settings. the cost of important bleeding would probably diminish as the treatment for pneumonia or bleeding. Thus. reduced present. use of drugs with different mechanisms of Recommendation (pediatrics): Stress ulcer prophylaxis is not recommended for pediatric general medical and surgical action would seem logical. Three patients required transfusion in the place. The risk of clinically agent regardless of the cost of prophylaxis. $6128 to treat an episode of bleeding. Data are insufficient to activity of sucralfate with neutral or alkaline gastric pH. transplanta. (Strength specific guidelines for prophylaxis. viewpoint of the payer. If tive recommendation regarding this issue is difficult. frequency of bleeding or nosocomial pneumonia. antacids. able trials prohibits definitive recommendations for pre- venting recurrent bleeding after an episode of stress-induced but implementing guidelines may decrease the inap- GI bleeding. by Ben-Men- 368 Am J Health-Syst Pharm Vol 56 Feb 15 1999 .271 Published econom- creasing the dosage of the prophylactic agent. and H2- hematocrit. The study was conducted from the surgical hospital ward in Spain. different medication. In the first investiga- Prophylaxis in non-ICU settings tion. In others. propriateness and the expense. by Schumock et al. strength of evidence = D for patients with two or more risk factors) (Table 3) ered in a patient who bled while receiving single-agent prophylaxis. prophylaxis was discontinued without evidence of clin. (Strength of evidence = D). The difference in costs between sucralfate or antacids and Discontinuation of prophylaxis H2-receptor antagonists was related to the assumed An increase in the number of risk factors has been higher rates of bleeding and nosocomial pneumonia associated with a higher risk of bleeding in multiple with H2-receptor antagonists. (Strength of evidence = D) The assumption is. In contrast. receptor antagonists. In most clinical trials. The net saving group without subsequent complications. the fate but increased by approximately 7% with antacids bleeding stopped in the three patients in the placebo and 13% with H2-receptor antagonists. transplantation) in non- tween prophylactic agents from different classes have ICU settings if fewer than two risk factors for bleeding are not been well studied but could occur (e.g.v. laxis in non-ICU settings. Upon institu. The second cost-effectiveness study.. However. adding an.. it should be discontinued once risk factors have resolved. bleeding was defined cy of bleeding would be approximately 70%. or the addition of another agent. 300 mg i. with hospital charges measured cantly (p < 0. Providing any defini. GI bleeding was $7373 for sucralfate and $4321 for tant) was significantly lower with prophylaxis only if antacids.. Recommendation (adults): Stress ulcer prophylaxis is not plus gastric lavage. that any medication is of benefit in preventing recurrent bleeding. nists (ranitidine 50 mg i. when fewer than two risk factors for clinically important bleeding.g.v. 80%. therapy with an H2-receptor an- two or more risk factors for bleeding were present before tagonist would cost between $6655 and $7986 to pre- prophylaxis was initiated. overt. (Strength pared the various medication options for preventing a of evidence = B for general medical and surgical patients with recurrence of stress-induced bleeding.272 an antacid regimen of 30 mL It is possible that patients in non-ICU settings could given every 4 hours was compared with sucralfate 1 g have coagulopathy or other conditions that have been given four times daily and three H2-receptor antago- identified as risk factors for bleeding (e. usually an increase in assume that prophylaxis can be stopped once risk fac- the dosage of the current medication. it is reasonable to vative measures were instituted. regardless of whether they required trans. Bleeding was signifi. laxis in pediatric patients with two or more risk factors. Potential interactions be- patients or special populations (e. The frequen.270. prophylaxis is given. vent one episode of acute upper GI bleeding. respectively.g. or the presumed number of risk factors is reduced. and that it cost fusion.g. Two cost-effective- of evidence = D) ness analyses have been completed concerning prophy- laxis for stress-induced bleeding. or switching to a different agent. although consideration could be given to in. the patients’ ically important bleeding upon extubation or the pa- bleeding often stopped and did not recur when conser. of course. combination therapy for prophylaxis is being consid.. However. and broadly to include patients who had a decrease in 36% lower with the use of sucralfate.. in 1994 dollars. all of which were based on a seven-day adults and was conducted on a general medical and course of therapy.v. a switch to a tors have resolved. every 6 hours.ASHP Report Stress ulcer prophylaxis ously without intervention. every 8 hours.001) less frequent with antacid prophylax. ic analyses can be useful for developing institution- other medication.54 The study involved 100 every 12 hours). One-way sensitivity anal- studies conducted in the ICU setting and one study ysis showed that sucralfate remained the preferred conducted on a hospital ward. The frequency of bo group and none in the antacid group. allow recommendations to be made about the use of prophy- binding of agents by sucralfate). No large controlled trials have com. and famotidine 20 mg i. cimetidine tion). pneumonia was assumed to be unchanged with sucral- tion of antacid and H2-receptor antagonist therapy.

Estimate the reduction in clinically important Readers are encouraged to make institution-specific deci. making Antacids every two hours 78. The cost-effectiveness ratio for ranitidine was were presumed to be equal.v. Cimetidine (300 mg i. costs9. even when rates of pneumonia averted.v. Estimate the cost per patient of treating GI bleeding at the institution.185.185.8% for acid was used. percentage).64 was based on the perspective of the reflect laboratory or consultation estimates that would health care provider. Drug and administration costs9.. It was assumed that the number of presumed that both therapies would decrease the fre. quency of bleeding by 50%. It was some of the events. costs.v.277. Costs and benefits Cardiovascular toxicity 500 Clogged tubes 160 were assumed to occur within the same period. was more cost-effective than cimetidine ($7538 per with a saving of $4913 for each episode of bleeding bleeding event averted).273 Ten patients were assigned to receive raniti. Stress ulcer prophylaxis ASHP Report achem et al. sucralfate and orally admin- ed to be at least 48% less with the enteral administra.. both dosages were given by onists. they are similar in efficacy.276 and frequency61. Because of the cost of Variable of Therapy ($)a commercial sucralfate suspension. and performance of a sensitivity analysis.g. Any estimates not based on Histamine H2-receptor antagonist the literature were mentioned. Step 4. The differences are particularly notable if the costs of enteral and i. ing events without prophylaxis (baseline rate stated as a statement of time frame. administration was assumed. Ranitidine was Cost Assumptions per chosen as the representative H2-receptor antagonist. Vol 56 Feb 15 1999 Am J Health-Syst Pharm 369 . Estimate the cost of using sucralfate prophylaxis The medications were assumed to have equal pro. Figure 1 is the decision tree used for the economic the percent reduction was varied over the range of 10– analysis associated with these guidelines. Episode or Course i. administration. lower. The cost estimates for three times dailyb 61.194-199. the cost analysis was Pneumonia 10. ness ratio. bleeding events associated with prophylaxis.176. Drug acquisition because it was assumed that the effects would be readily costs are average wholesale costs. The costs b Ranitidine used as the example.5 Although both the meta-analysis and the patients if all 100 are given prophylaxis. A formal economic analysis from an institutional The following is a template for evaluating the cost- perspective was conducted as part of the guideline effectiveness of stress ulcer prophylaxis regimens on development process. Step 5. results are consistent with those of other published tion by Schumock et al.64 and adverse event Table 9.50 Sucralfate four times daily 33. determination of cost-effective. every six be incurred even if the problem were eventually found hours) was compared with sucralfate (1 g every six to be unrelated to the medication.. The overall 90%.64. If it is assumed that none of the medications nasogastric tube. One notable differ. institution-specific economic analysis.64. CNS toxicity 500 gastric tube. istered H2-receptor antagonists would have similar tion than with i. cost-effectiveness analysis were followed: identification Step 1. The general steps of acceptable the basis of institution-specific data.v. both given for seven days.000 done under the assumption that nursing staff would Hepatitis 500 administer sucralfate tablets as a slurry through a naso.276 trapolated from the literature (Table 9). ranitidine administration the pH-altering medications are assumed to cause a were compared. Despite different assumptions from the investiga.278 were ex. Drug costs were calculat. Cost Assumptions 9. although only enteral administration higher rate of nosocomial pneumonia (0. with a cost saving of $1766. the results were similar in that cost-effectiveness analyses that concluded that sucral- sucralfate (cost of $1144 per bleeding event averted) fate is the most cost-effective agent for prophylaxis. reversible or found to have a different cause. recent large RCT met our criteria for a grade of A. Estimate the cost of treating bleeding per 100 meta-analysis had a level of evidence of I and the RCT a level of evidence of I– (see Table 1 for definitions).00 discounting unnecessary. phylactic efficacy on the basis of the most recent meta. a A course of therapy was assumed to be five days. One hundred pa- hours).80 many of the adverse effects were small (e. Estimate the risk of clinically important bleed- of clinical choices. in the sensitivity analysis. Estimate the cost of adverse events per 100 analysis. cost neutral. suppressants and 0 for sucralfate). The medication cost figures were based on Cytopenia 500 a five-day course of prophylaxis.275. the Step 6.274 Step 2. Both therapies reduced stimulated cause adverse effects (including pneumonia) and that acid secretion by at least 50%. sions and to use the template to construct their own Step 3. $500). this is true regardless dine 150 mg every 12 hours and eight patients to receive of the route of administration for the H2-receptor antag- 300 mg every 12 hours. Antacids were nearly In one study involving a small number of patients.275. events would not vary with the number of patients. determination of costs and benefits. in 100 patients.062 Bleeding 7. tients were assumed to be in each treatment group in ence from the previous analysis was the assumption our decision model because of the small probabilities of that it would cost $595 to treat a GI bleed.

156 n = 100 TOTAL $78 per No adverse drug reactions 81.000 patients patients treated [(risk of bleeding without prophylaxis) Step 9.731 per Bleeding Adverse therapy Pneumonia 0.062 per episode 97% drug 7. Determine the cost-effectiveness ratio [(margin- × (estimated cost of treating GI bleed per patient)]. patient-specific informa- Note that positive numbers represent a cost liability. tion should always be used for determining prophylaxis negative numbers a cost saving.2% 6. CV = cardiovascular. prophylaxis) (risk reduction with prophylaxis expressed Table 10 provides an example of how the cost- as a decimal)] × (cost of treating GI bleed per patient)}.856 No bleeding Adverse 97% drug Hepatitis 0.50 per 100 patients course of No adverse drug reactions 97.613 Yes therapy n = 300 Pneumonia 0. al cost of prophylaxis in 100 patients)/(risk of Step 7.384 prophylaxis Sucralfate 100 patients n = 400 n = 100 No adverse drug reactions 82% patients at $33.144 No bleeding Adverse Pneumonia 0. A negative value indicates a saving.885 $7000 per episode No adverse drug reactions 81.242 (antacids) course of $39.6% (H2-RAs) n = 100 $500 per episode 327 $37.80 per 17.8% $10. Step 8.6% $500 per episode 136 No adverse drug reactions 82% 2.062 per episode 7.062 per episode 411 Bleeding Adverse 3% drug Hepatitis 0.ASHP Report Stress ulcer prophylaxis Figure 1. 100 patients treated {[(cost of medication per 100 pa. Estimate the savings with stress ulcer prophy.8% $10. As with any guidelines.804 Pneumonia 0.8% $500 per episode 980 Cytopenia 0.3% 20. Decision tree for stress ulcer prophylaxis.0023% $500 per episode 1 CV toxicity 0.0023% $500 per episode 1 TOTAL H2-RAs CV toxicity 0. clogged tubes 18% $160 per episode $27. bleeding)(risk reduction with prophylaxis expressed as a laxis per 100 patients treated {[(risk of bleeding without decimal)].688 TOTAL No bleeding (sucralfate) Stress ulcer 97% Adverse drug reactions.909 No bleeding 94% 0 TOTAL No (no prophylaxis) n = 100 Bleeding 6% $7000 per episode $42.8% $10. for the individual patient.2% 17.869 reactions Antacids Clogged tubes 18% $160 per episode 4.6% $500 per episode 327 reactions CNS toxicity 1. To perform a sensitivity 370 Am J Health-Syst Pharm Vol 56 Feb 15 1999 .3% 5. H2-RAs = histamine H2-receptor antagonists.8% $500 per episode 408 episode Cytopenia 0. clogged tubes 18% $160 per episode therapy 3.6% $500 per episode 136 $7000 per reactions CNS toxicity 1.000 per $61.260 per 3.000 per 100 42. agent. Cost per 100 patients ($) No adverse drug reactions 97.303 Bleeding risk course of 3% Adverse drug reactions. Determine the marginal cost of prophylaxis per effectiveness calculation for sucralfate was performed.8% $10. The cost-effectiveness ratios for the various therapies tients) + (cost of adverse drug events per 100 patients)] can be compared in order to choose the appropriate – (savings with stress ulcer prophylaxis in 100 patients)}.062 per episode 100 patients 3% drug 411 $7000 per reactions episode Clogged tubes 18% $160 per episode 3.

bleeding per patient ($) Recommendation (pediatrics): There are also unresolved Cost of sucralfate per 100 3380 patients ($) issues for pediatric patients. so there is no clear agent of choice treatment)] at this time.433 (1.522) (4.1% to 39% and from 10% to 90%.200 5. Exceptions to Table 10.553) (6. values in step 9. many issues remain unresolved. because no RCTs are available that have com- ≥10) of risk factors for clinically important bleeding pared i. but the Figure 2 is an algorithm for stress ulcer prophylaxis recommendation must be graded D because patients in adult patients that is based on the recommendations with recent histories of GI pathology were often excluded contained in this document. with oral H2-receptor antagonists administra- have been elucidated. If ranitidine is as- Risk of bleeding without sumed to be more effective than sucralfate without increas- 6. The values represent the cost or saving (in parentheses) for each bleeding episode averted.748) (6.261) (5. simply vary the substantially from one risk factor to the next (Table 3).764) (5.528) (4. should be used for prophylaxis.300 8. and thus it is un- involving medications and the age stratification in known whether these patients are at increased risk for those studies that did include pediatric patients pre.650 3. Table 11 shows the results of the ICU patients with a history of recent GI pathology are sensitivity analysis for sucralfate.913) (5.867 3.66 the reader is referred to the tion for preventing clinically important bleeding.870) (5. ranitidine (and presumably Risk reduction with 50 (10–90)64 other H2-receptor antagonists) would be the drug of choice prophylaxis (%) and would also result in a cost saving.509) (6. a Pediatric Savings with stress ulcer 21.64 prophylaxis (%) ing the risk of pneumonia. Whether prophylaxis in 100 patients ($) prophylaxis will reduce the risk of bleeding is yet to be [(Three episodes of bleeding) × ($7000 cost of proven in this population. it is recommended tion.0 (0. the accompanying economic analysis found su- cralfate to be the most cost-effective agent.679) 70 82. potentially. While pro- Table 11.913) (5. Vol 56 Feb 15 1999 Am J Health-Syst Pharm 371 . respi. making discounting unnecessary. Marginal cost of prophylaxis –14. Costs and benefits were presumed to occur within a similar period. and thermal injuries.957) (6.374) (6.395) 30 201.783) (3. Stress ulcer prophylaxis ASHP Report analysis for various rates of bleeding and reductions in data.433 (740) (3.1 1 2 4 6 10 20 39 10 619.000 Risk of Mortality Score of ≥10.600 24. For institutions willing to accept the assumption that H2-receptor antagonists and sucralfate have equal efficacy. discussion in the section titled “Adverse effects of pro.943 (2.465) 50 118. the use of sucralfate include lack of oral or other gastric Cost-effectiveness Calculations for Sucralfate access for administration and.000)] Cost-effectiveness ratio 4913 for each Although medications such as antacids have been bleeding episode used for at least two decades to prevent stress-induced averted bleeding. but the percentages and costs need to be Cost of treating GI bleeding in 42.304) (6.522) (5. clinically important bleeding. that institution-specific guidelines be developed on the The adult algorithm is intended to serve as a template basis of economic models such as the one included in this that can be modified according to institution-specific document. coagulopathy. Institution-specific guidelines Cost of adverse drug events 2880 can be developed by using the economic models included in per 100 patients treated ($) this document. if any. tioning GI tracts (Figure 2) is based on presumptive ratory failure.841) (6. The lack of pediatric RCTs from the published investigations.652) (6.870) (4.556 (44) (3.771) 90 62. respectively. use of oral H2-receptor antagonists in patients with func- Because the number (≥2) and type (coagulopathy.1–39)61.520 (740) (3.429 1. deemed appropriate candidates for prophylaxis. The strength of the evidence for prophylaxis varies bleeding associated with prophylaxis.106) (6. although less than Cost of treating episode of GI 7000 that achieved with sucralfate. The recommendation for clude development of a separate pediatric algorithm. issues regarding stress ulcer prophylaxis. documented Variable Value failure of prophylaxis with sucralfate. Recommendation (adults): Given some of the unresolved phylactic agents” for help in deciding which medica.000 55.667 13. and Pediatric Risk of Mortality Score of efficacy. There is supporting evidence in the literature [(Six episodes of bleeding) × that the risk of stress-induced bleeding is greater in pediatric ($7000 cost of treatment)] patients with respiratory failure. Cost-effectiveness Ratio for Sucralfate Prophylaxis: Results of Sensitivity Analysisa % Reduction in Risk Risk of Bleeding (%) with Prophylaxis 0.822) a Assumptions about the risk of bleeding and the effectiveness of prophylaxis were varied from 0.v.740 in 100 patients ($) Conclusion [($3380 + $2880) – ($21.000 tailored to this population on the basis of institution- 100 patients ($) specific data.

372 Am J Health-Syst Pharm Vol 56 Feb 15 1999 . Guyatt GH. absorption of feedings)? Yes No Enteral H2. recommendations. Although the recom. Sackett DL. 1995. JAMA. 85:935-7. 106:562-7. Clinical recommenda- wait for revised guidelines. H2- blocker blocker Continue periodic assessments phylactic agents have demonstrated efficacy in pre. Laupacis A et al. A method for grading health care be needed as information evolves. Guyatt GH et al. Dasta JF. Halpern NA. 20(suppl 110):101-4. 1996. 1987. Peura DA. Tryba M.) Yes No Continue periodic assessment Does patient have gastric access via oral route. 6. changes may 9.ASHP Report Stress ulcer prophylaxis Figure 2. Algorithm for stress ulcer prophylaxis in adult patients. Crit clude that the frequency of clinically important stress. Scand J Gastroenterol. the frequency of stress ulcers. Cook DJ. Guyatt GH. I. 1994. The collection of institution-specific 5. 1985. the recommendations con.e. Prophylaxis and management of controlled trials (and meta-analyses). nasogastric tube. advances in technology and patient care. (via nasoenteral tube stop suction for or ostomy) two hours after and adequate giving sucralfate) GI function (i. Sinclair JC et al. Crit Care Med. 1994. tained in these guidelines can serve as a model for 7. 1. aged to consider such changes as they occur rather than 10. Anderberg B.V. Zuckerman GR. Bettes L. intensive care units and healthcare costs: 1986-1992. Federal and nationwide very effective if used appropriately. Arch mendations were made on the basis of data published Intern Med. References venting clinically important bleeding in randomized. Stress ulcer prophylaxis—quo vadis? Intensive Care Med. Prophylactic therapy of stress-related mucosal When institution-specific rates of stress-induced damage: why. Cook DJ. User’s guide to the medical literature: IX. Stress ulcer prophylaxis data should help clinicians to resolve this issue. 20:311-3. The ethics of practice guidelines. Greenstein R. Ann Intern Med. which. Care Med. Shuman RB. up to the final guideline review process. 8. 22:2001-7. 4. 22:909-12.. Is stress ulcer prophylaxis needed? (Prophylaxis is appropriate for patients admitted to the ICU with one or more of the risk factors listed in Table 3. This has led apy for stress ulcer bleeding: a reappraisal. who. Prophylactic ther- study to study since approximately 1978. Reeve BK. at least in critically ill patients: resolving discordant meta-analyses. Berger JT. tion prophylaxis. bleeding are not available. Rosner F. 156:2051-6. JAMA. 1994. 274:1800-4. for their particular patient populations. tions using levels of evidence for antithrombotic agents. Sjodahl R. not medica. adaptation by the institution. Drug prescribing issues in the intensive care unit: induced bleeding has been decreasing as a result of finding answers to common questions. other experts con. some experts to suggest that prophylactic agents are 3. 275:308-14. Schuster DP. The reader is encour. 1990. stress-induced bleeding has varied substantially from 2. 1996. and so what? Am J Gastroenterol. or gastrostomy? Yes No Sucralfate (if Does patient have continuous enteral access nasogastric suction.

factors have resolved. (Strength of evidence = D) following risk factors: sepsis. will reduce the risk of bleeding is yet to be proven in this popula- nates) because of the possibility of adverse effects (e. ICU stay of more than one week. unless the benefits patients with respiratory failure. (Strength of evidence = D) tution-specific basis. and use of high-dose For adults and pediatrics: It is recommended that all patients receiving corticosteroids (>250 mg per day of hydrocortisone or the medications for stress ulcer prophylaxis be monitored for bleeding equivalent). This choice should take into account con. documented failure of prophylaxis with plantation patients) precludes definitive recommendations as sucralfate. insufficient evi. bezoar tion. the accompanying economic analysis found trials of these agents in pediatric and special populations (e. ranitidine (and should be made on an institution-specific basis and should take presumably other H2-receptor antagonists) would be the drug of into account concerns about administration (e. proton- ed with bleeding in pediatric patients. published randomized. adverse-effect profile. The choice of agent fate without increasing the risk of pneumonia. (Strength of evidence = D) For medical and surgical patients with fewer than two risk factors for other pediatric surgery or trauma patients. and ICU patients with spinal cord medication.. it is recommended that sucralfate and Mortality Score of ≥10. prophylaxis is recommended... associated with a higher rate of pneumonia than sucralfate is unre- quiring mechanical ventilation for more than 48 hours. H2-receptor antagonists. (Strength of evidence = D) ulcer prophylaxis. (Strength of therapy.g. that achieved with sucralfate. Institution-specific guidelines can be developed by using history of serious reactions to antacids. strength of evidence = D for patients dence is available to allow recommendations about prophylaxis with two or more risk factors) (Table 3) to be made. and reliability. (Strength of evidence = D) (Table 3) D) For pediatrics: For pediatric patients (one month of age or older) Non-ICU patients with thermal injuries.g. Despite the lack of supporting data. solved. (Strength of evidence = D) (Table 3) Recommenda.. renal dysfunction. transplantation) in non-ICU settings if fewer than two and a recent RCT (both with strengths of evidence = A). pump inhibitors) on the basis of these measurements influences controlled trials (RCTs) have either not used clinically impor. If ranitidine is assumed to be more effective than sucral- to the agent of choice in these situations. (Strength of evidence = B for general any given percentage of BSA. (Strength of evidence = D) evidence = C) Other options Indications in special populations For adults and pediatrics: It is premature to recommend the use of For adults: Prophylaxis is recommended for ICU patients with a novel therapies (e. patient morbidity or mortality. functioning choice and would also result in a cost saving. Exceptions to the use patients with burns. Risk factors that have been associated with clinical. it should be discontinued once risk general medical and surgical ICUs should be made on an insti. in pediatric patients). of sucralfate include lack of oral or other gastric access for adminis- rosurgical procedures or with neurologic disorders. potentially. H2-receptor antagonists.g. There are no other absolute contraindications institution-specific data.. to increasing the dosage of the prophylactic agent. adding another tients with hepatic failure. it is recommended that institution-specific Insufficient data on misoprostol or the proton-pump inhibitors guidelines be developed on the basis of economic models such as are available to allow any recommendation about these agents the one included in this document. Vol 56 Feb 15 1999 Am J Health-Syst Pharm 373 . accumulation of aluminum and magnesium). although consideration could be given transplantation patients in the ICU perioperatively. for increased dosages due to perceived failure of thy. standard dosage regimens might not be appropriate (e. There is supporting evidence in the litera- that would preclude the short-term use of any of these medica.5–4). the risk factors for bleeding are present. but the percent- proton-pump inhibitors. For adults: Given some of the unresolved issues regarding stress adverse-effect profile.g. ture that the risk of stress-induced bleeding is greater in pediatric tions for stress ulcer prophylaxis.g. H2-receptor antagonists. a Pediatric Risk of clearly exceed the risks.. and adverse drug effects (see Adverse effects of prophylactic agents). and trans. coagulopathy. Adverse effects For pediatrics: There are also unresolved issues for pediatric pa- For adults and pediatrics: It is recommended that patients with a tients. tration and. Whether acid-suppressing agents are recommended in patients with coagulopathy or patients re. functioning GI tract). Institution-specific guidelines cerns regarding administration (e. of stress-induced GI bleeding. and a Pediatric Risk of Mortality Score of ≥10. (Strength of For adults and pediatrics: The lack of available trials prohibits definitive evidence = C) Prophylaxis may also be indicated in ICU pa. although less than GI tract). coagulopa. and thermal injuries. and total costs. tions for specific prophylactic medications can be found in the Paper techniques for measuring gastric pH have questionable validity Medications used for prophylaxis section. free-radical scavengers) in place of conventional Glasgow Coma Score of ≤10 (or the inability to obey simple agents for stress ulcer prophylaxis. the economic models included in this document. trauma patients. so there is no clear agent of choice at this time.. sucralfate to be the most cost-effective agent. However. Prophylaxis is has not been well established. and total costs. If prophylaxis is given. accept the assumption that H2-receptor antagonists and sucralfate For pediatrics and special populations: The lack of comparative have equal efficacy. although the limited number of commands) or thermal injuries to >35% of their body surface studies have had promising results. it is For adults: Risk factors for ICU patients have been delineated in recommended that aluminum-containing products such as sucralfate trials comparing prophylaxis with no prophylaxis by using be avoided in children with renal failure because dosing information clinically important bleeding as an endpoint. (Strength of evidence = D) area (BSA). in cases of ly important bleeding include respiratory failure. (Strength of evidence = D) choice among antacids. (Strength of evidence = B) ICU patients with partial Prevention of recurrent bleeding hepatectomy may also benefit from prophylaxis. For pediatrics: Stress ulcer prophylaxis is not recommended for Agent of choice pediatric general medical and surgical patients or special popula- For adults: Given the conflicting results of several meta-analyses tions (e. Whether prophylaxis antacids be avoided in neonates (particularly premature neo. although any difference between these medications would (Strength of evidence = C) Prophylaxis is also recommended in appear to be small. but there For adults: Stress ulcer prophylaxis is not recommended for adult is insufficient evidence to recommend prophylaxis based on patients in non-ICU settings. recommendations for preventing recurrent bleeding after an episode tients with multiple trauma (e.. Monitoring occult bleeding lasting six days or more. pH-altering medications (antacids. Recommendations Stress ulcer prophylaxis ASHP Report Indications for prophylaxis formation. Also. ICU pa. and sucralfate Data are insufficient to allow recommendations to be made about for use as prophylactic agents to prevent clinically important the use of prophylaxis in pediatric patients with two or more risk bleeding associated with stress in adult patients admitted to factors.g. clinically important bleeding. Injury Severity Score of ≥16).g. and there is no evidence that adjusting the dosage of For pediatrics: Although various risk factors have been associat. or sucralfate avoid future use of the ages and costs need to be tailored to this population on the basis of offending agent. For institutions willing to to be made. tant bleeding as an outcome or had insufficient power to en. able a definitive conclusion that prophylaxis provides Such monitoring may also be useful for H2-receptor antagonists when protection. pH monitoring for antacids may be appropriate (goal pH of >3. patients undergoing neu. (Strength of evidence = injuries. It is recommended that potential adverse effects patients with a history of GI ulceration or bleeding within one be considered as part of the economic analysis when an agent is year before admission and in patients with at least two of the chosen (see Economic analysis). or switching to a different agent.g.

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