- Email: [email protected]
Stress ulcer prophylaxis in the critically III: A meta-analysis
I
]REVIEW
Stress Ulcer Prophylaxis in the Critically I11:A Meta-Analysis DEBORAH J. COOK, M.D., Hamilton, Ontario, Canada, LANA G. WlTT, Ph.D., Stanford, California, RICHARD J. COOK, M.Sc., GORDON H. GUYATT, M.D., Hamilton, Ontario, Canada
PURPOSF~To e~rnmine the differential effect of stress ulcer prophylaxis on overt bleeding, clinically important bleeding, and mortality in critically ill patients. DATA IDENTIFICATION:Computerized bibliographic search of published and unpublished research. STUDY SELECTION:Independent review of 168 articles identified 42 relevant randomized trials for inclusion. DATAABSTRACTION:The validity, population, intervention, and outcomes of each trial were evaluated. RESULTS: Stress ulcer prophyl~xi~ with antacids (odds ratio 0.40 [95% confidence interval (CI) 0.20 to 0.79]) or hist~mlne-2-receptor antagonists (odds ratio 0~9 [95% CI 0.17 to 0.45]) decreases the incidence of overt gastrointestinal bleeding. Hist~mine-2-receptor antagonists are more effective than antacids at reducing overt hemorrhage (odds ratio 036 [95% CI 0.33 to 0.97]). A significant reduction in clinically important gastrointestlnai hemorrhage is evident only with hist~mlne-2-receptor antagonist therapy. There is a trend favoring antacids over sucralfate in the outcome of clinically important bleeding (odds ratio 0.65 [95% CI 0.16 to 2.49]); however, there are insufficient data to evaluate histamine-2-receptor antagonists versus sucralfate. No difference in mortality between treated and untreated patients was found. CONCLUSIONS: O v e r t gastrointestinal bleeding in critically ill patients is reduced by prophylaxis with antacids or hist~mine-2-receptor antagonists. Hist~mlne-2-receptor antagonists are more effective than antacids at decreasing overt bleeding and are more effective than no treatFrom the Department of Medicine (DJC), Division of Critical Care, and the Department of Clinical Epidemiology and Biostatistics (DJC, RJC, GHG), McMaster Faculty of Health Sciences, Hamilton, Ontario, Canada, and the Department of Pharmacy (LGW), Stanford Medical Center, Stanford, California. Dr. Deborah Cook is a St. Joseph's Hospital Research Scholar. Drs. Cook and Guyatt are Career Scientists of the Ontario Ministry of Health. Requests for reprints should be addressed to Deborah J. Cook, M.D., Department of Medicine, Division of Critical Care, St. Joseph's Hospital, 50 Charlton Avenue East, Hamilton, Ontario L8N 4A6, Canada. Manuscript submitted January 4, 1991, and accepted in revised form June 5, 1991.
ment at reducing the incidence of clinically important bleeding. Mortality rates in the intensive care unit are not decreased by stress ulcer prophylaxis.
inor upper gastrointestinal bleeding due to stress ulceration is common in morbidly ill hospitalized patients [1]. The incidence of serious hemorrhage, which is accompanied by a high degree of morbidity and mortality, is substantially lower [2-4]. The pathogenesis of stress ulceration in the critically ill involves disruption of the usual mechanisms of gastric mucosal integrity. Hypotension and systemic acidosis decrease gastric blood flow, resulting in impaired turnover of gastric epithelium, loss of the protective mucous and bicarbonate barrier, and back diffusion of hydrogen ions across the gastric mucosa [5]. Prophylactic therapy against stress ulceration has focused on cytoprotection (with sucralfate), and reduction (histamine-2-receptor antagonists) or neutralization (antacids) of gastric acid. The positive results of randomized trials in stress ulcer prophylaxis have led to recommendations that prophylaxis be administered to a large proportion of critically ill patients [4,6-13]. As such, control of gastric pH has been described as standard practice in intensive care units in North America and Europe [14-17]. However, many of these trials have included occult bleeding (positive results of guaiac tests of either gastric contents or stool) in their definition of stress ulcer bleeding. Studies employing a guaiacpositive nasogastric aspirate as a criterion for stress ulceration will therefore assign all bleeding to stress ulcers, including trauma from a nasogastric tube. In addition, results of guaiac testing are nonspecific [18]; cimetidine itself may produce a false-positive occult blood test [19-21]. Moreover, occult bleeding, even in the absence of prophylactic therapy, rarely progresses to overt bleeding [11] or is clinically important [13,22-25]. Even in studies using overt bleeding (such as hematemesis) in the definition of bleeding, the profile of a patient with overt bleeding may range from a transiently bloody nasogastric aspirate to hypovo-
M
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lemic shock. Accordingly, there may only be a small proportion of critically ill patients who actually develop clinically important bleeding. No single trial of prophylactic therapy has shown a reduction in clinically important bleeding. We therefore addressed the issue of whether ulcer prophylaxis in the critically ill results in a reduction in clinically important bleeding.
REVIEW OF THE LITERATURE Several descriptive review articles of stress ulcer prophylaxis have been published [26-29]. One scientific overview combined the data from 16 randomized trials to evaluate the efficacy of antacid and cimetidine therapy [1]. Both agents were more effective than placebo in preventing overall, occult, and overt bleeding (p <0.05). When data were pooled from trials using occult blood as the minimum criterion for bleeding, antacids appeared to have a prophylactic advantage over cimetidine (p <0.003). However, when detection of overt bleeding was used as the minimum criterion for bleeding, these drugs appeared equally efficacious. Another quantitative review of studies evaluating antacids and cimetidine in the overall incidence of bleeding produced congruent results with respect to their equivalence (common odds ratio of 1.61 [95% confidence interval (CI) 0.97 to 2.65]), and superiority over placebo [30]. None of these overviews have examined the differential effect of prophylaxis on clinically important bleeding in critically ill patients. A systematic approach to locating and retrieving unpublished research was not described. Moreover, several randomized trials of gastrointestinal bleeding prophylaxis not included in these analyses have since been published. Many of these have evaluated alternate forms of prophylaxis (ranitidine, sucralfate, prostaglandin congeners, and pirenzipine). To examine the differential effect of prophylaxis on overt and clinically important bleeding in critically ill patients, and to ascertain the relative impact of different therapies, we performed a metaanalysis of the results of 42 randomized clinical trials of stress ulcer prophylaxis. Meta-analysis entails critically reviewing and statistically combining the results of independent studies, thereby increasing statistical power and improving both the precision and accuracy of the estimate of treatment effect.
Locating Research MEDLINE and EMBASE (Excerpta Medica online) were searched from 1966 onwards. Paired MeSH (Medical Subject Headings) terms used for key and text word searching included hemorrhage (gastrointestinal) and critical care; hemorrhage 520
(gastrointestinal) and clinical trials; and critical care and clinical trials. Frequently cited references were identified and SCISEARCH (Science Citation Index) was used to locate any additional studies that cited these articles. Reference lists of all articles obtained were scanned to identify additional articles not found in the computerized bibliographic data base searching. Strategies to obtain unpublished material included searching Federal Research in Progress, Foundations, Medical Research Directory, Information Exc h a n g e C e n t r e of C a n a d a (IEC), N a t i o n a l Technical Information Service (NTIS), Microlog, Conference Papers Index, and BIOSIS Previews. A comprehensive list of all relevant articles was sent to authors of the primary studies, and information on further published or unpublished material was requested. The National Institutes of Health and Medical Research Council of Canada were contacted to identify research projects previously or presently funded by these institutions. Finally, pharmaceutical companies marketing prophylactic drugs (cimetidine, ranitidine, famotidine, Mylanta, Maalox, ALternaGEL, sucralfate, misoprostil, and enprostil) were contacted by letter, and subsequently by telephone, to identify industry research presently or previously ongoing in the area of stress ulcer prophylaxis. Responses were followed up through contact with the identified investigators. The titles and abstracts of all printouts were reviewed by two of us. Any article identified by either person as potentially meeting the inclusion criteria noted below were photocopied. Authors of articles published in abstract form were contacted to request full manuscripts and data sets.
Selecting Research The following inclusion criteria were used to select studies for the overview: (1) design criterion: randomized or quasi-randomized (by hospital identification number or date) clinical trials comparing one or more prophylactic drugs with each other, or with an untreated control group, (2) target population: critically ill patients, and (3) outcome measure: gastrointestinal bleeding. For the first eligibility screening, these three criteria were applied in duplicate, independently by two of us who did not have knowledge of the abstracts of each reference. Articles identified by one or both authors were retrieved. Subsequently, the selection criteria were again applied independently to the sample of articles that met the first eligibility screening, in order to make a final selection.
Methodologic Quality Criteria used to assess the methodologic quality of the primary studies are found in Table I. Each
November1991 The American Journal of Medicine Volume 91
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TABLE I Gastrointestinal Bleeding Prophylaxis: Methodologic Quality
Meta.Analysis of Randomized Trials of Stress Ulcer Prophylaxis
Population Patient selection + Consecutive eligible consenting patients/random series with no exceptions 0 Attempt made to enroll as such, with failure due to reasons outlined explicitly in text - Selected patients/not described Patient characteristics (yes/no) *Age (mean differs by < 10%) *Sex (proportion males differs < 10%) *Diagnoses (proportion of the following differs < 10%) Respiratory failure Coagulopathy/anticoagulant therapy Sepsis Hypotension Hepatic failure Renal failure Central nervous system disease Trauma Burns Postoperative (major surgery) Hx ASA/NSAID/steroid use Hx peptic ulcer/gastritis/gastrectomy *APACHE/TISS/ISS Score (differs < 10%) To score previous question: + Groups comparable on 7 or more characteristics 0 Groups comparable on 3 to 6 characteristics - Groups comparable on <2 characteristics or inadequate description of patients Randomization + Nonmanipulable (call to data coordinating center, masked drug packages) 0 Potentially manipulable (sealed envelope, computer-generated, or open-listed random number table) OR randomization stated with no further information - Quasi-randomization (medical record number, date)
Comparison
N
Common Odds Ratio (95% CI)
x2
Antacids vs. placebo/control Overt bleeding Clin impt Mortality
5 3 6
7.38 2.07 0.02
0.40 (0.20-0.79) 0.35 (0.08-1.33) 1.06 (0.67-1.66)
Histamine-2-receptor antagonistsvs. placebo/control Overt bleeding Clin impt Mortality
9 6 9
30.21 7.66 1.18
0.29 (0.17-0.45)* 0.35 (0.15-0.76) 0,80 (0.54-1.18)
9 5 8
O. 17 0.15 0.92
1.19 (0.62-2.29) 0.65 (0.16-2.49) 1.22 (0.83-1.79)
0.99 0.46 0.15
0.99 (0-22026.00) 1.04 (0.03-38.86) 0.80 (0.39-1.79)
Antacids vs. sucralfate Overt bleeding Clin impt Mortality
Antacids vs. prostaglandins Overt bleeding Clin impt Mortality
1 2 2
Histamine-2-receptor antagonistsvs. antacids Overt bleeding Clin impt Mortality
13 9 14
4.25 0.25 0.67
0.56 (0.33-0.97) 0.84 (0.45-1.56) 1.16 (0.83-1.61)
Histamine-2-receptor antagonistsvs. sucralfate Overt bleeding Clin impt Mortality
4 1 3
1.71 0.30 0.23
1.77 (0.78-3.96) 0.95 (0.06-15.40) 1.25 (0.61-2.58)
Histamine-2-receptor antagonistsvs. pirenzipine Overt bleeding Clin impt Mortality
3 1 1
6.96 1.01 0.65
3.78 (1.33-14.45) 7.11 (0.42-26.46) 1.89 (0.54-7.04)
= numberof trials includedin analysis; X2 = chi-squarestatistic; 95% CI = 95% confidence interval;clin impt = clinicallyimportantgastrointestinalbleeding. *Denotesstatisticalheterogeneity,
Intervention Blinding of attending physicians AND blinding of physicians evaluating bleeding to the drug administered + Blinded in both instances 0 Blindedin one instance - Potentially unblinded, unblinded, or can't tell
Outcome Definition of bleeding + Description of direct evidence of bleeding (including any of: bloody gastric aspirate, coffee grounds, or hematemesis) OR endoscopically visible bleeding OR chromium-labeled red blood cell count 0 Objective description of indirect evidence of upper gastrointestinal bleeding (including melena or hematochezia) OR if the outcome is microscopic bleeding, an explicit description (i.e., 3 consecutive guaiac-positive stools) OR endoscopic stigmata of recent bleeding - Inexact description of bleeding, whether direct or indirect evidence Hx = history of; ASA = acetylsalicylicacid; NSND = nonsteroidalanti-inflammatorydrug; APACHE= AcutePhysiologyand ChronicHealth Evaluation;TISS = TherapeuticScoringSystem; ISS= IllnessSeverityScoreTable3-3. *Code"CT" if not described;code"Y" if no patientsin eithergrouphad this characteristic(i.e., this subsetof patientswasexcluded).
study was evaluated based on specification of the population, intervention, and outcome. One unblinded reviewer and two other reviewers who were unaware of the author, institution, journal, and study results independently assessed the validity of each trial. Total scores were then used to rank studies. In the case of a tie, studies were ranked according to their "population score."
Data Collection Duplicate independent data extraction was performed by two of us according to the criteria listed
in Table II. Full manuscripts of articles published in abstract form were used for coding when available. Missing data were solicited from authors of the primary research. Available abstracted data were checked in the following manner: the corresponding author of every article received an introductory letter and a copy of the completed validity and data abstraction forms; he or she was then requested to correct erroneous assessments and provide missing information where necessary. This letter was followed up with a phone call 4 weeks later to obtain data still missing. Overt bleeding was defined as hematemesis, bloody gastric aspirate, melena, or hematochezia. Clinically important bleeding was defined as overt bleeding and one of the following: (1) decrease in blood pressure of 20 mm Hg within 24 hours of bleeding, (2) blood pressure reduction of 10 mm Hg and heart rate increase of 20 beats/minute on orthostatic change, or (3) decrease of 20 g/L in hemoglobin level and transfusion of 2 units of blood within 24 hours.
Data Analysis Agreement between coders for research selection was measured by kappa with quadratic w e i g h t s . D i s a g r e e m e n t was r e s o l v e d by consensus.
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In assessing validity, each study received a sum- quently excluded [31,32], because their patients mary score for the population, intervention, and were a subset of the population from trials puboutcome. In order to evaluate the effect of blinding lished by the same author [15,17]. Two additional on the assessment of validity, the rankings of the trials involving renal transplant patients were two blinded reviewers were compared with each also excluded [33,34]. Of the 42 remaining studies, other and with the rankings of the unblinded re- 31 of these were located by searching the pubviewer using kappa with quadratic weights. lished literature, three were located by searching The measure of association used in this meta-anal- unpublished bibliographic data bases, three were ysis is the common odds ratio, which is the weighted identified by experts in the field, three were obaverage of the individual study odds ratios. The val- tained through communication with pharmaceuue of the common odds ratio indicates the extent of tical companies, and two were found by scanning risk; an odds ratio of I implies that a patient's chance bibliographies. Four trials published in abstract of developing the outcome of interest is the same, form [35-39] and three studies published in Gerregardless of allocation to the treatment or control man [17,24,40] are included in the analysis. The group. A common odds ratio of 0.7 means that a kappa for selection of relevant articles from the patient in the treatment group would be 70% as like- list of citations was 0.71; the kappa for selection of ly to develop the outcome of interest as a patient in articles for meta-analysis was 0.84. the control group; conversely, an odds ratio of 2.0 means that a patient in the treatment group would Assessment of Methodologic Quality Agreement on the five items describing methodobe twice as likely to have the outcome of interest as a logic quality for each relevant article ranged from patient in the control group. 0.72 to 0.94, and was similar whether the blinded To avoid the problems of bias and instability associated with odds ratio estimation in sparse tables, reviewers were compared with each other or with we used a Monte Carlo simulation to determine the the unblinded reviewer. Causes of disagreement best estimator under these conditions. The Mantel- were errors of oversight as often as differences in Haenszel technique adding one half to each cell interpretation. The methodologic quality of these trials was proved to be the most precise estimator with the judged on the basis of five questions evaluating the least bias, and was adopted for this analysis. Therefore, using overt bleeding, clinically important patient selection, patient characteristics, randombleeding, and mortality as the outcomes of interest, ization procedure, blinding, and definition of bleedodds ratios comparing one treatment with another or ing. Seventy percent of trials scored in the middle or placebo/control were calculated using the corrected highest category for each of these questions. Mantel-Haenszel chi-square test (plus one half in each cell) (two-tailed). The two histamine-2-receptor antag- Bleeding Incidence Thirty-four trials involved comparisons of antonists, ranitidine and cimetidine, were grouped together for purposes of analysis. The 95% CIs were calculat- acids, histamine receptor antagonists, and sucraled using the Cornfield method. For articles assessing fate with each other or with placebo. Prostaglanthe same treatment combinations, the Breslow-Day dins were compared with antacids in two trials method was used to test for homogeneity under the [23,41] and with placebo in another [42]. The antinull hypothesis that the odds ratios were the same for cholinergic pirenzipine was compared with histaall studies. A p value of greater than 0.05 for the test of mine receptor antagonists in three additional homogeneity indicates that the differences in study studies [24,37,43] and with placebo in another results are consistent with random variation alone [40], and one study compared meciadanol, a histidine decarboxylase inhibitor, with antacids and when testing at the 5% significance level. When heterogeneity of trial results was found, sucralfate [44]. Of the 28 trials evaluating antacids, 21 titrated the individual study odds ratios were plotted against a number of covariates in an attempt to t h e r a p y to m a i n t a i n a pH of 3.5 to 7.0 explain the variability. These covariates included [4,8-16,23,31,41,45-52]. Twenty-four of 29 trials each criterion used to assess the methodologic qual- evaluating histamine receptor antagonists used ciity, the type of intensive care unit, the mean age of metidine (five of these in continuous infusion form patients, the proportion of males, the titration of [25,35,53-55]). Four others employed ranitidine therapy to gastric pH, and the year of publication. [16,24,38,39,43], one as a continuous infusion [24]. Therapy was titrated to maintain a pH of 3.5 to 5.0 RESULTS in 11 of these studies [12,13,16,38,39,47-52l. The dosage of cimetidine ranged from 300 to 1,200 Research Location and Selection Of 168 references, 46 relevant randomized con- rag/day, and the dosage of sucralfate ranged from 4 trolled trials were identified. Two were subse- to 6 g/day. Eight of the 17 trials randomizing pa522
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PREVENTION OF GASTROINTESTINAL BLEEDING / COOK ET AL
H2RA
versus
placebo/control
Meta-Analyses - clinically important
Exper. Obs Tot 0 2 1 0 0 5
Typical
odds
ratio
and
95% .01
Figure 1. Trials comparing histamine-2-receptor antagonist (H2RA) therapy versus placebo/control in the prevention of clinically important bleeding. Exper. Obs = experimental observations; Tot = total; Control Obs = control observations.
Typical
odds
bleeding
Control Obs Tot
114 26 54 21 19 i00
0 8 7 0 0 7
107 24 33 18 21 I00
CI Log odds .I
Ratios .5
1
2
Odds Ratio
95% Lo
1.00 0.21 0.i0 1.00 1.00 0.70
1.00 0.05 0.02 1.00 1.00 0.22
0.36
0.15-0.76
I0
CI Hi 1.00 0.82 0.45 1.00 1.00 2.25
i00
ratio
tients to control groups administered placebos [30,35,36,40,53,55-57], while the remaining nine did not. A total of 4,409 subjects were studied, with a wide spectrum of medical and surgical illnesses. Some trials enrolled only particular subgroups of critically ill p a t i e n t s , such as v e n t i l a t e d p a t i e n t s [7,9,38,39,46,47,55,58], patients with head injury [57], burn patients [10,52], patients with hepatic failure [48], and patients who had undergone abdominal aortic surgery [14]. Populations were d r a w n f r o m m e d i c a l i n t e n s i v e care u n i t s [7,17,36,58,59], surgical intensive care units [4,11-14,22-24,44,49,54,57], medical/surgical intensive care units [7,15,16,25,35,37,40,42,43, 45,46,50,53,55,56], r e s p i r a t o r y / s u r g e r y units [8,41,51], neurosurgery units [6,38,39,53], burn units [10,45,52], a coronary care unit [47], a respiratory intensive care unit [9], a pediatric intensive care unit [30], and a liver failure unit [48]. To examine the issue of the potential differential effect of prophylaxis on overt bleeding, we abstracted data from the 32 trials that allowed ascertainment of this endpoint. In Table II, each of the treatment groups is compared with each other. The common odds ratio of 0.40 (95% CI 0.20 to 0.79) comparing antacids with placebo, and the common odds ratio of 0.29 (95% CI 0.17 to 0.45) comparing histamine receptor antagonists with placebo, indicate that these two forms of prophylaxis significantly reduce overt gastrointestinal bleeding. Analysis of the nine trials allowing comparison of histamine receptor antagonists and antacids yields a common odds ratio of 0.56 (95% CI 0.33 to 0.97),
indicating a benefit of histamine receptor antagonists over antacids with regard to the outcome of overt bleeding. Analysis of the five trials comparing antacids and sucralfate (common odds ratio 1.19, 95% CI 0.62 to 2.29) suggests their equivalence. In the three trials comparing histamine receptor antagonists with pirenzipine, the common odds ratio of 3.78 (95% CI 1.33 to 14.45) suggests a benefit of pirenzipine over histamine receptor antagonists. We then abstracted information from the 26 trials evaluable to determine the incidence of clinically important bleeding in experimental and control groups. Comparison of the prophylactic agents is shown in Table II. The common odds ratio of 0.35 (95% CI 0.15 to 0.76) comparing histamine-2-receptot antagonists with no therapy (Figure 1) confirms the efficacy of histamine-2-receptor antagonists in significantly reducing the incidence of both clinically important as well as overt bleeding. The common odds ratio of 0.35 (95% CI 0.08 to 1.33) comparing antacid with no treatment (Figure 2) suggests that the best estimate of the effect of antacids on clinically important bleeding is a 65% risk reduction. Therefore, when these two agents are compared indirectly (odds ratio for histamine-2antagonists versus control compared with odds ratio for antacids versus control), the odds ratios are identical. The wide CI around the common odds ratio for antacids, which is due to the fact that three studies are contributing to the data (as opposed to six for histamine-2-receptor antagonists), leaves open the possibility that antacids have an effect on the incidence of clinically significant bleeding. In other words, the point estimates of effect are the
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PREVENTION OF GASTROINTESTINAL BLEEDING / COOK ET AL Meta-A~alyses antacids versus placebo/control- clinically important bleeding
Exper.
Obs 1 0 1
Typical
Control
Tot
Obs
50 65 i00
Tot 0 1 7
Odds Ratio
49 61 I00
7.24 0.13 0.21
odds ratio and 95% CI .01
95% CI Lo Hi 0.14 99.99 0.00 6.40 0.05 0.87
0.35 Log Odds Ratios .I .5
2
0.08-1.33 10
I00
Figure 2. Trials comparing antacid therapy versus placebo/control in the prevention of clinically important bleeding. Abbreviations as in Figure 1.
Typical odds ratio
same. However, in the case of histamine-2-receptor antagonists, we can be 95% certain that the effect is significant; in the case of antacids, the overlapping CIs suggest that the effect is similar. Although a direct comparison of histamine-2-receptor antagonists with antacids suggested the superiority of histamine-2-receptor antagonists in the prevention of overt bleeding (common odds ratio 0.56, 95% CI
H 2 R A versus antacids
0.33 to 0.97), this finding was not reproduced for the outcome of clinically important bleeding (common odds ratio 0.84, 95% CI 0.45 to 1.56) (Figure 3). When antacids are compared with sucralfate, there is a trend favoring antacids in decreasing clinicaUy significant bleeding (0.65, 95% CI 0.16 to 2.49), although this trend does not reach statistical significance (Figure 4). There appears to be no dif-
- clinically important bleeding
Exper.
Obs
Tot 3 0 0 1 2 0 6 1 5
Control Obs Tot
II0 21 38 65 61 13 125 40 i00
14 0 0 0 0 0 9 1 1
196 16 37 58 16 14 124 37 i00
T y p i c a l odds r a t i o and 95% CI
Odds
95% CI Lo Hi
Ratio 0.43 1.00 1.00 6.63 3.59 1.00 0.65 0.92 3.93
0.16 1.00 1.00 0.13 0.12 1.00 0.23 0.06 0.78
0.84
1.20 1.00 1.00 99.99 99.99 1.00 1.84 15.08 19.86
0.45-1.56
Log Odds R a t i o s .01
.i
.5
1
2
I0
i00
..i Typical odds r a t i o
524
i
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Figure 3. Trials comparing histamine-2-receptor antagonists (H2RA) with antacids in prevention of clinically important bleeding. Abbreviations as in Figure 1,
PREVENTION OF GASTROINTESTINALBLEEDING / COOK ET AL
antacids
versus
sucralfate
Meta-Analyses - clinically important
Exper. Obs Tot 0 0 0 2 0
Typical
odds
ratio
and
95%
.01
Figure 4. Trials comparing antacids with sucralfate in prevention of clinically important bleeding. Abbreviations as in Figure 1.
Typical
odds
bleeding
Control Obs Tot
25 75 36 46 50
0 0 1 2 1
25 80 38 40 50
CI
Odds Ratio
95% Lo
1.00 1.00 0.14 0.86 0.14
1.00 1.00 0.00 0.12 0.00
0.65 Log Odds .1
Ratios .5
1
2
Cl Hi 1.00 i°00 7.20 6.39 6.82
0.16-2.49 i0
i00
ratio
ference between antacids and prostaglandins in their effect on clinically important bleeding. None of the foregoing point estimates or CIs changed significantly when unpublished data were excluded from the analyses. However, in most situations, the CIs narrowed with inclusion of the unpublished data. Comparison of various prophylactic drugs in trials from which mortality rates are available (Table II) shows that all of the 95% CIs include unity (an odds ratio of 1 suggesting no treatment effect). However, the CIs around the mortality difference between antacids and placebo/controls (common odds ratio 1.06, 95% CI 0.67 to 1.66) and histamine2-receptor antagonists and placebo/controls (common odds ratio 0.80, 95% CI 0.54 to 1.18) include a clinically important reduction in mortality. Therefore, this overview does not exclude the possibility that mortality is reduced by drugs used for stress ulcer prophylaxis. There was no statistical heterogeneity of the results of trials evaluating the outcome of clinically significant bleeding or mortality. However, with regard to overt bleeding, when the comparison between histamine receptor antagonists and no treatment was made, there was variation beyond the degree that one would expect by chance if the true effect size were the same in each study. Although the common odds ratio calculated from the results of heterogeneous studies does not take into account variability between studies, on the other hand, in the presence of heterogeneity, a common odds ratio
may be a more accurate estimate of the effectiveness of treatment than the odds ratio of any one of the individual studies. Most authorities would agree that a systematic search for an explanation of the source of heterogeneity is in order when its presence is found. Odds ratios did not differ systematically across studies according to any of the study covariates or the individual methodology scores. Therefore, we postulated that the heterogeneity of this subset of odds ratios comparing histamine-2-receptor antagonists and no treatment for overt bleeding could be due to some other unmeasured interstudy variation. For example, the proportion of patients in each group with risk factors for bleeding, such as coagulopathy, was not recorded in every study.
COMMENTS This meta-analysis was performed to examine the differential effect of stress ulcer prophylaxis on overt bleeding, clinically significant bleeding, and mortality in the critically ill population. Meta-analysis takes a more structured approach to data synthesis than does a traditional narrative review. Our search for relevant literature was comprehensive; an extensive search of both published and unpublished literature was performed, and experts and governing agents were contacted to minimize the possibility of a publication bias. The study selection criteria were well defined, and qualiW assessment of the primary studies was performed by two authors unaware of the study results. The techniques
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PREVENTION OF GASTROINTESTINAL BLEEDING / COOK ET AL
of statisticalanalysis used in this meta-analysis were among those that have become standard for scientificoverviews [60,61].Therefore, methodologic criteriafor scientificoverviews [61,62]were met in this meta-analysis. Our results confirm previous findings that stress ulcer prophylaxis with antacids or histamine receptor antagonists significantlyreduces the incidence of overt hemorrhage in the criticallyillpopulation [1].This isthe firstquantitative review, however, in which a significantreduction in clinicallyimportant gastrointestinal hemorrhage is documented with administration of histamine-2-receptor antagonist therapy as compared with no treatment. Furthermore, resultsof this meta-analysis indicate that histamine receptor antagonists are superior to antacids in their ability to prevent overt bleeding, in contrast to previous reviews suggesting their equivalence [1,30].Results also suggest a trend favoring histamine-2-receptor antagonists over antacids in the prevention of clinically important bleeding. Data are insufficientto determine the effect of sucralfate in comparison with antacids and histamine-2-receptor antagonists in preventing clinically important bleeding. Results of this meta-analysis support the recommendation that prophylaxis be administered to a large proportion of critically ill patients [4,6-10,12,13,57].In fact, control of gastric p H has been described as standard practice in intensive care units in North America and Europe [14-16]. However, there are several reasons why this practice m a y not be in the best interest of patients. First, many investigators believe that the incidence of clinically important gastrointestinal bleeding has, independent of the use of prophylaxis, decreased considerably in the last decade [1,2,50]. Factors responsible may include improved methods of ventilatory support, more aggressive shock management, early attention to nutrition in the critically ill,control of bleeding diatheses,and the decreasing use of steroids in septic shock. Second, there may be patients at appreciable risk and patients at negligible risk of bleeding. The characteristicsof the latter group, from which prophylaxis can be safely withheld, are yet to be precisely defined. Finally, the decision as to which criticallyillpatients warrant stress ulcer prophylaxis and which agent should be administered must be based upon clinicalcriteriaevaluating risk factors for bleeding, and an assessment of the risk/benefitratio of each prophylactic agent. For a prophylactic intervention to be useful,itshould prevent a clinicallyimportant outcome, and itsbenefits should outweigh potential side effects. Concern has been raised that gastric pH-altering drugs, through decreased gastricacidi526
ty, result in colonization of the stomach with gramnegative organisms, which leads to an increased incidence of aspiration pneumonia. However, results have not been consistent [17,22,35,38,39,47,53].A scientificoverview of these randomized trials has not supported this hypothesis; in fact, the trends were for a decreasing incidence of pneumonia in patients receiving pH-altering drugs [63]. This overview was limited by the fact that only eight of the 42 randomized trialsof stressulcer prophylaxis reported pneumonia prevalence. Therefore, further trialsdirectly addressing this issue are warranted. In summary, the 50% reduction in clinicallyimportant bleeding mandates use of prophylaxis in criticallyillpatients at appreciable risk of bleeding. Further research is needed to profilethe patients in w h o m the risk of bleeding is sufficientlylow that stress ulcer prophylaxis can be safely withheld.
ACKNOWLEDGMENT We are indebted to the authors of the primary studies included in this review for their participation and support. We would also like to thank Dr. Loren Laine for his thoughtful review of the manuscript.
REFERENCES 1. Shuman RB, Schuster DP, Zuckermann GR. Prophylactic therapy for stress ulcer bleeding: a reappraisal. Ann Intern Med 1987; 106: 562-7. 2. Schuster DP, Rowley H, Feinstein S, etaL Prospective evaluation of the risk of upper gastrointestinal bleeding after admission to a medical intensive care unit. Am J Med 1984; 76: 623-30. 3. Harris SK, Bone RC, Ruth WE. Gastrointestinal hemorrhage in patients in a respiratory care unit. Chest 1977; 72: 301-4. 4. Zinner MJ, Zuidema GD, Smith PL, et al. The prevention of upper gastrointestinal tract bleeding in patients in an intensive care unit. Surg Gynecol Obstet 1981; 153: 214-20. 5. Gottlieb JE, Menashe PI, Cruz E. Gastrointestinal complications in critically ill patients: the intensivist's overview. Am J Gastroenterol 1986; 81: 227-38. 6. Basso N, Baragani M, Materia A, et al. Cimetidine and antacid prophylaxis of acute upper gastrointestinal bleeding in high risk patients. Am J Surg 1981; 141: 339-41. 7. Friedman CJ, Oblinger MJ, Surrat PM, etaL Prophylaxis of upper gastrointestinal hemorrhage in patients requiring mechanical ventilation. Crit Care Med 1982; 10: 316-9. S. Hastings PR, Skillman JJ, Bushnell LS, etaL Antacid titration in the prevention of acute gastrointestinal bleeding. N Engl J Med 1978; 298: 1041-5. 9. Kahn F, Parekh A, Chitkara R, et aL Results of gastric neutralization with hourly antacids and cimetidine in 320 intubated patients with respiratory failure. Chest 1981; 79: 409-12, 10. McAIhany JC, CzajaAJ, Pruitt B. Antacid control of complications from acute gastrointestinal disease after burns. J Trauma 1976; 16: 645-9. 11. Pinilla JC, Oleniuk FH, Reed D, et aL Does antacid prophylaxis prevent upper gastrointestinal bleeding in critically ill patients? Crit Care Med 1985; 13: 646-50. 12. Stothert JC, Siminowitz DA, Dellinger EP, et aL Randomized prospective evaluation of cimitidine and antacid control of gastric pH in the critically ill, Ann Surg 1980; 192: 169-73. 13. Weigelt LA, Aurbakken CM, Geweitz BL, et aL Cimetidine versus antacid in prophylaxis for stress ulceration. Arch Surg 1981; 116: 597-601. 14. Borerro E, Ciervo J, Chang JB. Antacid versus sucralfate in preventing acute gastrointestinal tract bleeding in abdominal-aortic surgery. Arch Surg 1986: 121: 810-2. 15. Borrero E, BankS, MargolisIB, et al. Comparisonof antacidand sucralfatein the preventionof gastrointestinalbleedingin patients who are critically ill. Am J Med 1985; 79 Suppl 2C: 62-4. 16, NoseworthyTRW,ShustackA, Johnston RG, et al. A randomizedclinical trial
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PREVENTION OF GASTROINTESTINAL BLEEDING / COOK ET AL comparing ranitidine and antacids in critically ill patients. Crit Care Med 1987; 15: 817-9. 17. LaggnerAN, LenzK, GraningerW, et aL Stresbluntungsprophylaxeauf einer internen intensivstation: sucralfat versus ranitidin. Anaesthesist 1988; 37: 704-10, 18. Layne EA, Mellow MH, Lipman TO. Insensitivity of guaiac slide tests for detection of blood in gastric juice. Ann Intern Med 1981; 94: 774-6. 19. Norfleet RG, Rhodes IRA,Saviage K. False positive "hemoccult" reaction with cimetidine. N Engl J Med 1980; 302: 467. 20. SchentagJJ. Falsepositive "hemoccult" reactionwith cimetidine. N EnglJ Med 1980; 303: 110. 21. Hauser A, Quigley ML, Driever CW, eta/. More on false positive "hemoccult" reaction with cimetidine [letter]. N Engl J Med 1981; 304: 847~8. 22. Tryba M. Risk of acute stress bleeding and nosocomial pneumonia in ventilated intensive care unit patients: sucralfate versus antacids. Am J Med 1987; 83: 117-24. 23. Zinner MJ, Rypins EB, Martin L, etal. Misoprostol versus antacid titration for preventing stress ulcers in postoperative surgical ICU patients. Ann Surg 1989; 210: 590-5. 24. Tryba M, Zevounou F, Wruck G. Stresblutungen und postoperative pneumonien bei intensivpatienten unter ranitidin oder pirenzepin. Dtsch Med Wochenschr 1988; 113: 930-6. 25, Kingsley AN. Prophylaxis for acute stress ulcers: antacids or cimetidine. Am Surg 1985; 51: 545-7. 26. Greene WL Bollinger RR. Cimetidine for stress-ulcer prophylaxis. Crit Care Mecl 1984; 12: 571-5. 27. Wilcox CM, Spenney JG. Stress ulcer prophylaxis in medical patients: who, what and how much ? Am J Gastroenterol 1988; 83:1199-211. 28. Preibe HJ, Skillman JJ. Methods of prophylaxis in stress ulcer disease. World J Surg 1981; 5: 223-33. 29. HiHman K, Acute stress ulceration. Anaesth Intensive Care 1985; 13: 230-40. 30. Lacroix J, Infante-Rivard C, Gauthier M, et aL Upper gastrointestinal tract bleeding acquired in a pediatric intensive care unit: prophylaxis trial with cimetidine. J Pediatr 1986; 108: 1015-8. 31. Borrero E, Margolis IB, Bank S. Antacid versus sucralfate in preventing acute gastrointestinal bleeding. Am J Surg 1984; 148: 809-12. 32. Laggner AN, Lenz K, Base W, et aL Prevention of upper gastrointestinal bleeding in long term ventilated patients. Am J Med 1989; 86 Suppl 6A: 81-4. 33. Jones RH, Rudge CJ, Bewick M, etaL Cimetidine: prophylaxis against upper gastrointestinal hemorrhage after renal transplant. BMJ 1978; 1: 398-400. 34. Schiessel R, Starlinger M, Wolf A, et aL Failure of cimetidine to prevent gastroduodenal ulceration and bleeding after renal transplantation. Surgery 1981; 90: 456-8. 35. Karlstadt R, Herson J, Palmer R, et al. Cimetidine reduces upper gastrointestinal bleeding and nosocomial pneumonia in intensive care unit patients [abstract]. Am J Gastroenterol 1989; 84: A93. 36. Luk GD, Summer WR, Messersmith JF, etaL Cimetidine and antacid prophylaxis of acute gastrointestinal bleeding. A randomized double-blind controlled study [abstract]. Gastroenterology 1982; 82: 1121. 37. Jmelnitzky AC, Moday MC, Gallardo EA, et aL Prophylaxis of acute gastric hemorrhage from stress induced lesions--comparison of pirenzipine and cimetidine in intensive care units [abstract]. Dig Dis Sci 1986; 31: A814. 38. Reusser P, Gyr K, Scheidel~er D, etaL A randomized controlled endoscopic study of ranitidine and antacids for the prevention of gastroduodenal stress lesions and bleeding in critically ill patients [abstract]. Gastroenterology 1988; 94 (Part 2): A373. 39. Reusser P, Zimmerli W, Scheide~er D, etaL Role of gastric colonization in nosocomial infections and endotoxemia: a prospective study in neurosurgical patients on mechanical ventilation. J Infect Dis 1989; 160: 414-21. 40. Mattes P, Peros S, Belohlavek D, et al. Stresulkus-prophylaxe mit pirenzipin-
eine kontrollierte studie. Z Gastroenterol 1980; 18: 325-7. 41. Ski,man JJ, Lisbon A, Long PC, et aL 15(R)-15-methyl prostaglandin E2 does not prevent gastrointestinal bleeding in seriously ill patients. Am J Surg 1984; 147: 451-5. 42. Van EssenHA, Van Blankenstein M, Wilson P, etaL Intragastric prostaglandin E2 and the prevention of gastrointestinal hemorrhage in ICU patients. Crit Care Med 1985; 13: 957-60. 43. More DG, Raper RF, Watson CJ, et aL Combination therapy with ranitidine and pirenzepine for control of intragastric pH in the critically ill. Crit Care Med 1985; 13: 651-5. 44. Mundinger GH, Hays A, AIIo M, et aL Effect of meciadanol and sucralfate as compared with antacid titration regimen on prevention of acute gastrointestinal hemorrhage in post-operative intensive care patients. Surg Forum 1985; 36: 121-3. 45. Bresalier RS, Grendell JH, Cello JP, et aL Sucralfate suspension versus titrated antacids in the prophylaxis of acute stress-related gastrointestinal hemorrhage in critically ill patients. Am J Med 1987; 83 Suppl 3B: 110-6. 46. Cannon LA, Heiselman DE, Gardner WG, et aL Prophylaxis of upper gastrointestinal tract bleeding in mechanically ventilated patients. Arch Intern Med 1987; 147: 2101-6. 47. Driks MR, Craven DE, Bartolome RC, eta/. Nosocomial pneumonia in intubated patients given sucralfate as compared with antacids or histamine type 2 blockers. N Engl J Med 1987; 317: 1376-82. 48. MacDougall BRD, Bailey RJ, Williams R. Histamine-2 receptor antagonists and antacids in the prevention of acute gastrointestinal hemorrhage in fulminant hepatic failure. Lancet 1977; 1: 617-9. 49. Martin LF, Max MH, Polk HC. Failure of gastric pH control by antacids or cimetidine in the critically ill: a valid sign of sepsis. Surgery 1980; 88: 59-68. 50. Polesky MH, Spanier AH. Cimetidine versus antacids in the prevention of stress erosions in critically ill patients. Am J Gastroentero11986; 81: 107-11. 51. Priebe HJ, Skillman JJ, Bushnell LS, et aL Antacid versus cimetidine in preventing acute gastrointestinal bleeding. N Engl J Med 1980; 302: 425-7. 52. McEIwee HP, Sirinek KR, Levine 8A. Cimetidine affords protection equal to antacids in prevention of stress ulceration following thermal injury. Surgery 1979; 86: 620-6. 53. Karlstadt R, Frank W, Palmer R, etaL Comparison of cimetidine and placebo in the prophylaxis of stress bleeding. J Intensive Care Med 1990; 5: 226-32. 54. Tryba M, Zevounou F, Torok M, et aL Prevention of acute stress bleeding with sucralfate, antacids or cimetidine. Am J Med 1985; 79 Suppl 2C: 55-61. 55. Van den Berg B, Van Blankenstein M. Prevention of stress-induced gastrointestinal bleeding by cimetidine in patients on assisted ventilation. Digestion 1985; 31: 1--8. 56. Grolt A, Simon JB, Wigle RD, etaL Cimetidine prophylaxisforgastrointestinal bleeding in an intensive care unit. Gut 1986; 27: 135-40. 57. Halloran LG, Zfass AM, Gayle WE. Prevention of acute gastrointestinal complications after severe head injury: a controlled trial of cimetidine prophylaxis. Am J Surg 1980; 139: 44-8. 58. Israsena S, Kladcharoen N, Limthongkul S, etaL Sucralfate versus antacid in the prevention of stress ulcer bleeding in patients on mechanical ventilation. J Med Assoc Thai 1987; 70: 678-82. 59. Peura DA, Johnson LF. Cimetidine for prevention and treatment of gastroduodenal mucosal lesions in patients in an intensive care unit. Ann Intern Med 1985; 103: 173-7. 60. Boissel JP, Blanchard J, Panak E, et aL Considerations for the meta-analysis of randomized clinical trials. Controlled Clin Trials 1989; 10: 254-81. 61. L'Abbe KA, Detsky AS, O'Rourke K. Meta-analysis in clinical research. Ann Intern Med 1987; 107: 224-33. 62, Oxman AD, Guyatt GH. Guidelines for reading literature reviews. Can Med Assoc J 1988; 138: 697-703. 63. Cook DJ, Laine LA, Guyatt GH, eta/. Nosocomial pneumonia and the role of gastric pH: a meta-analysis. Chest 1991; 100: 7-13.
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]REVIEW
Stress Ulcer Prophylaxis in the Critically I11:A Meta-Analysis DEBORAH J. COOK, M.D., Hamilton, Ontario, Canada, LANA G. WlTT, Ph.D., Stanford, California, RICHARD J. COOK, M.Sc., GORDON H. GUYATT, M.D., Hamilton, Ontario, Canada
PURPOSF~To e~rnmine the differential effect of stress ulcer prophylaxis on overt bleeding, clinically important bleeding, and mortality in critically ill patients. DATA IDENTIFICATION:Computerized bibliographic search of published and unpublished research. STUDY SELECTION:Independent review of 168 articles identified 42 relevant randomized trials for inclusion. DATAABSTRACTION:The validity, population, intervention, and outcomes of each trial were evaluated. RESULTS: Stress ulcer prophyl~xi~ with antacids (odds ratio 0.40 [95% confidence interval (CI) 0.20 to 0.79]) or hist~mlne-2-receptor antagonists (odds ratio 0~9 [95% CI 0.17 to 0.45]) decreases the incidence of overt gastrointestinal bleeding. Hist~mine-2-receptor antagonists are more effective than antacids at reducing overt hemorrhage (odds ratio 036 [95% CI 0.33 to 0.97]). A significant reduction in clinically important gastrointestlnai hemorrhage is evident only with hist~mlne-2-receptor antagonist therapy. There is a trend favoring antacids over sucralfate in the outcome of clinically important bleeding (odds ratio 0.65 [95% CI 0.16 to 2.49]); however, there are insufficient data to evaluate histamine-2-receptor antagonists versus sucralfate. No difference in mortality between treated and untreated patients was found. CONCLUSIONS: O v e r t gastrointestinal bleeding in critically ill patients is reduced by prophylaxis with antacids or hist~mine-2-receptor antagonists. Hist~mlne-2-receptor antagonists are more effective than antacids at decreasing overt bleeding and are more effective than no treatFrom the Department of Medicine (DJC), Division of Critical Care, and the Department of Clinical Epidemiology and Biostatistics (DJC, RJC, GHG), McMaster Faculty of Health Sciences, Hamilton, Ontario, Canada, and the Department of Pharmacy (LGW), Stanford Medical Center, Stanford, California. Dr. Deborah Cook is a St. Joseph's Hospital Research Scholar. Drs. Cook and Guyatt are Career Scientists of the Ontario Ministry of Health. Requests for reprints should be addressed to Deborah J. Cook, M.D., Department of Medicine, Division of Critical Care, St. Joseph's Hospital, 50 Charlton Avenue East, Hamilton, Ontario L8N 4A6, Canada. Manuscript submitted January 4, 1991, and accepted in revised form June 5, 1991.
ment at reducing the incidence of clinically important bleeding. Mortality rates in the intensive care unit are not decreased by stress ulcer prophylaxis.
inor upper gastrointestinal bleeding due to stress ulceration is common in morbidly ill hospitalized patients [1]. The incidence of serious hemorrhage, which is accompanied by a high degree of morbidity and mortality, is substantially lower [2-4]. The pathogenesis of stress ulceration in the critically ill involves disruption of the usual mechanisms of gastric mucosal integrity. Hypotension and systemic acidosis decrease gastric blood flow, resulting in impaired turnover of gastric epithelium, loss of the protective mucous and bicarbonate barrier, and back diffusion of hydrogen ions across the gastric mucosa [5]. Prophylactic therapy against stress ulceration has focused on cytoprotection (with sucralfate), and reduction (histamine-2-receptor antagonists) or neutralization (antacids) of gastric acid. The positive results of randomized trials in stress ulcer prophylaxis have led to recommendations that prophylaxis be administered to a large proportion of critically ill patients [4,6-13]. As such, control of gastric pH has been described as standard practice in intensive care units in North America and Europe [14-17]. However, many of these trials have included occult bleeding (positive results of guaiac tests of either gastric contents or stool) in their definition of stress ulcer bleeding. Studies employing a guaiacpositive nasogastric aspirate as a criterion for stress ulceration will therefore assign all bleeding to stress ulcers, including trauma from a nasogastric tube. In addition, results of guaiac testing are nonspecific [18]; cimetidine itself may produce a false-positive occult blood test [19-21]. Moreover, occult bleeding, even in the absence of prophylactic therapy, rarely progresses to overt bleeding [11] or is clinically important [13,22-25]. Even in studies using overt bleeding (such as hematemesis) in the definition of bleeding, the profile of a patient with overt bleeding may range from a transiently bloody nasogastric aspirate to hypovo-
M
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lemic shock. Accordingly, there may only be a small proportion of critically ill patients who actually develop clinically important bleeding. No single trial of prophylactic therapy has shown a reduction in clinically important bleeding. We therefore addressed the issue of whether ulcer prophylaxis in the critically ill results in a reduction in clinically important bleeding.
REVIEW OF THE LITERATURE Several descriptive review articles of stress ulcer prophylaxis have been published [26-29]. One scientific overview combined the data from 16 randomized trials to evaluate the efficacy of antacid and cimetidine therapy [1]. Both agents were more effective than placebo in preventing overall, occult, and overt bleeding (p <0.05). When data were pooled from trials using occult blood as the minimum criterion for bleeding, antacids appeared to have a prophylactic advantage over cimetidine (p <0.003). However, when detection of overt bleeding was used as the minimum criterion for bleeding, these drugs appeared equally efficacious. Another quantitative review of studies evaluating antacids and cimetidine in the overall incidence of bleeding produced congruent results with respect to their equivalence (common odds ratio of 1.61 [95% confidence interval (CI) 0.97 to 2.65]), and superiority over placebo [30]. None of these overviews have examined the differential effect of prophylaxis on clinically important bleeding in critically ill patients. A systematic approach to locating and retrieving unpublished research was not described. Moreover, several randomized trials of gastrointestinal bleeding prophylaxis not included in these analyses have since been published. Many of these have evaluated alternate forms of prophylaxis (ranitidine, sucralfate, prostaglandin congeners, and pirenzipine). To examine the differential effect of prophylaxis on overt and clinically important bleeding in critically ill patients, and to ascertain the relative impact of different therapies, we performed a metaanalysis of the results of 42 randomized clinical trials of stress ulcer prophylaxis. Meta-analysis entails critically reviewing and statistically combining the results of independent studies, thereby increasing statistical power and improving both the precision and accuracy of the estimate of treatment effect.
Locating Research MEDLINE and EMBASE (Excerpta Medica online) were searched from 1966 onwards. Paired MeSH (Medical Subject Headings) terms used for key and text word searching included hemorrhage (gastrointestinal) and critical care; hemorrhage 520
(gastrointestinal) and clinical trials; and critical care and clinical trials. Frequently cited references were identified and SCISEARCH (Science Citation Index) was used to locate any additional studies that cited these articles. Reference lists of all articles obtained were scanned to identify additional articles not found in the computerized bibliographic data base searching. Strategies to obtain unpublished material included searching Federal Research in Progress, Foundations, Medical Research Directory, Information Exc h a n g e C e n t r e of C a n a d a (IEC), N a t i o n a l Technical Information Service (NTIS), Microlog, Conference Papers Index, and BIOSIS Previews. A comprehensive list of all relevant articles was sent to authors of the primary studies, and information on further published or unpublished material was requested. The National Institutes of Health and Medical Research Council of Canada were contacted to identify research projects previously or presently funded by these institutions. Finally, pharmaceutical companies marketing prophylactic drugs (cimetidine, ranitidine, famotidine, Mylanta, Maalox, ALternaGEL, sucralfate, misoprostil, and enprostil) were contacted by letter, and subsequently by telephone, to identify industry research presently or previously ongoing in the area of stress ulcer prophylaxis. Responses were followed up through contact with the identified investigators. The titles and abstracts of all printouts were reviewed by two of us. Any article identified by either person as potentially meeting the inclusion criteria noted below were photocopied. Authors of articles published in abstract form were contacted to request full manuscripts and data sets.
Selecting Research The following inclusion criteria were used to select studies for the overview: (1) design criterion: randomized or quasi-randomized (by hospital identification number or date) clinical trials comparing one or more prophylactic drugs with each other, or with an untreated control group, (2) target population: critically ill patients, and (3) outcome measure: gastrointestinal bleeding. For the first eligibility screening, these three criteria were applied in duplicate, independently by two of us who did not have knowledge of the abstracts of each reference. Articles identified by one or both authors were retrieved. Subsequently, the selection criteria were again applied independently to the sample of articles that met the first eligibility screening, in order to make a final selection.
Methodologic Quality Criteria used to assess the methodologic quality of the primary studies are found in Table I. Each
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PREVENTION OF GASTROINTESTINAL BLEEDING / COOK ET AL TABLE II
TABLE I Gastrointestinal Bleeding Prophylaxis: Methodologic Quality
Meta.Analysis of Randomized Trials of Stress Ulcer Prophylaxis
Population Patient selection + Consecutive eligible consenting patients/random series with no exceptions 0 Attempt made to enroll as such, with failure due to reasons outlined explicitly in text - Selected patients/not described Patient characteristics (yes/no) *Age (mean differs by < 10%) *Sex (proportion males differs < 10%) *Diagnoses (proportion of the following differs < 10%) Respiratory failure Coagulopathy/anticoagulant therapy Sepsis Hypotension Hepatic failure Renal failure Central nervous system disease Trauma Burns Postoperative (major surgery) Hx ASA/NSAID/steroid use Hx peptic ulcer/gastritis/gastrectomy *APACHE/TISS/ISS Score (differs < 10%) To score previous question: + Groups comparable on 7 or more characteristics 0 Groups comparable on 3 to 6 characteristics - Groups comparable on <2 characteristics or inadequate description of patients Randomization + Nonmanipulable (call to data coordinating center, masked drug packages) 0 Potentially manipulable (sealed envelope, computer-generated, or open-listed random number table) OR randomization stated with no further information - Quasi-randomization (medical record number, date)
Comparison
N
Common Odds Ratio (95% CI)
x2
Antacids vs. placebo/control Overt bleeding Clin impt Mortality
5 3 6
7.38 2.07 0.02
0.40 (0.20-0.79) 0.35 (0.08-1.33) 1.06 (0.67-1.66)
Histamine-2-receptor antagonistsvs. placebo/control Overt bleeding Clin impt Mortality
9 6 9
30.21 7.66 1.18
0.29 (0.17-0.45)* 0.35 (0.15-0.76) 0,80 (0.54-1.18)
9 5 8
O. 17 0.15 0.92
1.19 (0.62-2.29) 0.65 (0.16-2.49) 1.22 (0.83-1.79)
0.99 0.46 0.15
0.99 (0-22026.00) 1.04 (0.03-38.86) 0.80 (0.39-1.79)
Antacids vs. sucralfate Overt bleeding Clin impt Mortality
Antacids vs. prostaglandins Overt bleeding Clin impt Mortality
1 2 2
Histamine-2-receptor antagonistsvs. antacids Overt bleeding Clin impt Mortality
13 9 14
4.25 0.25 0.67
0.56 (0.33-0.97) 0.84 (0.45-1.56) 1.16 (0.83-1.61)
Histamine-2-receptor antagonistsvs. sucralfate Overt bleeding Clin impt Mortality
4 1 3
1.71 0.30 0.23
1.77 (0.78-3.96) 0.95 (0.06-15.40) 1.25 (0.61-2.58)
Histamine-2-receptor antagonistsvs. pirenzipine Overt bleeding Clin impt Mortality
3 1 1
6.96 1.01 0.65
3.78 (1.33-14.45) 7.11 (0.42-26.46) 1.89 (0.54-7.04)
= numberof trials includedin analysis; X2 = chi-squarestatistic; 95% CI = 95% confidence interval;clin impt = clinicallyimportantgastrointestinalbleeding. *Denotesstatisticalheterogeneity,
Intervention Blinding of attending physicians AND blinding of physicians evaluating bleeding to the drug administered + Blinded in both instances 0 Blindedin one instance - Potentially unblinded, unblinded, or can't tell
Outcome Definition of bleeding + Description of direct evidence of bleeding (including any of: bloody gastric aspirate, coffee grounds, or hematemesis) OR endoscopically visible bleeding OR chromium-labeled red blood cell count 0 Objective description of indirect evidence of upper gastrointestinal bleeding (including melena or hematochezia) OR if the outcome is microscopic bleeding, an explicit description (i.e., 3 consecutive guaiac-positive stools) OR endoscopic stigmata of recent bleeding - Inexact description of bleeding, whether direct or indirect evidence Hx = history of; ASA = acetylsalicylicacid; NSND = nonsteroidalanti-inflammatorydrug; APACHE= AcutePhysiologyand ChronicHealth Evaluation;TISS = TherapeuticScoringSystem; ISS= IllnessSeverityScoreTable3-3. *Code"CT" if not described;code"Y" if no patientsin eithergrouphad this characteristic(i.e., this subsetof patientswasexcluded).
study was evaluated based on specification of the population, intervention, and outcome. One unblinded reviewer and two other reviewers who were unaware of the author, institution, journal, and study results independently assessed the validity of each trial. Total scores were then used to rank studies. In the case of a tie, studies were ranked according to their "population score."
Data Collection Duplicate independent data extraction was performed by two of us according to the criteria listed
in Table II. Full manuscripts of articles published in abstract form were used for coding when available. Missing data were solicited from authors of the primary research. Available abstracted data were checked in the following manner: the corresponding author of every article received an introductory letter and a copy of the completed validity and data abstraction forms; he or she was then requested to correct erroneous assessments and provide missing information where necessary. This letter was followed up with a phone call 4 weeks later to obtain data still missing. Overt bleeding was defined as hematemesis, bloody gastric aspirate, melena, or hematochezia. Clinically important bleeding was defined as overt bleeding and one of the following: (1) decrease in blood pressure of 20 mm Hg within 24 hours of bleeding, (2) blood pressure reduction of 10 mm Hg and heart rate increase of 20 beats/minute on orthostatic change, or (3) decrease of 20 g/L in hemoglobin level and transfusion of 2 units of blood within 24 hours.
Data Analysis Agreement between coders for research selection was measured by kappa with quadratic w e i g h t s . D i s a g r e e m e n t was r e s o l v e d by consensus.
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In assessing validity, each study received a sum- quently excluded [31,32], because their patients mary score for the population, intervention, and were a subset of the population from trials puboutcome. In order to evaluate the effect of blinding lished by the same author [15,17]. Two additional on the assessment of validity, the rankings of the trials involving renal transplant patients were two blinded reviewers were compared with each also excluded [33,34]. Of the 42 remaining studies, other and with the rankings of the unblinded re- 31 of these were located by searching the pubviewer using kappa with quadratic weights. lished literature, three were located by searching The measure of association used in this meta-anal- unpublished bibliographic data bases, three were ysis is the common odds ratio, which is the weighted identified by experts in the field, three were obaverage of the individual study odds ratios. The val- tained through communication with pharmaceuue of the common odds ratio indicates the extent of tical companies, and two were found by scanning risk; an odds ratio of I implies that a patient's chance bibliographies. Four trials published in abstract of developing the outcome of interest is the same, form [35-39] and three studies published in Gerregardless of allocation to the treatment or control man [17,24,40] are included in the analysis. The group. A common odds ratio of 0.7 means that a kappa for selection of relevant articles from the patient in the treatment group would be 70% as like- list of citations was 0.71; the kappa for selection of ly to develop the outcome of interest as a patient in articles for meta-analysis was 0.84. the control group; conversely, an odds ratio of 2.0 means that a patient in the treatment group would Assessment of Methodologic Quality Agreement on the five items describing methodobe twice as likely to have the outcome of interest as a logic quality for each relevant article ranged from patient in the control group. 0.72 to 0.94, and was similar whether the blinded To avoid the problems of bias and instability associated with odds ratio estimation in sparse tables, reviewers were compared with each other or with we used a Monte Carlo simulation to determine the the unblinded reviewer. Causes of disagreement best estimator under these conditions. The Mantel- were errors of oversight as often as differences in Haenszel technique adding one half to each cell interpretation. The methodologic quality of these trials was proved to be the most precise estimator with the judged on the basis of five questions evaluating the least bias, and was adopted for this analysis. Therefore, using overt bleeding, clinically important patient selection, patient characteristics, randombleeding, and mortality as the outcomes of interest, ization procedure, blinding, and definition of bleedodds ratios comparing one treatment with another or ing. Seventy percent of trials scored in the middle or placebo/control were calculated using the corrected highest category for each of these questions. Mantel-Haenszel chi-square test (plus one half in each cell) (two-tailed). The two histamine-2-receptor antag- Bleeding Incidence Thirty-four trials involved comparisons of antonists, ranitidine and cimetidine, were grouped together for purposes of analysis. The 95% CIs were calculat- acids, histamine receptor antagonists, and sucraled using the Cornfield method. For articles assessing fate with each other or with placebo. Prostaglanthe same treatment combinations, the Breslow-Day dins were compared with antacids in two trials method was used to test for homogeneity under the [23,41] and with placebo in another [42]. The antinull hypothesis that the odds ratios were the same for cholinergic pirenzipine was compared with histaall studies. A p value of greater than 0.05 for the test of mine receptor antagonists in three additional homogeneity indicates that the differences in study studies [24,37,43] and with placebo in another results are consistent with random variation alone [40], and one study compared meciadanol, a histidine decarboxylase inhibitor, with antacids and when testing at the 5% significance level. When heterogeneity of trial results was found, sucralfate [44]. Of the 28 trials evaluating antacids, 21 titrated the individual study odds ratios were plotted against a number of covariates in an attempt to t h e r a p y to m a i n t a i n a pH of 3.5 to 7.0 explain the variability. These covariates included [4,8-16,23,31,41,45-52]. Twenty-four of 29 trials each criterion used to assess the methodologic qual- evaluating histamine receptor antagonists used ciity, the type of intensive care unit, the mean age of metidine (five of these in continuous infusion form patients, the proportion of males, the titration of [25,35,53-55]). Four others employed ranitidine therapy to gastric pH, and the year of publication. [16,24,38,39,43], one as a continuous infusion [24]. Therapy was titrated to maintain a pH of 3.5 to 5.0 RESULTS in 11 of these studies [12,13,16,38,39,47-52l. The dosage of cimetidine ranged from 300 to 1,200 Research Location and Selection Of 168 references, 46 relevant randomized con- rag/day, and the dosage of sucralfate ranged from 4 trolled trials were identified. Two were subse- to 6 g/day. Eight of the 17 trials randomizing pa522
November1991 The American Journal of Medicine Volume91
PREVENTION OF GASTROINTESTINAL BLEEDING / COOK ET AL
H2RA
versus
placebo/control
Meta-Analyses - clinically important
Exper. Obs Tot 0 2 1 0 0 5
Typical
odds
ratio
and
95% .01
Figure 1. Trials comparing histamine-2-receptor antagonist (H2RA) therapy versus placebo/control in the prevention of clinically important bleeding. Exper. Obs = experimental observations; Tot = total; Control Obs = control observations.
Typical
odds
bleeding
Control Obs Tot
114 26 54 21 19 i00
0 8 7 0 0 7
107 24 33 18 21 I00
CI Log odds .I
Ratios .5
1
2
Odds Ratio
95% Lo
1.00 0.21 0.i0 1.00 1.00 0.70
1.00 0.05 0.02 1.00 1.00 0.22
0.36
0.15-0.76
I0
CI Hi 1.00 0.82 0.45 1.00 1.00 2.25
i00
ratio
tients to control groups administered placebos [30,35,36,40,53,55-57], while the remaining nine did not. A total of 4,409 subjects were studied, with a wide spectrum of medical and surgical illnesses. Some trials enrolled only particular subgroups of critically ill p a t i e n t s , such as v e n t i l a t e d p a t i e n t s [7,9,38,39,46,47,55,58], patients with head injury [57], burn patients [10,52], patients with hepatic failure [48], and patients who had undergone abdominal aortic surgery [14]. Populations were d r a w n f r o m m e d i c a l i n t e n s i v e care u n i t s [7,17,36,58,59], surgical intensive care units [4,11-14,22-24,44,49,54,57], medical/surgical intensive care units [7,15,16,25,35,37,40,42,43, 45,46,50,53,55,56], r e s p i r a t o r y / s u r g e r y units [8,41,51], neurosurgery units [6,38,39,53], burn units [10,45,52], a coronary care unit [47], a respiratory intensive care unit [9], a pediatric intensive care unit [30], and a liver failure unit [48]. To examine the issue of the potential differential effect of prophylaxis on overt bleeding, we abstracted data from the 32 trials that allowed ascertainment of this endpoint. In Table II, each of the treatment groups is compared with each other. The common odds ratio of 0.40 (95% CI 0.20 to 0.79) comparing antacids with placebo, and the common odds ratio of 0.29 (95% CI 0.17 to 0.45) comparing histamine receptor antagonists with placebo, indicate that these two forms of prophylaxis significantly reduce overt gastrointestinal bleeding. Analysis of the nine trials allowing comparison of histamine receptor antagonists and antacids yields a common odds ratio of 0.56 (95% CI 0.33 to 0.97),
indicating a benefit of histamine receptor antagonists over antacids with regard to the outcome of overt bleeding. Analysis of the five trials comparing antacids and sucralfate (common odds ratio 1.19, 95% CI 0.62 to 2.29) suggests their equivalence. In the three trials comparing histamine receptor antagonists with pirenzipine, the common odds ratio of 3.78 (95% CI 1.33 to 14.45) suggests a benefit of pirenzipine over histamine receptor antagonists. We then abstracted information from the 26 trials evaluable to determine the incidence of clinically important bleeding in experimental and control groups. Comparison of the prophylactic agents is shown in Table II. The common odds ratio of 0.35 (95% CI 0.15 to 0.76) comparing histamine-2-receptot antagonists with no therapy (Figure 1) confirms the efficacy of histamine-2-receptor antagonists in significantly reducing the incidence of both clinically important as well as overt bleeding. The common odds ratio of 0.35 (95% CI 0.08 to 1.33) comparing antacid with no treatment (Figure 2) suggests that the best estimate of the effect of antacids on clinically important bleeding is a 65% risk reduction. Therefore, when these two agents are compared indirectly (odds ratio for histamine-2antagonists versus control compared with odds ratio for antacids versus control), the odds ratios are identical. The wide CI around the common odds ratio for antacids, which is due to the fact that three studies are contributing to the data (as opposed to six for histamine-2-receptor antagonists), leaves open the possibility that antacids have an effect on the incidence of clinically significant bleeding. In other words, the point estimates of effect are the
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PREVENTION OF GASTROINTESTINAL BLEEDING / COOK ET AL Meta-A~alyses antacids versus placebo/control- clinically important bleeding
Exper.
Obs 1 0 1
Typical
Control
Tot
Obs
50 65 i00
Tot 0 1 7
Odds Ratio
49 61 I00
7.24 0.13 0.21
odds ratio and 95% CI .01
95% CI Lo Hi 0.14 99.99 0.00 6.40 0.05 0.87
0.35 Log Odds Ratios .I .5
2
0.08-1.33 10
I00
Figure 2. Trials comparing antacid therapy versus placebo/control in the prevention of clinically important bleeding. Abbreviations as in Figure 1.
Typical odds ratio
same. However, in the case of histamine-2-receptor antagonists, we can be 95% certain that the effect is significant; in the case of antacids, the overlapping CIs suggest that the effect is similar. Although a direct comparison of histamine-2-receptor antagonists with antacids suggested the superiority of histamine-2-receptor antagonists in the prevention of overt bleeding (common odds ratio 0.56, 95% CI
H 2 R A versus antacids
0.33 to 0.97), this finding was not reproduced for the outcome of clinically important bleeding (common odds ratio 0.84, 95% CI 0.45 to 1.56) (Figure 3). When antacids are compared with sucralfate, there is a trend favoring antacids in decreasing clinicaUy significant bleeding (0.65, 95% CI 0.16 to 2.49), although this trend does not reach statistical significance (Figure 4). There appears to be no dif-
- clinically important bleeding
Exper.
Obs
Tot 3 0 0 1 2 0 6 1 5
Control Obs Tot
II0 21 38 65 61 13 125 40 i00
14 0 0 0 0 0 9 1 1
196 16 37 58 16 14 124 37 i00
T y p i c a l odds r a t i o and 95% CI
Odds
95% CI Lo Hi
Ratio 0.43 1.00 1.00 6.63 3.59 1.00 0.65 0.92 3.93
0.16 1.00 1.00 0.13 0.12 1.00 0.23 0.06 0.78
0.84
1.20 1.00 1.00 99.99 99.99 1.00 1.84 15.08 19.86
0.45-1.56
Log Odds R a t i o s .01
.i
.5
1
2
I0
i00
..i Typical odds r a t i o
524
i
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Figure 3. Trials comparing histamine-2-receptor antagonists (H2RA) with antacids in prevention of clinically important bleeding. Abbreviations as in Figure 1,
PREVENTION OF GASTROINTESTINALBLEEDING / COOK ET AL
antacids
versus
sucralfate
Meta-Analyses - clinically important
Exper. Obs Tot 0 0 0 2 0
Typical
odds
ratio
and
95%
.01
Figure 4. Trials comparing antacids with sucralfate in prevention of clinically important bleeding. Abbreviations as in Figure 1.
Typical
odds
bleeding
Control Obs Tot
25 75 36 46 50
0 0 1 2 1
25 80 38 40 50
CI
Odds Ratio
95% Lo
1.00 1.00 0.14 0.86 0.14
1.00 1.00 0.00 0.12 0.00
0.65 Log Odds .1
Ratios .5
1
2
Cl Hi 1.00 i°00 7.20 6.39 6.82
0.16-2.49 i0
i00
ratio
ference between antacids and prostaglandins in their effect on clinically important bleeding. None of the foregoing point estimates or CIs changed significantly when unpublished data were excluded from the analyses. However, in most situations, the CIs narrowed with inclusion of the unpublished data. Comparison of various prophylactic drugs in trials from which mortality rates are available (Table II) shows that all of the 95% CIs include unity (an odds ratio of 1 suggesting no treatment effect). However, the CIs around the mortality difference between antacids and placebo/controls (common odds ratio 1.06, 95% CI 0.67 to 1.66) and histamine2-receptor antagonists and placebo/controls (common odds ratio 0.80, 95% CI 0.54 to 1.18) include a clinically important reduction in mortality. Therefore, this overview does not exclude the possibility that mortality is reduced by drugs used for stress ulcer prophylaxis. There was no statistical heterogeneity of the results of trials evaluating the outcome of clinically significant bleeding or mortality. However, with regard to overt bleeding, when the comparison between histamine receptor antagonists and no treatment was made, there was variation beyond the degree that one would expect by chance if the true effect size were the same in each study. Although the common odds ratio calculated from the results of heterogeneous studies does not take into account variability between studies, on the other hand, in the presence of heterogeneity, a common odds ratio
may be a more accurate estimate of the effectiveness of treatment than the odds ratio of any one of the individual studies. Most authorities would agree that a systematic search for an explanation of the source of heterogeneity is in order when its presence is found. Odds ratios did not differ systematically across studies according to any of the study covariates or the individual methodology scores. Therefore, we postulated that the heterogeneity of this subset of odds ratios comparing histamine-2-receptor antagonists and no treatment for overt bleeding could be due to some other unmeasured interstudy variation. For example, the proportion of patients in each group with risk factors for bleeding, such as coagulopathy, was not recorded in every study.
COMMENTS This meta-analysis was performed to examine the differential effect of stress ulcer prophylaxis on overt bleeding, clinically significant bleeding, and mortality in the critically ill population. Meta-analysis takes a more structured approach to data synthesis than does a traditional narrative review. Our search for relevant literature was comprehensive; an extensive search of both published and unpublished literature was performed, and experts and governing agents were contacted to minimize the possibility of a publication bias. The study selection criteria were well defined, and qualiW assessment of the primary studies was performed by two authors unaware of the study results. The techniques
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of statisticalanalysis used in this meta-analysis were among those that have become standard for scientificoverviews [60,61].Therefore, methodologic criteriafor scientificoverviews [61,62]were met in this meta-analysis. Our results confirm previous findings that stress ulcer prophylaxis with antacids or histamine receptor antagonists significantlyreduces the incidence of overt hemorrhage in the criticallyillpopulation [1].This isthe firstquantitative review, however, in which a significantreduction in clinicallyimportant gastrointestinal hemorrhage is documented with administration of histamine-2-receptor antagonist therapy as compared with no treatment. Furthermore, resultsof this meta-analysis indicate that histamine receptor antagonists are superior to antacids in their ability to prevent overt bleeding, in contrast to previous reviews suggesting their equivalence [1,30].Results also suggest a trend favoring histamine-2-receptor antagonists over antacids in the prevention of clinically important bleeding. Data are insufficientto determine the effect of sucralfate in comparison with antacids and histamine-2-receptor antagonists in preventing clinically important bleeding. Results of this meta-analysis support the recommendation that prophylaxis be administered to a large proportion of critically ill patients [4,6-10,12,13,57].In fact, control of gastric p H has been described as standard practice in intensive care units in North America and Europe [14-16]. However, there are several reasons why this practice m a y not be in the best interest of patients. First, many investigators believe that the incidence of clinically important gastrointestinal bleeding has, independent of the use of prophylaxis, decreased considerably in the last decade [1,2,50]. Factors responsible may include improved methods of ventilatory support, more aggressive shock management, early attention to nutrition in the critically ill,control of bleeding diatheses,and the decreasing use of steroids in septic shock. Second, there may be patients at appreciable risk and patients at negligible risk of bleeding. The characteristicsof the latter group, from which prophylaxis can be safely withheld, are yet to be precisely defined. Finally, the decision as to which criticallyillpatients warrant stress ulcer prophylaxis and which agent should be administered must be based upon clinicalcriteriaevaluating risk factors for bleeding, and an assessment of the risk/benefitratio of each prophylactic agent. For a prophylactic intervention to be useful,itshould prevent a clinicallyimportant outcome, and itsbenefits should outweigh potential side effects. Concern has been raised that gastric pH-altering drugs, through decreased gastricacidi526
ty, result in colonization of the stomach with gramnegative organisms, which leads to an increased incidence of aspiration pneumonia. However, results have not been consistent [17,22,35,38,39,47,53].A scientificoverview of these randomized trials has not supported this hypothesis; in fact, the trends were for a decreasing incidence of pneumonia in patients receiving pH-altering drugs [63]. This overview was limited by the fact that only eight of the 42 randomized trialsof stressulcer prophylaxis reported pneumonia prevalence. Therefore, further trialsdirectly addressing this issue are warranted. In summary, the 50% reduction in clinicallyimportant bleeding mandates use of prophylaxis in criticallyillpatients at appreciable risk of bleeding. Further research is needed to profilethe patients in w h o m the risk of bleeding is sufficientlylow that stress ulcer prophylaxis can be safely withheld.
ACKNOWLEDGMENT We are indebted to the authors of the primary studies included in this review for their participation and support. We would also like to thank Dr. Loren Laine for his thoughtful review of the manuscript.
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