Misoprostol Versus Antacid Titration for Preventing
`Stress Ulcers in Postoperative Surgical ICU Patients
`
`MICHAEL J. ZINNER, M.D., ERIC B. RYPINS, M.D., LOUIS R. MARTIN, M.D., OLGA JONASSON, M.D.,
`EDDIE L. HOOVER, M.D., EDWARD A. SWAB, M.D., PH.D., and T. DANIEL FAKOUHI, PH.D.
`
`Bleeding from gastroduodenal lesions is a potentially life-threat-
`ening complication in patients subjected to overwhelming phys-
`iologic stress. Titration of gastric contents with antacid was the
`first prophylactic treatment regimen proved to decrease the in-
`cidence of bleeding and remains the standard by which other
`methods are compared. We designed a prospective double-blind,
`double-placebo study comparing the effectiveness of antacid ti-
`tration with fixed doses of a synthetic prostaglandin El analog
`(misoprostol) for preventing stress gastritis and bleeding. To
`assess the success of each treatment regimen, we did endoscopic
`examinations before operation, 72 hours after operation, and
`after the patient had completed the study. A total of 281 patients
`entered the study (140 misoprostol, 141 antacid). The two groups
`were comparable with respect to preoperative parameters and
`type of operation. We found no statistically significant differences
`between the two treatment groups concerning upper gastroin-
`testinal tract lesions or serious adverse effects. No clinically ev-
`ident upper gastrointestinal hemorrhage occurred in either group.
`Mean gastric pH, measured at two-hour intervals during the
`initial 72 hours, was maintained at 4.0 or higher in both groups.
`We conclude that fixed-dose misoprostol is as effective as in-
`tensive antacid titration in preventing stress ulcers and bleeding
`in surgical ICU patients.
`
`Ni r EARLY ALL UNTREATED patients in intensive
`care units develop either endoscopically proved
`gastroduodenitis or stress ulcers unless prophy-
`laxis is instituted. 1-3 Without preventive treatment, stress
`bleeding will occur in 6% to 25% of patients, and in this
`group the mortality rate approached 80%.2 Respiratory
`failure, sepsis, trauma, heart failure, peritonitis, and renal
`failure are associated with higher rates of stress ulcers and
`bleeding.2'4'5 Currently the most effective prophylaxis is
`hourly titration of gastric pH to approximately 4.0 with
`antacid.6 While antacid treatment has proved efficacy, it
`is very labor intensive.
`
`Correspondence and reprint requests: Michael J. Zinner, M.D., Pro-
`fessor and Chairman, Department ofSurgery, UCLA School ofMedicine,
`Los Angeles, CA 90024-1749.
`Accepted for publication: February 21, 1989.
`
`From the Departments of Surgery, Johns Hopkins Medical
`Institutions, Baltimore, Maryland, University of California,
`Irvine, California, the Long Beach VA Medical Center, Long
`Beach, California, Milton S. Hershey Medical Center,
`Hershey, Pennsylvania, Cook County Hospital, Chicago,
`Illinois, Health Science Center, Brooklyn, New York,
`and from G. D. Searle & Co., Skokie, Illinois
`
`An alternative to antacids are H-2 blockers; the best
`studied is cimetidine. However cimetidine may not be as
`effective as antacids for preventing stress-induced lesions
`and bleeding. Some reports claim that they are equally
`effective,6 while others suggest that fixed-dose cimetidine
`does not consistently maintain gastric pH higher than 3.5.7
`Failure of cimetidine to control acidity in stressed surgical
`ICU patients ranges from 15% to 35% and is associated
`with upper gastrointestinal bleeding, especially in patients
`with high stress-severity indexes and sepsis.7'8
`A new alternative to cimetidine and antacids is miso-
`prostol, a prostaglandin E, analog that has cytoprotective
`properties and diminishes gastric acid secretion. It is thus
`potentially useful for preventing stress ulcers.2'9 In animals
`it has been shown to protect the gastric mucosa against
`salicylate injury and ulcer formation.10 In man miso-
`prostol inhibits basal and stimulated gastric acid secretion
`and protects the gastric and duodenal mucosa against a
`variety of injurious substances." We designed this study
`to compare the efficacy of misoprostol with antacid titra-
`tion ofgastric pH for preventing stress ulcers and bleeding
`in postoperative surgical ICU patients.
`
`Materials and Methods
`Fifteen physician-investigators at 16 university-asso-
`ciated medical centers enrolled 371 patients scheduled to
`undergo major surgical procedures. The patients were ex-
`pected to require at least 48 hours of postoperative mon-
`itoring in an ICU. Subjects with additional risk factors
`
`590
`
`

`

`Vol. 210 . No. 5
`
`IN SURGICAL ICU PATIENTS
`STRESS ULCER PREVENTION:
`
`such as sepsis, trauma, electrolyte imbalance, diabetes,
`major burns, respiratory failure requiring ventilator as-
`sistance, congestive heart failure, arrhythmias requiring
`medication, or a need for steroids were included. Major
`exclusion criteria were active peptic ulcer disease, esoph-
`ageal, gastric, or duodenal malignancies, esophageal var-
`ices, gastric outlet obstruction, acute renal failure, con-
`current therapy with salicylates, nonsteroidal anti-in-
`flammatory drugs, anti-ulcer therapy, or anti-neoplastic
`agents. The Institutional Review Board at each of the
`study sites approved the protocol. Each patient gave writ-
`ten informed consent.
`Before randomization each patient underwent an en-
`doscopic examination of the upper gastrointestinal tract
`to exclude pre-existing lesions. The appearance ofthe gas-
`tric and duodenal mucosa was rated according to a stan-
`dard grading scale (Table 1). Endoscopic examinations
`were repeated after 72 hours of drug administration and
`at completion of the study.
`Acceptable candidates were randomly assigned to each
`group and they received either tablets containing 200 mcg
`of misoprostol (Searle Inc., Skokie, IL) every four hours
`plus placebo liquid antacid every two hours, or placebo
`tablets every four hours plus magnesium-aluminum hy-
`droxide liquid antacid (Maalox TC, Rohrer Pharmaceu-
`ticals, Fort Washington, PA) every two hours.
`Tablets were dissolved in 20 mL of water and admin-
`istered six times daily through a nasogastric tube, or were
`given orally if no tube was in place. Antacid or placebo
`liquid was administered every two hours at a dose of 10,
`20, 40, or 80 mL, increasing the dose upward as necessary
`during the first 72 hours to maintain gastric pH at 4.0 or
`higher. Samples were aspirated through the nasogastric
`tube every two hours and gastric pH was measured using
`litmus paper. After 72 hours repeat endoscopic exami-
`nations were done and the liquid antacid or placebo was
`titrated downward to 20 mL every four hours. Study pa-
`tients were treated for a maximum of 14 days or until
`they were able to take 1500 calories orally for at least one
`day. All patients entered into the protocol were evaluated
`
`TABLE 1. Endoscopic Evaluation of Gastroduodenal Mucosa
`
`Grade
`
`Description
`
`0
`I
`2
`
`3
`4
`
`5
`6
`
`7
`
`Normal Mucosa
`Slight diffuse mucosal hyperemic changes
`A single hemorrhagic lesion or one area of marked
`patchy erythema
`2-5 hemorrhagic lesions
`6-10 hemorrhagic lesions partially confluent or connected
`with areas of patchy erythema
`Large area of confluent hemorrhagic lesions
`Erosions with white bases surrounded by erythematous
`edges
`Well-defined ulcer craters
`
`591
`for safety. Patients who met the following four criteria
`were evaluated for outcome: (1) completed at least three
`days in the study; (2) took at least 80% of the assigned
`medication; (3) did not withdraw from the study except
`for side effects ofthe medication; (4) had sufficient follow-
`up endoscopy information to permit outcome evaluation.
`Therapeutic success required absence of clinically ev-
`ident upper gastrointestinal bleeding and satisfactory pre-
`vention of endoscopically proved gastrointestinal lesions
`during the treatment period. We defined clinically signif-
`icant bleeding as hematemesis, melena, hematochezia, or
`red blood through the nasogastric tube that did not im-
`mediately clear after a 500-mL normal saline lavage; or
`a drop in hemoglobin of 2 g/% or more for which other
`causes of bleeding had been ruled out. The cause of any
`significant postoperative bleeding was investigated en-
`doscopically.
`Endoscopic scores were used in two ways to evaluate
`therapeutic success. In the first case, we used a strict cri-
`terion and defined successful prophylaxis as no increase
`from the initial preoperative endoscopic score. In the sec-
`ond case, we used a looser criterion and considered pro-
`phylaxis successful if the gastric or duodenal lesion score
`did not increase to 5 or more (erosions or ulcer craters).
`
`Statistical Analysis
`
`The results from all 16 study sites were pooled. The
`principal objective was to compare the efficacy of miso-
`prostol and antacid in preventing peptic stress bleeding
`and ulcers in surgical ICU patients. Because this was a
`multicenter trial, the analysis tested for consistency of re-
`sults among investigators using log-linear analysis with a
`model that included investigator, treatment group, out-
`come, and interactions factors. To assess whether the ran-
`domization was successful, the two treatment groups were
`compared with respect to sex, race, and age using the
`Pearson chi square test. Outcome assessment was based
`on gastrointestinal lesion scores or upper gastrointestinal
`bleeding and required that the patient complete the study.
`The ratio of patients satisfying the four criteria described
`above for successful prophylaxis were compared for both
`groups. In addition the ratio of patients in each group
`with initial endoscopic scores of 0 or 1 and follow-up
`scores of less than 2 (lesion prevention) or less than 5
`(prevention ofclinically significant lesions) was compared.
`These comparisons were made using Pearson's chi square
`test or Fisher's exact test. The distribution of initial lesion
`scores in both treatment groups was tested using a Wil-
`coxon two-sample test. The proportions of patients in the
`two treatment groups experiencing diarrhea were com-
`pared using log-linear analysis. Differences between the
`two groups with respect to laboratory values were com-
`pared using analysis of variance. The protocol was de-
`
`

`

`592
`signed to require a minimum of 270 fully evaluable pa-
`tients to complete the study (135 in each group). This
`sample size is sufficient to detect differences of 20% or
`more between two treatment groups (p = 0.05; power
`= 0.90) with two-sided tests of significance. That is, this
`study size should detect a clinically significant difference
`between misoprostol and antacid that is greater than 20%.
`
`Results
`
`A total of 371 subjects were enrolled; 187 patients re-
`ceived misoprostol and 184 received antacids titrated to
`maintain gastric pH at or above 4.0. The study population
`included the following operative categories: trauma 72
`(19.4%); emergency general surgery 95 (26.6%); elective
`general surgery 93 (25.1 %); elective cardiothoracic surgery
`10 (2.6%); elective vascular surgery 87 (23.5%); and renal
`transplant 14 (3.8%).
`There were no statistical differences between the two
`treatment groups with respect to age, sex, or race (Table
`2). They were also comparable in mean height, weight,
`and vital signs on admission, and these did not differ with
`respect to study site. Initial gastric lesion scores were 0 or
`1 in 88% ofthe patients, and initial duodenal lesion scores
`were 0 or 1 in 96% of the patients, with no significant
`differences between the two treatment groups (p = 0.141
`and 0.848, respectively).
`All 371 patients were evaluated for safety of the pro-
`phylaxis regimen. Of these, 141 receiving misoprostol and
`140 receiving antacid met the four criteria for evaluation
`of primary outcome.
`
`TABLE 2. Characteristics ofStudy Population
`
`Treatment Group
`
`Misoprostol
`
`Antacid
`
`p value
`
`Total number with complete
`information
`Age (years)
`<30
`30-39
`40-49
`50-59
`60-69
`>70
`Sex
`Male
`Female
`Race
`Caucasian
`Negro
`Hispanic
`Other
`
`* Wilcoxon Rank-Sum.
`t Chi square, 1 d.f.
`t Chi square, 3 d.f.
`
`187
`
`25
`13
`19
`38
`60
`32
`
`152
`35
`
`100
`62
`18
`7
`
`0.686*
`
`0.638t
`
`0. 146t
`
`181
`
`24
`17
`19
`46
`51
`24
`
`153
`24
`
`99
`72
`8
`4
`
`ZINNER AND OTHERS
`
`Ann. Surg. * November 1989
`
`TABLE 3. Patients with Follow-up Endoscopic Scores Less than 2
`
`Treatment Group
`
`Misoprostol*
`
`Antacid*
`
`p valuet
`
`72-hour gastric
`Endoscopy
`72-hour duodenal
`Endoscopy
`Final gastric
`Endoscopy
`Final duodenal
`Endoscopy
`
`56/147
`(38.1%)
`143/156
`(91.7%)
`61/120
`(50.8%)
`117/124
`(94.4%)
`
`53/142
`(37.3%)
`150/159
`(94.3%)
`63/123
`(51.2%)
`126/136
`(92.6%)
`
`0.892
`
`0.352
`
`0.952
`
`0.578
`
`* All enrolled patients with initial endoscopic scores of 0 or 1.
`t Chi square comparison.
`
`Evaluation ofEfficacy
`The proportion of patients satisfying the strict criteria
`of therapeutic success (no change in lesion score) was
`slightly higher in the antacid group (31.4% antacid vs.
`26.2% misoprostol), but the difference was not statistically
`significant (p = 0.337). Using the looser criteria (mucosal
`scores remaining less than 5), the overall success rates
`were also similar (69.2% antacid vs. 70.5% misoprostol;
`p = 0.820). No clinically evident bleeding occurred among
`the patients ofeither treatment group. Comparable num-
`bers of patients completed the 14 days of treatment or
`were released earlier, having met the dietary requirement.
`By the eighth day, only 16% ofthe misoprostol group and
`21% of the antacid group remained in the ICU (p = ns).
`Total time of nasogastric medication administration was
`also somewhat shorter in the misoprostol group (655 pa-
`tient days vs. 731 patient days in the antacid group), but
`again these differences were not statistically significant.
`Follow-up lesion scores were compared for all patients
`enrolled in the two groups with initial endoscopic scores
`of 0 or 1 and follow-up scores of less than 2. Results for
`the 72-hour and final gastric follow-ups and for the 72-
`hour and final duodenal follow-ups were comparable be-
`tween treatments, with no statistically significant differ-
`ences (Table 3). When follow-up lesion scores of less than
`5 were counted as successful prevention of clinically sig-
`nificant lesions (Table 4), the numbers and proportions
`of successes were greater in both treatment groups, but
`there were no statistically significant differences between
`groups. We repeated these analyses, stratifying by the
`number of risk factors present (all patients, 2 or more
`factors, 3 or more factors) to determine if there were
`subgroups in whom one of the treatments may have been
`more effective but we found no significant differences be-
`tween the treatment groups.
`
`Analysis ofpH
`The initial pH measurements were similar in the two
`groups. On the first postoperative day, pH was higher in
`
`

`

`TABLE 4. Patients with Follow-up Endoscopic Scores Less than 5
`
`VOl. 210 *-NO. S
`
`Treatment Group
`
`72-hour gastric
`Endoscopy
`72-hour duodenal
`Endoscopy
`Final gastric
`Endoscopy
`Final duodenal
`Endoscopy
`
`Misoprostol*
`
`Antacid*
`
`pValuet
`
`121/147
`(82.3%)
`153/156
`(98.1%)
`108/120
`(90.0%)
`120/124
`(96.8%)
`
`115/142
`(81.0%)
`158/159
`(99.4%)
`108/123
`(87.8%)
`134/136
`(98.5%)
`
`0.771
`
`0.305
`
`0.586
`
`0.346
`
`STRESS ULCER PREVENTION IN SURGICAL ICU PATIENTS
`593
`due to underlying disease states or surgical complications.
`All deaths and serious complications were reviewed by
`the Institutional Review Boards ofeach respective medical
`center and none of these deaths were attributed to study
`medications.
`The most common adverse event was diarrhea, defined
`as three or more watery stools within a 24-hour period,
`representing a clinically significant change from the pa-
`tient's normal habits. We found this in 25.3% ofthe miso-
`prostol group and in 22.8% of the antacid group, an in-
`significant difference (p = 0.58). This difference was sim-
`ilar to those found in other studies.'3
`Statistically
`significant differences between the two groups were ob-
`served in some laboratory tests, namely serum bicarbonate
`and serum phosphorus levels. An average increase of 1.75
`mEq/l in serum bicarbonate concentration occurred in
`the antacid treated group compared to a decline of 0.23
`mEq/L in those treated with misoprostol. While this dif-
`ference is statistically significant (p = 0.001) it is of ques-
`tionable clinical significance. Of 163 patients treated with
`antacid, 33 (20%) developed final serum bicarbonate con-
`centration elevated to 30 mEq/L. Among misoprostol re-
`cipients only 16 of 175 (9%) had similar elevations (p
`= 0.004).
`Phosphorus concentrations fell 0.38 mg/dL in the ant-
`acid group, but rose by a similar amount in misoprostol
`recipients (p = 0.003). Of 132 patients treated with ant-
`acid, 32 (24%) developed final inorganic phosphorus con-
`centrations ofless than 2.5 mg/dL. Only 21 of 144 patients
`
`* All enrolled patients with initial endoscopic scores of 0 or 1.
`t Chi-square comparison.
`
`both groups, probably reflecting the stress and trauma of
`anesthesia and operations on acid secretion. Thereafter
`pH levels fell in both groups, but remained consistently
`higher in the antacid group. Mean pH levels in the miso-
`prostol group were always at or above 4.0 (Fig. 1), reflect-
`ing the antisecretory properties of misoprostol in doses
`greater than 100 ,ug.'2 In both groups there were statisti-
`cally significant inverse correlations between follow-up
`lesion scores and average pH levels in individual patients.
`
`Safety
`
`Fifteen patients in the misoprostol group and 13 in the
`antacid group died during the study or shortly thereafter
`
`MISOPROSTOL VS. ANTACID IN PREVENTING UGI STRESS
`ULCER/BLEEDING IN ICU PATIENTS
`
`to~~~~~~~~~~~~~~ .IS
`
`!
`
`..
`
`.
`
`--.......
`
`I... *-o..- -. S... 0. 0 .
`
`S...
`
`W..- -.
`
`D...
`
`-.----.. a @
`
`..
`
`*..
`
`-----------------------------
`
`4
`
`8
`
`12
`
`16
`
`20
`
`24
`
`4
`
`S
`
`12
`
`16
`
`20
`
`24
`
`4
`
`S
`
`12
`
`16
`
`20
`
`24
`
`7 6 5
`
`4 3 2
`
`0
`
`a
`D
`
`GASTRIC
`pH
`
`HOUR
`------------ Day 1--------------------------------- Day 2-----------------f------------------ Day 3-------------
`a Antacid
`°
`Misoprostol
`FIG. 1. Graph showing the pooled values for pH at 1-hour intervals. The gastric pH levels fell in both groups but were consistently higher in the
`antacid group. The average pH in both groups remained greater than 4.0.
`
`

`

`594
`(15%) in the misoprostol group had phosphorus levels of
`less than 2.5 (p = 0.042).
`
`Discussion
`Because acute gastrointestinal bleeding from stress ul-
`ceration can be life-threatening in postoperative ICU pa-
`tients,'i3 some form of preventive medication is usually
`given. Maintaining the gastric pH of 4.0 or greater by
`titrating with antacids is the most effective prevention of
`stress ulcer bleeding, although it is time-consuming.5'8 In
`their prospective controlled trial ofthis regimen, Hastings
`et al.'4 reduced bleeding rates in ICU patients from 25%
`in a placebo group to 4% in a group receiving antacid.
`A fixed-dose drug regimen that does not require pH
`monitoring and is as effective as antacid titration, would
`be an important advance in ICU care, allowing more ef-
`ficient use of nursing staff. Initially H-2 blockers seemed
`promising. However several studies have shown that ci-
`metidine is not as effective as antacid in preventing stress-
`induced bleeding and is most likely to fail in patients with
`multiple risk factors or sepsis.7 8 The association between
`successful prophylaxis of stress bleeding by antacid and
`the maintenance of pH level at 4.0 or greater has been
`described repeatedly in the literature. In Hastings' study,'4
`gastric pH in the antacid group stayed between 7.0 and
`8.0, but in untreated controls it varied widely (from 1.0
`to 8.0). Zinner et al.8 found that antacids consistently
`kept the pH at 4.0 or greater, cimetidine was less reliable
`than antacids, and untreated patients had a mean pH
`value of 3.0. In a placebo-controlled trial of cimetidine
`for preventing upper gastrointestinal bleeding in medical
`ICU ventilator-dependent patients, mean pH during ci-
`metidine treatment was 4.8, compared to 3.1 in patients
`give a placebo.'5 An explanation of the disparate results
`of studies of H-2 blockers is suggested by Martin et al.7
`and may reflect the incidence ofsepsis in the various study
`populations. They found that cimetidine was most likely
`to fail to maintain gastric pH greater than 4.0 in patients
`with sepsis as a risk factor. However stratifying the groups
`with respect to the number of risk factors did not produce
`data supporting the use of either treatment in our study.
`Mean pH levels were consistently higher in the antacid
`group, an expected result of periodic antacid titration. In
`the misoprostol group, the mean pH level was consistently
`greater than 4.0. This pH level can probably be attributed
`to the acid antisecretory effect of misoprostol in doses
`greater than 100 ,tg as were given in this study.'2"16
`A unique feature ofthis study was routine postoperative
`evaluation of the upper gastrointestinal tract by endos-
`copy. Previous prospective trials used bleeding as the de-
`pendent variable. However we did not believe that this
`variable was sensitive enough to determine the condition
`of the mucosa. We wanted to learn whether effective
`treatment prevents stress ulcers as well as decreases the
`
`ZINNER AND OTHERS
`
`Ann. Surg. * November 1989
`
`rate of upper gastrointestinal tract bleeding. We found
`that misoprostol and antacid were equally effective in
`preventing upper gastrointestinal lesions, success being
`defined as no increase in gastric or duodenal lesion scores
`at 72 hours. Misoprostol had a success rate of 39.4% and
`the antacid success rate was 39.3% (p = 0.991), that is,
`approximately 60% of patients developed some increase
`in gastric lesion score, and the increases were equal in the
`two groups.
`With respect to side effects, the two medications were
`similar. Both misoprostol and antacids have been reported
`to produce diarrhea. In this study both treatment groups
`experienced a similar incidence of diarrhea (misoprostol,
`23%; antacid, 25%) in rates similar to previous trials.'3
`There were statistically significant differences in some
`laboratory studies between the two groups that we believe
`were probably not clinically significant. Patients receiving
`antacids developed a significant increase in serum C02,
`while patients receiving misoprostol did not. The slight
`difference in serum CO2 levels is probably not clinically
`significant, although in individual patients hypercarbia
`associated with metabolic alkalosis can impair the weaning
`of patients from ventilators. The decrease in serum phos-
`phate levels seen in the antacid group could be due to
`binding of phosphate to antacid in the gastrointestinal
`tract.
`Essentially we could find no important differences with
`respect to safety and efficacy between fixed-dose miso-
`prostol and antacid titration ofgastric acidity with a mag-
`nesium aluminum hydroxide antacid in a randomized
`group of 281 patients. Thus the appropriate choice of a
`drug for stress ulcer prophylaxis must rest on other factors
`such as price and convenience. To date no price has been
`determined for misoprostol. However it is probably fair
`to say that it will be more expensive than antacids. If
`fixed-dose misoprostol is to be compared with antacids
`for stress ulcer prophylaxis, the additional time and
`equipment required for nurses to titrate gastric acid to
`levels greater than 4.0 with antacids should also be con-
`sidered. We expect that this cost is considerable.
`We conclude that fixed-dose misoprostol and antacid
`titration are similarly effective in preventing clinically ev-
`ident upper gastrointestinal tract hemorrhage and the de-
`velopment of endoscopically proved stress lesions. Al-
`though at this time the cost of treatment with misoprostol
`is not known, it will probably be more expensive than
`antacids. However misoprostol has advantages over ant-
`acid titration in ease of administration and should sig-
`nificantly reduce the amount of nursing time required for
`stress ulcer prophylaxis.
`
`Acknowledgments
`This study represents the work ofthe following participating physicians:
`P. Bright-Asare, M.D., King/Drew Medical Center, Los Angeles, CA;
`
`

`

`Vol. 210-No. 5
`
`STRESS ULCER PREVENTION IN SURGICAL ICU PATIENTS
`
`F.C. Cerra, M.D., University of Minnesota Hospitals, Minneapolis, MN;
`M.L. Foegh, M.D., Georgetown University Hospital, Washington, DC;
`S.D. Hershey, M.D., Denver General Hospital, Denver, CO; E.L. Hoover,
`M.D., Health Science Center, Brooklyn, NY; 0. Jonasson, M.D., Cook
`County Hospital, Chicago, IL; R.G. Knodell, M.D., Minneapolis VA
`Medical Center, Minneapolis, MN; C.M. Kruss, M.D., Hines VA Hos-
`pital, Hines, IL; L.F. Martin, M.D., Milton S. Hershey Medical Center,
`Hershey, PA; K.M. Quint, M.D., VA Medical Center, Fresno, CA; W.P.
`Ritchie, M.D., Temple University Hospital, Philadelphia, PA; E.B. Ry-
`pins, M.D., University of California, Irvine, CA; L.W. Way, M.D., VA
`Medical Center, San Francisco, CA; J.W. Weigelt, M.D.: University Texas
`Health Science Center, Dallas, TX; M.J. Zinner, M.D., Johns Hopkins
`Medical Institutions, Baltimore, MD.
`We also wish to thank L.G. Deysach, M.A., C. Lino, W. Martin-
`Barron, M. Moran, M.D., C.H. Nisses, B.A., and J. Souchek, Ph.D.,
`G.D. Searle & Co., Skokie IL, for help in preparing this study report.
`
`References
`
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`dilemma of stress gastric bleeding. Arch Surg 1971; 102:266-
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`2. Banks S. Stress ulcers-prevention of gastrointestinal bleeding in
`critical care units. Med J Aust 1985; 142:517-520.
`3. Robbins R, Idjadi F, Stahl WM, Essiet G. Studies ofgastric secretion
`in stressed patients. Ann Surg 1972; 175:555-562.
`4. Schuster DP, Rowley H, Feinstein S, et al. Prospective evaluation
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`5. Skillman JJ, Bushnell LS, Goldman H, Silen W. Respiratory failure,
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