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Considerations for selection of parenteral histamine (H2)-receptor antagonists
Considerations for Selection of Parenteral Histamine (H&Receptor Antagonists
M. MICHAEL Boston.
WOLFE,
M.D.
Parenteral histamine (H&receptor antagonists are safe and effective therapy for the prophylaxis of stress-related erosive syndrome. Of the three agents available, parenteral cimetidine is the most widely studied; parenteral formulations of ranitidine and famotidine have not been investigated as extensively. Parenteral cimetidine appears to be effective in reducing incidence and complications associated with gastrointestinal hemorrhage caused by stressrelated erosive syndrome, although its effects on bleeding that has already begun are not clear. Antacids are also effective in decreasing the incidence of stress-related gastrointestinal hemorrhage, but they are inconvenient and expensive to administer. Primed continuous infusions of cimetidine may be the most useful regimen for prophylaxis of stress-related erosive syndrome in critically ill patients; the evidence available on the efficacy of continuous infusions of ranitidine is inconsistent, and very few data are available on the value of famotidlne. Direct comparative cllnical trials are needed to assess definitively the efficacy of primed continuous infusions of cimetidine or other Hz-receptor antagonists versus that of antacid therapy.
Massachusetts
From the Harvard Digestive Diseases Center, the Harvard-Thorndike Laboratory and Charles A. Dana Research Institute, Division of Gastroenterology, Beth Israel Hospital and Harvard Medical School, Boston, Massachusetts. Requests for reprints should be addressed to Dr. M. Michael Wolfe, Assistant Professor of Medicine, Division of Gastroenterology, Beth Israel Hospital, 330 Brookline Avenue, Boston, Massachusetts 02215.
82
December
18,1987
The American
Journal
The physiology of gastric acid secretion is very complex. Much has been learned in the past decade through the establishment of methods for study of parietal cells. These techniques include both the preparation of oxyntic glands, as well as methods for isolating dispersed parietal cells. The latter technique has enabled investigators to identify specific receptors on the parietal cell basolateral membrane that regulate hydrogen ion generation and secretion. It has long been known that histamine provides a potent stimulus for the secretion of acid by parietal cells. Recent data suggest that histamine binds to a specific receptor on the parietal cell basolateral membrane; this interaction causes an increase in adenylate cyclase activity, which in turn increases the level of intracellular cyclic adenosine monophosphate. Protein kinase activity is enhanced and, eventually, the generation of hydrogen ions is stimulated. Despite the recognition that histamine stimulates acid secretion, it was not until 1966, when Ash and Schield [l] described HI and H2 receptors for histamine, that the possibility of inhibiting acid secretion with antihistamines was proposed. Beginning in 1968, Black and colleagues [2,3] described selective histamine (Hz)-receptor blockade for acid secretion, thus beginning the search for pharmacologic agents that could be used clinically to effectively suppress acid secretion. Widespread use of the first selective H-receptor antagonist, burimamide, was limited by its decreased oral bioavailability. The first oral Hz-
of Medicine
Volume
83
(suppl8A)
SYMPOSIUM
TABLE
I
Use of Histamine
Hz-Receptor
Antagonists
Approved indications Duodenal ulcer (active and prophylaxis) Gastric ulcer Zollinger-Ellison syndrome Gastroesophageal reflux disease Systemic mastocytosis Unapproved indications but used with good rationale NSAID therapy (active erosion/ulcer and prophylaxis) Stress-related erosive syndrome prophylaxis Prophylaxis against acid aspiration Impaired T lymphocyte-mediated immunity Active upper gastrointestinal hemorrhage due to acid-peptic disease Unapproved indications and used without good evidence for benefit Idiopathic gastritis Nonulcer dyspepsia Active upper gastrointestinal hemorrhage (unknown cause) Nonspecific symptoms (i.e., diarrhea, nausea) l
l
l l l
l
l
l
l
l
l
l
l
l
NSAID
= nonsteroidal
anti-inflammatory
drug.
antagonist to be reliably absorbed in the gastrointestinal tract was metiamide. Although metiamide was shown to be effective in decreasing gastric acid secretion and was useful for treating patients with duodenal ulcer disease and Zollinger-Ellison syndrome, clinical application of this agent was limited by serious adverse effects, principally agranulocytosis [3]. This serious effect was caused by the presence of a thiourea group on the side chain of the metiamide molecule. When this side chain was replaced with a cyanoguanidine group, cimetidine was created. Cimetidine became the first Hz-receptor antagonist to be clinically useful in the suppression of gastric acid secretion. Following the introduction of cimetidine in the United States in 1977, ranitidine and, more recently, famotidine have become available for treatment of acid and peptic disorders. As a class, the Hz-receptor antagonists are unrivaled in their efficacy in treating duodenal ulcer disease, as well as in their safety profile. Although differences do exist with regard to their potency and biologic half-life, all three drugs are similar in their ability to heal duodenal ulcers and, when used orally, are virtually free of adverse effects. The parenteral formulation of cimetidine has been thoroughly studied; less information is available regarding the efficacy of parenteral ranitidine. Although initial reports appear favorable, information presently available regarding the parenteral use of famotidine, particularly in critically ill patients, is scarce. Minor differences do exist among these three drugs. When selecting a specific Hz-receptor antagonist (or any class of drug) for clinical use, two primary selection criteria should be considered. The more important of these is the efficacy of the drug. After efficacy is demonstrated, the risk-benefit ratio of the drug must be evaluated. receptor
December
18, 1987
INDICATIONS
ON Hz-RECEPTOR
ANTAGONIST
FOR PARENTERAL
THERAPY-WOLFE
USE
In general, parenteral Hz-receptor antagonists are indicated for use in hospitalized patients with pathologic hypersecretory conditions or with intractable duodenal ulcer disease. They are also approved as alternatives to the oral dosage form for short-term use in patients who are unable to take oral medications. Although these are the only Food and Drug Administration-approved indications for these drugs, Hz-receptor antagonists are used clinically for many other pathologic conditions (Table I). Among the disorders listed in Table I, the use of HPreceptor antagonists in gastrointestinal hemorrhage has been studied most extensively. Although these drugs have been used for treatment of gastrointestinal hemorrhage, unequivocal evidence for efficacy is lacking. Zuckerman and colleagues [4] reported the results of a large, multicenter trial evaluating cimetidine in the treatment of patients with upper gastrointestinal hemorrhage. Cimetidine was found to be no better than placebo for either the treatment of active gastrointestinal bleeding or in prevention of rebleeding. Basso and colleagues [5] also reported that ranitidine did not alter the rate of bleeding and death, surgical intervention, or transfusion requirements in patients with upper gastrointestinal bleeding when compared with placebo. Because of the relatively small number of patients enrolled in these studies, Collins and Langman [6] compiled data from 27 randomized trials performed worldwide to evaluate the use of cimetidine and ranitidine in the treatment of upper gastrointestinal hemorrhage. Unfortunately, there was a marked lack of uniformity in these trials with regard to inclusion and exclusion criteria, dose of medication, and the clinical monitoring parameters. The authors demonstrated that Hz-receptor antagonists were effective in reducing both the need for surgery and mortality from gastrointestinal bleeding. However, no significant effect of Hz-receptor antagonists on hemorrhage itself was apparent. The authors also stated that the randomization of at least 10,000 patients would be required in order for a prospective trial to demonstrate a significant effect of these drugs on the incidence of bleeding. Therefore, although it is difficult to recommend the unrestricted use of Hz-receptor antagonists for all gastrointestinal hemorrhage at this time, there appears to be good rationale for their use when bleeding caused by acid-peptic disease is suspected. STRESS
ULCER PROPHYLAXIS
The precise pathophysiology of stress-related erosive syndrome is not firmly established; however, it is clear that gastric acid and pepsin play an integral role in the erosive process. Although significant gastrointestinal hemorrhage occurs only in 5 to 10 percent of patients with extensive stress-related mucosal damage, the mortality rate in this group of patients can exceed 50 percent [7]. Stress-
The American
Journal
of Medicine
Volume
83
(suppl 8A)
83
SYMPOSIUM
ON H,-RECEPTOR
ANTAGONIST
THERAPY-WOLFE
6
Figure 1. Nomogram illustrating the relationship between intramural pH in stomach and the number of risk factors (RF) and the probability (p) of massive bleeding from stress-induced mucosal damage. Reproduced with permission from [8].
i Intramural pH
related erosive syndrome is observed in a wide variety of clinical settings, including significant trauma, burns, acute respiratory failure, shock, sepsis, and increased intracranial pressure, as well as following major operative procedures [7]. Because of the prognostic implications of progression of stress-related syndrome, the cornerstone of therapy has been prophylaxis rather than active treatment. The method used most extensively to achieve this goal has been decreasing the concentration of hydrogen ion in the stomach. When intragastric pH values are increased from 3.5 to 4.0, the conversion of pepsinogen to pepsin is decreased; proteolytic activity in the stomach is subsequently diminished. Moreover, when the intragastric pH value approaches 7.0, pepsinogen is irreversibly inactivated and clotting factors become operable, enabling the clotting cascade to proceed. Although it has been demonstrated that maintenance of the intragastric pH value to
a4
December
16, 1967
The American
Journal
of Medicine
close to 7.0 would be ideal [8] (Figure l), most studies have aimed at maintaining intragastric pH value above 4.0. Antacids. Hastings and co-workers [9] demonstrated that antacids were effective in decreasing the incidence of stress-induced gastrointestinal hemorrhage. However, as noted in this and subsequent studies [I O-l 21, the dose of antacid required to maintain gastric pH near 4.0 is significant, and antacids are quite cumbersome to use [12] (Figure 2). Other problems with antacids include the high incidence of diarrhea caused by the high magnesium hydroxide content of many antacid preparations, the need for nasogastric intubation with its inherent complications, the requirement for increased nursing time, the occurrence of metabolic alkalosis, the price of antacids themselves, and other costs associated with their administration. Hz-Receptor Antagonists. The introduction of paren-
Volume
63 (suppl
6A)
SYMPOSIUM
teral cimetidine in 1977 led to the hope that intravenous cimetidine would serve as a suitable substitute for antacids. Both cimetidine [13] and ranitidine [14] have been proved superior to placebo in the prevention of stressinduced gastrointestinal bleeding. However, when Priebe and colleagues [I 0) compared antacids and cimetidine in the prevention of acute gastrointestinal bleeding in critically ill patients in the intensive care unit, they concluded that antacids were superior to cimetidine in preventing bleeding (Figure 3). Recently, Shuman and associates [I 51 reviewed trials in which antacids and cimetidine were compared for stress prophylaxis. Although antacids appeared to be slightly superior to cimetidine in reducing the incidence of occult bleeding, both regimens were equally effective in the prevention of overt gastrointestinal blood loss. As stated above, one of the historical goals of prophylactic regimens has been to maintain intragastric pH values at a level greater than 4.0 in order to decrease the conversion of pepsinogen to pepsin and thereby diminish proteolytic activity. Weigelt and colleagues [l l] found that antacids, given in doses titrated to maintain a preset pH level (15 ml/hour to 120 ml/hour), were superior to intravenously administered cimetidine in achieving this goal, even when cimetidine was given at a dose of 400 mg every four hours [l 11. Peterson and Richardson [16] compared the effect of intravenous cimetidine and ranitidine on raising gastric pH values and found that ranitidine was slightly superior in maintaining intragastric pH values above 4.0 when both drugs were infused intravenously every six hours. Another single-dose study of acid suppression by cimetidine and ranitidine in 36 healthy adult volunteers demonstrated that single doses of intravenous cimetidine (300 mg) and ranitidine (50 mg) were equivalent in acid suppression as measured by gastric pH, titratable acidity, gastric volume, and gastric acid output [17]. The time course of acid suppression was similar with both regimens; intragastric pH increased to at least 3.5 within 30 minutes of drug dosing and this elevation was maintained for three to four hours. However, the persons examined in these studies were not critically ill, but were ambulatory volunteers. If gastric pH neutrality is the goal of therapy with these agents, these regimens were not optimal. In another study by Peterson and Richardson [18], eight patients with previously documented duodenal ulcers were examined. In this study, intravenous cimetidine was given by an unprimed continuous infusion of 50 mg/hour, and antacid was given by continuous gastric infusion at a rate of 0.5 ml/minute. Both regimens increased intragastric pH values to approximately 5.0; however, the combination of both medications achieved sustained fasting achlorhydria (Figure 4), prompting the authors to conclude that this may be the preferred regimen for treatment of patients with bleeding ulcers [18].
December
18, 1987
ON Hz-RECEPTOR
Aspirate
Rr weat
ANTAGONIST
THERAPY-WOLFE
stomach
Instill Maalox - 10 ml followed by H,O I
I
-until Clamp
pH24.0 tube - 1 hr
Irrigate stomach contents
Aspirate
stomach
I Drainage 1 hr straight or Gomco I
I
Instill double Maalox followed by H,O
I
igure 2. Antacid titration regimen followed to maintain an intragastric pH value of more than 4.0. Reproduced with permission from [12].
PRIMED CONTINUOUS INFUSION The administration of medication by a continuous intravenous infusion has a historical precedent. In the past, patients with thromboembolic disorders were treated with intermittent infusions of the anticoagulant heparin. Both bleeding and clotting complications ‘were commonly obsewed using this regimen, the former presumably occurring soon after heparin administration and the latter prior to the next dose of medication. However, Salzman and colleagues [19] demonstrated that the administration of’ heparin by continuous infusion was at least as effective, and definitely safer, than intermittent infusion of the drug. It is important to emphasize that a loading dose of heparin was administered initially to achieve an effective serum level, followed by the continuous intravenous infusion of the drug. Other such examples include the use of continu-
The American
Journal
of,Medlcine
Volume
63 (suppl
6A)
85
SYMPOSIUM
ON Hz-RECEPTOR
ANTAGONIST
51 hrs - 8 days
0 - 50 hrs
Cimetidine
THERAPY-WOLFE
Antacid
Cimetidine
m
Total number
m
Patients
Antacid
Figure 4. Patterns of gastric pH with infusion regimens ( cimetidine (top), antacid (middle), and the combination of cimetidine and antacid (bottom), in six patients with duodenal ulcer. Medications were given in doses and frequency shown. Reproduced with permission from [17].
December
18, 1987
The
American
who bleed
Figure 3. Duration of study and incidence of bleeding in cimetidine and antacid groups. Reproduced with permission from [lo].
ous infusions of insulin for diabetes and ketoacidosis, and of penicillin for the treatment of serious systemic infections. Using this rationale, Ostro and co-workers [20] studied 23 critically ill patients and compared two cimetidine regimens: intermittent intravenous therapy versus a primed continuous infusion. lntragastric pH values were maintained above 4.0 in 87 percent of patients receiving continuous primed infusions of up to 50 mg/hour, whereas intragastric pH values were maintained above 4.0 in only 22 percent of patients when cimetidine was given by intermittent infusions of 300 mg every six hours. Although this study was conducted in a small number of patients, the therapeutic approach is quite rational and provides a basis for a larger trial aimed at determining the efficacy of
88
of patients
Journal
of Medicine
cimetidine in the prevention of gastrointestinal hemorrhage from stress-related mucosal damage. To date, information regarding the use of intravenous ranitidine for prophylaxis against stress-related syndrome is less extensive. In one study comparing intermittent infusions of cimetidine and ranitidine in critically ill patients, the two drugs were equal in their ability to decrease the incidence of stress-induced bleeding [22]. In a third study, ranitidine appeared to be slightly more effective than cimetidine in maintaining intragastric pH values above 4.0, but neither regimen was superior to antacids [21]. Studies using continuous infusions of ranitidine are difficult to evaluate due to a lack of uniformity in dosing and endpoint evaluation. In a recent study by Rigaud and co-workers [23], patients with acute respiratory failure received a primed continuous infusion of ranitidine (0.5 mg/kg followed by a continuous infusion of 0.25 mg/kg/hour). Despite this very high dose, ranitidine failed to maintain intragastric pH values greater than 4.0 during 35 percent of the study period, a pH profile no different from that achieved using placebo [23]. The investigators suggested that a rise in serum gastrin levels during ranitidine treatment might be partially responsible for failure to maintain adequate pH control. It would appear, then, that of the single-drug regimens examined, a primed continuous infusion of cimetidine can best achieve sustained hypochlorhydria [20]. Neither this regimen nor a continuous infusion of ranitidine has been extensively evaluated with regard to decreasing stressinduced bleeding. However, on the basis of placebocontrolled trials demonstrating the efficacy of cimetidine [13] and of studies showing the potential value of sustained achlorhydria [8], patients who are at risk for developing stress-related erosive syndrome can safely and effectively be treated with a primed continuous infusion of cimetidine. Patients should be monitored for evidence of gross bleeding because the mere presence of blood in a gastric aspirate is probably of little clinical significance [15]. Endoscopy should not be performed routinely but
Volume
83
(suppl 8A)
SYMPOSIUM
rather should be reserved for those in whom significant bleeding is demonstrated. An intragastric pH value of at least 4.0 and, ideally, of 7.0 should be demonstrated prior to cessation of routine monitoring of gastric pH. Nevertheless, further evaluation is required to determine whether a primed continuous infusion of cimetidine affords benefits over antacid therapy in terms of efficacy, patient acceptability, and safety. In addition, the role of other agents, such as sucralfate [24] and prostaglandins in the prevention of stress-related erosive syndrome, needs to be determined. SAFETY
PROFILE
OF Hz-RECEPTOR
2.
3.
4.
5.
6.
7.
Stress-related erosive syndrome is a complication observed in critically ill patients. Because bleeding caused by stress-related syndrome can worsen prognosis, prophylactic therapy appears to be warranted. Although the precise pathophysiology of stress-induced damage is not entirely clear, acid and pepsin play an integral role, and acid neutralization has been the mainstay of therapy. Antacids have been proved reliable and effective, but are inconvenient and costly to administer. Evidence regarding the efficacy of intravenous Hz-receptor antagonists has been conflicting, but most recent data indicate that they are probably equal to antacids in their ability to prevent significant bleeding in this group of patients. Based on presently available information, it would appear that the most suitable regimen for stress ulcer prophylaxis would be a primed continuous infusion of cimetidine. This approach has been demonstrated to effectively and economically maintain gastric pH values above 4.0. Primed continuous infusions minimize expense by decreasing nursing time and pharmacy costs associated with intermittent administrations of either Hz-receptor antagonists or antacids. Additionally, prolonged use of a nasogastric tube, which can lead to complications such as esophageal stricture and aspiration, is avoided. Further studies are needed, however, to precisely define the patient population at risk and to directly compare primed infusions of cimetidine with antacids.
Ash ASF, Schield HO: Receptors mediating some action of histamine. Br J Pharmacol Chemother 1966; 27: 427-439. Black JW, Duncan WAM, Durant CJ, Ganellin CR, Parsons EM: Definition and antagonism of histamine H,-receptors. Nature 1972; 236: 365-390. Brimblecombe RW, Duncan WAM, Durant CJ, et al: Characterization and development of cimetidine as a histamine HPreceptor antagonist. Gastroenterology 1978; 74: 339-347. Zuckerman G, Welch R, Douglas A, et al: Controlled trial of medical therapy for active upper gastrointestinal bleeding and prevention of rebleeding. Am J Med 1964; 76: 361-386. Basso N, Bagarani M, Bracci F, et al: Ranitidine and somatostatin. Their effects on bleeding from the upper gastrointestinal tract. Arch Surg 1986; 121: 633-635. Collins R, Langman M: Treatment with histamine H2-antagonists in acute upper gastrointestinal hemorrhage. Implications of randomized trials. N Engl J Med 1985; 313: 660-666. Robert A, Kauffman GL Jr: Stress ulcers. In: Sleisenger MH, Fordtran JS, eds. Gastrointestinal disease, ed 3. Philadel-
l&1987
THERAPY-WOLFE
COMMENTS
ANTAGONISTS
December
ANTAGONIST
sional elevation in serum aminotransferase levels seen when high doses of intravenous ranitidine are administered for several days. Although the increases in serum aminotransferases appear to be reversible, the clinical relevance of this effect warrants a thorough evaluation.
As stated earlier, Hz-receptor antagonists probably constitute one of the safest classes of drugs to be introduced in recent decades. Although clinical experience with parenteral cimetidine is extensive, less information regarding ranitidine is available, and there is presently insufficient information regarding the safety and efficacy of parenteral famotidine [25] to recommend its unmonitored use in stress ulcer prophylaxis. Both cimetidine and ranitidine cross the blood-brain barrier and are capable of producing reversible changes in mental status, caused in all likelihood by binding of the drugs to cerebral histamine receptors. Cimetidine and, to a lesser extent, ranitidine interfere with the cytochrome P-450 mixed-function oxidasemediated drug metabolism. Although rarely of clinical significance, patients receiving concomitant warfarin, theophylline, diazepam, and other drugs that are metabolized by this route should be monitored for serum drug concentrations and clinical parameters, such as prothrombin time, when either cimetidine or ranitidine is given. Both cimetidine and ranitidine cause mild, reversible increases in serum creatinine levels that are of no clinical significance. Another effect of unknown significance is the occa-
1.
ON HZ-RECEPTOR
6.
9.
10.
11.
12.
The
phia: WB Saunders, 1983; 612-625. Fiddian-Green RG, McGough E, Pittenger G, Rothman E: Predictive value of intramural pH and other risk factors for massive bleeding from stress ulceration. Gastroenterotogy 1983; 85: 613-620. Hastings PR, Skillman JJ, Bushnell LS, Silen W: Antacid titration in the prevention of acute gastrointestinal bleeding. A controlled randomized trial in 100 critically ill patients. N Engl J Med 1978; 298: 1041-1045. Priebe HJ, Skillman JJ, Bushnell LS, Long PC, Silen W: Antacid versus cimetidine in preventing acute gastrointestinal bleeding. A randomized trial in 75 critically ill patients. N Engl J Med 1980; 302: 426-430. Weigelt JA, Aurbakken CM, Gewertz BL, Snyder WH Ill: Cimetidine vs antacid in prophylaxis for stress ulceration. Arch Surg 1981; 116: 597-601. Zinner MJ, Zuidema GD, Smith PL, Mignosa M: The prevention of upper gastrointestinal tract bleeding in patients in an intensive care unit. Surg Gynecol Obstet 1981; 153: 214-220.
American
Journal
of Mdlcine
Volume
83 (suppl
BA)
87
SYMPOSIUM
13.
14.
15.
16.
17.
18.
19.
20.
88
ON Hz-RECEPTOR
ANTAGONIST
THERAPY-WOLFE
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: 173-177. More DG, Raper RF, Watson CJ, Shenfield CM: Combination therapy with ranitidine and pirenzepine for control of intragastric pH in the critically ill. Crit Care Med 1985; 13: 651-655. Shuman RB, Schuster DP, Zuckerman GR: Prophylactic therapy for stress ulcer bleeding: a reappraisal. Ann Intern Med 1987; 106: 562-567. Peterson WL, Richardson CT: Intravenous cimetidine or two regimens of ranitidine to reduce fasting gastric acidity. Ann Intern Med 1986; 104: 505-507. Frank WO, Peace KE, Watson M, et al: The effect of single intravenous doses of cimetidine or ranitidine on gastric secretion Clin Pharmacol Ther 1986; 40: 665-672. Peterson WL, Richardson CT: Sustained fasting achlorhydria: a comparison of medical regimens. Gastroenterology 1985; 88: 666-669. Salzman EW, Deykin D, Shapiro RM, Rosenberg R: Management of heparin therapy. Controlled prospective trial. N Engl J Med 1975; 292: 1046-1050. Ostro MJ, Russell JA, Soldin SJ, Malhon WA, Jeejeebhoy KN:
December
18,1987
The American
Journal
of Medicine
21.
22.
23.
24.
25.
Volume
Control of gastric pH with cimetidine: boluses versus primed infusion. Gastroenterology 1985; 89: 532-537. More DG, Raper RF, Munro IA, Watson CJ, Boutagy JS, Shenfield GM: Randomized, prospective trial of cimetidine and ranitidine for control of intragastric pH in the critically ill. Surgery 1985; 97: 215-223. Barth HO, Brunner G, Berg F, et al: Ranitidine versus cimetidine in preventing acute gastrointestinal bleeding: a randomized trial in 193 critically ill patients-a multicentre study in Germany. lntensivmedizin 1984; 21: 15-I 8. Rigaud D, Chastre J, Accary JP, Bonfils S, Gibert C, Hance AJ: lntragastric pH profile during acute respiratory failure in patients with chronic obstructive pulmonary disease. Effect of ranitidine and enteral feeding. Chest 1986; 90: 58-63. Borrero E, Bank S, Margolis I, Schulman ND, Chardavoyna R: Comparison of antacid and sucralfate in the prevention of gastrointestinal bleeding in patients who are critically ill. Am J Med 1985; 79 (suppl 2C): 62-64. Ryan JR, Vargas R, McMahon FG, Chremos AN: Comparison of effects of oral and intravenous famotidine on inhibition of nocturnal gastric acid secretion. Am J Med 1986; 81 (suppl 48): 60-64.
83 (suppl
8A)
M. MICHAEL Boston.
WOLFE,
M.D.
Parenteral histamine (H&receptor antagonists are safe and effective therapy for the prophylaxis of stress-related erosive syndrome. Of the three agents available, parenteral cimetidine is the most widely studied; parenteral formulations of ranitidine and famotidine have not been investigated as extensively. Parenteral cimetidine appears to be effective in reducing incidence and complications associated with gastrointestinal hemorrhage caused by stressrelated erosive syndrome, although its effects on bleeding that has already begun are not clear. Antacids are also effective in decreasing the incidence of stress-related gastrointestinal hemorrhage, but they are inconvenient and expensive to administer. Primed continuous infusions of cimetidine may be the most useful regimen for prophylaxis of stress-related erosive syndrome in critically ill patients; the evidence available on the efficacy of continuous infusions of ranitidine is inconsistent, and very few data are available on the value of famotidlne. Direct comparative cllnical trials are needed to assess definitively the efficacy of primed continuous infusions of cimetidine or other Hz-receptor antagonists versus that of antacid therapy.
Massachusetts
From the Harvard Digestive Diseases Center, the Harvard-Thorndike Laboratory and Charles A. Dana Research Institute, Division of Gastroenterology, Beth Israel Hospital and Harvard Medical School, Boston, Massachusetts. Requests for reprints should be addressed to Dr. M. Michael Wolfe, Assistant Professor of Medicine, Division of Gastroenterology, Beth Israel Hospital, 330 Brookline Avenue, Boston, Massachusetts 02215.
82
December
18,1987
The American
Journal
The physiology of gastric acid secretion is very complex. Much has been learned in the past decade through the establishment of methods for study of parietal cells. These techniques include both the preparation of oxyntic glands, as well as methods for isolating dispersed parietal cells. The latter technique has enabled investigators to identify specific receptors on the parietal cell basolateral membrane that regulate hydrogen ion generation and secretion. It has long been known that histamine provides a potent stimulus for the secretion of acid by parietal cells. Recent data suggest that histamine binds to a specific receptor on the parietal cell basolateral membrane; this interaction causes an increase in adenylate cyclase activity, which in turn increases the level of intracellular cyclic adenosine monophosphate. Protein kinase activity is enhanced and, eventually, the generation of hydrogen ions is stimulated. Despite the recognition that histamine stimulates acid secretion, it was not until 1966, when Ash and Schield [l] described HI and H2 receptors for histamine, that the possibility of inhibiting acid secretion with antihistamines was proposed. Beginning in 1968, Black and colleagues [2,3] described selective histamine (Hz)-receptor blockade for acid secretion, thus beginning the search for pharmacologic agents that could be used clinically to effectively suppress acid secretion. Widespread use of the first selective H-receptor antagonist, burimamide, was limited by its decreased oral bioavailability. The first oral Hz-
of Medicine
Volume
83
(suppl8A)
SYMPOSIUM
TABLE
I
Use of Histamine
Hz-Receptor
Antagonists
Approved indications Duodenal ulcer (active and prophylaxis) Gastric ulcer Zollinger-Ellison syndrome Gastroesophageal reflux disease Systemic mastocytosis Unapproved indications but used with good rationale NSAID therapy (active erosion/ulcer and prophylaxis) Stress-related erosive syndrome prophylaxis Prophylaxis against acid aspiration Impaired T lymphocyte-mediated immunity Active upper gastrointestinal hemorrhage due to acid-peptic disease Unapproved indications and used without good evidence for benefit Idiopathic gastritis Nonulcer dyspepsia Active upper gastrointestinal hemorrhage (unknown cause) Nonspecific symptoms (i.e., diarrhea, nausea) l
l
l l l
l
l
l
l
l
l
l
l
l
NSAID
= nonsteroidal
anti-inflammatory
drug.
antagonist to be reliably absorbed in the gastrointestinal tract was metiamide. Although metiamide was shown to be effective in decreasing gastric acid secretion and was useful for treating patients with duodenal ulcer disease and Zollinger-Ellison syndrome, clinical application of this agent was limited by serious adverse effects, principally agranulocytosis [3]. This serious effect was caused by the presence of a thiourea group on the side chain of the metiamide molecule. When this side chain was replaced with a cyanoguanidine group, cimetidine was created. Cimetidine became the first Hz-receptor antagonist to be clinically useful in the suppression of gastric acid secretion. Following the introduction of cimetidine in the United States in 1977, ranitidine and, more recently, famotidine have become available for treatment of acid and peptic disorders. As a class, the Hz-receptor antagonists are unrivaled in their efficacy in treating duodenal ulcer disease, as well as in their safety profile. Although differences do exist with regard to their potency and biologic half-life, all three drugs are similar in their ability to heal duodenal ulcers and, when used orally, are virtually free of adverse effects. The parenteral formulation of cimetidine has been thoroughly studied; less information is available regarding the efficacy of parenteral ranitidine. Although initial reports appear favorable, information presently available regarding the parenteral use of famotidine, particularly in critically ill patients, is scarce. Minor differences do exist among these three drugs. When selecting a specific Hz-receptor antagonist (or any class of drug) for clinical use, two primary selection criteria should be considered. The more important of these is the efficacy of the drug. After efficacy is demonstrated, the risk-benefit ratio of the drug must be evaluated. receptor
December
18, 1987
INDICATIONS
ON Hz-RECEPTOR
ANTAGONIST
FOR PARENTERAL
THERAPY-WOLFE
USE
In general, parenteral Hz-receptor antagonists are indicated for use in hospitalized patients with pathologic hypersecretory conditions or with intractable duodenal ulcer disease. They are also approved as alternatives to the oral dosage form for short-term use in patients who are unable to take oral medications. Although these are the only Food and Drug Administration-approved indications for these drugs, Hz-receptor antagonists are used clinically for many other pathologic conditions (Table I). Among the disorders listed in Table I, the use of HPreceptor antagonists in gastrointestinal hemorrhage has been studied most extensively. Although these drugs have been used for treatment of gastrointestinal hemorrhage, unequivocal evidence for efficacy is lacking. Zuckerman and colleagues [4] reported the results of a large, multicenter trial evaluating cimetidine in the treatment of patients with upper gastrointestinal hemorrhage. Cimetidine was found to be no better than placebo for either the treatment of active gastrointestinal bleeding or in prevention of rebleeding. Basso and colleagues [5] also reported that ranitidine did not alter the rate of bleeding and death, surgical intervention, or transfusion requirements in patients with upper gastrointestinal bleeding when compared with placebo. Because of the relatively small number of patients enrolled in these studies, Collins and Langman [6] compiled data from 27 randomized trials performed worldwide to evaluate the use of cimetidine and ranitidine in the treatment of upper gastrointestinal hemorrhage. Unfortunately, there was a marked lack of uniformity in these trials with regard to inclusion and exclusion criteria, dose of medication, and the clinical monitoring parameters. The authors demonstrated that Hz-receptor antagonists were effective in reducing both the need for surgery and mortality from gastrointestinal bleeding. However, no significant effect of Hz-receptor antagonists on hemorrhage itself was apparent. The authors also stated that the randomization of at least 10,000 patients would be required in order for a prospective trial to demonstrate a significant effect of these drugs on the incidence of bleeding. Therefore, although it is difficult to recommend the unrestricted use of Hz-receptor antagonists for all gastrointestinal hemorrhage at this time, there appears to be good rationale for their use when bleeding caused by acid-peptic disease is suspected. STRESS
ULCER PROPHYLAXIS
The precise pathophysiology of stress-related erosive syndrome is not firmly established; however, it is clear that gastric acid and pepsin play an integral role in the erosive process. Although significant gastrointestinal hemorrhage occurs only in 5 to 10 percent of patients with extensive stress-related mucosal damage, the mortality rate in this group of patients can exceed 50 percent [7]. Stress-
The American
Journal
of Medicine
Volume
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Figure 1. Nomogram illustrating the relationship between intramural pH in stomach and the number of risk factors (RF) and the probability (p) of massive bleeding from stress-induced mucosal damage. Reproduced with permission from [8].
i Intramural pH
related erosive syndrome is observed in a wide variety of clinical settings, including significant trauma, burns, acute respiratory failure, shock, sepsis, and increased intracranial pressure, as well as following major operative procedures [7]. Because of the prognostic implications of progression of stress-related syndrome, the cornerstone of therapy has been prophylaxis rather than active treatment. The method used most extensively to achieve this goal has been decreasing the concentration of hydrogen ion in the stomach. When intragastric pH values are increased from 3.5 to 4.0, the conversion of pepsinogen to pepsin is decreased; proteolytic activity in the stomach is subsequently diminished. Moreover, when the intragastric pH value approaches 7.0, pepsinogen is irreversibly inactivated and clotting factors become operable, enabling the clotting cascade to proceed. Although it has been demonstrated that maintenance of the intragastric pH value to
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close to 7.0 would be ideal [8] (Figure l), most studies have aimed at maintaining intragastric pH value above 4.0. Antacids. Hastings and co-workers [9] demonstrated that antacids were effective in decreasing the incidence of stress-induced gastrointestinal hemorrhage. However, as noted in this and subsequent studies [I O-l 21, the dose of antacid required to maintain gastric pH near 4.0 is significant, and antacids are quite cumbersome to use [12] (Figure 2). Other problems with antacids include the high incidence of diarrhea caused by the high magnesium hydroxide content of many antacid preparations, the need for nasogastric intubation with its inherent complications, the requirement for increased nursing time, the occurrence of metabolic alkalosis, the price of antacids themselves, and other costs associated with their administration. Hz-Receptor Antagonists. The introduction of paren-
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teral cimetidine in 1977 led to the hope that intravenous cimetidine would serve as a suitable substitute for antacids. Both cimetidine [13] and ranitidine [14] have been proved superior to placebo in the prevention of stressinduced gastrointestinal bleeding. However, when Priebe and colleagues [I 0) compared antacids and cimetidine in the prevention of acute gastrointestinal bleeding in critically ill patients in the intensive care unit, they concluded that antacids were superior to cimetidine in preventing bleeding (Figure 3). Recently, Shuman and associates [I 51 reviewed trials in which antacids and cimetidine were compared for stress prophylaxis. Although antacids appeared to be slightly superior to cimetidine in reducing the incidence of occult bleeding, both regimens were equally effective in the prevention of overt gastrointestinal blood loss. As stated above, one of the historical goals of prophylactic regimens has been to maintain intragastric pH values at a level greater than 4.0 in order to decrease the conversion of pepsinogen to pepsin and thereby diminish proteolytic activity. Weigelt and colleagues [l l] found that antacids, given in doses titrated to maintain a preset pH level (15 ml/hour to 120 ml/hour), were superior to intravenously administered cimetidine in achieving this goal, even when cimetidine was given at a dose of 400 mg every four hours [l 11. Peterson and Richardson [16] compared the effect of intravenous cimetidine and ranitidine on raising gastric pH values and found that ranitidine was slightly superior in maintaining intragastric pH values above 4.0 when both drugs were infused intravenously every six hours. Another single-dose study of acid suppression by cimetidine and ranitidine in 36 healthy adult volunteers demonstrated that single doses of intravenous cimetidine (300 mg) and ranitidine (50 mg) were equivalent in acid suppression as measured by gastric pH, titratable acidity, gastric volume, and gastric acid output [17]. The time course of acid suppression was similar with both regimens; intragastric pH increased to at least 3.5 within 30 minutes of drug dosing and this elevation was maintained for three to four hours. However, the persons examined in these studies were not critically ill, but were ambulatory volunteers. If gastric pH neutrality is the goal of therapy with these agents, these regimens were not optimal. In another study by Peterson and Richardson [18], eight patients with previously documented duodenal ulcers were examined. In this study, intravenous cimetidine was given by an unprimed continuous infusion of 50 mg/hour, and antacid was given by continuous gastric infusion at a rate of 0.5 ml/minute. Both regimens increased intragastric pH values to approximately 5.0; however, the combination of both medications achieved sustained fasting achlorhydria (Figure 4), prompting the authors to conclude that this may be the preferred regimen for treatment of patients with bleeding ulcers [18].
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18, 1987
ON Hz-RECEPTOR
Aspirate
Rr weat
ANTAGONIST
THERAPY-WOLFE
stomach
Instill Maalox - 10 ml followed by H,O I
I
-until Clamp
pH24.0 tube - 1 hr
Irrigate stomach contents
Aspirate
stomach
I Drainage 1 hr straight or Gomco I
I
Instill double Maalox followed by H,O
I
igure 2. Antacid titration regimen followed to maintain an intragastric pH value of more than 4.0. Reproduced with permission from [12].
PRIMED CONTINUOUS INFUSION The administration of medication by a continuous intravenous infusion has a historical precedent. In the past, patients with thromboembolic disorders were treated with intermittent infusions of the anticoagulant heparin. Both bleeding and clotting complications ‘were commonly obsewed using this regimen, the former presumably occurring soon after heparin administration and the latter prior to the next dose of medication. However, Salzman and colleagues [19] demonstrated that the administration of’ heparin by continuous infusion was at least as effective, and definitely safer, than intermittent infusion of the drug. It is important to emphasize that a loading dose of heparin was administered initially to achieve an effective serum level, followed by the continuous intravenous infusion of the drug. Other such examples include the use of continu-
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51 hrs - 8 days
0 - 50 hrs
Cimetidine
THERAPY-WOLFE
Antacid
Cimetidine
m
Total number
m
Patients
Antacid
Figure 4. Patterns of gastric pH with infusion regimens ( cimetidine (top), antacid (middle), and the combination of cimetidine and antacid (bottom), in six patients with duodenal ulcer. Medications were given in doses and frequency shown. Reproduced with permission from [17].
December
18, 1987
The
American
who bleed
Figure 3. Duration of study and incidence of bleeding in cimetidine and antacid groups. Reproduced with permission from [lo].
ous infusions of insulin for diabetes and ketoacidosis, and of penicillin for the treatment of serious systemic infections. Using this rationale, Ostro and co-workers [20] studied 23 critically ill patients and compared two cimetidine regimens: intermittent intravenous therapy versus a primed continuous infusion. lntragastric pH values were maintained above 4.0 in 87 percent of patients receiving continuous primed infusions of up to 50 mg/hour, whereas intragastric pH values were maintained above 4.0 in only 22 percent of patients when cimetidine was given by intermittent infusions of 300 mg every six hours. Although this study was conducted in a small number of patients, the therapeutic approach is quite rational and provides a basis for a larger trial aimed at determining the efficacy of
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cimetidine in the prevention of gastrointestinal hemorrhage from stress-related mucosal damage. To date, information regarding the use of intravenous ranitidine for prophylaxis against stress-related syndrome is less extensive. In one study comparing intermittent infusions of cimetidine and ranitidine in critically ill patients, the two drugs were equal in their ability to decrease the incidence of stress-induced bleeding [22]. In a third study, ranitidine appeared to be slightly more effective than cimetidine in maintaining intragastric pH values above 4.0, but neither regimen was superior to antacids [21]. Studies using continuous infusions of ranitidine are difficult to evaluate due to a lack of uniformity in dosing and endpoint evaluation. In a recent study by Rigaud and co-workers [23], patients with acute respiratory failure received a primed continuous infusion of ranitidine (0.5 mg/kg followed by a continuous infusion of 0.25 mg/kg/hour). Despite this very high dose, ranitidine failed to maintain intragastric pH values greater than 4.0 during 35 percent of the study period, a pH profile no different from that achieved using placebo [23]. The investigators suggested that a rise in serum gastrin levels during ranitidine treatment might be partially responsible for failure to maintain adequate pH control. It would appear, then, that of the single-drug regimens examined, a primed continuous infusion of cimetidine can best achieve sustained hypochlorhydria [20]. Neither this regimen nor a continuous infusion of ranitidine has been extensively evaluated with regard to decreasing stressinduced bleeding. However, on the basis of placebocontrolled trials demonstrating the efficacy of cimetidine [13] and of studies showing the potential value of sustained achlorhydria [8], patients who are at risk for developing stress-related erosive syndrome can safely and effectively be treated with a primed continuous infusion of cimetidine. Patients should be monitored for evidence of gross bleeding because the mere presence of blood in a gastric aspirate is probably of little clinical significance [15]. Endoscopy should not be performed routinely but
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rather should be reserved for those in whom significant bleeding is demonstrated. An intragastric pH value of at least 4.0 and, ideally, of 7.0 should be demonstrated prior to cessation of routine monitoring of gastric pH. Nevertheless, further evaluation is required to determine whether a primed continuous infusion of cimetidine affords benefits over antacid therapy in terms of efficacy, patient acceptability, and safety. In addition, the role of other agents, such as sucralfate [24] and prostaglandins in the prevention of stress-related erosive syndrome, needs to be determined. SAFETY
PROFILE
OF Hz-RECEPTOR
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3.
4.
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Stress-related erosive syndrome is a complication observed in critically ill patients. Because bleeding caused by stress-related syndrome can worsen prognosis, prophylactic therapy appears to be warranted. Although the precise pathophysiology of stress-induced damage is not entirely clear, acid and pepsin play an integral role, and acid neutralization has been the mainstay of therapy. Antacids have been proved reliable and effective, but are inconvenient and costly to administer. Evidence regarding the efficacy of intravenous Hz-receptor antagonists has been conflicting, but most recent data indicate that they are probably equal to antacids in their ability to prevent significant bleeding in this group of patients. Based on presently available information, it would appear that the most suitable regimen for stress ulcer prophylaxis would be a primed continuous infusion of cimetidine. This approach has been demonstrated to effectively and economically maintain gastric pH values above 4.0. Primed continuous infusions minimize expense by decreasing nursing time and pharmacy costs associated with intermittent administrations of either Hz-receptor antagonists or antacids. Additionally, prolonged use of a nasogastric tube, which can lead to complications such as esophageal stricture and aspiration, is avoided. Further studies are needed, however, to precisely define the patient population at risk and to directly compare primed infusions of cimetidine with antacids.
Ash ASF, Schield HO: Receptors mediating some action of histamine. Br J Pharmacol Chemother 1966; 27: 427-439. Black JW, Duncan WAM, Durant CJ, Ganellin CR, Parsons EM: Definition and antagonism of histamine H,-receptors. Nature 1972; 236: 365-390. Brimblecombe RW, Duncan WAM, Durant CJ, et al: Characterization and development of cimetidine as a histamine HPreceptor antagonist. Gastroenterology 1978; 74: 339-347. Zuckerman G, Welch R, Douglas A, et al: Controlled trial of medical therapy for active upper gastrointestinal bleeding and prevention of rebleeding. Am J Med 1964; 76: 361-386. Basso N, Bagarani M, Bracci F, et al: Ranitidine and somatostatin. Their effects on bleeding from the upper gastrointestinal tract. Arch Surg 1986; 121: 633-635. Collins R, Langman M: Treatment with histamine H2-antagonists in acute upper gastrointestinal hemorrhage. Implications of randomized trials. N Engl J Med 1985; 313: 660-666. Robert A, Kauffman GL Jr: Stress ulcers. In: Sleisenger MH, Fordtran JS, eds. Gastrointestinal disease, ed 3. Philadel-
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sional elevation in serum aminotransferase levels seen when high doses of intravenous ranitidine are administered for several days. Although the increases in serum aminotransferases appear to be reversible, the clinical relevance of this effect warrants a thorough evaluation.
As stated earlier, Hz-receptor antagonists probably constitute one of the safest classes of drugs to be introduced in recent decades. Although clinical experience with parenteral cimetidine is extensive, less information regarding ranitidine is available, and there is presently insufficient information regarding the safety and efficacy of parenteral famotidine [25] to recommend its unmonitored use in stress ulcer prophylaxis. Both cimetidine and ranitidine cross the blood-brain barrier and are capable of producing reversible changes in mental status, caused in all likelihood by binding of the drugs to cerebral histamine receptors. Cimetidine and, to a lesser extent, ranitidine interfere with the cytochrome P-450 mixed-function oxidasemediated drug metabolism. Although rarely of clinical significance, patients receiving concomitant warfarin, theophylline, diazepam, and other drugs that are metabolized by this route should be monitored for serum drug concentrations and clinical parameters, such as prothrombin time, when either cimetidine or ranitidine is given. Both cimetidine and ranitidine cause mild, reversible increases in serum creatinine levels that are of no clinical significance. Another effect of unknown significance is the occa-
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6.
9.
10.
11.
12.
The
phia: WB Saunders, 1983; 612-625. Fiddian-Green RG, McGough E, Pittenger G, Rothman E: Predictive value of intramural pH and other risk factors for massive bleeding from stress ulceration. Gastroenterotogy 1983; 85: 613-620. Hastings PR, Skillman JJ, Bushnell LS, Silen W: Antacid titration in the prevention of acute gastrointestinal bleeding. A controlled randomized trial in 100 critically ill patients. N Engl J Med 1978; 298: 1041-1045. Priebe HJ, Skillman JJ, Bushnell LS, Long PC, Silen W: Antacid versus cimetidine in preventing acute gastrointestinal bleeding. A randomized trial in 75 critically ill patients. N Engl J Med 1980; 302: 426-430. Weigelt JA, Aurbakken CM, Gewertz BL, Snyder WH Ill: Cimetidine vs antacid in prophylaxis for stress ulceration. Arch Surg 1981; 116: 597-601. Zinner MJ, Zuidema GD, Smith PL, Mignosa M: The prevention of upper gastrointestinal tract bleeding in patients in an intensive care unit. Surg Gynecol Obstet 1981; 153: 214-220.
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14.
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16.
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19.
20.
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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: 173-177. More DG, Raper RF, Watson CJ, Shenfield CM: Combination therapy with ranitidine and pirenzepine for control of intragastric pH in the critically ill. Crit Care Med 1985; 13: 651-655. Shuman RB, Schuster DP, Zuckerman GR: Prophylactic therapy for stress ulcer bleeding: a reappraisal. Ann Intern Med 1987; 106: 562-567. Peterson WL, Richardson CT: Intravenous cimetidine or two regimens of ranitidine to reduce fasting gastric acidity. Ann Intern Med 1986; 104: 505-507. Frank WO, Peace KE, Watson M, et al: The effect of single intravenous doses of cimetidine or ranitidine on gastric secretion Clin Pharmacol Ther 1986; 40: 665-672. Peterson WL, Richardson CT: Sustained fasting achlorhydria: a comparison of medical regimens. Gastroenterology 1985; 88: 666-669. Salzman EW, Deykin D, Shapiro RM, Rosenberg R: Management of heparin therapy. Controlled prospective trial. N Engl J Med 1975; 292: 1046-1050. Ostro MJ, Russell JA, Soldin SJ, Malhon WA, Jeejeebhoy KN:
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21.
22.
23.
24.
25.
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Control of gastric pH with cimetidine: boluses versus primed infusion. Gastroenterology 1985; 89: 532-537. More DG, Raper RF, Munro IA, Watson CJ, Boutagy JS, Shenfield GM: Randomized, prospective trial of cimetidine and ranitidine for control of intragastric pH in the critically ill. Surgery 1985; 97: 215-223. Barth HO, Brunner G, Berg F, et al: Ranitidine versus cimetidine in preventing acute gastrointestinal bleeding: a randomized trial in 193 critically ill patients-a multicentre study in Germany. lntensivmedizin 1984; 21: 15-I 8. Rigaud D, Chastre J, Accary JP, Bonfils S, Gibert C, Hance AJ: lntragastric pH profile during acute respiratory failure in patients with chronic obstructive pulmonary disease. Effect of ranitidine and enteral feeding. Chest 1986; 90: 58-63. Borrero E, Bank S, Margolis I, Schulman ND, Chardavoyna R: Comparison of antacid and sucralfate in the prevention of gastrointestinal bleeding in patients who are critically ill. Am J Med 1985; 79 (suppl 2C): 62-64. Ryan JR, Vargas R, McMahon FG, Chremos AN: Comparison of effects of oral and intravenous famotidine on inhibition of nocturnal gastric acid secretion. Am J Med 1986; 81 (suppl 48): 60-64.
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