British Journal of Anaesthesia 1992; 69: 404-^106
EFFECTS OF OMEPRAZOLE, RANITIDINE, FAMOTIDINE AND PLACEBO ON GASTRIC SECRETION IN PATIENTS UNDERGOING ELECTIVE SURGERY F. ESCOLANO, J. CASTANO, R. LOPEZ, E. BISBE AND A. ALCON
We have compared the effects of omeprazole, ranitidine, famotidine and placebo on gastric secretion in a double-blind study in 110 patients undergoing elective surgery. Three hours before operation, the patients received, orally, omeprazole 40 mg, ranitidine 150 mg, famotidine 40 mg or placebo. Gastric volume and pH were measured immediately after induction of anaesthesia. Omeprazole, ranitidine and famotidine produced a significant increase in gastric pH and a significant decrease in gastric volume compared with placebo. When the effects of omeprazole on gastric volume were compared with those of ranitidine and famotidine, no significant difference was found, but omeprazole was significantly less effective in increasing gastric pH. The number of patients having a pH less than 2.5 and a volume greater than 0.4 mlkgr' were: none in the ranitidine group, one (3%) in the famotidine group, four (15%) in the omeprazole group and six (23%) in the placebo group. We conclude that omeprazole 40 mg given 2-4 h before surgery does not afford adequate prophylaxis for the acid aspiration syndrome. KEY
WORDS
Gastrointestinal tract, gastric secretion. Pharmacology: famotidine, omeprazole. ranitidine. Premedication.
Several studies have shown that the gastric fluid pH is an important factor causing pulmonary damage after aspiration of gastric contents. A pH less than 2.5 and a gastric volume greater than 0.4 ml kg"1 are suggested as being risk factors for the acid aspiration syndrome in adults [1]. Thirty to fifty percent of normal adults undergoing elective surgery have a lesser gastric pH and greater volume [1,2] and one of the aims of preoperative treatment should be reducing these risk factors. Many drugs have been used to achieve this objective. The H2-receptor antagonists produce an effective reduction in gastric volume [1, 2], but do not modify the pH of the gastric fluid already present in the stomach. Therefore, the protection obtained with these agents depends on the dose of drug and the time elapsed between its administration and the aspiration of fluid [2]-
Omeprazole is a substituted benzimidazole, noncompetitive inhibitor of gastric secretion. It blocks H + /K + -ATPase, the proton pump of the parietal cell. Because of its pharmacokinetic characteristics, omeprazole may offer certain advantages compared with Hj-receptor antagonists, with respect to potency and duration of action [3]. The aim of this study was to compare the effects of omeprazole, ranitidine, famotidine and placebo on gastric volume and pH in patients undergoing elective surgery under general anaesthesia. METHODS AND RESULTS
The study was approved by the Hospital Ethics Committee and 110 patients (47 male), ASA I—III, aged 15-83 yr (mean 54 yr), undergoing elective surgery were studied after informed consent had been given. The patients were allocated randomly to one of four groups: group A (n = 27) received omeprazole 40 mg; group B (« = 17) received ranitidine 150 mg; group C (n = 30) received famotidine 40 mg; group D (n = 26) received placebo. The drugs were administered orally 3 h before induction of anaesthesia, together with 20 ml of water and oral lorazepam 1-2 mg, depending on the weight and physical condition of the patient. Patients with significant liver, kidney or gastrointestinal diseases, those who were pregnant, hypersensitive to drugs, receiving antacids or HE-receptor antagonists or undergoing gastrointestinal surgery were excluded. The study was carried out in a double-blind manner. Age, weight, sex, smoking and drinking habits, fasting period and time of drug administration were recorded, as was any side effect caused by the study agents. Anaesthesia was induced with thiopentone followed by atracurium. After 3 min of manual ventilation of the lungs, the trachea was intubated. Anaesthesia was maintained with 70 % nitrous oxide in oxygen supplemented with volatile agents or opioids. Anticholinergic agents were avoided until
F. ESCOLANO, L.M.C.(BARCELONE); J. CASTANO, L.M.C.(BARCELONE), D.A.(ENGL.); R. LOPEZ, L.M.C.(BARCELONE); E. BISBE, L.M.C(BARCELONE); A. ALCON, L.M.C.(BARCELONE); Department
of Anaesthesiology, Hospital Universitario de la Esperanza, Sant Josep de la Muntanya 12, 08024 Barcelone, Spain. Accepted for Publication: May 11, 1992.
Downloaded from http://bja.oxfordjournals.org/ at The Chinese University of Hong Kong on February 21, 2015
SUMMARY
405
REDUCTION OF GASTRIC SECRETION TABLE I. Volume and pH values of gastric fluid samples (mean (SD) [range]), and subjects deemed at risk of acid aspiration. * Significant with respect to placebo (P < 0.05) Volume Group
n
(ml)
Omeprazole Rani ti dine Famotidine Placebo
27 27 30 26
11.0 (12.0) 8.8(8.6) 8.5(8.8) 21.2 (17.6)
At risk
PH n [0-53]* [0-30]* [0-30]* [1-79]
5.1 (2.5) [1.5-8.1]* 7.1 (1.6) [1.3-8.0]* 6.5 (1.8) [1.6-7.8]* 3.1 (2.4) [1.1-7.2]
(%)
4 0 1 6
15 0 3 23
famotidine group, six (23%) in the placebo group and none in the ranitidine group. The difference with respect to placebo was significant only for the ranitidine group: %2 = 4.92 (P < 0.05). No side effects were observed.
COMMENT
The present study has shown that a single oral dose of omeprazole, ranitidine or famotidine, given 2-4 h before anaesthetic induction, produced a significant increase in gastric pH and a decrease in gastric fluid volume, compared with placebo. There was no significant difference in gastric volume when omeprazole was compared with ranitidine and famotidine, but ranitidine and famotidine produced a significantly greater increase in gastric pH compared with omeprazole. The number of patients deemed at risk for the acid aspiration syndrome was greater in the omeprazole group (15%) than in the ranitidine and famotidine groups (table I). This may be a reflection of individual differences in absorption of the drug after a single oral dose. Omeprazole is inactivated rapidly at a low gastric pH and, to avoid this, the drug is administered as enteric-coated granules for absorption in the small intestine, which may be relatively delayed. Consequently, the time to peak effect is delayed also [3]. In previous studies, doses of omeprazole 40 mg [4] and 80 mg [5] given the night before surgery reduced the number of patients deemed at risk to 5 %, while two doses of 40 mg resulted in no patients being deemed at risk [6]. It is concluded that omeprazole 40 mg given 2-4 h before operation does not increase gastric pH and decrease gastric volume to an acceptable degree in 15% of patients. A greater dose given a longer time before anaesthesia is recommended.
REFERENCES 1. Escolano F, Alcon A. Profilaxis de la aspiraci6n icida. Revisita EspaOola de Anestesiologia y Reanimacion 1990;,37:. .--304-308;2. Editorial. Routine H,-receptor antagonists before elective surgery. Lancet 1989; 1: 1363-1364. 3. Regardh CG, Andersson T, Lagerstron PO, Lundborg P, Skanberg I. The pharmacokinetics of omeprazole in humans—a study of single intravenous and oral doses. Therapeutic Drug Monitoring 1990; 12: 163-172. 4. Wingtin LN, Glomaud D, Hardy F, Phil S. Omeprazole for
Downloaded from http://bja.oxfordjournals.org/ at The Chinese University of Hong Kong on February 21, 2015
the sample of gastric fluid had been obtained. Immediately after induction, a 16-French gauge nasogastric tube was inserted into the stomach and its correct position checked by auscultation of injected air. The gastric contents were aspirated and the volume and pH measured. The pH was measured by a pH microelectrode attached to a digital pH meter (Microph, Crison). Data were analysed statistically using analysis of variance of a linear model in which the gastric fluid volume and pH were considered as dependent variables and were analysed separately. As independent variables, we considered: treatment (qualitative; three groups: omeprazole, ranitidine and famotidine), time elapsed between drug administration and sample extraction (min), sex (qualitative), weight (kg), age (yr), smoking (qualitative: yes or no). In this model, the constant term was represented by treatment with placebo. After the analysis of the model and the evaluation of main effects, several hypotheses were tested using an F test. These hypotheses were global comparisons between all the treatments and subsequent comparisons between pairs of treatments. The effect of treatment on the number of patients deemed "at risk" (gastric volume equal to or greater than 25 ml and gastric pH less than 2.5) were compared using the chi-square test, Yates' correction being applied when necessary. The four groups of patients were comparable in age, weight, sex and time from drug administration to sample extraction which ranged from 80 to 330 min, being 120-240 min for 78.9% of patients. Mean (SEM) values for the groups were: omeprazole, 180 (41.8) min; ranitidine, 185 (58.0) min; famotidine, 175 (47.5) min; placebo, 178 (58.1) min. The number of patients in each group and the gastric pH and volumes are shown in table I. The decrease in gastric volume and increase in pH in the omeprazole, ranitidine and famotidine groups were significantly different from those in the placebo group (P < 0.05). This was caused by drug administration and not any independent variable. No significant differences were found for gastric volume values between the treated groups (F = 0.84; P > 0.05). The increase in pH values produced by ranitidine and famotidine was significantly greater than that produced by omeprazole (ranitidine vs omeprazole, F = 7.25, .P_< 0.05; famotidine- -vs - omeprazole," F = 8.84, P < 0.05), but not between famotidine and ranitidine (F = 0.02, P > 0.05). The number of patients at risk according to the criteria of Roberts and Shirley [1] are shown in table I: four (15 %) in the omeprazole group, one (3 %) in
24 25 25 26
n
406 prophylaxis of acid aspiration in elective surgery. Anaesthesia 1990; 45: 436-438. 5. Gin T, Ewart MC, Yau G, Oh TE. Effect of oral omeprazole on intragastric pH and volume in women undergoing elective Caesarean section. British Journal of Anaesthesia 1990; 65: 616-619.
BRITISH JOURNAL OF ANAESTHESIA 6. Ewart MC, Yau G, Gin T, Kotur CF, Oh TE. A comparison of the effects of omeprazole and ranitidine on gastric secretion in women undergoing elective Caesarean section. Anaesthesia 1990; 45: 527-530.
Downloaded from http://bja.oxfordjournals.org/ at The Chinese University of Hong Kong on February 21, 2015
EFFECTS OF OMEPRAZOLE, RANITIDINE, FAMOTIDINE AND PLACEBO ON GASTRIC SECRETION IN PATIENTS UNDERGOING ELECTIVE SURGERY F. ESCOLANO, J. CASTANO, R. LOPEZ, E. BISBE AND A. ALCON
We have compared the effects of omeprazole, ranitidine, famotidine and placebo on gastric secretion in a double-blind study in 110 patients undergoing elective surgery. Three hours before operation, the patients received, orally, omeprazole 40 mg, ranitidine 150 mg, famotidine 40 mg or placebo. Gastric volume and pH were measured immediately after induction of anaesthesia. Omeprazole, ranitidine and famotidine produced a significant increase in gastric pH and a significant decrease in gastric volume compared with placebo. When the effects of omeprazole on gastric volume were compared with those of ranitidine and famotidine, no significant difference was found, but omeprazole was significantly less effective in increasing gastric pH. The number of patients having a pH less than 2.5 and a volume greater than 0.4 mlkgr' were: none in the ranitidine group, one (3%) in the famotidine group, four (15%) in the omeprazole group and six (23%) in the placebo group. We conclude that omeprazole 40 mg given 2-4 h before surgery does not afford adequate prophylaxis for the acid aspiration syndrome. KEY
WORDS
Gastrointestinal tract, gastric secretion. Pharmacology: famotidine, omeprazole. ranitidine. Premedication.
Several studies have shown that the gastric fluid pH is an important factor causing pulmonary damage after aspiration of gastric contents. A pH less than 2.5 and a gastric volume greater than 0.4 ml kg"1 are suggested as being risk factors for the acid aspiration syndrome in adults [1]. Thirty to fifty percent of normal adults undergoing elective surgery have a lesser gastric pH and greater volume [1,2] and one of the aims of preoperative treatment should be reducing these risk factors. Many drugs have been used to achieve this objective. The H2-receptor antagonists produce an effective reduction in gastric volume [1, 2], but do not modify the pH of the gastric fluid already present in the stomach. Therefore, the protection obtained with these agents depends on the dose of drug and the time elapsed between its administration and the aspiration of fluid [2]-
Omeprazole is a substituted benzimidazole, noncompetitive inhibitor of gastric secretion. It blocks H + /K + -ATPase, the proton pump of the parietal cell. Because of its pharmacokinetic characteristics, omeprazole may offer certain advantages compared with Hj-receptor antagonists, with respect to potency and duration of action [3]. The aim of this study was to compare the effects of omeprazole, ranitidine, famotidine and placebo on gastric volume and pH in patients undergoing elective surgery under general anaesthesia. METHODS AND RESULTS
The study was approved by the Hospital Ethics Committee and 110 patients (47 male), ASA I—III, aged 15-83 yr (mean 54 yr), undergoing elective surgery were studied after informed consent had been given. The patients were allocated randomly to one of four groups: group A (n = 27) received omeprazole 40 mg; group B (« = 17) received ranitidine 150 mg; group C (n = 30) received famotidine 40 mg; group D (n = 26) received placebo. The drugs were administered orally 3 h before induction of anaesthesia, together with 20 ml of water and oral lorazepam 1-2 mg, depending on the weight and physical condition of the patient. Patients with significant liver, kidney or gastrointestinal diseases, those who were pregnant, hypersensitive to drugs, receiving antacids or HE-receptor antagonists or undergoing gastrointestinal surgery were excluded. The study was carried out in a double-blind manner. Age, weight, sex, smoking and drinking habits, fasting period and time of drug administration were recorded, as was any side effect caused by the study agents. Anaesthesia was induced with thiopentone followed by atracurium. After 3 min of manual ventilation of the lungs, the trachea was intubated. Anaesthesia was maintained with 70 % nitrous oxide in oxygen supplemented with volatile agents or opioids. Anticholinergic agents were avoided until
F. ESCOLANO, L.M.C.(BARCELONE); J. CASTANO, L.M.C.(BARCELONE), D.A.(ENGL.); R. LOPEZ, L.M.C.(BARCELONE); E. BISBE, L.M.C(BARCELONE); A. ALCON, L.M.C.(BARCELONE); Department
of Anaesthesiology, Hospital Universitario de la Esperanza, Sant Josep de la Muntanya 12, 08024 Barcelone, Spain. Accepted for Publication: May 11, 1992.
Downloaded from http://bja.oxfordjournals.org/ at The Chinese University of Hong Kong on February 21, 2015
SUMMARY
405
REDUCTION OF GASTRIC SECRETION TABLE I. Volume and pH values of gastric fluid samples (mean (SD) [range]), and subjects deemed at risk of acid aspiration. * Significant with respect to placebo (P < 0.05) Volume Group
n
(ml)
Omeprazole Rani ti dine Famotidine Placebo
27 27 30 26
11.0 (12.0) 8.8(8.6) 8.5(8.8) 21.2 (17.6)
At risk
PH n [0-53]* [0-30]* [0-30]* [1-79]
5.1 (2.5) [1.5-8.1]* 7.1 (1.6) [1.3-8.0]* 6.5 (1.8) [1.6-7.8]* 3.1 (2.4) [1.1-7.2]
(%)
4 0 1 6
15 0 3 23
famotidine group, six (23%) in the placebo group and none in the ranitidine group. The difference with respect to placebo was significant only for the ranitidine group: %2 = 4.92 (P < 0.05). No side effects were observed.
COMMENT
The present study has shown that a single oral dose of omeprazole, ranitidine or famotidine, given 2-4 h before anaesthetic induction, produced a significant increase in gastric pH and a decrease in gastric fluid volume, compared with placebo. There was no significant difference in gastric volume when omeprazole was compared with ranitidine and famotidine, but ranitidine and famotidine produced a significantly greater increase in gastric pH compared with omeprazole. The number of patients deemed at risk for the acid aspiration syndrome was greater in the omeprazole group (15%) than in the ranitidine and famotidine groups (table I). This may be a reflection of individual differences in absorption of the drug after a single oral dose. Omeprazole is inactivated rapidly at a low gastric pH and, to avoid this, the drug is administered as enteric-coated granules for absorption in the small intestine, which may be relatively delayed. Consequently, the time to peak effect is delayed also [3]. In previous studies, doses of omeprazole 40 mg [4] and 80 mg [5] given the night before surgery reduced the number of patients deemed at risk to 5 %, while two doses of 40 mg resulted in no patients being deemed at risk [6]. It is concluded that omeprazole 40 mg given 2-4 h before operation does not increase gastric pH and decrease gastric volume to an acceptable degree in 15% of patients. A greater dose given a longer time before anaesthesia is recommended.
REFERENCES 1. Escolano F, Alcon A. Profilaxis de la aspiraci6n icida. Revisita EspaOola de Anestesiologia y Reanimacion 1990;,37:. .--304-308;2. Editorial. Routine H,-receptor antagonists before elective surgery. Lancet 1989; 1: 1363-1364. 3. Regardh CG, Andersson T, Lagerstron PO, Lundborg P, Skanberg I. The pharmacokinetics of omeprazole in humans—a study of single intravenous and oral doses. Therapeutic Drug Monitoring 1990; 12: 163-172. 4. Wingtin LN, Glomaud D, Hardy F, Phil S. Omeprazole for
Downloaded from http://bja.oxfordjournals.org/ at The Chinese University of Hong Kong on February 21, 2015
the sample of gastric fluid had been obtained. Immediately after induction, a 16-French gauge nasogastric tube was inserted into the stomach and its correct position checked by auscultation of injected air. The gastric contents were aspirated and the volume and pH measured. The pH was measured by a pH microelectrode attached to a digital pH meter (Microph, Crison). Data were analysed statistically using analysis of variance of a linear model in which the gastric fluid volume and pH were considered as dependent variables and were analysed separately. As independent variables, we considered: treatment (qualitative; three groups: omeprazole, ranitidine and famotidine), time elapsed between drug administration and sample extraction (min), sex (qualitative), weight (kg), age (yr), smoking (qualitative: yes or no). In this model, the constant term was represented by treatment with placebo. After the analysis of the model and the evaluation of main effects, several hypotheses were tested using an F test. These hypotheses were global comparisons between all the treatments and subsequent comparisons between pairs of treatments. The effect of treatment on the number of patients deemed "at risk" (gastric volume equal to or greater than 25 ml and gastric pH less than 2.5) were compared using the chi-square test, Yates' correction being applied when necessary. The four groups of patients were comparable in age, weight, sex and time from drug administration to sample extraction which ranged from 80 to 330 min, being 120-240 min for 78.9% of patients. Mean (SEM) values for the groups were: omeprazole, 180 (41.8) min; ranitidine, 185 (58.0) min; famotidine, 175 (47.5) min; placebo, 178 (58.1) min. The number of patients in each group and the gastric pH and volumes are shown in table I. The decrease in gastric volume and increase in pH in the omeprazole, ranitidine and famotidine groups were significantly different from those in the placebo group (P < 0.05). This was caused by drug administration and not any independent variable. No significant differences were found for gastric volume values between the treated groups (F = 0.84; P > 0.05). The increase in pH values produced by ranitidine and famotidine was significantly greater than that produced by omeprazole (ranitidine vs omeprazole, F = 7.25, .P_< 0.05; famotidine- -vs - omeprazole," F = 8.84, P < 0.05), but not between famotidine and ranitidine (F = 0.02, P > 0.05). The number of patients at risk according to the criteria of Roberts and Shirley [1] are shown in table I: four (15 %) in the omeprazole group, one (3 %) in
24 25 25 26
n
406 prophylaxis of acid aspiration in elective surgery. Anaesthesia 1990; 45: 436-438. 5. Gin T, Ewart MC, Yau G, Oh TE. Effect of oral omeprazole on intragastric pH and volume in women undergoing elective Caesarean section. British Journal of Anaesthesia 1990; 65: 616-619.
BRITISH JOURNAL OF ANAESTHESIA 6. Ewart MC, Yau G, Gin T, Kotur CF, Oh TE. A comparison of the effects of omeprazole and ranitidine on gastric secretion in women undergoing elective Caesarean section. Anaesthesia 1990; 45: 527-530.
Downloaded from http://bja.oxfordjournals.org/ at The Chinese University of Hong Kong on February 21, 2015
