It has been suggested that long-term H2 antagonist medication produces a reduction in antisecretory efficacy or tolerance (1,2). We have recently reported that patients receiving H2 antagonists for more than 4 wk show resistance to preanesthetic H2 antagonist treatment, used for acid aspiration pneumonia prophylaxis (3). If patients develop tolerance, then preanesthetic H2 antagonist medication would be essentially useless, and an alternative would be required.
Proton pump inhibitors (PPIs) may be a suitable alternative because they produce a similar or more potent antisecretory effect on gastric acid secretion than H2 antagonists (4,5). In addition, these clinical reports (4,5) suggest that tolerance to PPI treatment does not seem to develop. As PPIs inhibit the H+/K+-adenosine triphosphatase pump, which is the final step in gastric acid secretion from the parietal cell (6), tolerance to these drugs may not develop with chronic treatment. Thus, we hypothesized that PPIs may be effective for patients with tolerance to H2 antagonist therapy, although there are no studies showing the efficacy of PPIs for patients with the tolerance.
In the present study, to prove our hypothesis, we compared the antisecretory effects of a preanesthetic H2 antagonist (roxatidine) and a PPI inhibitor (rabeprazole) in patients who received regular famotidine (H2 antagonist) for more than 4 wk. We measured gastric fluid acidity, volume of gastric contents, and plasma gastrin levels.
With University Ethics Committee approval and informed consent, 48 adult surgical patients receiving regular oral H2 antagonist (famotidine) medication for more than 4 wk to treat gastric ulcer or gastritis were recruited. These patients were randomly assigned to two groups: H2 group and PPI group (n = 24 each). Patients scheduled for gastrointestinal tract procedures were excluded.
In the H2 and PPI groups, patients were premedicated orally with triazolam 0.25 mg and roxatidine 75 mg or rabeprazole 20 mg at 9:00 pm on the day before the surgery and with diazepam 10 mg and roxatidine 75 mg or rabeprazole 20 mg 2 h before the induction of anesthesia, respectively. Because only roxatidine has been approved as an oral preanesthetic H2 antagonist by our Ministry of Health, Labor and Welfare in Japan, famotidine was not used as a preanesthetic H2 antagonist. All patients were hospitalized for at least the night before surgery and were fasted from the first anesthetic premedication (i.e., 9:00 pm). The researchers and patients were blinded to preanesthetic medication.
Anesthesia was induced with propofol 1.0–1.5 mg/kg, ketamine 0.5 mg/kg, and fentanyl 2 μg/kg and maintained with propofol 5–8 mg·kg−1·h−1, ketamine 0–0.5 mg·kg−1·h−1, and fentanyl 4–8 μg/kg. The trachea was intubated after muscle relaxation facilitated with succinylcholine 0.8 mg/kg IV. Muscle relaxation was maintained with an IV bolus of vecuronium 0.08 mg/kg, and then a further 1 mg was given IV every 30 min. After tracheal intubation, a gastric tube (Argyle® Salem Sump Tube, Japan Sherwood, Tokyo, Japan) was placed into the stomach, and its position was verified by auscultation of the epigastrium during insufflation of air.
Gastric fluid was obtained by aspiration using a 10- or 50-mL syringe while changing the patient's position (supine, Trendelenburg and reverse Trendelenburg, and right and left 20 degree semilateral positions) and with insufflation of 50-mL air plus upper-abdominal massage. The volume of gastric contents was recorded as well as the pH value, measured with a pH meter with 0.01 pH unit precision over the entire pH range (Ecoscan pH5 pH6; Iuchi Seieido Co, Ltd, Osaka, Japan) that was calibrated each morning.
Arterial blood was simultaneously collected and centrifuged at 3000 rpm for 10 min at −10°C to separate plasma, which was kept frozen at −70°C until assay. Plasma gastrin concentrations were analyzed using a commercially available enzyme-linked immunosorbent assay (Peninsula Laboratories Inc, San Carlos, CA) with a minimum sensitivity, inter- and intraassay coefficient of variation of 7.27 pg/mL, 6.5% and 3.7%, respectively.
Data are presented as mean ± sd. Statistical analysis was performed using unpaired t-test or χ2 test as appropriate, with P < 0.05 considered significant.
There were no differences between groups with respect to sex, age, height, and weight. These data are summarized in Table 1. Gastric contents of seven patients (four in the H2 group and three in the PPI group) were green in color, indicating the presence of bile.
Gastric pH and volume were significantly larger and smaller in the PPI group when compared to the H2 group, respectively (Fig. 1, A and B). Plasma gastrin levels were also significantly higher in the PPI group (Fig. 1C). In addition, there was a significant correlation between gastric pH and plasma gastrin (Fig. 2; r = 0.47; P < 0.01).
There were more patients with critical factors for acid aspiration pneumonia (pH < 2.5, volume of gastric contents >25 mL, and plasma gastrin concentration >200 pg/mL) in the H2 group (Table 2).
Patients in the H2 group had lower gastric pH values and larger gastric volume compared with the PPI group. Critical factors for acid aspiration pneumonia in adults have been considered to comprise gastric pH values less than 2.5 and a fluid volume larger than 25 mL (7). In the present study, 14 of 24 patients in the H2 group were at risk of acid aspiration pneumonia (12 for gastric pH <2.5 and 6 for the volume >25 mL), whereas only four patients were at risk in PPI group. In addition, when samples suggesting the presence of bile were excluded from the analysis, gastric pH value and volume in the H2 group were 2.58 ± 1.31 and 16.5 ± 14.9 mL, respectively, which are comparable to those reported by Haavik et al. (8) for patients with no prophylaxis (gastric pH = 2.2 ± 1.2; volume = 20 ± 18 mL). Therefore, in agreement with our previous data (3), patients receiving regular H2 antagonist medication for longer than four weeks displayed tolerance to preanesthetic roxatidine. In contrast, patients in the PPI group showed significantly higher gastric pH values and smaller gastric volume. In addition, only 4 of 24 patients were at risk of acid aspiration pneumonia (four patients with gastric pH <2.5 and 0 with a volume >25 mL). Our data clearly suggest that PPI treatment may be effective for the prevention of acid aspiration pneumonia in patients tolerant to H2 antagonists.
Several clinical studies (4,5) have shown that PPIs reduce gastric acid secretion and were similar to, or more potent than, H2 antagonists and were additionally devoid of tolerance liability. Because PPIs inhibit H+/K+-adenosine triphosphatase, the final step in gastric acid secretion from the parietal cell (9), it is unlikely that tolerance to PPIs would develop after chronic medication. Qvigstad et al. (10) reported that long-term treatment with PPI may induce tolerance to H2 antagonists in Helicobacter pylori-negative patients. This tolerance may be caused by PPI-induced hypergastrinemia, which causes an up-regulation of histamine synthesis in enterochromaffin-like (ECL) cells, thereby competing with the H2 antagonist. Thus, in surgical patients, PPIs may be preferable to H2 antagonists for preanesthetic medication for acid aspiration pneumonia prophylaxis.
The mechanism(s) underlying tolerance to H2 antagonist is still unknown. Several clinical reports (4,11) suggest that prolonged hypergastrinemia caused by H2 antagonists induces tolerance. In addition, the time course of ECL cell responsiveness to gastrin, which induces ECL cell hyperactivity (histamine release) in minutes to hours, hypertrophy in hours to days, hyperplasia in weeks to months, and dysplasia or neoplasia over years (12), suggests that tolerance may be due to hypergastrinemia competing with the H2 antagonist, which induces up-regulation of histamine synthesis. Therefore, hypergastrinemia would be a likely finding in tolerant patients, because up-regulation of histamine synthesis should be maintained by high levels of gastrin. However, in our previous study, plasma gastrin levels in tolerant patients were close to the normal range. In the present study, we confirm that patients with tolerance to H2 antagonists do not show hypergastrinemia. Therefore, hypergastrinemia may not be involved in the maintenance of tolerance. Other mechanisms, such as H2 receptor up-regulation (13), may be involved.
In conclusion, the present study suggests that PPI medication may be effective for prophylaxis of acid aspiration pneumonia in patients showing full tolerance to H2 antagonists.
The authors thank Dr D.G. Lambert (University Department of Cardiovascular Sciences [Pharmacology and Therapeutics Group], Division of Anesthesia, Critical Care and Pain Management, Leicester Royal Infirmary, UK) for his valuable comments.
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© 2005 International Anesthesia Research Society
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