Anesth Analg 2002;95:144-147
© 2002 International Anesthesia Research Society
ANESTHETIC PHARMACOLOGY
The Efficacy of Lafutidine in Improving Preoperative Gastric Fluid Property: A Comparison with Ranitidine and Rabeprazole
Takanobu Uesugi, MD,
Katsuya Mikawa, MD,
Kahoru Nishina, MD,
Osamu Morikawa, MD,
Yumiko Takao, MD, and
Hidefumi Obara, MD
Department of Anesthesia and Perioperative Medicine, Faculty of Medical Sciences, Kobe University Graduate School of Medicine, Kobe, Japan
Address correspondence and reprint requests to Dr. K. Mikawa, Department of Anesthesia and Perioperative Medicine, Faculty of Medical Sciences, Kobe University Graduate School of Medicine, Kusunoki-cho 7, Chuo-ku, Kobe 650-0017, Japan. Address e-mail to katz{at}post.med.kobe-u.ac.jp
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Abstract
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IMPLICATIONS: Acid aspiration syndrome remains a potentially critical perioperative complication. We compared lafutidine, ranitidine, and rabeprazole for reduction of preoperative gastric fluid acidity and volume in elective surgery and found that these variables were minimized with a single morning dose of lafutidine 20 mg compared with ranitidine or rabeprazole. Preoperative oral lafutidine may be an alternative to ranitidine as a prophylaxis against aspiration pneumonia.
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Introduction
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Many pharmacologic agents, including histamine H2-receptor antagonists and proton pump inhibitors (PPIs), have been used to minimize the risk of acid aspiration syndrome (1). Recently, lafutidine, a new H2-receptor antagonist, has become clinically available in Japan. Like other H2-receptor antagonists, preoperative oral lafutidine can be expected to reduce the number of patients at risk for aspiration pneumonia. The antisecretory effect of lafutidine is potent, long-lasting, and dose-dependent (2). Because of these properties of lafutidine, a single dose of the drug given the night before surgery may be as effective as a morning dose in decreasing gastric fluid acidity and volume. Furthermore, a single larger dose (bedtime or morning) or two consecutive doses (bedtime and morning) of lafutidine may be more effective than a single smaller dose. To test these hypotheses, we determined the optimal treatment regimen with lafutidine to improve the preoperative gastric fluid environment using five combinations consisting of different timing and doses for lafutidine (the first aim).
Lafutidine has a receptor-binding affinity 2–80 times higher than other representative H2-receptor antagonists (e.g., famotidine, ranitidine, and cimetidine) (3). Although the PPIs also have an experimentally potent inhibitory action on gastric acid secretion, the efficacy of preoperative PPIs seems to be similar to or less than ranitidine for controlling gastric fluid acidity and volume (4–6). Lafutidine, therefore, may reduce gastric content acidity and volume more effectively than ranitidine, a standard prophylaxis against this life-threatening complication (7,8), and rabeprazole (a representative PPI). Thus, to test these hypotheses, we compared the efficacy of lafutidine, ranitidine, and rabeprazole in this clinical setting (the second aim).
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Methods
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We studied 360 otherwise healthy adult patients (aged 21–78 yr, ASA physical status I or II) undergoing elective surgery, after institutional approval and informed consent. Obese (>120% of ideal body weight) and diabetic patients, and those who were taking medication known to affect gastric fluid composition or gastric emptying were excluded. The patients were randomly assigned to one of 8 groups (n = 45 each): PLA + PLA (control), PLA + LAF10, LAF10 + PLA, LAF10 + LAF10, PLA + LAF20, LAF20 + PLA, PLA + RAN, and RAB + RAB, where PLA, LAF, RAN, and RAB were placebo, lafutidine (10 or 20 mg per dose; Protecadin, Taiho, Japan), ranitidine (150 mg), and rabeprazole (20 mg per dose), respectively (Table 1). For each treatment regimen, the first medication was administered at bedtime on the day preceding surgery and the second was administered 3 h before surgery in the morning. Oral ranitidine 150 mg is a standard prophylaxis against aspiration pneumonia (7,8). Two consecutive doses of rabeprazole (20 mg per dose) are the most effective premedication for controlling gastric fluid properties among rabeprazole, lansoprazole, and omeprazole (5). Anesthesia was induced with thiopental (4–5 mg/kg) and maintained with sevoflurane (2%–5%) and nitrous oxide (50%–60%). The lungs were ventilated, taking care to avoid inflation of the stomach. Specifically, anesthesiologists carefully assisted ventilation until loss of spontaneous respiration of the patients. After loss of spontaneous respiration, the anesthesiologists used an oral airway or did not put excessive pressure (peak airway pressure <20 mm Hg) on the patients. Tracheal intubation was facilitated by vecuronium. All inductions were uneventful, without cough, laryngospasm, or vomiting.
After tracheal intubation, a 16F orogastric tube was inserted into the stomach. Placement of the tube in the stomach was verified by auscultation over the epigastrium during the introduction of 10 mL of air. Gastric fluid samples were obtained by gentle manual aspiration with a 50-mL syringe by an investigator who was unaware of group assignment. This blinded manual aspiration is a common method of measuring the volume of gastric contents (9–11). However, this manipulation leads to inevitable underestimation of gastric fluid volume because of the inability to empty the stomach completely (12). To maximize gastric emptying, we used manual aspiration with a syringe via a large-bore, multi-orifice orogastric tube, which was repositioned several times with the patient in the supine and reverse Trendelenburg positions. Gastric contents were visually inspected for particles, and the volume of gastric contents was measured with the syringe. The pH of the gastric fluid was immediately determined at intervals of 0.1 by using a series of pH indicator papers (Advantec, Toyo Roshi, Japan) which cover a pH range from 0.4 to 9.6. In our preliminary study and previous research (6), we confirmed that pH values measured by the pH test papers correlated well with the pH determined using a pH meter which has 0.01 pH units precision (r = 0.96–0.97). Blood samples were obtained to analyze hematologic and biochemical variables before the administration of the study drugs and postoperative day.
Parametric data were statistically analyzed by using one-way analysis of variance followed by the Tukey-Kramer post hoc test. Nonparametric data were tested by using Fisher’s exact test. P < 0.05 was deemed statistically significant. The number of patients per group was determined by using a priori power analysis: 42 patients would be required in each group for a 80% power of detecting a 0.10 difference in gastric pH at the 0.05 levels of significance. This sample size would have a 90% power of detecting a 22% difference in the percentage of patients deemed at risk of aspiration pneumonia at the 0.05 levels.
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Results
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There were no differences in demographic data among the groups (Table 1). Gastric fluid was obtained from all patients. However, because gastric fluid remaining in the orogastric tube could not be aspirated into the syringe in 145 patients, such a small quantity was recorded as a volume of 0 mL (Table 2). Aspirated gastric acidity and volume were lower in all the treatment regimens than in the control group (Table 2). A combination of bedtime and morning doses (10 mg each) of lafutidine was more effective in decreasing gastric fluid acidity and volume than a bedtime dose (10 mg) alone, and equal to a morning dose (10 mg) alone. The two consecutive doses of lafutidine (10 mg each) were inferior to a single 20-mg dose alone. A reduction rate of gastric content volume and acidity with these treatments of lafutidine was similar or superior to that with a single dose of ranitidine. A single bedtime dose of lafutidine 10 mg and the two consecutive doses of rabeprazole seemed to be the least effective in controlling the gastric fluid environment of all the treatments (Table 2). The risk for aspiration pneumonitis (pH 
2.5 and volume 
0.4 mL/kg) was eliminated by all the treatments (Table 2). Laboratory values before and after surgery were similar in all the groups (data not shown).
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Discussion
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In the current study, we have shown that preoperative gastric fluid acidity was decreased by the H2-receptor antagonists and PPI in the following order: morning dose of lafutidine 20 mg > bedtime dose of lafutidine 20 mg > morning dose of ranitidine > bedtime and morning doses of lafutidine 10 mg = morning dose of lafutidine 10 mg > bedtime and morning doses of rabeprazole > bedtime dose of lafutidine 10 mg. A single morning dose of lafutidine 20 mg seemed to be more effective in decreasing gastric fluid acidity and volume than ranitidine, which has been extensively used as prevention against acid aspiration syndrome (7,8). The rationale for the use of lafutidine 10–20 mg/d in total in the current study was based on the findings of clinical studies seeking efficacy and safety of the drug for peptic ulcer or gastritis (13,14). However, the use of 40 mg in total may have provided better results, because the extent and duration of acid inhibition by lafutidine is dose-dependent. Intragastric pH monitoring revealed that the antisecretory effect begins to appear one hour after oral lafutidine (15). Gastric acid output is inhibited until 11 hours after oral lafutidine 10 mg, with a return toward basal levels by 12 hours (15). This pharmacodynamic profile of lafutidine may explain our observation that improvement of the gastric contents environment with a single bedtime dose was less than with a single morning dose.
Lafutidine increases gastric mucosal blood flow through mechanisms involving the capsaicin-sensitive afferent neurons (16). This mechanism contributes to promotion of gastric epithelial wound repair with lafutidine (17). The drug, unlike cimetidine and famotidine (18–20), has been experimentally shown to stimulate mucin biosynthesis and mucus secretion in gastric mucosa and to prevent indomethacin-induced antral ulcer formation. No clinical evidence has been published concerning the efficacy of lafutidine in the prevention of postoperative stress ulcer. In clinical settings, lafutidine more effectively improves gastric ulcer and gastritis than famotidine or cimetidine (21,22), which have been used as a prophylaxis against stress ulceration (23). The gastroprotective actions of lafutidine may also encourage the use of the drug as a prophylaxis for postoperative stress ulcer formation.
Drawbacks of the current study include the use of otherwise healthy patients and surrogate endpoints (gastric fluid pH and volume): we should have used high-risk patients (e.g., obese, diabetics, esophageal dysfunction) and outcome data (e.g., incidence of aspiration pneumonia). Thus, clinical relevance of the current study may be weak. However, from a viewpoint of efficiency, we believe that the preliminary study seeking the optimal dose and timing of lafutidine is necessary before final research assessing the usefulness of the drug in high-risk patients. Lafutidine may be more cost-effective than ranitidine and rabeprazole (costs of lafutidine 10 mg, ranitidine 150 mg, and rabeprazole 20 mg are ¥69 (US $0.53), ¥71 (US $0.54), and ¥269 (US $2.06), respectively). However, the cost-benefit ratio is outside the scope of discussion. Further studies for cost-benefit analysis are required.
Preoperative lafutidine may be of limited value in otherwise healthy patients undergoing elective surgery, because the incidence of aspiration pneumonitis is small in this population (24). However, prophylactic treatment with lafutidine may be indicated in patients who are predisposed to pulmonary aspiration (e.g., ASA physical status IV or V, emergency, previous esophageal surgery, a recent meal (24), obesity, and diabetes). This speculation may be supported by a report in which famotidine and ranitidine effectively reduced gastric fluid acidity and volume in morbidly obese patients (25).
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References
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Accepted for publication February 5, 2002.
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Abstract
Introduction
