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PEDIATRIC ANESTHESIA: GENERAL ARTICLES

A Comparison of Rabeprazole, Lansoprazole, and Ranitidine for Improving Preoperative Gastric Fluid Property in Adults Undergoing Elective Surgery

Nishina, Kahoru MD; Mikawa, Katsuya MD; Takao, Yumiko MD; Shiga, Makoto MD; Maekawa, Nobuhiro MD; Obara, Hidefumi MD

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doi: 10.1097/00000539-200003000-00038
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Abstract

Although gastric content aspiration is a rare perioperative complication, it may be associated with postoperative mortality or pulmonary morbidity (1,2). The severity of aspiration pneumonitis depends on pH and volume of gastric juice aspirated. Many pharmacological agents, including H2 receptor antagonists and antacids, have been used in an attempt to eliminate the risk of pulmonary aspiration by decreasing acidity and volume of the gastric fluid (3). We previously reported that premedication with lansoprazole and omeprazole, proton pump inhibitors (PPIs), improved preoperative gastric fluid properties (4). Recently, rabeprazole, a new potent and fast acting PPI, has been available in several countries, including the United States (5). No reports concerning the effect of rabeprazole on preoperative gastric fluid volume and pH have been published. Our first aim was to determine whether rabeprazole can decrease risk of acid aspiration syndrome during the induction of anesthesia. In our previous study, two consecutive doses (bedtime and morning) of lansoprazole or omeprazole were more effective in reducing gastric fluid acidity and volume than a single dose of each drug alone (4). Our second aim, therefore, was to ascertain whether a similar phenomenon is also observed for rabeprazole. Furthermore, we documented that lansoprazole, given the preceding night and morning, minimized risk of lung damage by controlling gastric acid secretion, as with a morning dose of ranitidine (4). Thus, our final aim was to compare the efficacy of rabeprazole, lansoprazole (two successive doses), and ranitidine in this clinical setting. To make this assessment, we used three different times for administering rabeprazole: at bedtime before surgery, on the morning of the day of surgery, and a combination of the two.

Methods

We examined the effects of lansoprazole on gastric fluid volume and pH in 180 otherwise healthy adult patients (22–72 yr old, ASA physical status I) undergoing elective surgery, after institutional approval and written, informed consent of all patients. Obese patients who were more than 20% heavier than their ideal body weight and those taking medication known to affect gastric fluid composition or gastric emptying were excluded. The patients were randomly assigned to one of six groups as follows (n = 30 for each group): PLA-PLA (control), PLA-RAB, RAB-PLA, RAB-RAB, LAN-LAN, and PLA-RAN, where PLA, RAB, LAN, RAN were placebo consisting of starch and sucrose, rabeprazole (20 mg per dose), lansoprazole (30 mg per dose), and ranitidine (150 mg). For each treatment regimen, the first medication was orally administered with 20 mL of water at 9:00 PM on the day before surgery and the second with the same quantity of water at 5:30 AM on the day of surgery (see legends to Tables 1 and 2). Oral ranitidine 150 mg given 3 h before anesthesia is well established as a standard for prophylaxis against acid aspiration syndrome (6–9). The rationale for the dose and timing of rabeprazole treatment was based on many reports: Rabeprazole 20–40 mg/day is used to heal peptic ulceration, reflux esophagitis, and chronic active gastritis (10–12), and peak plasma concentrations of the drug occur approximately 3 h after oral administration of a 20-mg tablet in healthy volunteers (13). All patients fasted at least 10 h before the induction of anesthesia. No other premedicants were administered.

T1-38
Table 1:
Demographic Data
T2-38
Table 2:
Gastric Fluid Analysis

The induction of anesthesia in all cases was started at 8:30 AM. Anesthesia was induced with thiopental and maintained with sevoflurane and nitrous oxide in oxygen. The lungs were ventilated, taking care to avoid inflation of the stomach. Tracheal intubation was facilitated by vecuronium bromide. All inductions were uneventful, and no patients had coughing, laryngospasm, or vomiting during the induction.

After tracheal intubation, a 16F Argyle Salem Sump® (Argyle Sherwood Medical, St. Louis, MO) catheter was inserted into the stomach. Placement of the orogastric tube within the stomach was verified by auscultation over the epigastrium during introduction of 10 mL of air. Gastric fluid samples were obtained by gentle aspiration with a 50-mL syringe by an investigator who was unaware of the patients’ preanesthetic medication. Aspirations were attempted with the patient held in supine, reverse Trendelenburg’s, and both lateral positions to maximize gastric emptying. At any position, pressure was applied over the epigastrium, and gastric contents were aspirated intermittently during removal of the orogastric tube. 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 determined immediately using a pH meter, which was calibrated by using standard buffers at pH values of 2, 4, and 7. The pH meter has 0.01 pH units precision over the entire pH range.

The age, height, weight, gender, gastric fluid pH, and volume were recorded for each patient. Patients provided blood and urine samples for laboratory analyses to compare hematology, blood chemistry, and renal and hepatic variables before the administration of study drug and postoperative Day 1. Comparisons of data between the groups were made by using one-way analysis of variance and Bonferroni’s correction of multiple comparison for parametric data. The difference among the groups’ risk factors for pulmonary acid-aspiration syndrome were tested for statistical significance by Fisher’s exact test. P < 0.05 was deemed statistically significant. Power analysis revealed that the sample size (n = 30 in each group) of the current study is sufficient to detect medium differences ([mean1 − mean2]/standard deviation = 0.5∼0.7) in variables (pH and volume) at a significance level of 0.05 with the power of 0.6∼0.8 (14).

Results

There were no differences among the groups regarding age, weight, height, and gender (Table 1). Although gastric fluid was obtained from all patients, the volume from 14 patients was very small. It remained in the gastric tube and could not be aspirated into the syringe, precluding measurement; these small quantities were recorded as a volume of 0 mL. Aspirated gastric acidity and volume were lower in all the treatment groups than in the control group (PLA-PLA) (Table 2). A combination of bedtime and morning doses of rabeprazole was significantly more effective in decreasing gastric fluid acidity and volume than a bedtime dose alone. The two consecutive doses of rabeprazole also were superior to a single morning dose alone or two successive doses of lansoprazole, although not significantly. A single dose of ranitidine was the most effective in controlling gastric fluid environment of all the study drugs (Table 2). The two consecutive doses of rabeprazole were the second most effective regimen for the same purpose. Table 2 also shows that the proportion of patients considered at risk of aspiration pneumonitis [gastric fluid pH of < 2.5 and volume of > 0.4 mL/kg (15)] was significantly lower in all the treatment groups that in the control group and was minimized in Groups RAB-RAB and PLA-RAN (%).

Laboratory values before and after surgery were similar in all groups. No adverse effects (hypotension, eruption, headache, or diarrhea) considered to be related to study drugs were observed.

Discussion

Rabeprazole is more potent than omeprazole for inhibiting proton pump (H+, K+-adenosine triphosphatase) activity and acid output (5). The drug is activated in the acidic lumen of the gastric parietal cells (5). The active form of rabeprazole reacts with the sulfhydryl groups of the proton pump, resulting in inhibition of acid formation. Rabeprazole inhibits acid secretion provoked by histamine, pentagastrin, or dibutyryl cyclic adenosine monophosphate (16). The drug provides earlier healing and superior pain relief in peptic ulcer and gastroesophageal reflux disease compared with omeprazole or H2 receptor antagonists (5).

Our main findings are: 1) rabeprazole (20 or 40 mg in total) reduced the volume and acidity of gastric contents at the induction of anesthesia regardless of treatment timing; 2) a combination of bedtime and morning doses of rabeprazole was more effective in improving preoperative gastric fluid properties than a bedtime dose alone; 3) the two consecutive doses of rabeprazole were superior to a morning dose alone or to two consecutive doses of lansoprazole (but not significantly); and 4) the effectiveness produced by the two successive doses of rabeprazole was comparable to that of ranitidine, which is one of the most useful drugs used to prevent acid aspiration syndrome. Furthermore, improvement of gastric contents environment with a single preceding night dose of rabeprazole was less satisfactory, compared with that provided by a single morning dose. This observation may be explained by the following pharmacological characteristics of rabeprazole. A pharmacokinetic profile of the drug includes a more rapid onset and shorter duration of gastric antisecretory action than other members of PPIs. Gastric acid output almost recovered to basal levels within 12 h after the administration of rabeprazole (17). However, larger doses (e.g., 40 mg/dose) may have provided better results, because the extent and duration of acid inhibition by rabeprazole is dose-dependent.

As with many other studies concerning gastric fluid property (18–21), we used blind aspiration to measure the volume of gastric contents. This technique may incompletely empty the stomach and, therefore, underestimate gastric fluid volume. The alternative methods include gastric aspiration by using a visually guided gastroscope and the dye-dilution technique (22). Irritation by the gastroscope or insufflation of air may stimulate gastric secretion. Estimated gastric volume by the dye-dilution method has been shown to be similar to aspirated volume by blind aspiration despite being complicated and time consuming (23).

Unlike omeprazole or lansoprazole, rabeprazole has been experimentally shown to increase intracellular mucin content and new mucin synthesis in gastric mucosa (5). Another animal study revealed that the drug does not suppress collagen regeneration or delay healing of gastric lesions. Rabeprazole shows greater in vitro antimicrobial activity against Helicobacter Pylori than omeprazole and lansoprazole (5). The drug does not alter any endocrine function (testosterone, cortisol, insulin, glucagon, and renin levels, and thyroid function) (5). Similar to other PPIs, rabeprazole has been shown to lack clinically relevant interactions with other drugs often used during anesthesia administration, such as diazepam, warfarin, theophylline, and phenytoin (5). In our study, no patients had any adverse side effects or abnormal laboratory data caused by up to two doses of rabeprazole. This is in agreement with findings of many clinical trials in which no severe adverse effects developed (5,10,24). Thus, the advantages and safety of rabeprazole have encouraged us to use the drug preoperatively. Unlike ranitidine, parenteral preparation of the PPIs is not available at present, and we are unable to use the drugs in situations in which oral treatment is not feasible (e.g., unconscious patients or those with a full stomach). This disadvantage in formulation of the PPIs may limit prophylaxis against aspiration pneumonitis with the drugs.

Gastric acid secretion blockers can vary in their expense. Ranitidine 150 mg, lansoprazole 30 mg, omeprazole 40 mg, and rabeprazole 20 mg cost US$2.23, US$3.73, US$5.94, and US$3.70, respectively (patient charges). The price of two doses of rabeprazole (40 mg) was 3.3 times that of ranitidine (150 mg) for similar improvement of preoperative gastric fluid preparation. The cost/benefit ratio of rabeprazole may be more favorable than that of lansoprazole or omeprazole. However, such a high cost prevents us from recommending the routine use of rabeprazole solely for the control of gastric fluid properties at the induction of anesthesia. The incidence of pulmonary aspiration is as low as approximately 1:4000 in patients undergoing elective surgery; in particular, it is 1:9200 in ASA physical status I subjects (2). Thus, prophylaxis of aspiration pneumonitis with rabeprazole in otherwise healthy patients scheduled for elective procedures may not be indicated, although it may be useful in patients who are predisposed to pulmonary aspiration [e.g., ASA physical status IV or V, emergency, previous esophageal surgery, recent meal (2), pregnancy, diabetes, obesity, or ileus (25)]. Indeed, recent guidelines by the American Society of Anesthesiologists task force on preoperative fasting do not recommend routine preoperative use of gastric acid secretion blockers (H2 receptor antagonists or PPIs) or combinations of these and other drugs (antacids, antiemetics, or gastrointestinal stimulants) to decrease the risks of pulmonary aspiration in patients who have no apparent increased risk for pulmonary aspiration, because there is not sufficient published evidence to evaluate whether reduced gastric acid secretion is associated with decreased morbidity and mortality (25). We used ASA physical status I inpatients to ensure a safe approach to the initial evaluation of rabeprazole’s effects.

In conclusion, we have shown that the preoperative environment of gastric contents was improved by the PPIs and the H2 receptor antagonist in the following order; ranitidine (morning dose), rabeprazole (bedtime and morning doses), lansoprazole (bedtime and morning doses), rabeprazole (morning dose), and rabeprazole (bedtime dose). A single dose of ranitidine was the most effective regimen to control gastric fluid property, consequently minimizing the risk of aspiration pneumonitis. Administration of two consecutive doses of rabeprazole was the second most effective remedy. However, prophylaxis of acid aspiration syndrome with rabeprazole in otherwise healthy patients undergoing elective surgery may have the minimal indication.

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