Anesth Analg 2005;100:137-140
© 2005 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000140238.79041.73
ANESTHETIC PHARMACOLOGY
Atenolol Administration via a Nasogastric Tube After Abdominal Surgery: An Unreliable Route
Marilyn Gosgnach, MD*,
Guy Aymard, PharmD ,
Catherine Huraux, MD*,
Marie Hélène Fléron, MD*,
Pierre Coriat, MD*, and
Bertrand Diquet, PhD
Departments of *Anesthesiology and
Pharmacology, Hospital Pitié-Salpêtrière, Paris, France
Address correspondence and reprint requests to Pierre Coriat, MD, Département d’Anesthésie Réanimation, Groupe Hospitalier Pitié-Salpêtrière, 47-83 Boulevard de l’Hôpital, 75 561 Paris Cedex 13, France. Address e-mail to pierre.coriat{at}psl.ap-hop-paris.fr
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Abstract
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ß-Adrenoceptor antagonists, especially atenolol, reduce perioperative cardiac morbidity. Because there are no data on the bioavailability of atenolol given by nasogastric tube in the postoperative period, we assessed the efficacy of this route of administration in 18 patients scheduled for abdominal surgery. We found a 36% reduction in the area under the atenolol concentration curve and a 46% reduction in the peak concentration of atenolol in the postoperative period compared with preoperative values. In addition, patients had more rapid mean heart rates on the second postoperative day compared with the day before surgery. We conclude that the administration of atenolol via nasogastric tube in the postoperative period does not result in adequate plasma concentrations.
IMPLICATIONS: Atenolol administered at the same preoperative dose via a nasogastric tube after abdominal surgery leads to reduced bioavailability due to decreased absorption. The beneficial effects of perioperative IV atenolol cannot be expected from this route of administration.
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Introduction
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Numerous studies have shown that ß-adrenoceptor antagonists reduce the risk of intraoperative myocardial ischemia (1,2). Mangano et al. (3) showed that in high-risk patients scheduled for noncardiac surgery, atenolol (a cardiospecific ß-adrenoceptor antagonist) begun the day of surgery and maintained 7 days after surgery reduced cardiac morbidity and mortality for up to 2 yr after surgery. They administered atenolol IV during the first five postoperative days in patients undergoing abdominal surgery until oral administration was possible. Many physicians are reluctant to give IV cardiovascular drugs outside of intensive care units, where patients can be monitored, and when a patient is on the ward, they prefer to give atenolol via nasogastric tube, even if there is postoperative ileus. There are no data concerning the bioavailability of ß-adrenoceptor antagonists administered by this route after abdominal surgery. Therefore, we studied the bioavailability of atenolol administered via nasogastric tube in the postoperative period.
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Methods
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All patients gave written, informed consent. This study was approved by the local institutional human investigation committee (Comité Consultatifs de Protection des Personnes se prêtant à des Recherches Biomédicales Pitié-Salpêtrière).
Patients were eligible for inclusion in the study if they were scheduled for infrarenal aortic surgery or gastrointestinal (GI) tract surgery (excluding gastric or small-bowel surgery), needed a postoperative nasogastric tube, and were long-term recipients of a ß-adrenoceptor antagonist. Patients treated with a ß-adrenoceptor antagonist other than atenolol were switched to atenolol during the perioperative period. Preoperative treatment for at least 15 days was required. Exclusion criteria included prior gastric surgery or small-bowel resection, significant chronic liver or renal disease, and known malabsorption disorders.
Routine cardiac medications were continued until surgery. All patients underwent general anesthesia, and a nasogastric tube was placed. All clinical decisions concerning perioperative care, except for the route and time of the administration of atenolol, were under the control of an anesthesiologist not involved in the study.
Serum creatinine concentrations were measured before and after surgery (at least 2 days [D+2] and 7 days [D+7] after surgery). Heart rate was recorded before surgery and before each blood sample. Also, heart rate was continuously monitored on D+2 and D+7 (Cardiocap II; Datex, Helsinki, Finland; Datex Division of Instrumentarium Corp.).
Up to the morning of surgery, atenolol was given orally. In the postoperative period, it was given at the same dose through the nasogastric tube until its removal. Tablets of atenolol were crushed, suspended in 50 mL of water, and administered via the tube, which was flushed with an additional 50 mL of water. The tube was then clamped for 1 h, after which low intermittent suction was resumed.
Three series of blood samples were drawn for each patient: the day before surgery (D–1), on D+2, and on D+7. Blood samples were drawn immediately before the administration of atenolol and at 3, 9, 14, and 24 h afterward for patients taking atenolol once a day and immediately before administration and at 3, 6, 9, and 12 h afterward in patients taking the drug twice daily.
Atenolol was assayed in plasma by using a previously described method (4). Individual plasma atenolol concentrations were analyzed with a model-independent approach and Siphar software, Version 4.C (SIMED, Créteil, France). Peak concentration (Cmax) and time to Cmax (Tmax) were ascertained directly from the experimental data. The area under the atenolol plasma concentration curves (AUC0 t) was measured between two administrations (D–1, D+2, and D+7) and estimated according to the trapezoidal rule. Terminal half-life was derived from [(log2)/ß], where ß is the elimination rate constant for the terminal log linear phase estimated from at least the last three data points.
Data are expressed as mean ± SD or mean (coefficient of variation), range, and geometric mean (for Tmax). Statistical analysis was performed with SPSS (Version 10.0; SPSS Inc., Chicago, IL). For the bioequivalence test, we used two one-sided t-tests, performed after logarithmic transformation, for AUC0t and Cmax (5). D–1 was set as the reference formulation. Repeated-measures analysis of variance, followed by the Scheffé test, was used to evaluate the difference in mean and minimum heart rates during the three study periods. P < 0.05 was considered statistically significant.
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Results
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Eighteen patients were analyzed, and 14 patients had the complete series of 3 blood samples (Fig. 1). One patient was excluded from the pharmacokinetic analysis because of a significant increase in postoperative creatinine concentration. The mean age of the patients was 61 ± 14 yr. The dose of atenolol ranged from 25 to 200 mg (Table 1).
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Figure 1. Trial profile. All 17 patients were considered for samples of Day –1 (D–1) and D+2. D+7 samples (pharmacokinetics and heart rates) were analyzed without the four patients for whom we did not have data (three patients because of early discharge and one patient because of refusal of blood sample).
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Pharmacokinetics results are shown in Tables 2 and 3 and Figure 2. AUC0t values were significantly less at D+2 compared with D–1, indicating a reduced bioavailability at D+2. No significant difference remained at D+7. Cmax was significantly reduced at D+2 and D+7 compared with D–1. Tmax and terminal half-life were not significantly different among the three study periods. The mean and minimal heart rates are noted in Figure 3.
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Table 2. Area Under the Atenolol Plasma Concentration Curve (AUC) and Peak Concentration (Cmax) of Atenolol [mean coefficient of variation (%), minimal–maximal, and geometric mean] After Oral Administration at Day Before Surgery (D–1), Day 2 (D+2), and Day 7 (D+7)
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Figure 2. Mean ± SD atenolol plasma concentrations (normalized to a 1-mg dose) and mean ± SD heart rates at Day –1 (D–1), D+2, and D+7.
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Figure 3. Mean and minimum heart rates of the 14 patients who underwent the full 3 periods of the study. Mean heart rates were 61 ± 9 bpm at Day –1 (D–1), 82 ± 14 bpm at D+2, and 71 ± 9 bpm at D+7. Minimal heart rates were 55 ± 8 bpm, 70 ± 15 bpm, and 64 ± 8 bpm at D–1, D+2, and D+7, respectively. *Significant difference (P < 0.05).
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Discussion
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This study shows that atenolol administered via a nasogastric tube in the postoperative period does not produce blood concentrations equivalent to the preoperative values. These pharmacokinetic results were reflected in significantly more rapid heart rates in the immediate postoperative period; they returned to baseline values at D+7. This cannot be accounted for by an increase in catecholamine concentrations in the postoperative period, because plasma epinephrine concentrations usually return to basal levels within 6 to 12 hours after surgical procedures (6). The persisting increase in heart rates at D+2 could be a consequence of a ß-adrenoceptor antagonist withdrawal syndrome.
Approximately 50% of an oral dose of atenolol is absorbed by the GI tract, and steady state is attained in 2 days with once-daily administration (7). The drug is mainly eliminated by renal excretion, which is why we excluded patients whose creatinine was increased significantly (twofold increase) from the pharmacokinetic analysis (8). The effect of atenolol on maximal heart rate has been shown to be linearly related to the logarithm of plasma concentration (9), and strict control of heart rate seems to be essential to reduce cardiovascular morbidity (10).
Because little absorption occurs from the stomach compared with the small bowel, gastric emptying is one of the main factors that allows the drugs to reach absorption sites. In the postoperative period, the motility of the GI tract is temporarily impaired (postoperative ileus) (11–13). This could explain the decreased bioavailability of atenolol in the early postoperative period.
Because our study was descriptive, we did not include a control group to evaluate the contribution of anesthesia to the change in bioavailability, nor did we use a standardized anesthetic technique. Hence, it does not allow for full elucidation of the mechanism of the observed effect.
In conclusion, the postoperative administration of atenolol (given at the same preoperative and postoperative doses) via a nasogastric tube in patients undergoing abdominal surgery leads to decreased drug bioavailability. The reduced cardiac morbidity related to IV atenolol in the immediate postoperative period cannot be expected when the drug is given by nasogastric tube.
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Acknowledgments
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AstraZeneca Laboratory, Rueil-Malmaison Cedex, France, provided financial support for the plasma drug level assays.
The authors thank Clara Baechler, nurse in anesthesiology, who drew most of the blood samples for drug level assays.
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References
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Accepted for publication July 9, 2004.
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Abstract
Introduction
