John B. Bentley

Age and fentanyl pharmacokinetics.

Fentanyl pharmacokinetics was compared in two groups of adult patients, one group (n = 5) aged <50 years, and one group (n = 4) aged > 60 years. Despite equivalent doses of fentanyl (10 μ/kg IV), serum drug concentrations were significantly higher in the older patient group. This was reflected by a prolonged terminal elimination half-life in the elderly compared with the younger patients (945 versus 265 minutes, respectively, p < 0.005). Volumes of the central compartment and volumes of drug distribution were similar in both patient groups. However, drug clearance was markedly decreased in the elderly (265 versus 991 ml/min, p < 0.005). These data suggest that a given dose of fentanyl will be clinically effective for a longer period in older patients than in younger patients.

Halothane Biotransformation in Obese and Nonobese Patients

Serum levels of inorganic fluoride, trifluoracetic acid, and bromide ion were measured at various time intervals following two hours of halothane anesthesia in 17 morbidly obese and eight nonobese patients. Ionic fluoride, a marker of reductive halothane metabolism, increased in the obese but not the nonobese patients. This is of concern since reductive halothane metabolism is associated with hepatoxicity in animals. In addition, serum bromide levels were higher after 48 h in the obese patients compared to the nonobese patients (mean ± SE, 1,311 ± 114 vs. 787 ± 115 μM, P < 0.01). Sedative levels of bromide were not attained in any patient. Peak trifluoracetic acid levels were similar in the two patient groups. Sex, age, medication intake, and smoking history had no influence on the halothane metabolite levels found in this study.

Fentanyl preloading for rapid-sequence induction of anesthesia.

Protecting the patients airway is of paramount importance in the induction of general anesthesia. For the patient at risk of regurgitation of stomach contents, the rapid-sequence (crash) induction provides protection, but at the expense of increased stress response to laryngoscopy and intubation. This stress response is especially dangerous for the patient at risk for myocardial ischemia. The purpose of this study was to examine the efficacy of using low-dose fentanyl (5 μg/kg) to reduce cardiovascular and neuroendocrine stress responses to rapid-sequence induction. Thirty patients were randomly assigned to a rapid-sequence induction protocol either with or without fentanyl preloading. Fentanyl-preloaded patients (fentanyl group) received 2 mg/kg of thiopental whereas patients who were not preloaded with fentanyl (control group) received 4 mg/kg of thiopental. Data collected as indices of the stress response included heart rate, systolic, diastolic, and mean blood pressures, and plasma concentrations of catecholamines (epinephrine, norepinephrine, dopamine) and β-endorphin. Electrocardiograms (modified V5 lead) were monitored for dysrhythmias and ST segment depression. Control patients had higher systolic, diastolic, and mean blood pressures after intubation than did patients given fentanyl (P < 0.05). Although the incidence of dysrhythmias was decreased by fentanyl (20% vs 42%), this difference was not statistically significant. Plasma concentrations of β-endorphin and norepinephrine increased significantly in control patients but not in patients given fentanyl (P < 0.05). Low-dose fentanyl (5 μg/kg) reduces some aspects of the stress response to rapid-sequence induction of anesthesia.

General Anesthesia for Morbidly Obese Patients — An Examination of Postoperative Outcomes

Specific postoperative outcomes were assessed in 67 morbidly obese subjects who received general anesthesia for gastric stapling. Each patient was randomly assigned to receive N2O;O2 combined with fentanyl (n = 20), enlurane (n = 24), or halothane (n = 23). Time from last skin stitch until the patient opened eyes on command was significantly less for the fentanyl group (3.0 ± 0.7 min) than for the enflurane group (13.2 ± 1.9 min) or the halothane group (17.4 ± 2.9 min) with P < 0.05. However, no significant differences in time from last skin stitch to extubation were noted among the fentanyl (16.2 ± 7.4 min), enflurane(15.2 ± 1.6 min),and halothane (21.6 ± 5.8 min) groups (P > 0.05). Recovery room (RR) admission temperatures were similar for the three groups: fentanyl, 36.1 ± 0.1° C; enflurane, 35.7 ± 0.2° C; and halothane, 36.0 ± 0.1° C (P > 0.05). Total RR time was not significantly different: fentanyl, 108 ± 6 min, enflurane, 118 ± 4 min; and halothane, 112 ± 10 min (P > 0.05). In addition, no difference in RR and 24-hour postoperative narcotic (meperidine) requirements was demonstrated among the anesthetic groups. These data suggest that increased lipid solubility of volatile anesthetics (halothane or enflurane) produces neither delayed awakening nor prolonged recovery time in morbidly obese subjects. Considering the early (24 hour) postoperative outcomes studied, there is little to commend one general anesthetic technique over another in the obese subset of the population.

Serum Inorganic Fluoride Levels in Obese Patients during and after Enflurane Anesthesia

Serum ionic fluoride levels in 24 markedly obese patients (127.6 ± 6.0 kg) and seven nonobese control subjects (67.3 ± 1.2 kg) were compared during and following enflurane anesthesia (<2.0 MAC hr). Peak serum fluoride levels were higher (28.0 ± 1.9 vs 17.3 ± 1.3 μM/L, p < 0.01) and the rate at which fluoride levels increased was more rapid (slope 5.6 VS 2.5 μM/L/hr) in obese patients than in control patients. No clinical evidence of nephrotoxicity was found in either group. Vasopressin resistance tests were not performed, and thus it is unknown whether subclinical nephrotoxicity occurred in either study group. Possible reasons for increased enflurane metabolism in obesity are discussed. These possibilities include differences in fluoride ion kinetics, hepatic delivery and penetration of volatile anesthetics, and altered hepatic microsomal enzyme activity. Obesity rather than weight is an important determinant of anesthetic biotransformation.

Effects of histamine‐2 receptor blockade on lidocaine kinetics

The hypothesis that the H2‐receptor blockers cimetidine and ranitidine have different effects on the disposition of lidocaine, a microsomally metabolized drug dependent on hepatic blood flow for elimination, was tested. Six normal men received lidocaine infusions (2 mg/kg over 10 minutes) and lidocaine levels were determined by HPLC. Lidocaine kinetics were studied in the untreated state (O) and in a double‐blind, double‐dummy design after 2 days of placebo (P), cimetidine (C, 300 mg every 6 hours by mouth), or ranitidine (R, 160 mg every 12 hours by mouth). Model‐independent kinetics were estimated by the statistical moment theory. The steady‐state volume of distribution was lower after cimetidine (X̄ ± SD: O,156 ± 39 L; P, 156 ± 48 L; C, 123 ± 20 L; and R, 174 ± 38 L). A trend toward decreased lidocaine clearance after cimetidine was also noted (O,1011 ± 140 ml/min; P, 1087 ± 227 ml/min; C, 886 ± 214 ml/min; and R, 1143 ± 225 ml/min). Elimination rate constants were of the same order in all four treatments. Only higher levels of α1‐acid glycoprotein appeared to limit the lidocaine steady‐state volume of distribution. Cimetidine and ranitidine have distinctly different effects on lidocaine kinetics in normal subjects. The absence of ranitidine effects on the disposition of lidocaine, a high‐extraction, high‐clearance drug, suggests that H2‐receptor blockade may not decrease hepatic blood flow, and that cimetidine impairs drug elimination only by inhibition of hepatic microsomal enzymes. Such interactions are not likely to occur with ranitidine.

Enflurane blood-gas solubility: influence of weight and hemoglobin.

The blood-gas partition coefficient of enflurane was measured in nine nonobese and eight morbidly obese patients and correlated with weight, body mass index, and blood hemoglobin. The enflurane blood-gas partition coefficient was lower in the obese patients than in nonobese patients (mean ± SEM: 2.03 ± 0.02 versus 1.76 ± 0.03, respectively, p < 0.025). There was a negative correlation between enflurane blood solubility and both body mass index and weight (r = −0.59 and −0.55, respectively, p < 0.01). A positive correlation was found between hemoglobin and the enflurane blood-gas partition coefficient (r = 0.69, p < 0.01). Equilibrium between inspired and alveolar enflurane concentration should be faster in morbidly obese and anemic patients than in healthy, nonobese patients.

Does evidence of reductive halothane biotransformation correlate with hepatic binding of metabolites in obese patients

Covalent binding of fluorinated anesthetic metabolites was measured using intraoperative liver biopsies obtained from 48 morbidly obese patients randomly assigned to receive N2O-O2 combined with either fentanyl, enflurane, or halothane. No difference in binding was found between anesthetic groups. In addition, preoperative and postoperative levels of serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) did not differ among three groups of patients. However, hepatic organic fluoride binding significantly correlated with peak serum ionic fluoride in patients given halothane (p 0.001, r = 0.68). Thus, the fluorinated metabolites binding assay is a reliable index of reductive halothane metabolism. Possible application of this assay to aid in the diagnosis of postoperative liver dysfunction is suggested.

Minireview: Part II: Biochemical considerations of morbid obesity

Abstract Whereas the cardiorespiratory derangements of severe obesity have received careful scrutiny, the biochemical alterations unique to that state are not well known. This review will examine in morbidly obese patients the hepatic abnormalities related to morphology, function, and lipid metabolism. Altered xenobiotic biotransformation will then be discussed. Available studies in man will emphasize what is known about the biochemical aberrations exemplified by this abnormal biologic state.

Prone positioning in obesity.

We read with interest the article by Gelman et a1 (1) comparing hemodynamic responses in morbidly obese patients during thoracic epidural and during balanced general anesthesia. However, we question the authors’ use of the prone position for epidural catheter placement in severely obese patients. In severely obese patients the prone position can result in restriction of diaphragmatic movement and impaired venous return (2). Such physiologic derangements may be especially poorly tolerated in obese patients who, as the authors state, have well documented preexisting respiratory and circulatory disturbances. Indeed, Tsueda et a1 (3) have reported that some markedly obese subjects cannot tolerate even being in the horizontal supine position. We suggest that the intraoperative or postoperative benefits of thoracic epidural anesthesia in severely obese subjects may not be worth the cost incurred by the necessity of placing the patient in the prone position for catheter placement. If the prone position is required in a severely obese patient, we advocate the following: (a) proper padding of the chest wall and pelvis to allow unrestricted, free excursion of the diaphragm, (b) continuous monitoring of arterial blood pressure to detect decreases in cardiac output immediately, and (c) supplemental oxygen to maintain adequate arterial oxygenation as determined by period measurements of oxygen tensions. We feel that monitoring of the latter is critical in obese patients anytime ventilation may be compromised due to position, intra-abdominal surgery, or postoperative pain. Thoracic epidural anesthesia appears to offer little advantage in this regard over general anesthesia as Gelman et a1 (1) found with the semiclosed anesthesia circle system. When using an adult circle, the nebulizer is placed between the no difference in intra-operative or postoperative respiratory responses between the two groups of obese patients. In short, we agree with the authors’ conclusion that routine use of thoracic epidural anesthesia cannot be advocated in morbidly obese patients. John B. Bentley, MD Robert W. Vaughan, MD Department of Anesthesiology Arizona Health Sciences Center Tucson, AZ 85724