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 (means +/- 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 alpha 1-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.

Hepatotoxicological evaluation of dantrolene sodium.

The clinical use of dantrolene has been associated with hepatotoxicity, thus the toxicity of dantrolene in Swiss-Webster mice was characterized. Animals were treated orally (po) with single or multiple doses of up to 400 mg/kg of D without any increases in SGPT or alterations in hepato-cellular architecture. To possibly enhance the hepatotoxicity of dantrolene, its biotransformation was altered by inhibiting acetylation, depleting glutathione, inducing biotransformation, and promoting reductive metabolism. None of the metabolic alterations elicited any toxicity of dantrolene. Hepatic microsomal incubations were used to detect the possible bioactivation and covalent binding of 14C-dantrolene. Analysis for covalent adducts found only 20-30 pmol bound/mg microsomal protein. Thus the suspected hepatotoxicity of dantrolene does not appear to be linked to its biotransformation or bioactivation. Additional studies will be necessary to clarify if other parameters are necessary for dantrolene to be a hepatotoxin.

Fentanyl sequestration in lungs during cardiopulmonary bypass.

Serum fentanyl concentrations were measured before, during, and after cardiopulmonary bypass and correlated with changes in total protein, albumin, hematocrit, pH, and PCO2 in five patients undergoing cardiac surgery. Serum fentanyl concentrations, total protein, albumin, and hematocrit declined with initiation of bypass but remained unchanged thereafter. PCO2 and pH did not change. In an additional seven patients, simultaneous pulmonary-artery and radial-artery fentanyl concentrations were measured. During bypass, when little, if any blood flowed through the pulmonary circulation, pulmonary artery fentanyl concentrations were higher than systemic arterial concentrations, but when lung ventilation and perfusion were restored, radial artery concentrations rose and pulmonary artery concentrations fell, indicating fentanyl sequestration in the lungs during bypass.

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

The blood-gas partition coefficient of enflurane was measured in nine nonobese and eight morbidity 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 less than 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 less than 0.01). A positive correlation was found between hemoglobin and the enflurane blood-gas partition coefficient (r = 0.69, p less than 0.01). Equilibrium between inspired and alveolar enflurane concentration should be faster in morbidity obese and anemic patients than in healthy, nonobese patients.

Age and fentanyl pharmacokinetics.

Fentanyl pharmacokinetics was compared in two groups of adult patients, one group (n = 5) aged less than 50 years, and one group (n = 4) aged greater than 60 years. Despite equivalent doses of fentanyl (10 microgram/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 less than 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 less than 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, trifluoroacetic 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 microM, P less than 0.01). Sedative levels of bromide were not attained in any patient. Peak trifluoroacetic 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.

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.

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), enflurane (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 less than 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 greater than 0.05). Recovery room (RR) admission temperatures were similar for the three groups: fentanyl, 36.1 +/- 0.1 degrees C; enflurane, 35.7 +/- 0.2 degrees C; and halothane, 36.0 +/- 0.1 degrees C (P greater than 0.05). Total RR time was not significantly different: fentanyl, 108 +/- 6 min, enflurane, 118 +/- 4 min; and halothane, 112 +/- 10 min (P greater than 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.

Disposition of enflurane in obese patients.

The disposition of enflurane, a volatile halogenated anesthetic, was studied in obese (n = 26) and nonobese (n = 8) consenting adult subjects undergoing elective intra-abdominal surgical procedures. Enflurane and fluoride ion, a nephrotoxic metabolite of enflurane, were measured in the blood of subjects before, during and up to 24 hr after exposure to pharmacologically equivalent doses of enflurane [approximately 2.0 MAC hr (the minimal alveolar concentration at which 50% of humans do not respond to a painful stimulus)] Arterial enflurane in obese subjects reached maximal concentrations 3 times faster than nonobese subjects who reached similar blood levels 80 min after the initiation of anesthesia. The blood/gas partition coefficient for enflurane in the obese was found to be 30% lower than that in the nonobese (0.99 +/- 0.02 vs. 1.42 +/- 0.02) and may possibly explain the observed differences in enflurane uptake. The rate at which inorganic fluoride appeared in obese serum (5.5 microM/hr) was twice that seen in the nonobese group. No differences in urinary fluoride excretion were demonstrated. Maximum serum fluoride concentration occurred 2 hr postenflurane anesthesia in both groups with the obese having a 60% higher concentration (27.8 +/- 2.0 vs. 17.0 +/- 3.0 microM), indicating increased biotransformation in the obese. Hepatic triglyceride content was demonstrated to be unrelated to the increased enflurane biotransformation observed in obese subjects. Equations are presented for the estimation of mean maximum serum inorganic fluoride levels in both obese and nonobese subjects after enflurane anesthesia.

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 (less than 2.0 MAC hr). Peak serum fluoride levels were higher (28.0 +/- 1.9 vs 17.3 +/- 1.3 micrometers/L, p less than 0.01) and the rate at which fluoride levels increased was more rapid (slope 5.6 vs 2.5 micrometers/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 inknown 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.