Burnell R. Brown

The Effects of Sevoflurane, Halothane, Enflurane, and Isoflurane on Hepatic Blood Flow and Oxygenation in Chronically Instrumented Greyhound Dogs

Inhalational anesthetics produce differential effects on hepatic blood flow and oxygenation that may impact hepatocellular function and drug clearance. In this investigation, the effects of sevoflurane on hepatic blood flow and oxygenation were compared with those of enflurane, halothane, and isoflurane in ten chronically instrumented greyhound dogs. Each dog randomly received enflurane, halothane, isoflurane, and sevoflurane, each at 1.0, 1.5, and 2.0 MAC concentrations. Mean arterial blood pressure and cardiac output decreased in a dose-dependent fashion during all four anesthetics studied. Heart rate increased compared to control during enflurane, isoflurane, and sevoflurane anesthesia and did not change during halothane anesthesia. Hepatic arterial blood flow and portal venous blood flow were measured by chronically implanted electromagnetic flow probes. Hepatic O2 delivery and consumption were calculated after hepatic arterial, portal venous, and hepatic venous blood gas analysis. Hepatic arterial blood flow was maintained with sevoflurane and isoflurane. Halothane and enflurane reduced hepatic arterial blood flow during all anesthetic levels compared to control (P less than 0.05), with marked reductions occurring with 1.5 and 2.0 MAC halothane concomitant with an increase in hepatic arterial vascular resistance. Portal venous blood flow was reduced with isoflurane and sevoflurane at 1.5 and 2.0 MAC. A somewhat greater reduction in portal venous blood flow occurred during 2.0 MAC sevoflurane (P less than 0.05 compared to control and 1.0 MAC values for sevoflurane). Enflurane reduced portal venous blood flow at 1.0, 1.5, and 2.0 MAC compared to control. Halothane produced the greatest reduction in portal venous blood flow (P less than 0.05 compared to sevoflurane).(ABSTRACT TRUNCATED AT 250 WORDS)

Quantification of the Degradation Products of Sevoflurane in Two CO2 Absorbants during Low-flow Anesthesia in Surgical Patients

Sevoflurane, a new inhalational anesthetic agent has been shown to produce degradation products upon interaction with CO2 absorbants. Quantification of these sevoflurane degradation products during low-flow or closed circuit anesthesia in patients has not been well evaluated. The production of sevof

Mechanisms of acute hepatic toxicity: chloroform, halothane, and glutathione.

The effects of hepatic microsomal enzyme induction with phenobarbital and depletion of hepatic glutathions (CSH) with diethyl maleats on the acute hepatotoxic responses to chloroform and halothane anesthesia were studied in rats. Phenobarbital pretreatment markedly increased the hepatotoxic response to chloroform anesthesia, but had little effect on halothane hepatotoxicity. Hepatic CSH levels were decreased 70–80 per cent by 2 hour* of Chloroform anesthesia in induced rats, but were unchanged in non-induced rats and in animals anesthetized with halothane. Marked destruction of microsomal electron transfer components was observed in the chloroform-anesthetized, induced animals only. Induction caused a large increase in in-vitro covalent binding of 14CHCl3 metabolites to microsomal protein, which could be prevented by CSH. Diethyl maleate pretreatment lowers CSH content approximately 80 per cent. Chloroform anesthesia produced hepatic necrosis and destruction of microsomal enzymes in the absence of induction, but halothane did not. Hepatotoxicity of chloroform appears to be related to two factors: 1) rate of biotransformation; 2) availability of the hepatic antioxidant, CSH. Halothane hepatotoxicity does not proceed by the same sequence of events as does that of chloroform.

Plasma inorganic fluoride with sevoflurane anesthesia: Correlation with indices of hepatic and renal function

&NA; The biotransformation and plasma inorganic fluoride ion production of sevoflurane (the new volatile anesthetic) during and after surgical anesthesia was studied in 50 ASA I or II surgical patients. Twenty‐five additional patients served as controls by receiving isoflurane. Sevoflurane or isoflurane was administered with a semiclosed (total gas flow, 2 L/min O2) circle absorption system for durations of 1.0 to greater than 7.0 minimal alveolar concentration (MAC) hours for surgical anesthesia (sevoflurane MAC, 2.05%; isoflurane MAC, 1.15%). Preoperative and postoperative blood urea nitrogen and creatinine concentrations were determined. Blood samples were obtained during and after anesthesia in both groups for determining anesthetic blood concentration analysis and plasma fluoride level. Plasma fluoride concentrations did not significantly increase during isoflurane anesthesia. Sevoflurane biotransformation produced a mean peak plasma inorganic fluoride concentration of 29.3 ± 1.8 μmol/L, 2 h after anesthesia, which decreased to 18 μmol/L concentration by 8 h after anesthesia. The peak plasma inorganic fluoride ion concentration correlated with duration of sevoflurane anesthetic exposure. Five patients given sevoflurane had peak levels transiently exceeding 50 μmol/L, and one of these had a history of ingesting drugs potentially producing hepatic enzyme induction. No increases in postoperative levels of creatinine, blood urea nitrogen, direct bilirubin, or hepatic transaminase and no changes in serum electrolyte level occurred in either anesthetic group. Indirect bilirubin concentration increased significantly after sevoflurane anesthesia, but the increase was not of clinical significance (from 0.30 ± 0.03 to 0.38 ± 0.06 mg/dL). Indirect bilirubin concentrations did not increase after isoflurane anesthesia; the concentrations reached 0.31 ± 0.04 mg/dL and did not differ significantly from those found with sevoflurane. Even though plasma fluoride concentrations increased, no evidence of renal dysfunction occurred.

Renal concentrating function with prolonged sevoflurane or enflurane anesthesia in volunteers.

Background:Sevoflurane, a new inhalational anesthetic, is biotransformed, producing peak plasma inorganic fluoride concentrations that may exceed 50 mm. We evaluated plasma inorganic fluoride concentrations with prolonged (> 9 MAC-h) sevoflurane or enflurane anesthesia in volunteers and compared renal concentrating function with desmopressin testing 1 and 5 days after anesthesia. Methods:Fourteen healthy male volunteers received either enflurane or sevoflurane (1–1.2 MAC) for more than 9 MAC-h. Each volunteer was administered three tests of renal concentrating function, with intranasal desmopressin and urine collections performed 1 week before anesthesia and 1 and 5 days after anesthesia. Venous blood samples were obtained for plasma fluoride concentrations during and after anesthesia. Creatinine clearance was determined by 24-h urine collections 7 days before and 4 days after anesthesia. Urine samples were obtained before and 1, 2, and 5 days after anesthesia for determination of n-acetyl-β-glucosaminidase and creatinine concentrations. Results:Prolonged sevoflurane anesthesia (9.5 MAC-h) did not impair renal concentrating function on day 1 or 5 postanesthesia, as determined by desmopressin testing. Maximal urinary osmolality on day 1 postanesthesla was decreased (< 800 mOsm/kg) in two of seven enflurane-anesthetized volunteers; however, mean results did not differ from the those of the sevoflurane group. Mean peak plasma fluoride ion concentrations were 23 ± 1 μM 6 h postanesthesia for enflurane and 47 ± 3 μM at the end of anesthesia for sevoflurane (P < 0.01). There were no changes in creatinine clearance or urinary n-acetyl-β-glucosaminidase concentration in either anesthetic group. Discussion:Prolonged sevoflurane anesthesia did not impair renal concentrating function, as evaluated with desmopressin testing 1 and 5 days postanesthesia in healthy volunteers. Although with prolonged enflurane anesthesia, mean maximal osmolality values on day 1 postanesthesia did not differ from sevoflurane values, there was evidence in two volunteers at this time point of impairment in renal concentrating function, which normalized 5 days postanesthesia. These results occurred despite a higher peak plasma fluoride ion concentration and greater total inorganic fluoride renal exposure with sevoflurane anesthesia.

A comparative study of the effects of five general anesthetics on myocardial contractility. I. Isometric conditions.

Isolated cat papillary muscles driven at a rate of 12 beats/min at 37.5 C were exposed tojeoncen-trations of cyclopropane, diethyl ether, Ethrane, halothanc, and methoxyflurane similar to those required to produce general anesthesia m vivo. Each anesthetic depressed peak developed ten-sion, maximal dp/dt, and the force-time integral of the twitch, and each shortened the time to peak tension. These variables were altered in qualitatively similar ways by all anesthetics tested, implying a common mode of action on the con-tractile process. When administered in cquieffec-tivc concentrations from the standpoint of producing general anesthesia (i.e at equal MACs), the order of activity of the anesthetics in depressing contractility (from most to least depressant) was: Ethrane > halothanc > methoxyflurane > cyclopropane > diethyl ether.

Clinical Pharmacokinetics of the Inhalational Anaesthetics

SummaryAt present, the most widely used inhalational anaesthetics are the halogenated, inflammable vapours halothane, enflurane, isoflurane and the gas nitrous oxide. The anaesthetic effect of these agents is related to their tension or partial pressure in the brain, represented at equilibrium by the alveolar concentration. The minimum alveolar concentration for a specific agent is remarkably constant between individuals. The uptake and distribution of inhalational anaesthetics depends on inhaled concentration, pulmonary ventilation, solubility in blood, cardiac output and tissue uptake. Inhalational anaesthetics are mainly eliminated by pulmonary exhalation, but significant amounts of halothane are removed by hepatic metabolism. Inhalational agents currently in use have acceptable pharmacokinetic characteristics, and clinical acceptance depends on their potential for adverse effects.Induction of anaesthesia with halothane is rapid and relatively pleasant and it is the agent of choice for paediatric anaesthesia. Between 20 and 50% is metabolised, and the parent drug is a potent inhibitor of drug metabolism. Post-operatively enzyme induction may follow. The major disadvantages of halothane are myocardial depression, propensity to evoke cardiac arrhythmias and the rare but serious halothane hepatitis.Induction and recovery from enflurane anaesthesia is rapid. Metabolism accounts for 5 to 9% of the elimination. The metabolic product inorganic fluoride may in rare cases cause renal toxicity. Enflurane is a weak inhibitor of drug metabolism at anaesthetic concentrations. Enflurane depresses circulation more than halothane by reducing both myocardial contractility and systemic vascular resistance, but cardiac rhythm is stable. Enflurane anaesthesia may, unlike the other agents, induce epileptic activity. Enflurane is widely used as replacement for halothane in adults.Despite its low blood-gas solubility, the airway irritability of isoflurane precludes a faster induction of anaesthesia than with halothane. Isoflurane is almost resistant to biodegradation. Myocardial contractility is maintained during isoflurane anaesthesia and cardiac rhythm is stable except for the occurrence of tachycardia in some patients. Isoflurane is the inhalational agent of choice for neurosurgical operations.Sevoflurane is an experimental ether vapour: induction and recovery is fast and pleasant. It is metabolised to the same extent as enflurane and subnephrotoxic concentrations of inorganic fluoride may result. Sevoflurane has fewer respiratory and cardiovascular depressant effects than halothane and may be a future alternative for paediatric anaesthesia.Nitrous oxide is the only anaesthetic gas widely used today. A rapid induction and recovery follows from its low blood-gas solubility. No metabolism occurs and the cardiovascular effects are small compared with the volatile agents. Nitrous oxide reacts chemically with vitamin B12 and signs of megaloblastic bone marrow are present after 6 hours of anaesthesia.

An animal model of hepatotoxicity associated with halothane anesthesia.

: Hepatic necrosis was induced in rats by a single exposure to 1 per cent halothane in oxygen following pretreatment with a single dose of Aroclor 1254, a polychlorinated biphenyl. The hepatic lesion was centrilobular and multifocal, and morphologically similar to that reported to occur in man. In-vitro incubation with 14C-halothane indicated an enhanced covalent binding of halothane metabolites to hepatic microsomal macromolecules, particularly lipids, following Aroclor 1254 pretreatment. Lipoperoxidation of microsomal unsaturated fatty acids was not observed with these animals.

Compound A concentrations during sevoflurane anesthesia in children

Background Sevoflurane is a new inhalation agent that should be useful for pediatric anesthesia. Sevoflurane undergoes degradation in the presence of carbon dioxide absorbents; however, quantification of the major degradation product (compound A) has not been evaluated during pediatric anesthesia. This study evaluates sevoflurane degradation compound concentrations during sevoflurane anesthesia using a 2–1 fresh gas flow and a circle system with carbon dioxide absorber in children with normal renal and hepatic function. Methods The concentrations of compound A were evaluated during sevoflurane anesthesia in children using fresh soda lime as the carbon dioxide absorbent. Nineteen patients aged 3 months‐7 yr were anesthetized with sevoflurane (2.8% mean end‐tidal concentration) using a total fresh gas flow of 2 l in a circle absorption system. Inspiratory and expiratory limb circuit gas samples were obtained at hourly intervals, and the samples were analyzed using a gas chromatography‐flame ionization detection technique. Carbon dioxide absorbent temperatures were measured in the soda lime during anesthesia. Blood samples were obtained before and after anesthesia for hepatic and renal function studies. Venous blood samples were obtained before anesthesia, at the end of anesthesia, and 2 h after anesthesia for plasma inorganic fluoride ion concentration. Results The maximum inspiratory concentration of compound A was 5.4 +/‐4.4 ppm (mean+/‐SD), and the corresponding expiratory concentration was 3.7+/‐2.7 ppm (mean+/‐SD). The maximum inspiratory compound A concentration in any patient was 15 ppm. Mean concentrations of compound A peaked at intubation and remained stable, declining slightly after 120 min of anesthesia. The duration of anesthesia was 240+/‐139 min (mean+/‐SD). Maximum soda lime temperature ranged between 23.1 degrees C and 40.9 degrees C. There was a positive correlation between maximum absorbent temperature and maximum compound A concentration (r2 = 0.58), as well as between the childs body surface area and maximum compound A concentration (r2 = 0.59). Peak plasma inorganic fluoride ion concentration was 21.5 +/‐6.1 micro mol/l. There were no clinically significant changes in hepatic or renal function studies performed 24 h postanesthesia. Conclusions Sevoflurane anesthesia of 4 h in normal children using a 2‐l flow circle system produced concentrations of compound A of 15 ppm or less. There was no evidence of abnormality of renal or hepatic function up to 24 h after anesthesia; however, larger studies will be required to confirm the absence of organ toxicity.

Factors influencing halothane hepatotoxicity in the rat hypoxic model

Abstract Halothane, a widely used inhalation anesthetic, was shown to be hepatotoxic to male, phenobarbital-pretreated rats, only when administered under hypoxic conditions (fraction of inspired oxygen = 0.14). The degree of hepatotoxicity as determined from morphological alterations and serum glutamic-pyruvic transaminase (SGPT) activities, correlated well with concentrations of hepatic cytochrome P -450 and concentration of inspired halothane. Maximal lesion intensity developed within 12 to 24 hr after exposure to 1% halothane for as little as 30 min. By 4 days after exposure, the liver had repaired, since no morphological alterations were apparent and SGPT activities had returned to normal values. Female rats, when pretreated with phenobarbital and exposed to 1% halothane under hypoxic conditions did not develop liver injury. SKF-525A and metyrapone reduced the severity of liver injury when administered preanesthesia and 4 hr postanesthesia. The free sulhydryl-containing compounds, cysteine, cystamine, and N -acetylcysteine afforded protection when administered at 4 or 8 hr (cystamine) after ending anesthesia. These results support the hypothesis that reductive or noxoxygen-dependent biotransformation of halothane results in toxic intermediates that can initiate halothane-induced liver injury.