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The mechanism of action of volatile anesthetics is the subject of some debate. Much of the controversy has centered on whether the site of such actions is purely lipid in nature or may contain a protein target. This report studies the interaction of stereoisomers of halothane on the wild type and on a variety of genetic mutants of Caenorhabditis elegans. The mutants studied have previously been shown to have altered sensitivities to volatile anesthetics. In one mutant, fc34, (R)-halothane [the (+) isomer] was 3 times more potent than its S (-) isomer. Other mutants and wild-type animals displayed more modest differences in sensitivity to the enantiomers. The results indicate that a genetic pathway exists in C. elegans controlling sensitivity to halothane and that both lipid and protein targets may mediate halothane's effects.

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The authors studied the wild type strain, N2, and three mutant strains of the nematode, Caenorhabditis elegans, in order to measure genetically produced changes in responses to nine volatile anesthetics. They determined the anesthetic ED50s of N2 for thiomethoxyflurane, methoxyflurane, chloroform, halothane, enflurane, isoflurane, fluroxene, flurothyl, and diethylether. The log-log relationship of the oil-gas partition coefficients (O/G) and the ED50s of these agents for N2 yields a straight line with a slope of -.997 with a R2 of .98 over a range of O/G (at 37 degrees C) from 48 to 7230. When the O/Gs are corrected to 22 degrees C, the slope is -.964 with an R2 of .98. This relationship is similar to that found in other animals. Two mutant strains, unc-79 and unc-80, show altered responses to these anesthetics. These strains are two to three times more sensitive than N2 to anesthetics with an O/G greater than that of halothane (220 at 37 degrees C), yet they differ little from N2 in response to anesthetics with lower O/Gs. unc-79 and unc-80 are about 30% more sensitive than N2 to diethylether. The double mutant unc-79; unc-80 is more sensitive to halothane, isoflurane, and fluroxene than is either mutant alone. The authors believe these data indicate an alteration at the site of action of volatile anesthetics in unc-79 and unc-80. They also postulate that the interaction of unc-79 and unc-80 indicate these genes code for enzymes in a common pathway, and that unc-79 precedes unc-80 in this pathway.

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The authors have developed a method for studying the action of volatile anesthetics in Caenorhabditis elegans (C.e.), a free living nematode. C.e. appears to be a useful model for the study of the influence of genetics on susceptibility to anesthetics. This worm has a small, completely defined nervous system, easily manipulated genetics, and a large number of nervous system mutants. Under normal conditions C.e. moves almost constantly. When exposed to anesthetics there is an initial phase of increased locomotion, followed by uncoordinated motion that progresses to immobility. Motion returns quickly when the nematodes are removed from the anesthetic. The authors called loss of locomotion "anesthesia." The ED50S of various anesthetics with C.e. are as follows: methoxyflurane 0.45%, chloroform 1.25%, halothane 2.7%, enflurane 4.2%, isoflurane 5.6%, fluroxene 9.9%. The authors also studied the action of a convulsant, flurothyl, on C.e. Flurothyl has anesthetizing properties in these animals with an ED50 of 8.1%. No convulsant activity was noted. However, mixtures of halothane and flurothyl were antagonistic in their effects, while halothane and enflurane were additive. Furthermore, the authors isolated a mutant strain (HS1) of C.e. that shows altered responses to several anesthetics and a convulsant. HS1 is uncoordinated when not exposed to anesthetics. Like the normal strain (N2) HS1 loses mobility when exposed to anesthetics. The ED50S for various anesthetics in HS1 were as follows: methoxyflurane 0.04%, chloroform 0.52%, halothane 0.85%, isoflurane 4.9%, enflurane 6.0%, fluroxene 10.9%.(ABSTRACT TRUNCATED AT 250 WORDS)

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We compared the effects of morphine and fentanyl in the presence of 60% N2O on somatosensory cortical-evoked potentials (SCEP). Both drugs were administered by intravenous bolus (n = 12) and infusion (n = 20) techniques. SCEPs were recorded preoperatively and intraoperatively in 32 patients undergoing corrective surgery for scoliosis. Records were taken at the contralateral cerebral cortex by individual stimulation of the posterior tibial nerves at the ankle. Both drugs increased the latencies of the N1, P2, and N2 peaks and affected the peak-to-peak amplitudes of the primary complex. Intravenous bolus injections and continuous infusions of equianalgesic doses produced similar effects. The increase in N1 latency was significantly greater (morphine, P less than 0.05; fentanyl, P less than 0.01) with the bolus than with the infusion technique. The doses of morphine and fentanyl given by bolus injections were 1/3 times and 3 1/3 times greater than doses given by infusion. Changes in latency were more consistent than changes in amplitude. Both fentanyl and morphine increase latencies while affecting amplitudes unpredictably. Equianalgesic doses of fentanyl and morphine have similar effects on SCEP latencies. Low-dose continuous infusions of narcotics depress SCEPs less than intermittent bolus injections.

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Paraplegia is the major risk involved in reconstructive surgery for scoliosis with fusion. To detect spinal cord dysfunction intraoperatively, somatosensory cortical-evoked potential (SCEP) monitoring and a wake-up test or a combination of the two is generally used. Our pilot studies indicated that a balanced anesthesia technique consisting of nitrous oxide, narcotics, and a muscle relaxant is well-suited both for SCEP monitoring as well as for wake-up tests. However, at times the intermittent administration of narcotics adversely affected SCEP interpretation and wake-up tests. To facilitate both SCEP interpretation and wake-up tests, we employed N2O/O2 with continuous infusion of narcotics and compared it with intermittent bolus administration of narcotics in 35 patients. For our purposes fentanyl (FE) was assumed to be 100 times more potent than morphine (MS). Our first 13 patients were studied using bolus increments of either MS (5-10 mg) every 30-40 minutes or FE (50-100 micrograms) every 20-30 minutes. The remaining 22 patients were studied during continuous infusions of either MS at a rate ranging from 150-250 micrograms X kg-1 X hr-1 or FE at a rate ranging from 1.5 to 2.5 micrograms X kg-1 X hr-1. Continuous infusions reduced total narcotic requirements (P less than 0.005). In addition, the technique produced stable suppression of SCEPs and made it easier to interpret surgically induced SCEP changes. Wake-up tests were smooth and repeatable. Patients who received fentanyl infusions fared better than those receiving MS in that they did not require postoperative respiratory support. Continuous infusions of fentanyl are useful in reconstructive spinal surgery for scoliosis with monitoring.

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1,1,2-trifluoro-1-bromo-2-chloro ethane, an isomer of halothane, was tested for its anesthetic and toxic properties in rats. The isomer is about one-half as potent as halothane and is metabolized to a lethal compound.

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Other investigators have demonstrated halothane-induced hepatic injury in rats anesthetized in hypoxic environments. The authors examined this phenomenon in mice and investigated plasma fluoride levels in mice and rats anesthetized with halothane in 40, 21 and 7 per cent oxygen with or without pretreatment with phenobarbital or carbon tetrachloride. They found no hepatic necrosis in mice. Mice produced less fluoride than rats. This difference in halothane metabolism between Sprague-Dawley rats and Swiss-Webster mice may explain the failure to observe hepatic necrosis in mice.

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