Pharmacology of modern volatile anaesthetics

The volatile anaesthetics sevoflurane and desflurane feature new and promising properties. Their low blood and tissue solubility enables rapid onset of and emergence from anaesthesia, thus enhancing patient safety and comfort. This article is designed as an up-to-date review of the pharmacokinetic and pharmacodynamic properties of modern volatile anaesthetics. The first part focuses on pharmacokinetic issues such as substance properties, uptake and elimination. The second part covers the effects of inhaled anaesthetics on organ systems, with emphasis on the central nervous system, the cardiovascular system, the respiratory tract, liver and kidneys.     

Illicit use of modern volatile anaesthetics

Sixteen reported cases of abuse of modern volatile anaesthetics are summarized. Twelve of the sixteen subjects died. Halothane was ingested or injected intravenously for suicidal purpose, and sniffed for mood elevation. Abuse of modern volatile anaesthetics deserves more attention than it has received in the past.     

Uptake of volatile anaesthetics in children

The uptake of halothane is known to be more rapid in children than in adults, but comparable clinical data regarding other inhalational anaesthetics are not available. In this study, the rates of uptake of halothane, enflurane, isoflurane and methoxyflurane were compared in children of different ages. Expired (FE') and inspired (FI) vapour concentrations were measured with an infrared analyser, and FE'/FI ratios were used to determine rates of uptake. Uptake rates of halothane, enflurane and methoxyflurane were more rapid in the younger than in the older children, but age had no effect on the uptake of isoflurane which was uniformly rapid in all the children studied.     

Early postoperative vomiting and volatile anaesthetics or nitrous oxide

Editor—The article by Apfel and colleagues¹ on volatileanaesthetics being the main cause of early postoperative vomitingis interesting. They separate out the effect of nitrous oxideand consider volatile anaesthetics to be the emetogenic factor.Have they considered the combined synergistic effect of nitrousoxide and volatile anaesthetics as the cause of postoperativenausea and vomiting? Furthermore, propofol may attenuate theeffect of the nitrous oxide if given before the inhalationalaspects. Buffington² has noted a 3.5-fold greater incidence of vomitingin patients given isoflurane     

Nociceptin system does not affect MAC of volatile anaesthetics

BACKGROUND: Nociceptin is the endogenous agonist of the opioid receptor-like (ORL) 1 receptor (NOP), and both nociceptin and NOP are widely expressed in the brain and spinal cord, which are target organs of general anaesthetics. As nociceptin has been reported to be involved in modulating pain mechanisms and stress responses, it is possible that the activity of the nociceptin system affects the anaesthetic potency of general anaesthetics. To address this possibility, we investigated the minimum alveolar concentrations (MACs) of various volatile anaesthetics in nociceptin receptor knockout mice (NOP-/-) and wild-type mice (NOP+/+). METHODS: We used male NOP-/- mice and NOP+/+ mice. MACs for halothane, isoflurane and sevoflurane were determined by the tail-clamp method. RESULTS: MACs for halothane, isoflurane and sevoflurane in NOP-/- mice were 1.60 (SD 0.06), 1.68 (0.08) and 3.36 (0.07)%, respectively. In NOP+/+ mice, MACs for halothane, isoflurane and sevoflurane were 1.59 (SD 0.07), 1.72 (0.07) and 3.38 (0.09)%, respectively. CONCLUSION: MACs in NOP-/- mice did not significantly differ from those in NOP+/+ mice for halothane, isoflurane and sevoflurane. This result suggests that the nociceptin system does not affect the anaesthetic potency of volatile anaesthetics.     

Effect of nitrous oxide and volatile anaesthetics on platelet function in man

Twelve otherwise healthy male volunteers scheduled for arthroscopy of the knee were studied. The influence in vivo of nitrous oxide (N₂O) per se and the addition of a halogenated volatile anaesthetic (halothane or isoflurane) on ADP–induced platelet aggregation and release of beta–thromboglobulin into plasma was evaluated. All measurements were made before surgery. We found that N₂O increased platelet aggregation. Adding a halogenated anaesthetic reversed the relative hyperaggregation induced by N_aO. The concentrations in plasma of the platelet release product beta thromboglobulin were not influenced by the anaesthetics.     

Suppressive actions of volatile anaesthetics on the response capability in cats

Purpose  Suppression of response to a given stimulus by anaesthetics might be considered as a summation of the suppression of basal (pre-stimulus) activity and response capability (increased by stimulus). Anaesthetic suppression of each component in brain and cardiovascular variables by halothane, isoflurane or sevoflurane was compared in cats. Methods  Thirty cats were allocated to one of three groups (n = 10 in each) according to the anaesthetic given. The sciatic nerve was stimulated after maintaining the end-tidal concentration of the anaesthetic at 1.3 or 2.0 MAC for at least 30 min. Cortical electroencephalogram (EEG), multi-unit activity in the mid-brain reticular formation (R-MUA), mean arterial pressure (MAP) and heart rate (HR) were measured before and after electrical sciatic nerve stimulation. Results  The EEG patterns and R-MUA indicated greater suppression of activity in the brain by isoflurane (31 ±4% of awake state at 1.3 MAC, mean ± SEM) and sevoflurane (38 ± 5%) than by halothane (61 ± 5%,P < 0.05), before stimulation. The R-MUA following the stimulation was not different among agents. The MAP and HR were not different among groups before stimulation, but following stimulation were greater in the sevoflurane group (137 ± 9 and 103 ± 9 mmHg at 1.3 and 2.0 MAC) than in the halothane group (103 ± 5 and 76 ± 3 mmHg,P < 0.05). Conclusion  Isoflurane and sevoflurane have greater suppressive action on the basal CNS activity than halothane at the same MAC, and that these two anaesthetics have a weak suppressive action on the response capability to peripheral stimulation.

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Résumé Objectif  La suppression de la réponse à un stimulus par les anesthésiques peut être considérée comme la sommation de la suppression de l’activité basale (pré-stimulus) et de la capacité de réponse (augmentée par le stimulus). La suppression par l’anesthésie de chacune de ces composantes au niveau du cerveau ainsi que des variables cardiovasculaires a été comparée chez le chat pour l’halothane, l’isoflurane et le sevoflurane. Méthodes  Trente chats ont été répartis en 3 groupes (n = 10) selon l’agent anesthésique administré. Après avoir maintenu la concentration en fin d’expiration de l’agent anesthésique à 1,3 et 2,0 CAM pour 30 minutes, on a stimulé le nerf sciatique. Avant et après cette stimulation, on a enregistré l’électroencéphalogramme cortical (EEG), l’activité plurisynaptique de la formation réticulée mésencéphalique (R-MVA), la pression artérielle moyenne (PAM) et la fréquence cardiaque (FC). Résultats  Les tracés d’EEG et de R-MVA indiquent une plus grande dépression de l’activité cérébrale avant stimulation par l’isoflurane (31 ± 4% des valeurs d’éveils à 1,3 CAM, moyenne ± écart type moyen) et le sevoflurane (38 ± 5%) que par l’halothane (61 ± 5%,P< 0,05). à la suite de stimulation, la R-MVA ne montrait pas de différence entre les agents. Avant stimulation, la PAM et la FC des différents groupes n’affichaient aucune différence, mais après stimulation les valeurs de PAM étaient plus élevées dans le groupe sevoflurane (137 ± 9 et 103 ± 9 mmHg à 1,3 et 2,0 CAM) que dans le groupe halothane (103 ± 5 et 76 ± 3 mmHg,P< 0,05). Conclusion  Pour une même CAM, l’isoflurane et le sevoflurane ont une action suppressive plus intense sur l’activité de base du SNC que l’halothane; d’autre part, ces deux agents ont une action suppressive faible de la réponse à une stimulation périphérique.

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This study was supported in part by Grants-in-Aid for Scientific Research No. 07771275 and 08457415, from the Ministry of Education, Science and Culture, Japan.     

Application of semilinear canonical correlation to the measurement of the electroencephalographic effects of volatile anaesthetics

BACKGROUND AND OBJECTIVE: The common parameters of the electroencephalogram quantify a shift of its power spectrum towards lower frequencies with increasing anaesthetic drug concentrations (e.g. spectral-edge frequency 95). These ad hoc parameters are not optimized for the content of information with regard to drug effect. Using semilinear canonical correlation, different frequency ranges (bins) of the power spectrum can be weighted for sensitivity to changes of drug concentration by multiplying their power with iteratively determined coefficients, yielding a new (canonical univariate) electroencephalographic parameter. METHODS: Electroencephalographic data obtained during application of volatile anaesthetics were used: isoflurane (n = 6), desflurane (7), sevoflurane (7), desflurane during surgical stimulation (12). Volatile anaesthetic end-tidal concentrations varied between 0.5 and 1.6 minimum alveolar concentration (MAC). The canonical univariate parameter and spectral-edge frequency 95 were determined and their correlation with the volatile anaesthetic effect compartment concentration, obtained by simultaneous pharmacokinetic-pharmacodynamic modelling, were compared. RESULTS: The canonical univariate parameter with individually optimized coefficients, but not with mean coefficients, was superior to the spectral-edge frequency 95 as a measure of anaesthetic drug effect. No significant differences of the coefficients were found between the three volatile anaesthetics or between the data with or without surgical stimulus. The coefficients for volatile anaesthetics were similar to the coefficients for opioids, but different from coefficients for propofol and midazolam. CONCLUSIONS: The canonical univariate parameter calculated with individually optimized coefficients, but not with mean coefficients, correlates more accurately and consistently with the effect site concentrations of volatile anaesthetics than with spectral-edge frequency 95.     

Effects of anaesthesia and surgery on the solubility of volatile anaesthetics in blood

To determine the effects of anaesthesia and surgery on the solubility of volatile anaesthetics in blood, we measured the blood/gas partition coefficients of enflurane, halothane, isoflurane, and methoxyflurane in vitro in blood obtained from six healthy unpremedicated adults at three different times during isoflurane anaesthesia: awake; 20 minutes after induction of anaesthesia, but before surgical incision; and, 90 minutes after surgical incision. The blood/gas partition coefficients of the four volatile anaesthetics decreased significantly after induction of anaesthesia and after surgical incision (p less than 0.05). Values for haematocrit and the serum concentrations of albumin, globulin, and cholesterol decreased parallel to the decrease in blood/gas partition coefficients.     

Changes in mucociliary activity may be used to investigate the airway- irritating potency of volatile anaesthetics

We have examined the short-term effects of three volatile anaesthetics, halothane, isoflurane and desflurane, on mucociliary activity in the rabbit maxillary sinus in vivo. Mucociliary activity was recorded photoelectrically and the signal processed by fast Fourier transformation. Administration of 1.0 MAC of halothane, isoflurane or desflurane caused a temporary increase in mucociliary activity, with mean peak responses of 47.8 (SEM 13.0)%, 44.0 (9.6)% and 45.1 (23.7)% (n = 6), respectively. The response to all three compounds was biphasic; an initial peak was observed within 2 min and a second peak at 3-8 min. The second response was not significant for halothane. In contrast, desflurane produced a significant second peak while the first was small and failed to reach significance. Halothane displayed an initial peak within 2 min which was blocked by atropine but not by the neurokinin 1 (NK1) receptor antagonist CP-99. The second peak at 3-5 min was less pronounced for halothane than for isoflurane or desflurane. The second peak was not affected by atropine pretreatment, but was blocked by pretreatment with CP-99. A combination of atropine and CP-99 pretreatment abolished the mucociliary response to halothane. Atropine pretreatment did not affect, whereas CP-99 significantly reduced, the response to desflurane. We conclude that the NK1-mediated response was most pronounced for desflurane which is considered the most airway irritating compound of the three. It is likely that the size of the NK1-mediated response reflects the airway-irritating properties of the volatile anaesthetic used.      

Effect of different volatile anaesthetics on suxamethonium-induced jaw muscle contracture in rats

Previous work has demonstrated that the interaction of hyperthermiaand halothane may greatly increase the jaw muscle contractureproduced by suxamethonium. We have compared the interactionof temperature and suxamethonium in the presence of halothanewith the suxamethonium/temperature interaction of two othervolatile anaesthetics, isoflurane and desflurane. Rats wereanaesthetized with 1.35 MAC of halothane, isoflurane or desflurane.The jaw area was heated to 36–41 °C by a heating lampwhile rectal temperature was maintained at 37 °C. Isometrictension was recorded from the jaw muscles. Suxamethonium 750µg kg^–1 i.v. induced a transient jaw muscle contracture(JMC) during halothane, isoflurane and desflurane anaesthesia.JMC exhibited significant dependence on jaw muscle temperaturewith all three volatile anaesthetics. Increasing the temperatureof the jaw area from 37 °C to 41 °C increased JMC 8.7-foldwith halothane, 8.8-fold with isoflurane and 3.1 -fold withdesflurane. The difference between halothane and desfluranewas significant. While suxamethonium-induced JMC was dependenton temperature for all three volatile anaesthetic, the temperaturedependence appeared to be less with desflurane.