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Anesthetic indices for methoxyflurane, enflurane, and isoflurane in oxygen and halothane in nitrous oxide and oxygen (50:50), were determined in rats using measurements of heart and brain concentrations of the volatile agents at the endpoints of anesthesia, respiratory arrest and cardiac failure. The indices related respiratory arrest to anesthesia (respiratory index-A1r), cardiac failure to anesthesia (cardiac index-AIc) and respiratory arrest to cardiac failure (cardiorespiratory index-AIcr). Isoflurane had a significantly higher AIr (3.1) and AIc (5.7) than enflurane (AIr 1.8, AIc 3.3), methoxyflurane (AIr 2.2, AIc 3.7) and halothane in nitrous oxide and oxygen (AIr 2.4, AIc 3.7). These indices were also higher than those previously determined for halothane (AIr 2.3, AIc 3.0). Isoflurane had a higher AIcr (1.9) than halothane (1.6). Enflurane had a significantly lower AIr (1.8) than any of the other agents studied. These findings suggested a greater margin of safety for isoflurane, especially with respect to the heart, and a greater potential for respiratory depression for enflurane than for the other agents. Nitrous oxide decreased the amount of halothane necessary to produce anesthesia, but also that needed to produce respiratory arrest or cardiac failure. The addition of nitrous oxide, therefore, did not significantly enhance the overall safety of halothane anesthesia with respect to potential respiratory or cardiac depression.
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PMID:Anesthetic indices--further data. 62 24

The cardiocirculatory responses to equianaesthetic concentrations (MAC 0.5 and MAC 1.0 plus 67% N2O) of halothane, methoxyflurane, enflurane and isoflurane were studied in a total of 35 closed-chest dogs during ventilation controlled to produce normocapnia. Each anaesthetic produced a dose-related decrease in mean arterial pressure and in values reflecting cardiac function. These included cardiac output, stroke volume, left ventricular max dp/dt and ejection fraction. Isoflurane seemed slightly less depressant to the heart than the other 3 anaesthetics. Total peripheral resistance remained nearly unaffected during halothane and methoxyflurane anaesthesia but decreased significantly with MAC 1.0 enflurane and isoflurane. There was no change in heart rate at low anaesthetic concentrations. The deeper levels of anaesthesia were associated with moderate increases in heart rate. In spite of the obvious depression of myocardial contractility there was a fall in pulmonary artery and left ventricular end-diastolic pressures and in left ventricular end-diastolic volumes with each of the agents. We take this as an expression of decreased ventricular filling resulted from pooling of blood in peripheral capacitive vessels. With the exception of isoflurane, each of the other three anaesthetics reduced coronary blood flow. Coronary vascular resistance was not substantially influenced by halothane and methoxyflurane, but decreased with MAC 1.0 enflurane and isoflurane. Myocardial oxygen availability was always found to be adequate. Isoflurane even produced a significant rise in coronary venous oxygen saturation indicating coronary vasodilation. Parallel with the depression in cardiac performance and blood pressure as two of the main predictors of energy demand, myocardial oxygen consumption was found to be significantly reduced by each of the anaesthetics. The ratio of the external work of the left ventricle to its oxygen consumption indicated that myocardial efficiency deterioated. The clinical implications are discussed.
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PMID:[Influence of modern inhalation anaesthetics on haemodynamics, myocardial contractility, left ventricular volumes and myocardial oxygen supply (author's transl)]. 87 90

The present study evaluates the action of volatile anesthetics on the voltage-dependent Ca2+ channels in isolated rat brain membranes, measured as changes in binding of the Ca2+ channel blocker [3H]isradipine to these membranes. Equilibrium binding studies with increasing concentrations of [3H]isradipine (0.01-1 nM) in the presence of halothane (1.9%), isoflurane (2.3%), and enflurane (4.8%) at 25 degrees C were performed. Only halothane produced a significant depression in the specific binding of isradipine to the brain membranes at 0.5 and 1.0 nM [3H]isradipine (P = 0.028 and 0.018, respectively). Isoflurane and enflurane had such inconsistent effects that the data were inconclusive. Halothane produced a significant dose-dependent inhibition of binding, the maximum inhibition being 44% (P less than 0.005). Nonlinear regression analysis fit of the binding data indicates halothane produced a 48% decrease (P less than 0.05) in the maximal number of binding sites (Bmax) with no effect on the dissociation constant (Kd). As voltage-dependent Ca2+ channels are important in mediating neurotransmission, the marked decrease in channel number (Bmax) associated with halothane exposure suggests that this phenomenon might be related to the mechanism of general anesthesia.
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PMID:Depression of calcium channel blocker binding to rat brain membranes by halothane. 131 28

The purpose of this investigation was to study the effect of isoflurane on excitatory synaptic transmission. Rat hippocampal slices maintained in vitro were used as a model. Isoflurane caused a dose-dependent reduction of the excitatory postsynaptic potential (EPSP); 1.5% isoflurane reduced the EPSP by 35 +/- 9% (mean +/- s.d.) and 3% by 57 +/- 11%. Neither spontaneous nor potassium-stimulated efflux of the glutamate analogue D-(3H)aspartate was changed, but the content of D-(3H)aspartate in slices loaded during isoflurane was reduced to 83 +/- 12% of control (P less than 0.05). The intracellularly recorded response to direct application of glutamate increased by 37 +/- 20% during isoflurane (3%) and 50 +/- 5% during halothane (2%). Isoflurane (3%) enhanced the response to the glutamate receptor agonist quisqualate by 44 +/- 19%, whereas the N-methyl-D-aspartate response was unchanged. Isoflurane enhanced the tetanic depression of the population spike. The present results suggest that isoflurane reduces excitatory synaptic transmission by a presynaptic mechanism.
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PMID:The effect of isoflurane on excitatory synaptic transmission in the rat hippocampus. 131 34

General anaesthesia is the reversible depression of central nervous system function. There is still no agreement over what constitutes depth of anaesthesia, and the clinical anaesthetist must thus titrate drug input according to clinical signs (heart rate, blood pressure, somatic movement, autonomic responses). The potency of inhalational agents may be expressed in terms of the MAC (minimum alveolar concentration); comparable end-points (including blood concentrations) have been proposed for the intravenous agents. Kinetic infusion regimens can be constructed for the intravenous agents to achieve the ED95 concentrations required to provide clinically adequate anaesthesia. However, because of individual differences in drug kinetics and dynamics, as well as the influences of disease states and intercurrent therapy, the clinician will titrate the dose according to response. Administration of volatile or intravenous anaesthetics by fixed regimens may result in either overdosage or the risk of patient awareness. The choice of anaesthetic drug is usually based on the nonhypnotic side effects of the different agents--including their central and regional cardiovascular effects, the speed and completeness of recovery, and the need to provide intraoperative analgesia. In addition, special techniques and drugs are often needed for neurosurgical, cardiothoracic and obstetric anaesthesia. All anaesthetic agents (inhalation and intravenous) have other side effects (such as cardiorespiratory depression and organ toxicity related to the liver or kidney). Both halothane and enflurane may be responsible for postoperative hepatic dysfunction, while the metabolism of enflurane can also result in nephrotoxicity in patients with pre-existing renal dysfunction. Isoflurane has been reported to cause 'coronary steal' in patients with ischaemic heart disease through its coronary vasodilator properties.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Practical treatment recommendations for the safe use of anaesthetics. 137 60

Speed of onset, duration of action and recovery time for a bolus injection of atracurium were measured in two groups of patients. In group I anaesthesia considered of propofol, fentanyl, nitrous oxide and oxygen mixture. The induction dose of propofol was 2 mg/kg-1 followed by an infusion of 9.0 mg/kg-1/h-1 for first half hour and 4.5 mg/Kg-1/h-1 subsequently. In group II anaesthesia consisted of isoflurane, fentanyl, nitrous oxide and oxygen mixture. Isoflurane was given upon clinical needs. Speed of onset, duration of action, and recovery time for atracurium were measured in the two groups. No statistically significant differences between speed of onset and duration of action between the two groups were found. The recovery period from T1 = 10% to T1 = 70% twitch response was considerably longer with isoflurane (25 min +/- 6) than with propofol (18 min +/- 3) (p less than 0.01). Results obtained suggest that for adequate relaxation during tracheal intubation smaller doses of atracurium are not needed during isoflurane than propofol administration. Because of the longer recovery period of residual neuromuscular blockade during isoflurane anaesthesia decreasing doses of atracurium and careful monitoring of twitch depression tension are also suggested.
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PMID:[Effects of propofol and isoflurane on the neuromuscular block induced by atracurium]. 150 46

Depression of rested state contractions (RSCs) and 0.1-0.25 Hz contractions by equianesthetic concentrations of isoflurane (2.5%), halothane (1.5%), and enflurane (3.5%) was studied in guinea pig papillary muscles in which tension development was enhanced by 0.1 microM isoproterenol. In a second series of experiments, an RSC was elicited, followed by a second contraction elicited with stimulus intervals of 300-600 ms. In both types of experiments, the results were similar. Halothane and enflurane depressed rapid initial tension development more than isoflurane. This initial tension development was also selectively depressed by 0.1 microM ryanodine, which specifically decreases Ca2+ release from the sarcoplasmic reticulum (SR). Isoflurane and also enflurane depressed a delayed and late peaking component of tension development, which was very prominent after rest and was depressed by 200 microM procaine or 500 microM benzocaine. Although isoflurane and enflurane were similar to the local anesthetics in depressing late tension, unlike the local anesthetics they prolonged the late phase of tension development as well. The late tension of the RSC is associated with Ca2+, which enters the rested myocyte on depolarization and may be transiently sequestered in the SR before release. Both early initial and late tension development are depressed to a similar degree by application of 10-20 nM nifedipine. These results emphasize the multiple differing actions of the volatile anesthetics on myocardial contractions, with halothane and isoflurane possessing distinct depressant characteristics.
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PMID:Differential depression of myocardial contractility by volatile anesthetics in vitro: comparison with uncouplers of excitation-contraction coupling. 169 97

In order to analyze direct action of isoflurane on myocardium, we studied effects of isoflurane on membrane potentials and transmembrane ionic currents in single ventricular myocytes isolated enzymatically from rabbit hearts. Membrane potentials were recorded with a suction microelectrode technique, and an action potential was elicited by a brief intracellular stimulus. Isoflurane 3% depressed the action potential overshoot, plateau phase and duration without changing resting potential. Isoflurane decreased the refractory period of the action potential and prolonged the time-constant (tau) of the recovery process. In corresponding voltage clamp experiments, isoflurane significantly depressed the Ca2+ current (ICa), which generates the plateau phase. However, isoflurane had no effect on the transient outward current (I(t)), which triggers repolarization of the action potential. In rabbit ventricular cells, the time- and voltage-dependent outward K+ current (IK) was nearly absent. In conclusion, the depression of the action potential plateau by isoflurane is due to the decrease of ICa. Since isoflurane has no effect on It, the depression of the plateau phase by isoflurane may explain the shortening in the duration and the refractory period of the action potential.
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PMID:[Effects of isoflurane on membrane potentials, refractory periods and membrane ionic currents in rabbit single ventricular myocytes]. 176 99

We studied 60 children undergoing elective surgery to evaluate the effect of interactions between vecuronium and isoflurane or halothane on the potency and duration of neuromuscular blockade, as measured by electromyography. Vecuronium was first administered by a logarithm-based cumulative method (14, 22, 35, 56, 89 micrograms/kg) in 10 children anesthetized with thiopental (5 mg/kg), alfentanil (15 micrograms/kg first dose, then 10 micrograms/kg), and N2O/O2 (60:40) until a 95% +/- 2% twitch depression (ED95) was obtained. Thirty children given the same balanced anesthesia were then randomly assigned to three groups (n = 10 in each) to receive a single ED20 (21 micrograms/kg), ED50 (33 micrograms/kg), or ED80 (47 micrograms/kg) intravenous bolus of vecuronium calculated from the mean regression line of twitch responses of the first 10 children. In the second part of the study, 20 children were anesthetized with isoflurane (1.2%) or halothane (0.7%) and compared with the previous 10 children anesthetized with alfentanil-N2O. Potency of vecuronium determined by single-bolus or logarithm-based cumulative techniques was not significantly different. Isoflurane and halothane significantly decreased ED50 (22.3 +/- 1.6 and 25.4 +/- 1.4 micrograms/kg, respectively; mean +/- SE) and ED95 (41.5 +/- 3.3 and 46.7 +/- 3.2 micrograms/kg, respectively) compared with alfentanil-N2O (ED50: 32.8 +/- 0.8 micrograms/kg, ED95: 70.5 +/- 2.6 micrograms/kg). Recovery rate from vecuronium-induced neuromuscular blockade was significantly longer with isoflurane than with alfentanil-N2O or halothane. We conclude that in children single-bolus and logarithm-based cumulative techniques give similar potency estimates for vecuronium. Isoflurane and halothane increase by similar amounts the neuromuscular potency of vecuronium.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of volatile anesthetics on vecuronium-induced neuromuscular blockade in children. 196 20

Volatile anesthetics produce their negative inotropic effect on the heart mainly by interference with calcium homeostasis in the myocardial cell. In order to elucidate the mechanism of the depression, we have evaluated the effect of the volatile anesthetics on the binding of the calcium channel blocker [3H]nitrendipine to purified bovine cardiac sarcolemma. The radioligand binding studies were carried out at 25 degrees C, with increasing concentrations of [3H]nitrendipine (0.01-1 nM), in the presence or absence of unlabeled nitrendipine to determine specific binding, and with or without 1.9% halothane, 2.3% isoflurane, and 4.8% enflurane. Separately, [3H]nitrendipine was measured in the presence of increasing doses of halothane (0.78, 1.33, 1.90, and 2.57%). Kinetic studies of association and dissociation rate were performed with 1.90% halothane and 1 nM [3H]nitrendipine at different time intervals. All three volatile anesthetics produced depression of [3H]nitrendipine binding to the isolated cardiac sarcolemma. Only halothane produced a significant depression in binding, ranging between 59 and 66% (P less than 0.05), depending on the concentration of [3H]nitrendipine used. Isoflurane produced 29-38% depression, and enflurane produced 5-22% depression. Halothane also produced a significant (P less than 0.01) dose-dependent decrease in [3H]nitrendipine-specific binding. The kinetic binding experiments demonstrated that the time course for halothane's effect on association and dissociation of [3H]nitrendipine was 5 min for the half-maximum effect; the maximal reduction in binding capacity was at 15-30 min (P less than 0.05). Scatchard analysis revealed that all three volatile anesthetics produced reduction in the maximal number of binding sites; however, they varied in their effect on binding affinity. Only halothane produced a homogenous increase in the dissociation constant, signifying reduced affinity of the Ca2+ blocker to the channel. We suggest that the volatile anesthetics produce conformational changes in these channels consistent with their ability to depress channel-mediated Ca2+ influx into myocytes.
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PMID:Volatile anesthetics depress calcium channel blocker binding to bovine cardiac sarcolemma. 198 41


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