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Delivered enflurane concentrations from two calibrated Ethrane vaporizers were determined with total gas flows of 3,5 and 8 L/min. Regardless of total gas flow the presence of 60% nitrous oxide increased enflurane concentrations by 20 to 40% above those concentrations present when only oxygen was flowing through the vaporizer. This nitrous oxide effect was present at all dial settings studied except the lowest engraved (0.25) concentration. Enflurane output at the 0.25% setting was 0.38% with or without nitrous oxide. Maximum changes in enflurane concentrations after adding nitrous oxide required about 5 minutes but the rapidity with which enflurane concentrations approached this maximum value were directly related to total gas flow. Similar effects of nitrous oxide on enflurane output from Cyprane Ethrane vaporizers were also measured. The mechanism of increased vaporizer enflurane output in the presence of nitrous oxide is unknown but may reflect increased gas flow through the vaporizing chamber secondary to increase in gas density associated with nitrous oxide. A similar mechanism has been proposed to explain increased halothane concentrations delivered by Fluotec Mark 2 vaporizers in the presence of nitrous oxide. Clinically, central system stimulation and anesthetic overdose may occur from increased enflurane concentrations delivered when nitrous oxide is added to the gases flowing through the Ethrane vaporizer. The ability to deliver low enflurane concentrations is limited since the measured concentration at the lowest dial setting was nearly 0.4%.
1. The effects of two general anaesthetics, propofol and enflurane, on electrical activity and contractions were investigated in single myocytes isolated from guinea-pig ventricles. 2. Propofol and enflurane depressed the plateau and shortened the duration of action potentials. 3. Under voltage-clamp conditions, propofol and enflurane reduced the amplitude of inward calcium current and of additional inward current activated by cytosolic calcium. 4. Contractions (measured with an optical technique) accompanying either action potentials or second inward currents (in response to depolarizations to 0 mV) were reduced by both anaesthetics. The mechanisms for calcium entry during contractions accompanying pulses to positive potentials such as +60 mV are thought to differ from those accompanying second inward currents which are evoked by pulses from -40 to 0 mV. Enflurane enhanced the amplitudes of contractions accompanying pulses to positive potentials; in contrast these contractions were depressed by propofol. 5. In experiments where recovery processes were investigated by use of pairs of voltage-clamp pulses with a variable interval between them, enflurane but not propofol slowed the recovery of contractions and calcium-activated 'tail' currents. These observations are consistent with the hypothesis that enflurane may impair calcium handling by the sarcoplasmic reticulum whereas propofol has little, if any, effect at this site. 6. In conclusion, the actions of propofol and enflurane on second inward currents contribute to their effects on action potentials and contraction. The negative inotropic effect of both anaesthetics may result partly from reduced calcium influx to trigger contraction, and for enflurane, partly from an impairment of calcium handling by the sarcoplasmic reticulum.
To determine the site and mechanism of action underlying the inhibition of adrenal medullary catecholamine release by enflurane, the authors measured the effects of enflurane on catecholamine secretion evoked by various secretagogues in isolated bovine adrenals perfused with Locke's solution. Catecholamine concentrations in the perfusate were measured spectrofluorometrically. Enflurane caused concentration-dependent inhibition of catecholamine release in response to activation of the nicotinic receptors in the chromaffin cells with acetylcholine or dimethylphenylpiperazinium (DMPP). An enflurane concentration of 0.88 mM caused 50 per cent inhibition of the DMPP-induced secretion. The inhibition induced by enflurane was shown to be noncompetitive. The catecholamine release evoked by activation of the muscarinic receptors with pilocarpine was only slightly decreased by 3.74 mM enflurane. At this concentration the release in response to KCl, 56 mM, was partially inhibited, whereas the output in response to tyramine (from glands perfused with calcium-free Locke's solution) was unaffected. It is concluded that the site of action of enflurane is the cell membrane. At concentrations above 1 mM, enflurane may impair calcium ion influx, but at lower concentrations it probably interacts with hydrophobic regions of the nicotinic receptor.
This study provides the first morphological evidence of significant structural damage following high doses of enflurane alone and confirms previous findings of transient renal functional abnormalities following high dosage enflurane. The study also indicates that enflurane may have a greater potential for renal toxicity in the presence of renal impairment. Treatment of Fischer 344 rats with a nephrotoxic dose of gentamicin prior to six hours of enflurane (GE) anaesthesia at 1 MAC resulted in increased serum concentration of the enflurance metabolite inorganic fluoride (GE, 43.9 +/- 1.5; E, 34.5 +/- 1.8 mu mol/L), increased urine flow rate and a greater degree of structural damage in renal proximal convoluted tubule cells than was observed with either gentamicin (G) or enflurane (E) alone. Treatment with gentamicin prior to enflurane also resulted in reduced urinary osmolality compared to enflurane or gentamicin alone (GE, 742 +/- 57; E, 1709 +/- 66; G, 985 +/- 32 m0sm/kg).
During anaesthesia for caesarean sections, the placental transfer and metabolism of Enflurane were investigated in 14 cases. In 3 cases, the administered concentration of 0.4 vol.% Enflurane showed too slight anaesthesia. In 11 cases, 0.6 vol.% Enflurane were delivered to the maternal respiratory mixture. A gaschromatographic method was used to measure the maternal and fetal blood concentrations of Enflurane. The calculated maternal mean value of Enflurane showed a concentration of 330 mumol/l which corresponds to 6.07 mg/100ml; the fetal mean value was 148 mumol/l or 2.72 mg/100 ml. This means that during operating time about 44.8% from the maternal Enflurane concentration has crossed to the fetus. The metabolic break down of Enflurane could be demonstrated by the measurement of inorganic fluorides in the maternal and fetal blood. The fluor concentration in the maternal blood increased during the operation and reached a mean value of 15.5 mumol/l at the time of birth; the mean value in the cord vein was at the same time 9.28 mumol/l which corresponds to 61% of the maternal concentration.
The neuromuscular effects of d-tubocurarine (dTc), pacuronium, and succinylcholien (SCh) were studied in 37 unpremedicated adult surgical patients anesthetized with 1.25 MAC enflurance in oxygen. The relaxant doses that produced 50 per cent depression of twitch height (ED50) were 1.57, 0.29, and 4.9 mg/m2 for dTc, pancuronium, and SCh, respectively. These doses are approximately 3.1, 1.7, and 1.0 times less than the amount of dTc, pancuronium, and SCh required to produce 50 per cent depression of twitch height during halothane anesthesia but are the same as ED50 values during isoflurane anesthesia. In eight additional unpremedicated patients anesthesia was maintained at 0.71 MAC enflurane in oxygen (five patients) or 1.67 MAC enflurane in oxygen (three patients). Twitch depression following dTc, 1.5 mg/m2, was related directly to alveolar enflurane concentration. Ability to sustain tetanus decreased progressively with increasing tetanic frequencies and decreased with increasing alveolar enflurane concentrations. The authors concluded that smaller doses of dTc and pancuronium are needed for adequate relaxation during enflurane anesthesia than during equi-MAC halothane anesthesia, and that higher alveolar enflurane concentrations reduce the dose of dTc necessary to produce a given amount of paralysis. Also, neuromuscular effects of enflurane in combination with dTc or pancuronium are not significantly different from those seen suring equi-MAC isoflurane anesthesia.
Male and female Beagle dogs and Cynomolgus monkeys were exposed to anaesthetic (1.5 MAC) and subanaesthetic (1/100 MAC) levels of enflurane and halothane for 3 hours on alternate days for 4 weeks. One-half of the animals were killed following the last exposure and the remainder after 4 weeks of recovery. The animals' condition was assessed during anaesthetic periods by measuring respiration, ECG, blood pressure, temperature and EEG. Haematology, urinalysis and clinical chemistry parameters were evaluated. Gross and microscopic pathological examinations were conducted at the end of the exposure and recovery periods. Two female monkeys in the mid- and high-dose halothane groups died during the study. No deaths were observed in the enflurane group. No quantitative differences were observed in respiration rate, heart rate, blood pressure and EEG activity of animals anaesthetized with enflurane or halothane. Muscle twitches were observed in some mid- and high-dose dogs inhaling enflurane, but not in monkeys. A number of liver function tests became abnormal in mid- and high-dose halothane-treated dogs and high-dose halothane-treated monkeys. This was not observed with enflurane. Histopathologic alterations were confined to the liver of animals exposed to halothane. In dogs, the lesions were characterized by centrilobular hepatocyte degeneration and/or necrosis, fibroblastic proliferation, hepatocyte enlargement, fat deposition and glycogen depletion; and in mid- and high-dose monkeys by moderate to marked hepatocyte vacuolation and fat deposition. Except for one high-dose dog, these lesions were not seen in animals killed after 4 weeks of recovery. No histopathologic alterations were observed with enflurane.
The effect of enflurane on uterine contractility was studied in sexually mature rabbits in which intrauterine balloon catheters had been implanted. Three animal groups were studied: untreated; treated with estrogen-progesterone; and 27 to 28 days pregnant. The effects of 1.5 percent or 3.0 percent enflurane were quantitated by measuring contraction frequency and amplitude during an anesthetically steady state. The effects of prior anesthesia with 1.5 percent enflurane on uterine responses to 1.5 IU oxytocin IV were also evaluated. Neither 1.5 percent of 3.0 percent enflurane altered contraction amplitude or frequency in the 3 groups of rabbits. However, the amplitude of the contractile response to oxytocin 30 minutes following enfluane was significantly depressed. The results indicate that, while the intact rabbit uterus under different hormonal influences is not depressed by 1.5 or 3.0 percent enflurane, its response to oxytocin following enflurane is decreased.
The effects of acute increases of intracranial pressure (ICP) on renal function before and during enflurane and enflurane-N2O anesthesia were determined in 12 mongrel dogs. Prior to anesthesia, acute elevations of 10 and 20 torr in ICP significantly increased urine osmolarity (Uosm), mean arterial blood pressure (MAP), and renal vascular resistance (RVR); significantly decreased urine volume (U vol), para-aminohippurate clearance (Cpah), and free water clearance (C/20); and had no effect on inuline clearance (Cin) or plasma levels of antidiuretic hormone (ADH). Thirty minutes of enflurane (2.2 percent end-tidal concentration) in 70 percent nitrogen and O2 in the presence of normal ICP caused significant increases in Uosm while MAP, CPAH, UVOL CH20, CIN, and osmolar clearance (CosM) were significantly decreased and ADH was unchanged. Substituting 70 percent N2O for nitrogen had no significant effect on any variable measured. Increasing ICP 10 torr during enflurane-N-2O anesthesia caused significant increases (compared to enflurane-N2O values in the presence of normal ICP) in UosM, RVR, and CosM, as well as significant decreases in UVOL, CH2O, AND CPAH, but had no effect on ADH, CIN, or MAP. Enflurane and N2O anesthesia moderates the elevation MAP in response to an acute increase in ICP but fails to alter the renal response to increased ICP.
Enflurane was compared with halothane for anaesthesia for short surgical procedures in paediatric out-patients. Induction of anaesthesia was more prolonged with enflurane and recovery times were similar with both agents. Coughing and laryngospasm during induction occurred more frequently with enflurane. The incidence of post-operative complications was essentially similar in both groups, but there was no evidence that the use of enflurane was followed by rapid recovery at home. Enflurane has no advantages over halothane in anaesthesia for short procedures for paediatric out-patients.
The ventilatory responses to isocapnic hypoxia and hypercapnia were studied in six dogs each with a tracheostomy, awake and during anaesthesia with halothane, enflurane and isoflurane (1-2.5 MAC). Isocapnic hypoxic ventilatory response (HVR) was expressed as the parameter A, such that the greater the value of A, the greater the hypoxic response. In the anaesthetized dogs HVR (A) was reduced significantly from the awake value of 2010 +/- 172 (mean + SEM) to 630 +/- 173 by 1 MAC halothane, 495 +/- 105 by 1 MAC enflurane and 952 +/- 157 by 1 MAC isoflurane (PL0.05). All three anaesthetic agents produced significant depression of HUR at 1 MAC, but enflurane was more depressant than isoflurane. At 1.5 MAC all three anaesthetics produced equal and significant depression of HVR at equianalgesic concentrations. Further increases in anaesthetic concentration caused no increase in depression. Hypercapnic drive, as measured by the slope of the VE/PACO2 response curve, was reduced significantly from 9.75 litre min-1 kPa-1 +/- 2.4 in awake dogs to 0.83 +/- 0.56 after 1 MAC halothane, 0.68 +/- 0.53 after 1 MAC enflurane and 1.58 +/- 0.75 after 1 MAC isoflurane. In addition, hypercapnia-induced augmentation of the hypoxic drive was abolished by 1 MAC halothane or enflurane and diminished markedly by 1 MAC isoflurane. It may be clinically significant that hypoxia and hypercapnia during anaesthesia with these agents did not produce optimal stimulation of ventilation.
The haemodynamic responses to minimum equipotent concentrations of halothane and enflurane were compared in seven dogs. The haemodynamic responses to increasing concentrations of enflurane, and to induced hypovolaemia during enflurane anaesthesia, were studied in the same dogs, both before and after administration of propranolol 0.3 mg kg-1 i.v. In equipotent concentrations, enflurane caused marginally greater impairment of left ventricular function than halothane, and caused a dose-dependent reduction of arterial pressure, cardiac output and myocardial contractility. Following administration of propranolol, these haemodynamic effects of enflurane were marked, and withdrawal of 20% of estimated blood volume was tolerated poorly.
The effect of thiopentone 0.5 and 1.0 mg/kg on the enflurane-induced cortical spike discharge has been examined. Seven cats were anaesthetized with enflurane in oxygen and ventilation was controlled to maintain eucapnia during e.e.g. recording. End-tidal enflurane concentrations of between 1.2 and 2.2% provoked dose-dependent spontaneous spike discharges reproducibly. It was found that, during light enflurane anaesthesia, intravenous thiopentone could exacerbate e.e.g. signs of seizure activity. However, at a greater depth of anaesthesia spike activity was suppressed. The e.e.g. changes following thiopentone resembled the effects of still greater concentrations of enflurane.
Enflurane was used in 150 non-selected patients and was found to be a most satisfactory inhalation anaesthetic. Induction and recovery times were rapid and these characteristics, together with its rather pleasant smell, made it readily acceptable to the patient. Although such features suggest that it would be an ideal agent for children, very high concentrations of enflurane were required to produce adequate anaesthesia in infants and small children. Normal sinus rhythm continued following the injection of adrenaline during enflurane anaesthesia and adequate muscle relaxation was obtained for lower abdominal surgery. The degree of metabolic breakdown of enflurane is considerably less than with other inhalation agents and, if this is reflected in terms of minimal renal and hepatic toxicity, there is every reason to believe that enflurane may be preferable to the volatile anaesthetics currently in use.
The metabolism and renal effects of enflurane were studied during and after anesthesia in ten surgical patients without renal disease; ten control patients received halothane. Enflurane was metabolized to inorganic fluoride with a mean peak serum level of 22.2 +/- 2.8 muM four hours after anesthesia. Urinary inorganic and organic fluoride excretions were increased but oxalic acid excretion was not, suggesting that the latter is not an enflurane metabolite. Postanesthetic renal function, including the response to vasopressin, was normal in both groups. During enflurane anesthesia renal blood flow, glomerular filtration rate, and urinary flow rate were 77, 79, and 67 per cent of control values, respectively. In this study of patients without renal disease, metabolism of enflurane to inorganic fluoride was insufficient to cause clinically significant renal dysfunction.
Arterial plasma lidocaine concentration of 1 to 3.5 microgram/ml produced dose-related decreases in enflurane requirement (MAC) ranging from 15 to 37 per cent in dogs. The ventilatory responses to carbon dioxide at comparable depths of anesthesia with enflurane alone and the enflurane-lidocaine combination were measured in each animal and compared. With both anesthetic regimens there were increases in resting arterial carbon dioxide tension (mean maximal increase = 18 torr) and a 69 per cent decrease in the slope of the ventilatory response as depth of anesthesia increased. The effect of the drug interaction appears to be additive, since the ventilatory depression produced by the enflurane-lidocaine combination was no greater than that produced by enflurane alone at equivalent levels of anesthesia.
Thermal conductively detection (TCD) in conjunction with gas-liquid chromatography was employed for the analysis of enflurane in n-heptane extracts of whole blood. Enflurane was estimated to be 98 per cent extracted from whole blood by n-heptane. Analysis of enflurane standards ranging in concentration from 4.1 to 813 muM demonstrated linearity, with a correlation coefficient of 0.9999. As little as 8 muM enflurane may be detected in whole blood. TCD gas-liquid chromatography is a rapid and sensitive method for quantifying enflurane in whole blood.