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Maternal and foetal effects of methoxyflurane anaesthesia in the pregnant ewe.

Maternal and foetal cardiovascular, blood gas and acid-base changes were studied during 90 minutes of methoxyflurane anaesthesia. At 1.0 and 1.5 MAC anaesthesia, despite slight to moderate falls in maternal blood pressure, cardiac output and uterine blood flow, no serious foetal deterioration was seen. 2.0 MAC methoxyflurane was associated with marked falls in maternal blood pressure, cardiac output and uterine blood flow. Foetal hypoxaemia and a mixed respiratory and metabolic acidosis developed. Little foetal cardiovascular depression was seen with any level of anaesthesia. There was no direct effect of methoxyflurane on the uterine vasculature.

Acid-Base Equilibrium

Doses of epinephrine causing arrhythmia during enflurane, methoxyflurane and halothane anaesthesia in dogs.

The arrhythmogenic dosage of epinephrine, administered by constant intravenous infusion, was measured in five dogs during enflurane, methoxyflurane and halothane anaesthesia. While premature ventricular contractions were observed in only one of five dogs with enflurane and methoxyflurane, epinephrine-induced arrhythmias were seen in all animals during halothane anaesthesia. Epinephrine dosage and the resultant increase in mean arterial blood pressure at which arrhythmias occurred during halothane anaesthesia were significantly less (p less than 0.05) than with the other anaesthetics. These observations indicate that enflurane and methoxyflurane, as compared to halothane, possess relatively less arrhythmogenic potential as sensitizing agents in the presence of increased circulating catecholamines.

Anesthesia, Inhalation

Changes in kidney and liver function after methoxyflurane (penthrane) anaesthesia.

Three groups of patients receiving methoxyflurane or halothane or pethidine after thiopentone suxamethonium induction were compared. Using multivariate Student t tests with simultaneous confidence intervals, significant differences in the test battery of uric acid, creatinine, blood urea nitrogen and sodium in the methoxyflurane series compared with the other series was found, indicating transient impaired kidney function. Likewise, there was a significant difference between the methoxyflurane and the other series in the s.g.p.t., s.g.o.t., alkaline phosphatase and bilirubin test battery, indicating impaired liver function. This was found after doses less than 16 ml which, so far, had been considered to be without any toxic effects.

Adult

Preservation of the hypoxic pulmonary vasoconstrictor mechanism during methoxyflurane anaesthesia in the dog.

The effect of methoxyflurane on the hypoxic pulmonary vasoconstrictor response in the dog lung was assessed by measuring the redistribution of pulmonary blood flow in response to two levels of unilateral alveolar hypoxia. Methoxyflurane 0.5% had no significant effect on the redistribution of blood flow resulting from the unilateral administration of oxygen 7% or nitrogen and there were no significant differences in PaO2 between the measurements made during unilateral hypoxia with methoxyflurane and those made during unilateral hypoxia in the control periods.

Anesthesia, Inhalation

Methoxyflurane anesthesia in pediatric patients: evaluation of anesthetic metabolism and renal function.

Serum ionic fluoride concentrations during and following low-dose (6.0 mg/100 ml, 3 hours) methoxyflurane anesthesia and elective operation were measured in 13 pediatric patients (mean age 10.2 years; mean weight 34.5 kg). Peak measured serum ionic fluoride concentration was 21.6 plus or minus 3.3 mumol/1 24 hours after anesthesia. In a previously reported study of adult patients (47.5 years; 71.9 kg), the peak measured serum ionic fluoride concentration was 43.9 plus or minus 5.7 mumol/1 24 hours after low-does (6.8 mg/100 ml,3 hours) methoxyflurane anesthesia. Possible explanations for lower serum ionic fluoride concentrations in pediatric patients comared with adults include 1) slower metabolism of nethoxyflurand; 2) increased renal clearance of ionic fluoride from the blood; 3) greater sorage of ionic fluride in bone; 4) more rapid methoxyflurane elimiantion in the postoperative period. Serum uric acid increased (4.4 to 6.4 mg/100 ml, not significant) 24 hours after anesthesia and operation, while blood urea nitrogen and serum creatinine and osmolality were unchanged postoperatively.

Anesthesia, Inhalation

Metabolism of methoxyflurane in man.

Excretion of methoxyflurane was studied in 12 patients receiving anesthesia in a closed rebreathing circuit at a constant alveolar concentration of approximately 0.24 per cent. The mean methoxyflurane uptake was 18 g (range 7.6-31 g) during a mean time of anesthesia administration of 2 hours, 18 minutes (range 55-309 minutes). An average of 19 per cent of the uptake was recovered unchanged in the exhaled air after anesthesia. Urinary excretion of organic fluorine, fluoride, and oxalic acid was equivalent to 29, 7.7 and 7.1 per cent of methoxyflurane uptake, respectively. Approximately a third of the uptake remained unrecovered. It is postulated that a portion of the unrecovered drug became permanently bound to tissues and hence its excretion was delayed beyond the period of the study.

Acetates

Kinetics of methoxyflurane biotransformation with reference to substrate inhibition.

The kinetics of biotransformation of methoxyflurane by rat hepatic microsomes in vitro was studied. The rate of biotransformation as measured by analysis of metabolites continued to increase even at near-saturation concentrations of the anesthetic. Methoxyflurane biotransformation followed either an unbounded curve with empirical formula y = a ln(bx + 1) or an asymptotic curve with formula (see article) No substrate inhibition was observed. Total fluoride Vmax of 135.1 mmumol F-/mg protein/30' was increased to 931.9 by phenobarbital induction; free fluoride Vmax from 39.2 to 403.2. Thus, enzyme induction shifted biotransformation to the production of greater amounts of inorganic free fluoride metabolites than organic fluoride-containing metabolites. Phenobarbital induction caused qualitative as well as quantitative alteration in the biotransformation of methoxyflurane.

Anesthesia, Inhalation

Blood circulation in the kidney of the cat under methoxyflurane (penthrane) anaesthesia.

In order to establish whether methoxyflurane causes any change in renal vascular resistance, the renal venous flow was measured by means of a drop recording technique in six cats under methoxyflurane anaesthesia. Arterial pressure was recorded simultaneously, and the renal vascular resistance was calculated. Methoxyflurane caused a significant reduction of the renal vascular resistance to about 85% of control value at an anaesthetic depth characterised by loss of the corneal reflex. At a deeper anaesthetic stage characterised by steady state circulation and absence of any reflexes, no further significant fall in renal vascular resistance occurred. Autoregulation and depression of the sympathetic activity are assumed to explain the reduction of the renal vascular resistance.

Anesthesia, Inhalation

Cardiac function during induction and early anesthesia with methoxyflurane. An evaluation using systolic time intervals and pressure time indices.

In addition to the standard monitoring of heart rate and blood pressure, the Systolic Time Intervals were used to evaluate cardiac performance, and the Pressure Time Indices (tension time index = TTI; diastolic pressure time index = DPTI) were used to estimate myocardial oxygen balance. Twelve patients with known heart disease were studied during induction with thiopental, intubation, and early anesthesia with methoxyflurane. Cardiac performance diminished after thiopental; and during methoxyflurane it was reflected in increases in pre-ejection period (PEP) and the ratio PEP/LVET. Intubation resulted in a hyperactive state of the heart, as shown by maximal decreases in PEP and PEP/LVET. Myocardial oxygen balance--estimated from the supply/demand ratio (DPTI/TTI)--was impaired after thiopental. After intubation, DPTI/TTI decreased to its lowest value due to an excess of myocardial oxygen demand (TTI) over myocardial oxygen supply (DPTI), signifying a transitory underperfusion of the subendocardium. During methoxyflurane the oxygen balance was gradually restored towards control value. The Systolic Time Intervals and the Pressure Time Indices provided valuable information on cardiac function not available from standard monitoring alone.

Adult

Recovery from anaesthesia in ponies: a comparative study of the effects of isoflurane, enflurane, methoxyflurane and halothane.

The duration and quality of recovery after separate 2 hour anaesthetic periods with equipotent alveolar concentrations of isoflurane, enflurane, halothane and methoxyflurane were evaluated in experimental ponies. Recovery was shortest after isoflurane anaesthesia, followed by enflurane, halothane and finally methoxyflurane, although standing was achieved more rapidly after enflurane than after isoflurane. This sequence of recovery times was compatible with the respective solubilities of the 4 agents. The smoothest recovery was obtained after isoflurane anaesthesia, followed by methoxyflurane, halothane and then enflurane. The isoflurane recovery was characterized by very quiet and prolonged sternal recumbency with excellent coordination upon standing. The chief difficulties with halothane recovery were shivering and delayed coordination upon standing. Enflurane anaesthesia was followed by a very brief period of sternal recumbency but there was considerable shivering and incoordination upon standing. This may have been due to central nervous stimulation during anaesthesia producing a residual excitatory effect. On the basis of this investigation, isoflurane was considered to be the most satisfactory volatile anaesthetic for the horse.

Anesthesia, Inhalation

General anesthesia with methoxyflurane given intravenously to the dog.

Dogs were anesthetized with liquid methoxyflurane administered intravenously by gaseous diffusion through sealed medical grade silicone rubber tubing placed in the femoral vein. A similar catheter placed in the other femoral vein and connected to a pressure transducer measured the increase in intraluminal pressure due to methoxyflurane diffusion into the 2nd catheter from the bloodstream 20 seconds after the catheter was flushed with room air. These pressures were plotted against venous blood methoxyflurane concentration, as determined by gas chromatography, for increasing lengths of anesthetic-administering catheter exposed to the bloodstream.

Anesthesia, Intravenous

Fluoride concentrations in urine of delivery ward personnel following exposure to low concentrations of methoxyflurane.

Midwives and other delivery ward personnel exposed to methoxyflurane do not have measurable traces of the agent in expired air when examined soon after exposure. This may imply a rapid uptake of the anesthetic. If this is the case, then the products of the metabolism of methoxyflurane, such as fluoride, may appear in the urine of such personnel. The present study investigated urinary fluoride levels in 24 delivery ward personnel and compared the values found after methoxyflurane/nitrous oxide analgesia with those measured in the same individuals after exposure to nitrous oxide alone. A highly significant difference was observed. Thus it would appear that, in spite of an apparently adequate system of environmental ventilation, there is a significant uptake of methoxyflurane by delivery ward personnel when this agent is employed for obstetrical analgesia.

Anesthesia, Obstetrical

[The effect of hypothermia and methoxyflurane-anaesthesia on sympatho-neuronal and sympatho-adrenal activity in the course of cardiac surgery (author's transl)].

The concentrations of adrenaline and noradrenaline, and dopamine-beta-hydroxylase in the plasma, and certain haemodynamic parameters, were determined in 14 children undergoing surgical correction of congenital cardiac defects under hypothermia at 30 degrees C and methoxyflurane anaesthesia. During the pre-operative phase of hypothermia at 30 degrees C, the adrenaline levels rose to about 300% of the inital levels, and the noradrenaline levels to about 200%. During the postoperative phase of re-warming at 34 degrees C, a further dysregulative release of catecholamines led to an increase in adrenaline levels to a critical concentration of about 800% of the norm, and in noradrenaline levels of about 400% of the norm. No change was seen in dopamine-beta-hydroxylase activity. Hypothermia thus results in a massive activation of the sympatho-neuronal and sympatho-adrenal systems, which is not prevented by methoxyflurane anaesthesia, and which may endanger the recently operated heart, particularly during the early post-operative period, because of the increased oxygen requirements imposed on the myocardium. In normothermia, on the other hand, methoxyflurane anaesthesia results in only a slight degree of activation of the sympathetic nervous system, which increased only slightly during the post-operative period. Under these conditions, the plasma dopamine-beta-hydroxylase activity remains unchanged. Unlike the changes in plasma catecholamine levels, dopamine-beta-hydroxylase activity cannot be regarded as an index of changes in sympatho-neuronal activity.

Adolescent

Enflurane and methoxyflurane metabolism at anesthetic and at subanesthetic concentrations.

In an attempt to determine the importance of concentration of an anesthetic agent as a determinant of the extent of its biotransformation, we measured fluoride excretion in groups of Fischer 344 rats treated with one of several subanesthetic or an anesthetic concentration (1 MAC) of either enflurane or methoxyflurane. Anesthetic administrations (2.0% enflurane or 0.26% methoxyflurane) ranged from 0.15 hours (9 minutes) to 4.8 hours. Subanesthetic exposures, all of 48 hours duration, ranged in concentration from 0.2% enflurane to 0.0016% methoxyflurane. Greatest metabolism occurred at the lowest concentration time (MAC-hours) of subanesthetic administrations and at the shortest duration of anesthetic exposure. Increasing time in the case of anesthetizing exposures, or concentration in subanesthetic exposures, increased the amount of metabolite produced. However, the increased production of metabolite was not proportional to the increase of concentration or duration of exposure. Enzyme induction was ruled out as an important factor in the larger amount of metabolism seen during the subanesthetic exposures. Therefore, the exposure of a patient to the metabolites of an anesthetic is actually low although the anesthetic is administered at a high concentration.

Anesthesia, Inhalation

[Aspects of the clinical use of methoxyflurane analgesia and of the determination of its concentration and distribution in the body].

As a supplement to local anesthesia in aortography, appendectomies and operations for hernia in 118 patients the authors employed through a mask an inhalation anesthetic methoxyflurane in subnorcotic concentrations. The patients were in the state of consciousness, analgesia was adequate, no complications relative to methoxyflurane inhalation were noted inhalation anesthesia with methoxyflurane proved to be safe and effective in combination with local anesthesia. The method is indicated in aortographies.

Analgesia

The effect of methoxyflurane on certain renal function parameters.

In 43 patients the effect of low concentrations of methoxyflurane on the renal function was studied. The blood levels of urea, creatinine, uric acid, sodium and potassium, and specific weight of urine was determined. It was found that the anaesthetic technique used and methoxyflurane concentrations in the range of 0.2-0.5 vol% caused no abnormalities in renal function. It seems that methoxyflurane in low concentrations (0.2-0.5 vol%) is the best method of anaesthesia with this agent, with the simultaneous use of a nitrous oxide-oxygen mixture and controlled ventilation.

Adult

Inhalation anesthesia with methoxyflurane for guinea pig ear surgery.

Anesthesia with methoxyflurane is ideal for long-term middle ear experiments on guinea pigs. This communication describes the use of a conventional pediatric anesthetic circuit that delivers a mixture of methoxyflurane and air by a face mask; it is effective, safe, and simple to use.

Anesthesia, Inhalation

Changes in serum uric acid concentrations after caesarean section using methoxyflurane.

In a study comparing the changes in serum uric acid concentration after methoxyflurane anaesthesia in 10 patients subjected to either Caesarean section or minor general surgical procedures, a significantly greater increase in serum uric acid concentration occurred in those patients undergoing Caesarean section. These results were compared with results from a control group of five patients undergoing Caesarean section, anaesthetized without methoxyflurance and with a second control group of five patients having uncomplicated spontaneous deliveries. Reasons are presented to suggest that although obstetric patients are unlikely to be more vulnerable to methoxyflurane nephrotoxicity, those with pre-eclamptic toxaemia may be more at risk.

Adult