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A replacement for methoxyflurane (Metofane) in open-circuit anaesthesia.

Methoxyflurane (Metofane) has been widely used as an open-circuit anaesthetic in small laboratory animals for several decades. Its low vapour pressure and high blood solubility have permitted its use in convenient and simple drop-chamber/nose-cone setups. Recently, following the decision by the primary manufacturer to discontinue production, it has become increasingly difficult to obtain methoxyflurane. We describe here a simple and effective adaptation of isoflurane, an excellent inhalation anaesthetic, to open-circuit drop-chamber/nose-cone anaesthesia. It was found that the vapour concentration of isoflurane could be continuously varied by dissolving the anaesthetic in propylene glycol and that a 20% solution produced effective anaesthesia such that in adult mice, 2 ml of 20% isoflurane in propylene glycol induced anaesthesia within 2 min in a one-litre drop chamber. Furthermore, anaesthesia maintenance with 20% isoflurane was tested in two sets of mice. In one set, surgical plane anaesthesia was maintained for 10 min in a head chamber. After removal of the chamber, the animals awoke within one minute and recovered without any indication of post-anaesthetic distress. The second set contained pregnant mice; here anaesthesia was maintained for between 10 and 12 min, during which laparotomy, exposure of one uterine horn, intrauterine injection and wound closure were completed. The recovery from anaesthesia was also within a minute and with no signs of distress. Healthy litters were delivered after a normal gestation. This isoflurane/propylene glycol procedure is simple, effective and humane, and is a good substitute for methoxyflurane.

Anesthesia, Inhalation↗

Effects of liver injury and cholestasis on microsomal enzyme activities and metabolism of halothane, enflurane and methoxyflurane in vivo in rats.

1. Cholestasis (bile-duct ligation 24 h before) had no effect on rat liver microsomal protein content, cytochrome P-450 or cytochrome c reductase activity, but depressed aniline hydroxylase activity and aminopyrine demethylase less so. Pretreatment with CCl4 (24 h before) decreased rat liver cytochrome P-450, aniline hydroxylase and aminopyrine demethylase. 2. Halothane, enflurane and methoxyflurane are metabolized via different pathways, resulting in different metabolic elimination rates in our exposure system (methoxyflurane greater than halothane greater than enflurane). Elimination half-lives of the three compounds from the atmosphere of the exposure system were three times longer in CCl4-injured rats; cholestasis had a weaker effect (30-50% increase). 3. Dehalogenation of enflurane, which is the preferred pathway, is affected to the same extent as the cytochrome P-450-dependent hydroxylation of halothane and the O-dealkylation of methoxyflurane.

Anesthetics↗

[Inorganic fluoride concentrations and their sequential changes in the five layers of the kidney in rabbits after sevoflurane or methoxyflurane anesthesia].

In this study, intrarenal inorganic fluoride concentrations (IR-F) in rabbits were measured after sevoflurane or methoxyflurane anesthesia (SA or MA) to investigate the mechanism of methoxy-flurane nephrotoxicity and to confirm the safety of SA in fluoride nephrotoxicity. At the end of SA of MA, IR-F was 1.5 to 5 times greater in the cortex to papilla region than serum fluoride concentrations (S-F). When S-F were nearly equal, IR-F after MA was not greater than IR-F after SA. IR-F after SA declined rapidly. In contrast, IR-F after MA was maintained at high levels for a protracted period due to the greater solubility of methoxyflurane in fatty tissue. The present study suggests that the most important factor in methoxyflurane nephrotoxicity is the high IR-F of long duration established by urine formation, and that sevoflurane, although it is not associated with fluoride nephrotoxicity under normal conditions, may not be safe when it is used for an extremely long period and at high concentrations.

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↗

Comparative effects of halothane, enflurane, and methoxyflurane on the incidence of abnormal development using sea urchin gametes as an in vitro model system.

The incidence of sea urchin embryos developing abnormally after their exposure to equimolar concentrations of halothane, enflurane, and methoxyflurane has been determined. Halothane concentrations in the 0.6-1.25 mM range caused 18-96% of the embryos to undergo abnormal cleavage at the first cell division. This is important because embryos exhibiting atypical cleavage patterns at the first cell division eventually involute and die before reaching gastrulation. Over the same range of concentrations, enflurane and methoxyflurane have minimal effects on development. However, when exposed to 2.5 mM methoxyflurane, nearly 40% of the cells did not fertilize. These results show that volatile anesthetic agents have decidedly different effects on development and suggest that the incidence of abnormal development may not correlate directly with the anesthetic potency of inhalational agents.

Abnormalities, Drug-Induced↗

The effect of cimetidine on the formation of methoxyflurane fluorometabolites in mice.

Pre-dosing of mice with cimetidine reduced the plasma levels of inorganic fluoride, one of the fluorometabolites of methoxyflurane. The reduction occurred as early as 10 and as late as 160 minutes after cimetidine injection, and it was seen at both 30 and 100 minutes after subsequent methoxyflurane administration. Multiple pre-dosings with cimetidine did not notably affect the fluoride response. These results may be of use in avoiding methoxyflurane toxicity, which is thought to be due to markedly elevated fluoride levels in some patients.

Animals↗

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↗

Developmental toxicity of methoxyflurane in mice.

The developmental toxicity of trace, subanesthetic, and anesthetic exposure to methoxyflurane was examined in Swiss/ICR mice. No adverse effects on reproduction or fetal development were demonstrated following exposure to trace (2 ppm) and subanesthetic (60 ppm) concentrations of methoxyflurane for 4 hours daily on days 6 through 15 of pregnancy. Exposure to an anesthetic concentration (2000 ppm; 0.2%) for the same period resulted in decreased fetal weight, decreased ossification, and delayed renal maturation. Additionally, the incidence of minor skeletal anomalies was increased. It is concluded that gestational exposure of mice to trace of subanesthetic concentrations of methoxyflurane does not result in reproductive loss or morphologic abnormalities in their offspring.

Abnormalities, Drug-Induced↗

Serum inorganic fluoride and renal function in dogs after methoxyflurane anesthesia, tetracycline treatment, and surgical manipulation.

Effects of 2 hours of methoxyflurane-induced anesthesia in 25 dogs were determined by serum inorganic fluoride, serum urea nitrogen, serum creatinine, water intake, urine excretion, and urine specific gravity measurements; arterial concentrations of the anesthetic were also determined. The dogs were allotted to 5 groups (PTM, CTM, PTML, CTML, ML) of 5 dogs in each group and were anesthetized (M, in group designations) for 2 hours. The dogs were injected with chemically pure tetracycline or commercial tetracycline (PT and CT, in group designations) before, on the day of, and after anesthesia. In 3 groups, laparotomy (L, in group designations) was done; group ML did not receive tetracycline but a laparotomy was performed. Serum inorganic fluoride increased (P less than 0.05) in all groups 24 hours after anesthesia when compared with the base-line values; the highest mean serum concentration was 81.1 +/- 7.91 mumol/L (group PTM) and the lowest was 32.7 +/- 4.53 mumol/L (group PTML). There was no difference (P greater than 0.05) seen in serum urea nitrogen concentrations between groups. Methoxyflurane and tetracycline treatment caused no difference (P greater than 0.05) on serum concentrations of inorganic fluoride and urea nitrogen. Serum creatinine concentrations differed (P less than 0.05) only for groups PTM, CTM, PTML, and CTML vs group ML. Water intake reached peak at 48 hours after anesthesia. Arterial concentrations of methoxyflurane determined at 60 and 120 minutes of anesthesia indicated no difference (P greater than 0.05) among groups. Neither clinical nor laboratory signs of severe kidney dysfunction were detected in any of the experimental dogs during a 5-day observation period after anesthesia.

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↗

METHOXYFLURANE ANESTHESIA IN PEDIATRICS: A CLINICAL REPORT.

Methoxyflurane has been used for general anesthesia at The Montreal Children's Hospital since its clinical introduction in 1960, and has been administered to more than 5000 patients undergoing most types of pediatric operations. From a study of the records of more than one-half of these patients, a clinical impression of its usefulness has been obtained.When vapourized in a standard ether apparatus it appears to have the same high degree of safety as ethyl ether. It differs from ether in that it is non-explosive, less noxious and less irritating upon inhalation, depresses ventilation more and produces little postoperative vomiting.While the present trend is to employ more labile or less potent inhalation anesthetics, this development is not completed in children and methoxyflurane is a good modern substitute for ether, if pulmonary ventilation is supported when this is indicated.

Adjuvants, Anesthesia↗

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↗

Hepatitis due to repeated inhalation of methoxyflurane in subanaesthetic concentrations.

The authors present a case of hepatitis, which was due to repeated self-administered inhalation of methoxyflurane in subanaesthetic concentrations for insomnia. The diagnosis of viral hepatitis, type A or type B, was excluded on the basis of serologic findings. This case is of particular interest in that methoxyflurane even in subanaesthetic concentrations caused hepatic damage on repeated exposure.

Adult↗

Precautions when using methoxyflurane.

Methoxyflurane has a high blood/gas partition coefficient and a low vapor pressure. Mask inductions may be excessively slow, necessitating early high vaporizer control knob settings or additional injectable induction agent. Recoveries may be very prolonged. Methoxyflurane is extensively metabolized, and this may be associated with hepatotoxicity and nephrotoxicity.

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↗