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The effects of methoxyflurane on pulmonary vascular resistance and the pulmonary vasoconstrictor response to alveolar hypoxia were studied in isolated cat lungs perfused at a constant flow. Methoxyflurane decreased pulmonary vascular resistance and depressed the pulmonary vasoconstrictor response to hypoxia.
Blood urea content and the serum concentrations of sodium, creatinine, uric acid, glutamic oxaloacetic transaminase (g.o.t.), glutamic pyruvate transaminase (g.p.t.) and bilirubin were measured before delivery, on the 2nd and 3rd days and on the 5th day after delivery. In two groups of mothers, one receiving nitrous oxide analgesia and the other a combination of nitrous oxide and methoxyflurane, blood urea and serum sodium and g.o.t. were increased following labour and nitrous oxide analgesia; s.g.p.t. was increased only in the late post-partum period. Serum sodium, creatinine, uric acid, urea, g.o.t. and g.p.t. increased following exposure to methoxyflurance. The increase in serum sodium, uric acid and urea was dose-dependent. Capillary concentrations of uric acid in the neonates showed dose-dependent changes in response to methoxyflurane.
Inorganic fluoride (F-) production and renal function were assessed in six groups of Fischer 344 rats administered either methoxyflurane (MOF) or deuterated methoxyflurane (d4-MOF). One untreated and one phenobarbital (PB)-treated group were exposed for two hours to either air, 0.5 per cent (V/v) MOF, or 0.5 per cent (v/v) d4-MOF. Serum and urinary F- and serum urea nitrogen and creatinine were measured. Urine volume and urinary F- excretion were only slightly greater among MOF than among d4-MOF exposed animals. Pretreatment with PB, however, greatly enhanced F- production in MOF-exposed animals leading to marked renal impairment but only slightly enhanced F- production in d4-MOF animals leading to mild renal impairment. Thus, only in PB-pretreated animals could a biologically significant difference in nephrotoxicity be demonstrated for MOF and d4-MOF.
The effects of ethanol on the metabolism of enflurane, isoflurane, and methoxyflurane were investigated to determine if alterations in biotransformation of these agents occur as a result of this treatment. In vitro incubations of hepatic microsomes from rats pretreated with 10 days' ethanol vapor inhalation revealed a fourfold increase in inorganic fluoride from enflurane when compared with incubations of microsomes from unpretreated rats and from phenobarbital-pretreated rats. Isoflurane, while metabolized to a lesser extent than enflurane, showed a similar stimulation of metabolism. Methoxyflurane, while metabolized to a greater extent than either enflurane or isoflurane, had lesser fluoride production by the microsomes from ethanol-pretreated rats than microsomes from phenobarbital-pretreated rats, but greater fluoride production than that found in microsomes from unpretreated rats. Ethanol pretreatment did not alter the levels of cytochrome P-450 which is the enzyme responsible for such metabolism. This suggests that the altered metabolism involves either a specific P-450 isozyme or an unidentified enzyme.
Methoxyflurane, a general anesthetic, is a known nephrotoxin. A case is presented that demonstrated diffuse, bilateral renal cortical calcification on CT secondary to repeated methoxyflurane inhalation.
Methoxyflurane was given by inhalation as the sole anesthetic agent to 42 New Zealand white rabbits, with no mortality. The depth of respiration as well as the changes in the color of the ears were monitored constantly. A technique for administering methoxyflurane without intubation is described.
A 34-year-old woman developed a crystalline retinopathy after 2 years of inhalational abuse of methoxyflurane. After the woman developed renal failure, a renal biopsy showed multiple birefringent crystals in the renal tubular lumens, epithelial cells, and interstitium compatible with calcium oxalate. Multiple bright yellow-white crystals were deposited throughout the retina and at the level of the retinal pigment epithelium with a retinal arterial and periarterial predilection. This is the first reported case of methoxyflurane abuse with secondary hyperoxaluria in which there was a widespread retinal distribution of crystalline deposits, especially along the retinal arteries and arterioles.
In a field trial of 1,257 patients receiving methoxyflurane, trichloroethylene, and nitrous-oxide/oxygen for the relief of pain in labour methoxyflurane has been shown to have certain advantages which support its use in midwifery practice. The trial confirms our objective method for screening an inhalational agent as an obstetric analgesic.
The effect of general anesthesia on control of breathing was studied by CO2 rebreathing and occlusion pressure measurements in six normal human subjects under methoxyflurane anesthesia. CO2 was found to increase the amplitude of the occlusion pressure wave without changing its shape, so that CO2 responses in terms of the occlusion pressure developed 100 ms after the onset of inspiration (Po/0.1) gave results equivalent to the responses in terms of Po/1.o or any other parameter of the pressure wave. Methoxyflurane depressed the ventilatory response to CO2 but not the occlusion pressure response, implying that the most important action of the anesthetic was to increase the effective elastance of the respiratory system rather than to depress the respiratory centers. The elastance was further increased by CO2, and this mechanical change had the effect of shifting the "apneic threshold" extrapolated from the ventilatory response curve to a lower PAco2. Frequency of breathing, inspiratory and expiratory times were not altered by CO2 in anesthetized subjects.
Digitalis tolerance in dogs anesthetized with enflurane, isoflurane, fluroxene, methoxyflurane, and diethyl ether was compared with that in dogs anesthetized with pentobarbital. Ouabain dosage needed to cause ventricular tachycardia was significantly higher than that of pentobarbital with all agents except fluroxene, as was the LD50. The relative potency of these anesthetics in converting ouabain-induced ventricular tachycardia to sinus rhythm, in order of descending effectiveness, was: diethyl ether, methoxyflurane, enflurane, fluroxene, isoflurane, pentobarbital.
During the course of surgical anesthesia, the majority of patients experience some arrhythmias, virtually all of which can be attributed to changes in cardiac pacemaker automaticity and/or alterations in cardiac conduction velocity. Therefore, a better understanding of these mechansims is of importance to anesthesiologists. Cardiac automaticity in the intact heart of dogs under methoxyflurane anesthesia was assessed by measuring changes in ventricular escape time (VET) and ventricular escape rate (VER). A slight shortening of VET was noted, while there was virtually no change from control in VER. Unexpectedly, however, a nonsinus supraventricular escape focus became prominent in many animals at a low anesthetic dose and in all animals at a higher anesthetic concentration. This effect was shown to be preventable by pretreatment with reserpine or a beta-blocking agent. It is concluded that methoxyflurane increases the automaticity of parts of the atrial conducting system, other than the sinus, either by a direct effect or by increasing the sensitivity to prevailing background adrenergic levels.
The cardiac arrhythmicity of epinephrine and dopamine was compared in awake goats and during approximate equivalent levels of halothane, enflurane, methoxyflurane, and fluroxene anesthesia. The arrhythmic threshold dose for epinephrine and dopamine was significantly (p less than 0.05) reduced during halothane anesthesia when compared to values determined in awake animals. Enflurane anesthesia had no significant affect on the arrhythmic threshold dose for either catecholamine. However, methoxyflurane and fluroxene anesthesia significantly (p less than 0.05) elevated the arrhythmic threshold dose for dopamine. Epinephrine produced greater elevations in mean arterial pressure than dopamine with all anesthetics except enflurane, and dopamine produced significantly (p less than 0.05) higher heart rates in the awake animals and those anesthetized with halothane and enflurane. The authors conclude that, in terms of arrhythmic potential, there is no advantage in the use of dopamine rather than epinephrine for the reversal of halothane-induced myocardial depression during halothane or enflurane anesthesia.
The concentration of anaesthetic gases in the expired air was studied for up to 17 days in patients who had been anaesthetized with methoxyflurane, enflurane or halothane. The estimation were made by means of gaschromatography. The rate and duration of elimination of the anaesthetic via the lungs depends on the fat stores of the patient (as calculated by the body weight/stature ratio), the length of anaesthesia and the Lutz index (calculated average concentration of the inhaled anaesthetic). The concentration of anaesthetic gases in the expired air fell steeply during the first 12 hours after anaesthetic and then decreased more gradually. The drop in concentration during the first 24 hours was steepest for methoxyflurane, followed by halothane and enflurane in that order. The results are in fair agreement with the rate of metabolization of the three anaesthetic agents. The investigation showed that during the first after anaesthesia appreciable quantities of anaesthetic gases are eliminated via the lungs and, consequently, released into the air of the recovery room.
A patient with normal preoperative hepatic and renal laboratory findings was exposed to relatively low concentrations of methoxyflurane during a routine anaesthetic procedure. For at least 12 postoperative days, the patient showed unusually high level of inorganic serum fluoride; his urinary excretion of fluoride and oxalic acid were also increased. However, he had no clinical signs of nephrotoxicity. This observation suggests that some patients with presumably normal renal function may have a low threshhold for the nephrotoxic effects of methoxyflurane.
The production of formaldehyde as a metabolite of enzymatic biotransformation of methoxyflurane was observed in vitro in hepatic microsomal preparations derived from Japanese monkeys, rabbits and Wistar strain rats. Production rates of formaldehyde were 0.80-2.50 n moles/mg protein/min in the induced group which was pretreated with phenobarbitone, and 0.15-0.68 n moles/mg protein/min in the non-induced group. This reaction needed the presence of NADPH and oxygen. Formaldehyde production was almost completely inhibited by addition of 25% CO. Further degradation of formaldehyde did not occur in microsomal suspension. No detectable species difference was observed among the animals used in this study. These results indicate that the biotransformation of methoxyflurane is preceded by interaction with cytochrome p-450 in hepatic microsomes in the presence of NADPH and oxygen.
The effect of acute anaesthetic (1,0 MAC) and chronic subanaesthetic (0,1 MAC) exposure to methoxyflurane and enflurane on the levels of several liver enzymes is reported. Methoxyflurane appears to be an enzyme-inducing agent similar to spironolactone, whereas enflurane does not appear to be an inducing agent for any of the enzymes studied.
During open heart surgery hemodynamic changes due to 1.5% enflurane, 0.75% halothane, 0.18% methoxyflurane and 3.4% fluroxene have been compared. The following parameters have been measured: arterial pressure, heart rate, cardiac output, right and left atrial pressure, left ventricular pressure and dp/dt. The strongest effects were found with enflurane and halothane. Marked reduction in cardiac index, stroke index, left ventricular dp/dt as well as reduction of peripheral resistance caused severe systemic hypotension. Because of its slow uptake methoxyflurane was followed by small hemodynamic changes in this study. The rapid acting fluroxene had caused only minor reductions of cardiac output, stroke volume and dp/dt. There was no decrease in peripheral resistance.
The biotransformation of methoxyflurane produces two fluorometabolites: inorganic fluoride (F) and an acid-labile fluorocompound (OALF). These have been assayed in the serum of male mice 10, 30, and 100 minutes after either ip or sc injections of 0.7 microliter of methoxyflurane (MOF) per gram of body weight, as either the volatile liquid itself or as a 1:10 dilution in corn oil. During the 10- to 100-minute intervals, the mice were observed for loss of the righting reflex. Corn oil dilution significantly altered the production of MOF fluorometabolites, usually decreasing them, but after 100 minutes, the serum concentration of OALF was 25% greater. Loss of righting reflex was also altered; 11 of 18 mice given undiluted MOF experienced it, whereas only 2 of 18 given the diluted agent did. Compared to the tip route, the sc route resulted in less fluoride at all three time intervals, but more of the OALF after 30 and 100 minutes. None of the sc-dosed mice lost his righting reflex.