Isoflurane Inhalation - Scientific Information
|Manufacture:||Fresenius Kabi USA, LLC|
|Form:||Liquid solution, Inhaler|
|Proper name:||Isoflurane, USP|
|Chemical name:||1-chloro-2,2,2-trifluoroethyl difluoromethyl ether|
|Molecular formula and molecular mass:||C3H2ClF5O 184.50|
|Description:||Isoflurane is a clear, colourless liquid having a slight odour. It is
nonflammable and soda lime stable. Easily miscible with organic
liquids including fats and oils. Insoluble in water. Boiling point is
48.5 °C (uncorrected).
|Boiling point at (760 mm Hg)||48.5 °C|
|Refractive index nD20||1.2990 1.3005|
|Specific gravity 25°/25°C||1.496|
|Vapour pressure in mm Hg||18 °C 218
20 °C 238
22 °C 261
24 °C 285
26 °C 311
|Equation for vapour pressure calculation:|
Isoflurane is a halogenated methyl ethyl ether.
The dose of epinephrine producing ventricular extrasystoles in 50 percent of humans anesthetized
with 1.25 MAC isoflurane is 6.7 μg per kg when the epinephrine is injected submucosally. This would equal 47 mL of a 1:100,000 epinephrine containing solution in a 70 kg man.
Isoflurane does not cause EEG spiking or convulsive activity either at high, normal or low levels of arterial PCO2. Myoclonus or other muscular movement suggesting increased central nervous system hyperactivity is not provoked by isoflurane.
Isoflurane produces general anesthesia on inhalation in mice, dogs, monkeys, rabbits, and rats. The low blood/gas partition coefficient (1.4 for isoflurane compared to 1.9 for enflurane and 2.4 for halothane) permits a rapid induction of and recovery from anesthesia. Recovery is free from nausea, vomiting, or evidence of malaise.
MAC in dogs, the minimum alveolar concentration at which 50% of the animals move in response to pain stimulation, is 1.46%. The anesthetic index in dogs (dose at apnea divided by MAC) is 2.5. The anesthetic index for other anesthetics is: enflurane 2.0, halothane 2.9, cyclopropane 2.4, and diethyl ether 2.9.
In rats, isoflurane is favored in either of two anesthetic indices indicating margin of safety (see Table: Anesthetic Indices). The respiratory anesthetic index is the ratio of the brain anesthetic concentration at respiratory arrest/minimum brain anesthetic concentration producing anesthesia. The cardiac arrest index is the ratio of the myocardial anesthetic concentration at circulatory collapse/minimum heart anesthetic concentration at which anesthesia is produced.
Like other halogenated agents, isoflurane causes respiratory depression and respiratory acidosis in dogs, rats, rabbits, monkeys, and humans.
The arrhythmic doses of epinephrine in dogs anesthetized with isoflurane do not differ from those which produce arrhythmias in the awake animal.
A single acute study in 4 week old female mice given isoflurane intraperitoneally in olive oil yielded an LD50 of 6.74 g/kg (5.87 to 7.77). The animals showed disorientation and hypnosis; at the higher doses some showed convulsions.
Subacute and Chronic
Groups of five mature beagle dogs were exposed to 1.5 MAC of isoflurane, enflurane, halothane, methoxyflurane, nitrous oxide, or thiopental. There was a control group of five animals. Each group was exposed for four hours per day every other day, for a total of 16 hours of anesthesia. Histopathological examination of liver and kidney tissues showed no cellular damage related to the anesthetics. Serum creatinine, BUN and SGPT were normal. Urine lysozyme measurements revealed no consistent change in the lysozyme excretion, with no differences among the anesthetics. It was concluded from these results that there was no renal or hepatic toxic effect from isoflurane or any other anesthetic.
Five groups of five Rhesus monkeys were exposed for four hours per day on alternate days for a total of 16 hours of anesthesia. The anesthetic agents used were isoflurane (1.5 to 2.5%), enflurane (1.5 to 2.0%), methoxyflurane (0.5 to 0.7%), and halothane (1.0 to 1.25%). No other drugs were administered. No significant changes in serum creatinine, BUN or SGPT were found. The minimal changes found in liver and kidney tissues did not indicate that isoflurane was nephrotoxic or hepatotoxic.
The chronic toxicity of isoflurane was compared to that of halothane and diethyl ether in mice, rats, and guinea pigs. Animals were exposed continuously for 35 days to 0.05% or 1/30th MAC isoflurane. At the end of this period, all species showed no effect other than a slightly lower weight gain compared to controls. By comparison, halothane animals tolerated only 1/200th MAC, or 0.005% concentration. At concentrations higher than this, halothane exhibited focal hepatic necrosis and lipoidosis which was not seen in the animals exposed to isoflurane.
Human volunteers given isoflurane at 1 to 2 MAC for 6 to 7.5 hours did not show postanesthetic evidence of significant liver or renal impairment. BSP retention was slightly increased 24 hours following anesthesia although the values remained in the normal range. This result differed from the result obtained in similar tests with halothane or fluroxene; the latter agents increased BSP significantly above normal. Isoflurane did not significantly affect SGOT, SGPT or LDH. Isoflurane did not increase BUN or serum creatinine.
A 15 month chronic toxicity study was also carried out in Swiss ICR mice. Isoflurane, enflurane, halothane, methoxyflurane and nitrous oxide were used; air and oxygen were given to groups of control mice. The anesthetics were given at 1/2, 1/8 and 1/32 MAC for four exposures to the mothers during pregnancy, and for 24 exposures to the pups post-partum. The pups were followed to 15 months, at which time they were sacrificed and autopsied. No significant differences were found between isoflurane treated animals and those exposed to halothane, enflurane, methoxyflurane or nitrous oxide.
Reproductive and Teratology
Reproduction studies, including fertility, general reproductive performance, teratogenicity, and lactation, did not show any abnormality in rats in concentration up to 2.34%.
The administration of 1.05% isoflurane to pregnant rats for 6 hours/day for 3 days during organogenesis, the administration of 1.63 - 1.73% isoflurane to pregnant rats for 1 hour/day for 5 days during organogenesis, and the administration of 2.28 - 2.34% isoflurane to pregnant rabbits for 1 hour/day for 4 days during organogenesis produced no fetotoxic effects. In contrast, the administration of isoflurane to pregnant mice has been shown to have a possible fetotoxic effect at anesthetic concentrations (0.6%) for 4 hours/day for 10 days during organogenesis. The relevance of these studies to the human is not known.