Brynte H. Johnson

Kinetics of desflurane, isoflurane, and halothane in humans.

The low solubility of desflurane in blood and tissues suggests that the partial pressures of this agent in blood and tissues should approach the inspired partial pressure more rapidly than would the blood and tissue partial pressures of other potent inhaled anesthetics. We tested this prediction, comparing the pharmacokinetics of desflurane with those of isoflurane, halothane, and nitrous oxide in eight volunteers. We measured the rate at which the alveolar (endtidal) (FA) concentration of nitrous oxide increased towards an inspired (FI) concentration of 65-70%, and then measured the concurrent increase in FA and mixed expired concentrations (FM) of desflurane, isoflurane, and halothane at respective FI values of 2.0%, 0.4%, 0.2%. Minute ventilation (VE) was measured concurrently with the measurements of anesthetic concentrations. The potent vapors were administered for 30 min; administration of nitrous oxide continued throughout the period of anesthesia. For the potent agents, we also measured VE, FA, and FM for 5-7 days of elimination. We used FA/FI and FA/FA0 (FA0 = the last FA during the administration of each anesthetic) to define the rate of increase of anesthetic in the lungs and the rate of elimination of anesthetic, respectively. FA/FI values at 30 min of administration were: (mean +/- SD) nitrous oxide 0.99 +/- 0.01, desflurane 0.90 +/- 0.01, isoflurane 0.73 +/- 0.03, and halothane 0.58 +/- 0.04. FA/FA0 values after 5 min of elimination were: desflurane 0.14 +/- 0.02, isoflurane 0.22 +/- 0.02, and halothane 0.25 +/- 0.02. Recovery (volume of anesthetic recovered during elimination per volume taken up) of desflurane (105 +/- 25%) equalled recovery of isoflurane (102 +/- 13%) and exceeded recovery of halothane (64 +/- 9%). Time constants for a five-compartment mammillary model for halothane and isoflurane differed for the lungs, fat group, and hepatic metabolism, and exceeded those for desflurane for all compartments. In summary, we found that FA/FI of desflurane increases more rapidly and that FA/FA0 decreases more rapidly in humans than do these variables with other available potent anesthetics. We also found that desflurane resists biodegradation in humans and so may have little or no toxic potential.

Rates of awakening from anesthesia with I-653, halothane, isoflurane, and sevoflurane : a test of the effect of anesthetic concentration and duration in rats

The low blood solubility of two new inhaled anesthetics, I-653 (human blood/gas partition coefficient, 0.42) and sevoflurane (0.69), suggested that awakening from these agents should be more rapid than awakening from currently available anesthetics such as isoflurane (1.4) and halothane (2.5). This prediction proved valid in a study of these four agents in rats given 0.4, 0.8, 1.2, or 1.6 MAC for 2.0 hr or 1.6 MAC for 0.5 or 1.0 hr. At a given dose and duration, awakening was most rapid with the least soluble agent and longest with the most soluble agent. For example, recovery of muscle coordination at 1.2 MAC administered for 2 hr required 4.7 ± 3.0 min (mean ± sd) with 1–653, 14.2 ± 8.1 min with sevoflurane, 23.2 ± 7.6 min with isoflurane, and 47.2 ± 4.7 min with halothane.

Cardiovascular actions of desflurane in normocarbic volunteers.

The cardiovascular actions of three concentrations of desflurane (formerly I-653), a new inhalation anesthetic, were examined in 12 unmedicated normocapnic, normothermic male volunteers. We compared the effects of 0.83, 1.24, and 1.66 MAC desflurane with measurements obtained while the same men were conscious. Desflurane caused a dose-dependent increase in right-heart filling pressure and a decrease in systemic vascular resistance and mean systemic arterial blood pressure. As measured by echocardiography, left ventricular end-diastolic area did not change except for a small increase at 1.66 MAC desflurane, and systolic wall stress was less at all concentrations of desflurane than during the conscious state. Desflurane did not change cardiac index or left ventricular ejection fraction. Heart rate did not change at 0.83 MAC, but progressively increased with deeper desflurane anesthesia. Stroke volume index was less at all concentrations of desflurane than while the men were conscious, but desflurane did not alter the velocity of ventricular circumferential fiber shortening. Mixed venous blood PO2 and oxyhemoglobin saturation were higher during all concentrations of desflurane anesthesia than during the conscious state. No volunteer developed a metabolic acidosis. We conclude that desflurane with controlled ventilation and constant PaCO2 causes cardiovascular depression, as indicated by the increased cardiac filling pressure and decreased stroke volume index and by no change in the velocity of circumferential fiber shortening in the presence of decreased systolic wall stress. However, cardiac output is well maintained, and heart rate does not increase at light levels of anesthesia. The cardiovascular actions of 0.83 and 1.66 MAC desflurane were also reexamined in 6 of the 12 men during the seventh hour of anesthesia. Prolonged desflurane anesthesia resulted in lesser cardiovascular depression than was evidenced during the first 90 min. The measures of cardiac filling (central venous pressure and left ventricular end-diastolic cross-sectional area) did not differ between the early and late periods of anesthesia. Systemic vascular resistance decreased further during the late period, but systolic wall stress did not differ between the two time periods. During the seventh hour of desflurane anesthesia, heart rate and cardiac index were higher at both anesthetic concentrations than during the first 90 min of anesthesia. Left ventricular ejection fraction and velocity of fiber shortening did not change with duration of desflurane anesthesia. Oxygen consumption, oxygen transport, the ratio of the two, mixed venous PO2, and mixed venous oxyhemoglobin saturation (SO2) increased late in the anesthetic in comparison with the first 90 min.

Minimum alveolar concentration of I-653 and isoflurane in pigs: definition of a supramaximal stimulus

We determined the anesthetic potencies of a new fluorinated anesthetic, 1–653, and isoflurane in pigs as a preliminary to a study of the relative cardiovascular and electroencephalographic effects of these agents. Clamps were sequentially applied to the dew claw and/or tail of each animal to determine the minimum alveolar concentration (MAC) that suppressed movement in response to each of these stimuli. MAC obtained by clamping the tail (8.28 ± 1.34% [mean ± standard deviation] for 1–653 and 1.653 ± 0.36% for isoflurane) was more variable and lower than MAC obtained by clamping the dew claw (10.00 ± 0.94% for 1–653 and 2.04 ± 0.19% for isoflurane). We conclude that the type of stimulus applied affects the MAC value obtained for 1–653 and isoflurane. Clamping the tail is not a supramaximal stimulus in pigs; a greater stimulus is provided by clamping the dew claw.

1653 and Isoflurane Produce Similar Dose-related Changes in the Electroencephalogram of Pigs

1653 is a new volatile anesthetic structurally similar to enflurane and isoflurane. Since enflurane can induce convulsions, whereas isoflurane progressively depresses cortical electrical activity, the authors believed it important to assess the effect of 1653 on the EEG (in both the “time” and “frequency” domain). The EEG was assessed visually and quantitatively, and a new EEG parameter was introduced. The burst-suppression ratio (percentage of time the EEG was isoelectric) quantified the extent of burst suppression phenomena. Eight swine were anesthetized with 1653 or isoflurane in oxygen and in random sequence, exposed to approximately 0.8, 1.2, or 1.6 MAC with normocapnea and to 1.2 MAC with hypocapnea (PETCO2 of 25 mmHg). Four animals were also anesthetized with 3.2% (1.2 MAC) enflurane in oxygen. Both 1653 and isoflurane produced a dose-related depression of cortical electrical activity. At 0.8 and 1.2 MAC of either agent, occasional sharp waves occurred singly, were apparently not related to external (auditory) stimuli, and probably represented normal variation in the EEG. No electrographic or gross motor seizures occurred with either 1653 or isoflurane. In contrast, all pigs given enflurane developed seizures during hypocapnea. At equipotent concentrations, 1653 and isoflurane had the same effect on EEG parameters. Increasing doses of either 1653 or isoflurane caused decreasing amplitude and frequency and increasing suppression. Hypocapnea during either agent slightly increased high-frequency activity, and slightly decreased burst suppression.

MAC of I-653 in rats, including a test of the effect of body temperature and anesthetic duration

The anesthetic potency of a new fluorinated volatile anesthetic, I-653, was tested preliminary to testing its toxic and metabolic characteristics in rats. The minimum alveolar concentration (MAC) of 1–653 at 37.9 ± 0.2°C (mean ± sd) in eight rats was 5.72 ± 0.40%. In five rats, we reduced the rectal temperature to 28°C in two steps of 5°C. MAC decreased by 0.238 ± 0.036% I-653 per degree centigrade decrease in temperature. That is, MAC decreased 42% as temperature decreased 10°C. We restored the temperature to38°C and redetermined MAC. This value (5.66 ± 0.75%) did not differ from the average MAC obtained before hypothermia (5.84 ± 0.36%).

Pharmacokinetics of inhaled anesthetics in humans: measurements during and after the simultaneous administration of enflurane, halothane, isoflurane, methoxyflurane, and nitrous oxide

To determine the relative washin and washout characteristics of isoflurane, enflurane, halothane, and methoxyflurane, we administered all four anesthetics simultaneously (total = 1.1 MAC) to nine healthy patients for 2 hr. Concentrations of anesthetics in end-tidal gases were measured during washin and for 5–9 days during washout. Multiex-ponential (multicompartment) models were fit to the washin and washout curves using least-squares analysis. Slowly equilibrating compartments could only be identified during washout. For 27 of the 36 data sets, five-compartment models fit the washout curves significantly better than four-compartment models. The time constant for our first compartment is consistent with that predicted for washout of the lungs. Time constants for the second, third, and fifth compartments were consistent with current data for blood flows and solubilities of vessel-rich, muscle, and fat tissue groups, respectively. The fourth compartment has a time constant that lies between the time constants predicted for muscle and fat.

Kinetics and Potency of Desflurane (I-653) in Volunteers

The inhalation anesthetic, desflurane (1–653), is a methyl ethyl ether halogenated entirely with fluorine and differing from isoflurane only in the substitution of fluorine for chlorine on the α-ethyl carbon. Relative to presently used potent inhalation anesthetics, desflurane has low blood/gas (0.42) and oil/gas (18.7) partition coefficients. These indicate that it will undergo rapid washin and washout (and hence rapid induction of and recovery from anesthesia) and have a MAC value of about 5%. In the present study we demonstrate that desflurane possesses these characteristics in healthy young volunteers. After a 10-min exposure to desflurane the ratio of alveolar (FA) (determined by end-tidal sampling) to inspired (FI) concentration (FA/FI) was 0.82. Washout was similarly rapid; 10 min after discontinuing administration of desflurane, the alveolar concentration relative to the last concentration during administration of anesthetic (FAO) was 0.11 (FA/FAO). These values are similar to those for nitrous oxide. Volunteers responded to commands an average of 2.7 min after discontinuing anesthetic administration. The values for MAC-awake and MAC (the latter determined by tetanic stimulation of the ulnar nerve using surface electrodes) were 2.42% and 4.58% and the ratio of the former to the latter was 0.53.

Stability of Sevoflurane in Soda Lime

Stability of halogenated volatile anesthetic is important because of the potential toxicity associated with the breakdown products. The authors enclosed 100 ml of gas containing sevoflurane with 100 g of soda lime in a 581-ml flask for periods up to 24 h. The rate of degradation of sevoflurane by soda lime was several-fold greater than previously reported, and the degradation was temperature-dependent. At 22 degrees C, soda lime degraded 6.5% of the sevoflurane per hour. The rate increased by 1.6% per hour per degree rise in temperature, reaching 57.4% degradation per hour at 54 degrees C. In contrast, isoflurane was not degraded by soda lime. Halothane did not degrade at 22 degrees C or 37 degrees C, but did degrade (2.2% per hour) at 54 degrees C.

Naloxone Does Not Antagonize General Anesthesia in the Rat

The administration of naloxone 2, 10, 50, or 250 mg/kg intravenously did not alter halothane requirement (MAC) in Sprague-Dawley rats (12 rats per group). Two rats convulsed when given 50 mg/kg while anesthetized with halothane. In a separate group of awake rats, seven of nine animals convulsed when given naloxone, 100 mg/kg. It is concluded that any effect of naloxone on anesthetic requirement must be small (not significant in our study), and that if an effect exists it is the result of a nonspecific analeptic action of naloxone rather than a specific action at opiate receptors.