Michael J. Halsey

The cardiovascular effects of a new inhalation anesthetic, Forane, in human volunteers at constant arterial carbon dioxide tension.

The cardiovascular effects of Forane, a new inhalation anesthetic, were examined in seven un-medicated volunteers under conditions of constant arterial carbon dioxide tension and body temperature. Comparison of results during anesthesia with awake values demonstrated maintenance of myocardial function but progressive vasodilatation as anesthesia deepened. No significant changes in the cardiac output, ballistocardiogram I-J wave amplitude, ejection time, mean rate of ventricular ejection, or pre-ejection period occurred with onset or deepening of anesthesia. Arterial pressure decreased, as did total peripheral resistance. Increased muscle and skin blood flow and forearm venous compliance suggested that the loss of resistance was due in part to dilatation of vessels in the skin and muscles. Cardiac output was maintained by an increased heart rate which compensated for the decreased stroke volume. Comparisons of results during the first and fifth hours of anesthesia demonstrated only minor changes with increased duration of anesthesia. These included further increases in forearm blood flow and an increase in base excess.

Polyhalogenated and perfluorinated compounds that disobey the meyer-overton hypothesis

Fourteen polyhalogenated, completely halogenated (perhalogenated), or perfluorinated compounds were examined for their anesthetic effects in rats. Anesthetic potency or minimum alveolar anesthetic concentration (MAC) was quantified using response/nonresponse to electrical stimulation of the tail as the end-point. For compounds that produced excitable behavior, and/or did not produce anesthesia when given alone, we determined MAC by additivity studies with desflurane. Nine of 14 compounds had measurable MAC values with products of MAC x oil/gas partition coefficient ranging from 3.7 to 24.8 atm. Because these products exceed that for conventional inhaled anesthetics (1.8 atm), they demonstrate a deviation from the Meyer-Overton hypothesis. Five compounds (CF3CCIFCF3, CF3CCIFCCIFCF3, perfluorocyclobutane, 1,2-dichloroperfluorocyclobutane, and 1,2-dimethylperfluorocyclobutane) had no anesthetic effect when given alone, had excitatory effects when given alone, and tended to increase the MAC for desflurane. These five compounds had no anesthetic properties in spite of their abilities to dissolve in lipids and tissues, to penetrate into the central nervous system, and to be administered at high enough partial pressures so that they should have an anesthetic effect as predicted by the Meyer-Overton hypothesis. Such compounds will be useful in identifying and differentiating anesthetic sites and mechanisms of action. Any physiologic or biophysical/biochemical change produced by conventional anesthetics and deemed important for the anesthetic state should not be produced by nonanesthetics.

What solvent best represents the site of action of inhaled anesthetics in humans, rats, and dogs ?

The correlation between the potency of inhaled anesthetics and their solubility in a hydrophobic phase provides an opportunity to define better the characteristics of the anesthetic site of action. The correlation implies that inhaled anesthetics act in a hydrophobic site and that the solvent used has properties representative of the true site of anesthetic action. We sought to characterize this site more accurately by testing for the solvent that provided the best correlation for a diverse group of anesthetics. We determined the solubility of halothane, enflurane, cyclopropane, fluroxene, isoflurane, sevoflurane, and desflurane in benzene, olive oil, Intralipid, n-octanol, and lecithin. We used established MAC values for rats, dogs, and humans for all but sevoflurane and desflurane, for which we determined MAC in rats to be 2.80% ± 0.24% (mean ± standard deviation) and 7.71% ± 0.65%, respectively. Lecithin gave the lowest coefficient of variation for the product of potency (MAC) × solubility, but the difference was statistically significant only for a comparison of the products for lecithin and olive oil. The values for lecithin were within the range of values produced by biological variation. More important, the correlation of log MAC and log solubility had an average slope of unity (−1.04 ± 0.07) for lecithin, but a slope differing from unity for benzene (−0.82 ± 0.05) and olive oil (−0.87 ± 0.05). We conclude that lecithin is probably more representative of the site of action of these anesthetics than the other solvents.

Hypothesis: Inhaled Anesthetics Produce Immobility and Amnesia by Different Mechanisms at Different Sites

Recent evidence supplies new insights regarding the two universal effects of inhaled anesthetics: 1) immobility in response to a noxious stimulus and 2) amnesia. We hypothesize that these two effects result from actions at separate molecular and anatomic sites and that they are produced by different mechanisms. We propose that inhaled anesthetics cause immobility in response to noxious stimuli by an action in the spinal cord at an interface between polar and nonpolar regions. Such a site might be an interfacial region adjacent to membranes or proteins. In contrast, we propose that production of amnesia occurs at a supraspinal site and occurs in a nonpolar environment. An example of such a nonpolar site could be the interior of a phospholipid bilayer or a hydrophobic pocket within a protein.

Minimum alveolar concentrations of noble gases, nitrogen, and sulfur hexafluoride in rats: helium and neon as nonimmobilizers (nonanesthetics)

We assessed the anesthetic properties of helium and neon at hyperbaric pressures by testing their capacity to decrease anesthetic requirement for desflurane using electrical stimulation of the tail as the anesthetic endpoint (i.e., the minimum alveolar anesthetic concentration [MAC]) in rats. Partial pressures of helium or neon near those predicted to produce anesthesia by the Meyer-Overton hypothesis (approximately 80-90 atm), tended to increase desflurane MAC, and these partial pressures of helium and neon produced convulsions when administered alone. In contrast, the noble gases argon, krypton, and xenon were anesthetic with mean MAC values of (+/- SD) of 27.0 +/- 2.6, 7.31 +/- 0.54, and 1.61 +/- 0.17 atm, respectively. Because the lethal partial pressures of nitrogen and sulfur hexafluoride overlapped their anesthetic partial pressures, MAC values were determined for these gases by additivity studies with desflurane. Nitrogen and sulfur hexafluoride MAC values were estimated to be 110 and 14.6 atm, respectively. Of the gases with anesthetic properties, nitrogen deviated the most from the Meyer-Overton hypothesis. Implications: It has been thought that the high pressures of helium and neon that might be needed to produce anesthesia antagonize their anesthetic properties (pressure reversal of anesthesia). We propose an alternative explanation: like other compounds with a low affinity to water, helium and neon are intrinsically without anesthetic effect. (Anesth Analg 1998;87:419-24)

The Ventilatory Effects of Forane, a New Inhaled Anesthetic

The ventilatory effects of Forane were studied in ten volunteers and compared with values obtained in eight volunteers anesthetized with halothane. Paco2 averaged 60 torr with both 1.9 per cent alveolar Forane (approximately 1.45 X MAC) and 1.6 per cent halothane (1.9 X MAC). The slopes of the CO2 response curves were depressed to 30 ± 6 per cent (Mean ± SE) of awake control values by 1.28 per cent Forane (approximately 1.0 X MAC) and to 45 ± 7 per cent of controls with 1.05 per cent halothane (1.25 X MAC). Therefore, when equivalent anesthetic doses are considered, less Forane than halothane was needed to increase Paco2 and depress the slope of the CO2 response curve. In contrast to halothane, Forane in increasing concentrations did not cause progressive increases in respiratory frequency. At equal multiples of MAC, Forane produces more profound respiratory depression than halothane, and this depression results from a unique failure of respiratory frequency to increase with increasing depth of anesthesia.

Molecular Properties of the “ideal” Inhaled Anesthetic: Studies of Fluorinated Methanes, Ethanes, Propanes, and Butanes

We examined 35 unfluorinated, partially fluorinated, and perfluorinated methanes, ethanes, propanes, and butanes to define those molecular properties that best correlated with optimum solubility (low) and potency (high). Limited additional data were obtained on longer-chained alkanes. Using standard techniques, we assessed anesthetic potency (minimum alveolar anesthetic concentration [MAC] in rats); vapor pressure; stability in soda lime; and solubility in saline, human blood, and oil. If nonflammability, stability, low solubility in blood, clinically useful vapor pressures, and potency permitting delivery of high concentrations of oxygen are essential components of an anesthetic that might supplant those presently available, our data indicate that such a drug would have three or four carbon atoms with single or dual hydrogenation of two carbons, especially terminal carbons. We conclude that: 1) smaller and larger molecules and lesser hydrogenation provide insufficient potency; 2) high vapor pressures of smaller molecules do not permit the use of variable bypass vaporizers; 3) greater hydrogenation enhances flammability, and complete hydrogenation decreases potency; 4) internal hydrogenation decreases stability; and 5) greater hydrogenation increases blood solubility.

Comparative Toxicities of Halothane, Isoflurane, and Diethyl Ether at Subanesthetic Concentrations in Laboratory Animals

Effects of 35-day exposures to subanesthetic concentrations of halothane, isoflurane, and diethyl ether were measured in mice, rats, and guinea pigs which were in a phase of rapid body growth. Halothane produced a greater decrement in weight gain and a greater incidence of hepatic degenerative changes than isoflurane or diethyl ether despite its administration at lower anesthetic concentrations. Isoflurane results were intermediate between those of halothane and diethyl ether. No consistent injury to any organ other than the liver was found.

A cutoff in potency exists in the perfluoroalkanes.

Anesthetic potencies (minimum alveolar anesthetic concentration [MAC]) of perfluoroalkanes from perfluoromethane to perfluorooctane were assessed in male rats to determine whether a cutoff in anesthetic effect (i.e., an absence of any anesthetic effect) exists for the larger compounds in this series. Although hyperbaric measurements suggested a MAC of 38.9 +/- 6 atm (mean +/- SD) for CF4, this pressure was nearly identical to the lethal pressure of 41.1 +/- 5.8 atm. Hyperbaric studies of C2F6 caused death without causing anesthesia, the lethal pressure being 23.8 +/- 2.6 atm. Results from studies of additivity with desflurane suggested that the MAC of CF4 was 66.5 +/- 13.4 atm at an average CF4 test partial pressure of 17.7 +/- 4.0 atm (i.e., 17.7 atm of CF4 decreased the MAC of desflurane by 26.6%). Studies of additivity with desflurane, isoflurane, or halothane did not reveal an anesthetic effect of C2F6 at a pressure of 7.2 +/- 0.4 atm, or of larger perfluoroalkanes near to or at their saturated vapor pressures. We conclude that a cutoff in anesthetic potency for perfluoroalkanes exists between perfluoromethane and perfluoroethane.

THE CARDIOVASCULAR AND RESPIRATORY EFFECTS OF ISOFLURANE-NITROUS OXIDE ANAESTHESIA

RéSUMéNous avons étudié les effets cardio-respiratoires de l’anesthésie à l’isoflurane (Forane) associé à un mélange de Protoxyde-Oxygène à 70 pour cent. Cette étude fut réalisée chez huit sujets volontaires, en bonne santé, en respiration contrôlée (PaCO2 35-45 torr) et en respiration spontanée. Nos résultats furent comparés à ceux rapportés dans d’auties études effectuées chez des volontaires avec usage d’isoflurane-oxygène.Sous respiration contrôlee, la pression artérielle moyenne était plus élevée de 10 à 25 pour cent chez les malades recevant du Protoxyde. Sous anesthésie profonde ( 2 MAC environ ) on retrouvait une pression moyenne de 72.5 torr dans le groupe avec usage de Protoxyde, alors qu’un chiffre moyen de 46 torr était obtenu avec usage d’Isoflurane-Oxygene.Tout comme chez les sujets endormis à llsoflurane-oxygène, nous avons observé chez nos sujets un bon maintien de la contractilité myocardique et du débit cardiaque, ceci à tous les niveaux d’anesthésie utilisés, et l’on n’a pas observé d’acidose métabolique.Le débit sanguin musculaire était de deux à quatre fois plus élevé qu’avant I’anesthésie.Des différences cardiovasculaires dans le même sens ont été observées chez les malades en respiration spontanée.Cependant, la présence de Protoxyde d’azote n’a pas modifié la dépression respiratoire observée avec l’usage d’isoflurane-oxygène, à une profondeur de 1.5 MAC, en respiration spontanée, les PaCO2 moyens observés étaient de 58± 3 torr. avec Protoxyde et de 58± 1.4 sans Protoxyde.