Edmond I. Eger

Inhaled anesthetics and immobility: Mechanisms, mysteries, and minimum alveolar anesthetic concentration

Studies using molecular modeling, genetic engineering, neurophysiology/pharmacology, and whole animals have advanced our understanding of where and how inhaled anesthetics act to produce immobility (minimum alveolar anesthetic concentration; MAC) by actions on the spinal cord. Numerous ligand- and voltage-gated channels might plausibly mediate MAC, and specific animo acid sites in certain receptors present likely candidates for mediation. However, in vivo studies to date suggest that several channels or receptors may not be mediators (e.g., &ggr;-aminobutyric acid A, acetylcholine, potassium, 5-hydroxytryptamine-3, opioids, and &agr;2-adrenergic), whereas other receptors/channels (e.g., glycine, N-methyl-d-aspartate, and sodium) remain credible candidates.

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.

Age, minimum alveolar anesthetic concentration, and minimum alveolar anesthetic concentration-awake.

Two defining effects of inhaled anesthetics (immobility in the face of noxious stimulation, and absence of memory) correlate with the end-tidal concentrations of the anesthetics. Such defining effects are characterized as MAC (the concentration producing immobility in 50% of patients subjected to a noxious stimulus) and MAC-Awake (the concentration suppressing appropriate response to command in 50% of patients; memory is usually lost at MAC-Awake). If the concentrations are monitored and corrected for the effects of age and temperature, the concentrations may be displayed as multiples of MAC for a standard age, usually 40 yr. This article provides an algorithm that might be used to produce such a display, including provision of an estimate of the effect of nitrous oxide.

Cerebral Blood Flow In Man at High Altitude: Role of Cerebrospinal Fluid pH in Normalization of Flow in Chronic Hypocapnia

Cerebral blood flow was determined by an N2O method in 7 normal men at sea level and after 6 to 12 hr and 3 to 5 days at 3810 m altitude. An infrared N2O analyzer was used both to measure end-tidal PN2O so that it could be kept constant for 15 min and to determine blood N2O, for which a simple gas extraction method was devised. In addition, acute changes in cerebral blood flow were estimated from cerebral A-V O2 differences. Control cerebral blood flow was 43 ml per 100 g per min; it increased 24% at 6 to 12 hours and 13% at 3 to 5 days at altitude. After 3 to 5 days, pH of cerebrospinal fluid was normal (7.31) in four subjects while arterial blood pH was alkaline (7.47); arterial blood Pco2 had fallen from 41 to 30 mm Hg. Acute correction of hypoxia restored cerebral blood flow to control while mean Pco2 was still 31 mm Hg. Addition of O2 and CO2 to inspired air raised cerebral blood flow 34% above control at Pao2 = 170, Paco2 = 35 mm Hg. Values obtained by extrapolation suggest that if arterial Pco2 was raised to control (41 mm Hg), cerebral blood flow would have been 60% above control. Cerebral blood flow thus appears to return to normal at the prevailing Paco2, probably because the pH of cerebrospinal fluid and of the extracellular fluid of cerebral vascular smooth muscle is kept normal by active transport across the ‘blood-brain’ barrier. It is postulated that an ion-impermeable barrier separates the blood stream from extracellular fluid of the smooth muscle of cerebral arterioles.

The Relationship between Age and Halothane Requirement in Man

The minimum alveolar concentration (MAC) values for halothane in eight age groups were determined. MAC was found to be highest in newborns and lowest in the elderly. These changes in anesthetic requirement with age parallel changes in cerebral oxygen consumption, cerebral blood flow and neuronal density.

Solubility of I-653, sevoflurane, isoflurane, and halothane in human tissues.

Tissue/blood partition coefficients of anesthetics are important indicators of the rate of tissue wash-in and wash-out, and wash-in and wash-out are determinants of the rates of induction of and recovery from anesthesia. In the present study of human tissues, we found that the tissue/blood partition coefficients (for brain, heart, liver, kidney, muscle, and fat) for the new anesthetic I-653 were smaller than those for isoflurane, sevoflurane, and halothane (anesthetics listed in order of increasing tissue/blood partition coefficients). For example, the respective brain/blood partition coefficients were 1.29 +/- 0.05 (mean +/- SD); 1.57 +/- 0.10; 1.70 +/- 0.09; and 1.94 +/- 0.17. This indicates that induction of and recovery from anesthesia with I-653 should be more rapid than with the other agents. The finding of a lower tissue/blood partition coefficient for I-653 parallels the previous finding of a lower blood/gas partition coefficient.

Effects of Isoflurane and Nitrous Oxide in Subanesthetic Concentrations on Memory and Responsiveness in Volunteers

Awareness, defined as conscious memory during anesthesia, has been a problem in anesthesia practice. To determine the effect of isoflurane and nitrous oxide (N2O) on memory, 17 healthy adult volunteers were randomly assigned to receive isoflurane or N2O and received the alternate agent 1-2 weeks later. Each volunteer was studied at four end-tidal concentrations of each agent, consecutively 0.15, 0.3, 0.45, and 0.15 times the minimum alveolar concentration (MAC) for isoflurane or 0.3, 0.45, 0.6, and 0.3 times MAC for N2O. After 15-min equilibration at each end-tidal concentration, volunteers were tested for voluntary response to command and were presented with verbal information to be recalled after anesthesia. Volunteers were interviewed on the day after the study and tested for conscious and unconscious memory of the information presented during anesthetic administration. MAC-awake (the end-tidal concentration preventing voluntary response in 50% of volunteers) was 0.38 (0.35-0.42) times MAC for isoflurane and 0.64 (0.61-0.68) MAC for N2O (means, 95% confidence limits), indicating isoflurane to be more potent than N2O in suppressing voluntary response (P = .0001). Memory data were analyzed in 12 volunteers who completed the study and in whom the allocation of information to be recalled was counterbalanced among agents and concentrations of agents. Memory was decreased by increasing concentrations of both agents. Conscious memory of the information presented during anesthetic administration was prevented by 0.45 MAC isoflurane but not completely prevented by 0.6 MAC N2O. Unconscious memory (defined as memory of information without conscious recognition) occurred during administration of both agents and was prevented by 0.45 MAC isoflurane but not by 0.6 MAC N2O. Isoflurane was more potent in suppressing memory than MAC-equivalent concentrations of N2O. Using models of the relationship between dose of agent and suppression of memory, a dose of both agents was estimated that suppressed memory by 50% (ED50). The ED50 was 0.20 MAC for isoflurane (95% confidence intervals, 0.15-0.25), and 0.50 MAC for N2O (95% confidence intervals 0.43-0.55). We conclude that isoflurane and N2O suppress memory in a dose-dependent manner, and that isoflurane is more potent in preventing memory and voluntary response to command than MAC-equivalent concentrations of N2O.

Biotransformation of halothane, enflurane, isoflurane, and desflurane to trifluoroacetylated liver proteins: association between protein acylation and hepatic injury.

In susceptible patients, halothane, enflurane, isoflurane, and desflurane can produce severe hepatic injury by an immune response directed against reactive anesthetic metabolites covalently bound to hepatic proteins.The incidence of hepatotoxicity appears to directly correlate with anesthetic metabolism catalyzed by cytochrome P450 2E1 to trifluoroacetylated hepatic proteins. In the present study, we examined whether the extent of acylation of hepatic proteins in rats by halothane, enflurane, isoflurane, and desflurane correlated with reported relative rates of metabolism. After pretreatment with the P450 2E1 inducer isoniazid, five groups of 10 rats breathed 1.25 minimum alveolar anesthetic concentration (MAC) of halothane, enflurane, isoflurane, or desflurane in oxygen, or oxygen alone, each for 8 h. Immunochemical analysis of livers harvested 18 h after anesthetic exposure showed tissue acylation (greatest to least) after exposure to halothane, enflurane, or isoflurane. Reactivity was not different between isoflurane as compared to desflurane or oxygen alone. An enzyme-linked immunosorbent assay showed halothane reactivity was significantly greater than that of enflurane, isoflurane, desflurane, or oxygen, and that enflurane reactivity was significantly greater than desflurane or oxygen. Sera from patients with a clinical diagnosis of halothane hepatitis showed antibody reactivity against hepatic proteins from rats exposed to halothane or enflurane. No reactivity was detected in rats exposed to isoflurane, desflurane, or oxygen alone. These results indicate that production of acylated proteins may be an important mediator of anesthetic-induced hepatotoxicity. (Anesth Analg 1997;84:173-8)

Effect of Nitrous Oxide and of Narcotic Premedication on the Alveolar Concentration of Halothane Required for Anesthesia

Sixty-eight surgical patients were divided into three groups and anesthetized with either halothane and ogygen, halo thane-oxygen following narcotic premedication, or halothanc-oxygen and 70 per cent nitrous oxide. The minimum alveolar concentration of halothane required to prevent movement in response to surgical incision was 0.74 per cent. Addition of narcotic premedication decreased this value to 0.69 per cent and addition of nitrous oxide (without narcotic premedication) allowed a reduction in the alveolar halothane concentration to 0.29 per cent. Advantages of administering nitrous oxide with halothane are: (1) decreased cost of anesthesia, (2) increased speed of recovery, and (3) possible decreased hepatotoxicity. We believe that these advantages outweigh the disadvantage of decreased percentage of oxygen administered. The narcotic premedication resulted in only a slight decrease in required alveolar halothane concentration. We believe this decrease is insignificant relative to the possible cardiovascular depression that may accompany narcotic premedication.

HAZARDS OF NITROUS OXIDE ANESTHESIA IN BOWEL OBSTRUCTION AND PNEUMOTHORAX.

An enclosed gas-filled space in the body will expand if gas within it is less soluble than the gas respired. Blood arriving at such a space can discharge a greater quantity of the soluble gas into the space than that blood can take up, assuming the tension gradient of each gas is equal. This results from the greater capacity of blood for the more soluble agent. When air was placed in the intestinal lumens of 3 dogs and nitrous oxide respired, intestinal gas volume increased 75 to 100 per cent in two hours and 100–200 per cent in four hours. Similarly, 300 ml. of air placed in the pleural space doubled in volume in 10 minutes, tripled in 45 minutes, and in one dog quadrupled in two hours. Nitrous oxide concentrations rose concomitantly in both the intestinal and pleural spaces. With cither gas in the intestine or in the pleural space, no volume changes were seen when the animal respired oxygen and halothane alone. These results suggest that nitrous oxide is relatively contraindicated in cases of intestinal obstruction or pneumothorax.