Absence of abundant saturable binding sites for halothane or isoflurane in rabbit brain: inhaled anesthetics obey Henry's law

We tested whether the existence of saturable binding sites for anesthetics causes the solubility of halothane or isoflurane in rabbit brain not to obey Henry's law. For each anesthetic, we measured brain/gas partition coefficients (paired samples) at approximately 0.05 MAC and 5 MAC at 38.5 degrees C. In addition, for halothane, brain/gas partition coefficients (paired samples) were determined at 0.05 MAC and 2 MAC. The values for halothane at 0.05 MAC, 2 MAC, and 5 MAC did not differ; values for isoflurane at 0.05 MAC and 5 MAC did not differ. Over the range of anesthetic partial pressures studied, no evidence for saturable binding was found. We conclude that the solubility of halothane and isoflurane in brain is independent of the partial pressure applied; inhaled anesthetics obey Henry's law.     

妊娠对大鼠吸入性全麻药血/气分配系数和组织/气分配系数的影响

目的 观察妊娠对大鼠吸人性全麻药血，气分配系数及组织，气分配系数的影响。方法 健康成年（3月龄）雌性妊娠（妊娠18—22d）和非妊娠SD大鼠各10只，分别为妊娠组和非妊娠组。腹腔注射戊巴比妥钠40mg／kg麻醉，经腹主动脉抽血用于测血，气分配系数，放血处死后，分别取心、肝、肾及脑组织并制成匀浆，采用注射器顶空二次平衡法经气相色谱仪测定七氟醚、异氟醚和氟烷的血，气分配系数及组织，气分配系数。结果与非妊娠组相比，妊娠组氟烷的血，气分配系数和脑，气分配系数降低（P〈0．05），七氟醚、异氟醚的血，气分配系数、肝，气分配系数、肾，气分配系数、心，气分配系数差异无统计学意义（P〉0．05）。结论 妊娠降低大鼠氟烷的血，气配系数和脑，气分配系数，但不影响七氟醚和异氟醚的血，气分配系数和组织，气分配系数。     

The blood/gas solubilities of sevoflurane, isoflurane, halothane, and serum constituent concentrations in neonates and adults

To determine the effect of prematurity on the solubility of volatile anesthetics in blood, the authors measured the blood/gas partition coefficients of sevoflurane, isoflurane, and halothane and the serum concentrations of albumin, globulin, cholesterol, and triglycerides in umbilical venous blood from ten preterm and eight full-term neonates and in venous blood from eight fasting adult volunteers. The authors found that the blood/gas partition coefficient of sevoflurane did not differ significantly among the three age groups. The partition coefficients of isoflurane and halothane in preterm neonates did not differ significantly from those in full-term neonates. However, the partition coefficients of both anesthetics in neonates were significantly less than those in adults. The blood/gas partition coefficients of the three volatile anesthetics in preterm neonates did not change significantly with gestational age. The blood/gas partition coefficients of sevoflurane, isoflurane and halothane for all three age groups combined correlated only with the serum concentration of cholesterol. The authors conclude that the blood/gas partition coefficients of isoflurane, halothane, and sevoflurane in preterm neonates are similar to those in full term neonates and that gestational age does not significantly affect the blood/gas solubility.     

Age and the solubility of volatile anesthetics in ovine tissues

To determine the effect of age on the solubility of volatile anesthetics in tissues, we measured the blood/gas and tissue/gas partition coefficients of isoflurane, enflurane, halothane, and methoxyflurane in vitro at 37 degrees C in newborn lambs and postpartum adult sheep. The tissue specimens examined were brain, heart, liver, kidney, muscle, and fat. Hematocrit and serum concentrations of albumin, globulin, cholesterol, and triglycerides were measured. The blood/gas partition coefficients, hematocrit, and the serum concentrations of albumin, globulin, cholesterol, and triglycerides in the newborn lambs did not differ from those in the adult sheep. The tissue/blood partition coefficients [the ratio of (tissue/gas)/(blood/gas)] in newborn lambs were 28% [mean value for the four anesthetics] less than those in the adults. The tissue/blood partition coefficients for enflurane and methoxyflurane in newborn tissues were significantly less (P less than 0.05) than those for halothane and isoflurane. We conclude that the blood/gas partition coefficients in sheep do not change significantly with age, and that the time required for equilibration of volatile anesthetics (particularly enflurane and methoxyflurane) in newborn tissues is probably less than in adult sheep.     

The effect of temperature on solubility of volatile anesthetics in human tissues.

Hypothermia often occurs during surgery, a factor influencing anesthetic pharmacokinetics through its influence on solubility. Information on the tissue solubility of volatile anesthetics under hypothermia is limited. The present study supplies this information for the solubility of volatile anesthetics in human tissues. Tissue specimens of brain, heart, liver, muscle, and fat were obtained from 10 postmortem males (27 +/- 8 yr). Tissue/gas partition coefficients of desflurane, sevoflurane, enflurane, isoflurane and halothane were measured at 37 degrees C, 33 degrees C, 29 degrees C, 25 degrees C, 21 degrees C, and 17 degrees C. For each given tissue, the order of tissue/gas partition coefficient was halothane >enflurane >isoflurane >sevoflurane >desflurane. Tissue/gas partition coefficients at 37 degrees C differed significantly (P < 0.05) across drugs, except that liver/gas partition coefficients for isoflurane and enflurane did not differ. The logarithm of all tissue/gas partition coefficients increased linearly with decreasing temperature (P < 0.05). In conclusion, hypothermia increases tissue/gas partition coefficients of volatile anesthetics. The increases are proportional to those for blood/gas partition coefficients, and therefore tissue/blood partition coefficients will not change during hypothermic conditions. Implications: Volatile anesthetics are often used during hypothermic conditions, and tissue solubility of volatile anesthetics is an important determinant for the wash-in and washout of the anesthetics in tissue. Tissue/gas partition coefficients during hypothermia have implications for understanding the pharmacokinetics of volatile anesthetics at hypothermic conditions.     

Pharmacokinetics of desflurane, sevoflurane, isoflurane, and halothane in pigs

We tested the prediction that the alveolar washin and washout, tissue time constants, and pulmonary recovery (volume of agent recovered during washout relative to the volume taken up during washin) of desflurane, sevoflurane, isoflurane, and halothane would be defined primarily by their respective solubilities in blood, by their solubilities in tissues, and by their metabolism. We concurrently administered approximately one-third the MAC of each of these anesthetics to five young female swine and determined (separately) their solubilities in pig blood and tissues. The blood/gas partition coefficient of desflurane (0.35 +/- 0.02) was significantly smaller (P less than 0.01) than that of sevoflurane (0.45 +/- 0.02), isoflurane (0.94 +/- 0.05), and halothane (2.54 +/- 0.21). Tissue/blood partition coefficients of desflurane and halothane were smaller than those for the other two anesthetics (P less than 0.05) for all tissue groups. As predicted from their blood solubilities, the order of washin and washout was desflurane, sevoflurane, isoflurane, and halothane (most to least rapid). As predicted from tissue solubilities, the tissue time constants for desflurane were smaller than those for sevoflurane, isoflurane, and halothane. Recovery (normalized to that of isoflurane) of the volume of anesthetic taken up was significantly greater (P less than 0.05) for desflurane (93% +/- 7% [mean +/- SD]) than for halothane (77% +/- 6%), was not different from that of isoflurane (100%), but was less than that for sevoflurane (111% +/- 17%). The lower value for halothane is consistent with its known metabolism, but the lower (than sevoflurane) value for desflurane is at variance with other presently available data for their respective biodegradations.     

The effect of Fluosol-DA on induction of inhalation anesthesia

The liquid/gas partition coefficients of three inhalation anesthetics in Fluosol-DA 20% (Fluosol), a perfluorocarbon blood substitute, were determined in vitro. The high values found (6.68 for halothane, 7.54 for enflurane, and 7.20 for isoflurane) suggested that induction with these agents would be prolonged in patients treated with Fluosol. Induction of isoflurane anesthesia (as a representative agent) at constant inspired concentration was studied in five mongrel dogs before and after replacement of about 25% of each animal's blood volume with Fluosol. Inspired and end-tidal isoflurane and carbon dioxide concentrations were recorded breath by breath, together with cardiac output. There was a significant delay in rise of end-tidal isoflurane concentration after Fluosol infusion. However, because cardiac output could not be held constant during each experiment, and because cardiac output also affects the rate of rise of alveolar anesthetic concentration, a physiological computer model was used to compare the isoflurane blood/gas partition coefficients that must have existed to account for the observed end-tidal levels before and after Fluosol infusion, while taking cardiac output variation into account. Post-Fluosol blood/gas partition coefficients calculated in this way (2.59 +/- 0.51 SD) were significantly different (P less than 0.001) from pre-Fluosol levels (1.45 +/- 0.15 SD) and were not significantly different from post-Fluosol partition coefficients calculated by volume-weighted averaging (2.91 +/- 0.36 SD). This indicates that the delay observed was attributable in large part to increased solubility of isoflurane in blood after addition of Fluosol. Based on their similar liquid/gas partition coefficients in Fluosol, similar delays should occur with halothane and enflurane.     

Effect of age on the solubility of volatile anesthetics in human tissues

To determine the effect of age on the solubility of volatile anesthetics in human tissues, the authors measured the solubilities of isoflurane, enflurane, halothane, and methoxyflurane in vitro at 37 degrees C in 35 postmortem human tissue specimens. Specimens were taken from neonates, and young (20-50 yr), middle-aged (50-70 yr), and elderly adults (greater than 70 yr). Brain/gas, heart/gas, and liver/gas partition coefficients for all four anesthetics increased significantly (P less than 0.05) between birth and adulthood, although brain/gas partition coefficients in young adults tended to be higher than those in middle-aged and elderly adults. Heart/gas and liver/gas partition coefficients tended to increase with aging. Muscle/gas partition coefficients for the four anesthetics increased linearly with age. Fat/gas partition coefficients did not change significantly with age. Tissue/blood solubilities for the four anesthetics were of the same order of magnitude for a given tissue and age group. Tissue/blood solubilities for enflurane were 30% lower than those for isoflurane in the same tissue and age group. In summary: the solubility of volatile anesthetics in human tissues increases with age; the lower solubility of anesthetics in neonates partially explains the more rapid increase of alveolar and tissue anesthetic partial pressures in neonates; despite the higher blood solubility of enflurane, its lower tissue solubility may explain a rate of recovery comparable with that of isoflurane.     

Comparison of the effects of volatile anesthetics on brain glucose metabolism in rats

The objective of this investigation was to compare the effects of the commonly used volatile anesthetics on concentrations of plasma and cerebral glucose and cerebral intermediary metabolites. Fasted male Long-Evans rats were anesthetized with a volatile anesthetic and, after tracheostomy and paralysis, were mechanically ventilated. Each of three groups received one MAC concentration of anesthesia with halothane, enflurane, or isoflurane. At the end of 60-75 min of anesthesia, blood was sampled for arterial blood gas and plasma glucose analysis, and the brain was rapidly sampled and frozen for analysis of energy metabolites. Physiologic variables were maintained as follows: PaCO2 30-40 mmHg, pHa 7.20-7.40, PaO2 greater than 60 mmHg, MAP greater than 60 mmHg, and rectal temperature 37.5-38.5 degrees C. Mean plasma glucose concentrations in the three groups were as follows (muMol/ml +/- SEM): halothane, 7.45 /- .62; enflurane, 6.95 +/- .22; isoflurane, 10.11 +/- 1.00. Mean brain glucose concentrations in the three groups were (muMol/gm wet weight): halothane, 2.04 +/- .20; enflurane, 2.07 +/- .26; isoflurane, 3.04 +/- .31. Plasma and brain glucose levels were significantly increased in the isoflurane group compared to the other two groups (P less than .05) with no differences occurring in the brain/plasma glucose ratio among the three groups. No differences were present between groups in brain lactate, pyruvate, fructose diphosphate, malate, alpha-ketoglutarate, phosphocreatine, or adenine nucleotides. Thus, at one MAC concentration, major differences between volatile anesthetics on brain energy availability are not present, although isoflurane raised cerebral glucose levels.     

The effect of nitrous oxide on cortical cerebral blood flow during anesthesia with halothane and isoflurane, with and without morphine, in the rabbit

The effect of nitrous oxide on cortical cerebral blood flow (CBF) was examined during a varying background anesthetic state in the New Zealand White rabbit. Seventy percent nitrous oxide resulted in significant and similar increases in CBF during anesthesia with both 0.5 MAC of halothane (44 +/- 14 to 63 +/- 17 ml.100 g-1.min-1) (mean +/- SD) and anesthesia with isoflurane (34 +/- 9 to 41 +/- 11 ml.100 g-1.min-1). During anesthesia with 1.0 MAC halothane or isoflurane, N2O also increased CBF, but the increments (halothane, 73 +/- 34 to 111 +/- 54 ml.100 g-1 min-1; isoflurane 34 +/- 13 to 69 +/- 34 ml.100 g-1.min-1) were significantly greater than those observed at 0.5 MAC. When 0.5 MAC halothane or isoflurane was supplemented with morphine (10 mg/kg followed by an infusion of 2 mg.kg-1.min-1), the CBF effect of N2O was not significantly different from that observed with 0.5 MAC alone. It was concluded that, in the rabbit, the effects of N2O on cortical CBF vary with the background anesthetic state and that the increase in CBF caused by N2O becomes greater as the end-tidal concentration of halothane or isoflurane increases from 0.5 to 1.0 MAC. Morphine, when added to 0.5 MAC of halothane or isoflurane, does not alter the effect of 70% N2O on cortical CBF.     

Effects of anaesthesia and surgery on the solubility of volatile anaesthetics in blood

To determine the effects of anaesthesia and surgery on the solubility of volatile anaesthetics in blood, we measured the blood/gas partition coefficients of enflurane, halothane, isoflurane, and methoxyflurane in vitro in blood obtained from six healthy unpremedicated adults at three different times during isoflurane anaesthesia: awake; 20 minutes after induction of anaesthesia, but before surgical incision; and, 90 minutes after surgical incision. The blood/gas partition coefficients of the four volatile anaesthetics decreased significantly after induction of anaesthesia and after surgical incision (p less than 0.05). Values for haematocrit and the serum concentrations of albumin, globulin, and cholesterol decreased parallel to the decrease in blood/gas partition coefficients.     

Solubility of desflurane (I-653), sevoflurane, isoflurane, and halothane in human blood

The blood/gas partition coefficients for the new volatile anesthetic agent desflurane (I-653), sevoflurane, isoflurane, and halothane were determined, simultaneously, in 8 human volunteers to compare the solubilities of these agents in blood. The blood/gas partition coefficient for desflurane [0.49 +/- 0.03 (mean +/- SD)] was smallest, followed by sevoflurane (0.62 +/- 0.04), isoflurane (1.27 +/- 0.06), and halothane (2.46 +/- 0.09). Differences among the anesthetic agents were significant (P less than 0.001). The results of this study confirm that among these agents the solubility of desflurane in human blood is the smallest. The results suggest that the washin and washout of desflurane will be more rapid than that of sevoflurane, isoflurane, and halothane, and the washin and washout of sevoflurane will be more rapid than that of isoflurane and halothane.     

Solubility of volatile anesthetics in plasma substitutes,albumin, intravenous fat emulsions,perfluorochemical emulsion,and aqueous solutions

Using the gas chromatographic headspace sampling technique, we determined the solubility of volatile anesthetics (halothane, enflurane, isoflurane, and sevoflurane) in plasma substitutes, albumin solution, intravenous fat emulsions, perfluorochemical FC-43 emulsion, and aqueous solutions at 37°C. The order of magnitude of λ value (liquid/gas partition coefficients) was halothane >enflurane>isoflurane> sevoflurane in all the parenteral infusion fluids except the perfluorochemical emulsion (FC-43). The FC-43/gas partition coefficients of the volatile anesthetics were almost the same at 5.5. The partition coefficients were affected by the osmolarity of solutions, hydrophobicity, and the structure of solutes. Also, the blood/gas partition coefficients in intravenous fat emulsions and FC-43 were calculated. It is suggested that fluid therapy, especially with intravenous fat emulsions or FC-43, may influence the blood/gas partition coefficients of anesthetics, and affect the induction of anesthesia.     

Relative amnesic potency of five inhalational anesthetics follows the Meyer-Overton rule

BACKGROUND: Doses of volatile anesthetics around 0.3 minimum alveolar concentration (MAC) inhibit learning. However, threshold amnesic doses and relative potencies between agents are not well established. The authors determined amnesic potency in rats for four common volatiles and nitrous oxide. METHODS: After institutional review board approval, adult Sprague-Dawley rats received inhibitory avoidance training during exposure to either air or various subanesthetic doses of desflurane, sevoflurane, isoflurane, halothane, or nitrous oxide (4-21 rats/dose). Animals were trained to remain in a starting "safe" compartment for 100 consecutive seconds by administering a foot shock (0.3 mA) each time they entered an adjacent "shock" compartment. Memory was assessed at 24 h. Anesthetic effects on pain thresholds were separately determined. RESULTS: Learning: Only relatively higher doses of sevoflurane, halothane, and desflurane increased the number of shocks required for task acquisition. Memory: Significantly decreased retention performance (P < 0.05) was found at relatively low inspired concentrations of 0.2% isoflurane, 0.3% sevoflurane and halothane, 0.44% desflurane, and 20% nitrous oxide. Amnesic potency was nitrous oxide >/= desflurane > sevoflurane >/= isoflurane > halothane, (rank-ordered ED50 values as %MAC). Amnesic potency correlated with oil:gas partition coefficients (r = -0.956, P < 0.007). Halothane, only at 0.08%, enhanced retention (P < 0.01). All agents were analgesic at higher doses. CONCLUSIONS: Amnesic potency differs between agents; nitrous oxide is most potent and halothane is least potent relative to MAC. The amnesic threshold ranges from 0.06 to 0.3 MAC. The correlation between potency and oil:gas partition coefficients suggests a fundamental role for hydrophobicity in mediating amnesia, similar to its association with MAC. Some agents (e.g., halothane) may enhance aversive memory retention at doses typically encountered during emergence.     

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 I-653, 14.2 +/- 8.1 min with sevoflurane, 23.2 +/- 7.6 min with isoflurane, and 47.2 +/- 4.7 min with halothane.     

The intracranial pressure effects of isoflurane and halothane administered following cryogenic brain injury in rabbits

The intracranial pressure (ICP) responses to administration of either halothane or isoflurane were compared in New Zealand white rabbits following a standardized cryogenic brain injury. Animals were tracheally intubated and paralyzed, and background anesthesia was maintained with morphine sulfate and nitrous oxide. Following injury and attainment of an elevated and stable ICP, animals were divided into four groups. Animals in groups I and III were maintained normocapnic throughout the experiment and administered 1 MAC halothane or isoflurane, respectively. Group II and IV animals were made hypocapnic (PaCO2 = 20 mmHg) prior to the administration of either 1 MAC halothane or isoflurane, respectively. Monitored variables were mean arterial blood pressure, ICP (ventriculostomy), end-tidal (ET) CO2, ET volatile anesthetic, the electroencephalogram, temperature, and arterial blood gases. Prior to producing the lesion, ICP was approximately 5 mmHg in all animals with no differences among groups. Sixty to ninety minutes after injury, ICP increased significantly to approximately 20 mmHg in all animals. Introduction of either halothane or isoflurane was associated with significant increases in ICP in all groups to approximately 30 mmHg. These data suggest that further significant increases in ICP may occur following introduction of either halothane or isoflurane in the presence of acute brain injury and elevated ICP. Furthermore, these ICP increases may not be altered by the prior establishment of hypocapnia.     

ALCOHOL INCREASES THE SOLUBILITY OF ANAESTHETICS IN THE LIVER

Liver/gas partition coefficients for isoflurane, enflurane,halothane and methoxyflurane increased two-fold in rats killed16 h after a single injection of 15% ethanol 7 g kg^–1.In contrast blood/gas and brain/gas partition coefficients didnot change. Chronic (21 days) ingestion of ethanol increasedliver/gas partition coefficients four-fold, although this increasewas largely attributable to nutritional changes rather thanto a direct effect of ethanol. Only minimal changes (usuallynot more than 15%) occurred in blood/gas and brain/gas partitioncoefficients. On account of this effect of ethanol on anaestheticsolubility in the liver, the ingestion of ethanol may modestlyincrease uptake of anaesthetic during the induction osf anaesthesia. ^*Present address: 57–59 Raftopoulou Street, Athens 405/1,Greece.     

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.     

Solubility of volatile anesthetics in bovine white matter, cortical gray matter, thalamus, hippocampus, and hypothalamic area

Although known for whole brain, values are lacking for solubilities of modern volatile anesthetics in specific brain regions. Some regions should differ from others (e.g., gray matter versus white matter) because they differ in lipid content and because potent inhaled anesthetics are lipophilic. In the present report, we examined this issue in bovine brain, finding that white matter/gas partition coefficients are 1.6 (desflurane) to 2.4 (halothane) times larger than gray matter/gas partition coefficients, with values for isoflurane and sevoflurane lying between these at 1.9. Values for thalamus/gas, hypothalamic area/gas, and hippocampal/gas partition coefficients lie between those for gray and white matter. These data may be useful in defining the parts of the brain involved with return to consciousness during recovery from anesthesia.     

Hematocrit and the solubility of volatile anesthetics in blood

To clarify the effect of hematocrit on the solubility of volatile anesthetics in blood, we measured the blood-gas partition coefficients of isoflurane, enflurane, halothane, and methoxyflurane concurrently at 37 degrees C in blood from four adults. We measured the blood-gas partition coefficients in the plasma (hematocrit 0%) and packed red cell fractions (hematocrit 80%), and in four mixtures of these two fractions (hematocrits 10%, 25%, 40%, and 55%). The mixtures were prepared by recombining appropriate amounts of plasma and packed red cells from each adult. As hematocrit increased, the blood-gas partition coefficient of isoflurane decreased linearly (P less than 0.01), whereas that of enflurane increased linearly (P less than 0.05). The partition coefficient for isoflurane in plasma was 20% greater than that in packed red cells, whereas the partition coefficient for enflurane in plasma was 10% less than that in packed cells. The blood-gas partition coefficients of halothane and methoxyflurane did not change significantly between measurements in plasma and packed red cells. We conclude that hematocrit exerts a statistically significant effect on the blood-gas partition coefficient of isoflurane and enflurane.