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.     

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.     

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.     

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.     

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.     

A second-generation blood substitute (perflubron emulsion) increases the blood solubility of modern volatile anesthetics in vitro

Perfluorocarbon-based emulsions increase the blood solubility of isoflurane, enflurane, and halothane, with a maximal effect reported for the less soluble isoflurane. Current volatile anesthetics are less soluble and may be more affected by this phenomenon. Perflubron (Oxygent(TM)) is a perfluorocarbon-based emulsion in late-stage clinical testing in surgical patients for use as a temporary oxygen carrier. We tested the hypothesis that perflubron increases the solubility of isoflurane, sevoflurane, and desflurane, as reflected by their blood/gas partition coefficient (lambda(Bl:g)). Fresh whole-blood samples were drawn from eight volunteers and mixed with perflubron to obtain concentrations of 1.2%, 1.8%, and 3.6% by volume (equivalent to in vivo doses of 1.8 to 5.4 g/kg, which represent up to twice the intended clinical dose range). By using the double-extraction method, we demonstrated increased lambda(Bl:g) for isoflurane, sevoflurane, and desflurane. However, the solubility in blood does not really change, because volatile anesthetics are actually partitioning into perflubron. Increasing the amount of emulsion in the blood consequently increases the amount of gas carried, as reflected by the measured linear correlation between the lambda(Bl:g) values of all three volatile anesthetics and perflubron doses. Even though the increase ranges from 0.9 (desflurane) to 2.6 (sevoflurane) times the normal value, the apparent lack of clinical implications in current trials with perflubron may trigger further in vivo experiments. IMPLICATIONS:Perflubron increases the in vitro solubility of volatile anesthetics when present in the blood at clinically relevant concentrations. Volatile anesthetics actually partition into the emulsion, but the solubility in the blood does not change. Further studies are needed to assess whether perflubron will affect the pharmacokinetics of volatile anesthetics in vivo.     

Age and solubility of volatile anesthetics in blood

The more rapid rate of rise of alveolar anesthetic partial pressure in children compared with adults may be explained in part by an increasing solubility of volatile anesthetics in blood with age. To investigate this possibility, the authors measured the blood-gas partition coefficients of isoflurane, enflurane, halothane, and methoxyflurane in four groups of fasting subjects: 10 full-term newborns (at delivery), 11 children (3-7 years old), 11 adults (20-40 years old), and 10 elderly adults (75-85 years old). The blood-gas partition coefficients were greatest in adults: isoflurane 1.46, enflurane 2.07, halothane 2.65, and methoxyflurane 16.0; and least in newborns: 1.19, 1.78, 2.14, 13.3, respectively. The blood-gas partition coefficients in children (1.28, 1.78, 2.39, 15.0, respectively), which were intermediate between those in newborns (P less than 0.005) and those in adults (P less than 0.005), were not significantly different from those in elderly adults (1.29, 1.79, 2.41, 15.0, respectively). The blood-gas partition coefficients of both isoflurane and enflurane correlated directly with the serum albumin and triglyceride concentrations; that of halothane correlated directly with the serum cholesterol, albumin, triglyceride, and globulin concentrations; and that of methoxyflurane correlated directly with the serum cholesterol, albumin, and globulin concentrations. The authors conclude that age significantly affects blood-gas partition coefficients, and the lower blood-gas partition coefficients in children explain in part the more rapid rise of alveolar anesthetic partial pressure in this age group.     

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 partial pressure of isoflurane or halothane does not affect their solubility in rabbit blood or brain or human brain: inhaled anesthetics obey Henry's Law

We tested the possibility that the solubility of halothane or isoflurane in rabbit blood or human or rabbit brain does not obey Henry's Law. We measured the blood/gas and brain/gas partition coefficients for both anesthetics at approximately 1 MAC and at 0.01 MAC at 37 degrees C. The partition coefficients determined at the high vs low partial pressures did not differ. We conclude that the solution of isoflurane and halothane in blood and brain obeys Henry's Law.     

Osmolarity determines the solubility of anesthetics in aqueous solutions at 37 degrees C

The authors determined whether they could predict accurately the solubility of anesthetics in aqueous solutions at 37 degrees C, knowing the osmolarity and the pH of the solution and the solute composition. The partition coefficients of the four volatile anesthetics, isoflurane, enflurane, halothane, and methoxyflurane, were determined concurrently at 37 degrees C between air and aqueous solutions containing sodium chloride, dextrose, mannitol, or heparin. The osmolarities of these solutions ranged from 0 to 7,000 mOsm/l. The partition coefficients decreased linearly with increasing osmolarity when plotted on a semilogarithmic scale. The effect of osmolarity on the partition coefficient of the alkane anesthetic, halothane, was 20% less (P less than 0.001) than the effect of osmolarity on the partition coefficients of the three methyl-ethyl ether anesthetics, isoflurane, enflurane, and methoxyflurane. The solubility of anesthetics in aqueous solutions did not depend on either the molecular structure of the solute or the pH of the solution. The solubility of volatile anesthetics in aqueous solutions at 37 degrees C is inversely and predictably dependent on the osmolarity of the solutions.     

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。     

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.     

The effects of sevoflurane, halothane, enflurane, and isoflurane on hepatic blood flow and oxygenation in chronically instrumented greyhound dogs.

Inhalational anesthetics produce differential effects on hepatic blood flow and oxygenation that may impact hepatocellular function and drug clearance. In this investigation, the effects of sevoflurane on hepatic blood flow and oxygenation were compared with those of enflurane, halothane, and isoflurane in ten chronically instrumented greyhound dogs. Each dog randomly received enflurane, halothane, isoflurane, and sevoflurane, each at 1.0, 1.5, and 2.0 MAC concentrations. Mean arterial blood pressure and cardiac output decreased in a dose-dependent fashion during all four anesthetics studied. Heart rate increased compared to control during enflurane, isoflurane, and sevoflurane anesthesia and did not change during halothane anesthesia. Hepatic arterial blood flow and portal venous blood flow were measured by chronically implanted electromagnetic flow probes. Hepatic O2 delivery and consumption were calculated after hepatic arterial, portal venous, and hepatic venous blood gas analysis. Hepatic arterial blood flow was maintained with sevoflurane and isoflurane. Halothane and enflurane reduced hepatic arterial blood flow during all anesthetic levels compared to control (P less than 0.05), with marked reductions occurring with 1.5 and 2.0 MAC halothane concomitant with an increase in hepatic arterial vascular resistance. Portal venous blood flow was reduced with isoflurane and sevoflurane at 1.5 and 2.0 MAC. A somewhat greater reduction in portal venous blood flow occurred during 2.0 MAC sevoflurane (P less than 0.05 compared to control and 1.0 MAC values for sevoflurane). Enflurane reduced portal venous blood flow at 1.0, 1.5, and 2.0 MAC compared to control. Halothane produced the greatest reduction in portal venous blood flow (P less than 0.05 compared to sevoflurane).(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

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.     

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.     

Comparative effects of halothane, isoflurane, and sevoflurane on the liver with hepatic artery ligation in the beagle.

Recently, there has been increasing interest in the alterations in splanchnic and hepatic circulation and preservation of hepatic oxygenation and function during anesthesia and surgery. However, the effects of volatile anesthetics under a condition of marginal hepatic oxygen supply are not well understood. Using a crossover design, we therefore studied the effects of equianesthetic concentrations (1.5 MAC) of halothane, isoflurane, and sevoflurane on hepatic oxygenation and function in nine beagles in which the hepatic artery had been ligated. Portal blood flow was measured by an electro-magnetic flow meter. Hepatic function was assessed by indocyanine green elimination kinetics. While cardiac output and mean arterial pressure were greater during halothane anesthesia than during isoflurane and sevoflurane anesthesia, portal blood flow and hepatic oxygen supply were significantly less during halothane and sevoflurane anesthesia than during isoflurane anesthesia. With regard to hepatic oxygen uptake, there was a significant difference between halothane (2.7 +/- 1.2 ml.min-1 x 100 g-1) and sevoflurane (3.7 +/- 2.0 ml.min-1 x 100 g-1; P less than 0.05). Consequently, the hepatic oxygen supply/uptake ratio and the hemoglobin oxygen saturation and oxygen partial pressure in hepatic venous blood during sevoflurane anesthesia were significantly less than they were with the other anesthetics. Indocyanine green clearance was better preserved during sevoflurane anesthesia (39.7 +/- 12.0 ml.min-1) than during halothane anesthesia (30.9 +/- 8.4 ml.min-1; P less than 0.05). We conclude that sevoflurane is accompanied by a smaller oxygen supply/uptake ratio than is halothane and isoflurane, while it preserves hepatic function.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

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.