Partition coefficients of I-653 in human blood, saline, and olive oil

The purpose of this study was to determine partition coefficients for a new, inhaled anesthetic, I-653. Blood samples were taken from 11 patients scheduled for elective surgery who were ASA physical status I-III and ranged in age from 25 to 76 yr. At 37 degrees C, we found a blood/gas partition coefficient of 0.424 +/- 0.024 (mean +/- SD); a saline/gas partition coefficient of 0.225 +/- 0.002; and an oil/gas partition coefficient of 18.7 +/- 1.1. These values indicate that I-653 will have a minimum alveolar concentration (MAC) required for anesthesia that is four to five times that of isoflurane and that I-653 will produce a rapid induction of and recovery from anesthesia.     

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.     

Halogenation and anesthetic potency

Previous studies have shown that the anesthetic potency of organic compounds increases as a given halogen is replaced with successively larger halogens. These studies often are limited in the accuracy of determination of potency, rarely correlate potency with physical properties, and usually fail to include ether compounds. Because establishing relationships between structure and activity may shed light on anesthetic action, we studied the new anesthetic, I-537 (CHF2-O-CHBr-CF3), relative to two other ether anesthetics, I-653 (CHF2-O-CHF-CF3) and isoflurane (CHF2-O-CHCl-CF3) for both of which MAC and oil/gas partition coefficients are accurately known. The oil/gas partition coefficient of I-537 at 37 degrees C was found to be 245 +/- 6 (mean +/- SD) and the MAC in Sprague-Dawley rats 0.52 +/- 0.07%. Increasing atomic weight of the 1-ethyl halogen (i.e., F in I-653, Cl in isoflurane, and Br in I-537) progressively decreases MAC (increases potency) and increases lipid solubility. Although potency and solubility change by more than 10-fold, the product of MAC and the oil/gas partition coefficient remains essentially constant (120 +/- 11). However, this product is significantly less than that for other inhaled anesthetics, a finding which either challenges the unitary theory of narcosis or suggests that the lipid solvent classically used to model the site of anesthetic action (olive oil) is inappropriate.     

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.     

Epinephrine-induced premature ventricular contractions and changes in arterial blood pressure and heart rate during I-653, isoflurane, and halothane anesthesia in swine

I653 is a new inhalation anesthetic having especially desirable recovery characteristics because of its very low blood and tissue solubility. Investigations of its cardiovascular and electroencephalographic effects have revealed actions similar to those of isoflurane. However, these studies did not evaluate the potential of I653 to predispose the heart to epinephrine-induced arrhythmias. In this investigation, we studied eight domestic swine to compare the effects of I653 with those of other anesthetics on the cardiac arrhythmogenic actions of intravenously infused epinephrine. I653, isoflurane, and halothane each were given, on separate days, at 0.7-0.8 and at 1.1-1.2 MAC. The rate of infusion of epinephrine needed to produce premature ventricular contractions (PVCs) when the animals were anesthetized with I653 (6.9 +/- 0.7 and 6.6 +/- 0.9 micrograms.kg-1.min-1 at 0.8 and 1.2 MAC) did not differ from that during isoflurane anesthesia (5.7 +/- 1.1 and 6.0 +/- 1.0 micrograms.kg-1.min-1 at 0.7 and 1.1 MAC), but was greater than that required during halothane anesthesia (1.3 +/- 0.2 and 1.1 +/- 0.3 micrograms.kg-1.min-1 at 0.7 and 1.1 MAC). Similar mean arterial blood pressures and heart rates resulted from like infusions of epinephrine during I653 and isoflurane anesthesia. PVCs occurred at lesser infusion rates of epinephrine and at lower mean arterial blood pressures and heart rates with halothane than with I653 or isoflurane. Anesthetic concentration, over the range studied, did not alter the infusion rate of epinephrine required to produce arrhythmias with any anesthetic. The authors conclude that I-653 and isoflurane have similar properties with respect to epinephrine-induced arrhythmias and increases in heart rate and arterial blood pressure.     

Partition coefficients for sevoflurane in human blood, saline, and olive oil

The purpose of this study was to determine partition coefficients for a new, rapid-acting inhaled anesthetic, sevoflurane. Blood samples were taken from 19 ASA physical status I-III patients ranging in age from 21 to 77 yr who were scheduled for elective surgery. At 37 degrees C, we found a blood/gas partition coefficient of 0.686 +/- 0.047 (mean +/- SD), a saline/gas partition coefficient of 0.370 +/- 0.016; and an oil/gas partition coefficient of 47.2 +/- 2.7. These values are consistent with the clinical observation that sevoflurane is a potent inhaled anesthetic that produces a rapid induction of and recovery from anesthesia.     

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.     

Studies of the toxicity of I-653, halothane, and isoflurane in enzyme-induced, hypoxic rats

The physical stability and low blood solubility of the new inhaled anesthetic, I-653, imply that this agent produces limited or no toxic effects. To test this possibility, its effects were compared with those of other volatile agents on hepatic, renal, and pulmonary specimens taken from enzyme-induced, hypoxic rats. Male Sprague-Dawley rats were pretreated with phenobarbital and exposed for 1 hr to 12% O2 and no anesthesia (control) or to 1.2 MAC of one of three anesthetics: I-653, isoflurane, or halothane. Liver, kidney, and lung specimens were taken 24 hr after exposure concluded. The livers of all rats given halothane (n = 6) had swelling (20.5 +/- 5.7% of a lobule [mean +/- SD]) and centrilobular necrosis (6.7 +/- 2.1% of a lobule). Isoflurane produced only slight injury (6.7 +/- 3.5% swelling and 1.0 +/- 0.0% necrosis in 3 of 15 rats). No hepatic injury occurred in control rats (n = 20) or in those given I-653 (n = 16). Pulmonary and renal injury were not evident with any agent. Results suggest that I-653 has equivalent or less effect on hepatic, renal, and pulmonary integrity than currently available inhaled anesthetics.     

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.     

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.     

Solubility of I-653, sevoflurane, isoflurane, and halothane in plastics and rubber composing a conventional anesthetic circuit

This study defines some characteristics of a standard anesthetic circuit that may impede anesthetic induction and recovery with I-653, sevoflurane, isoflurane, and halothane. Partition coefficients for anesthetic circuit components (masks, bellows, bags, airways, and circuit tubes) consistently ranked halothane greater than isoflurane greater than sevoflurane greater than I-653, suggesting a reverse order of washin and washout rates for an anesthetic circuit constructed from similar components. Consistent with this prediction, the concentrations of I-653 increased and decreased more rapidly than those of the other agents at any flow rate during washin (0.5, 1, or 2 L/min gas inflow rates) or washout (1, 3, or 5 L/min) in a conventional anesthetic circuit. The rates of change in I-653 concentration closely approximated the maximal possible theoretical rates. Our results suggest that absorption of I-653 by circuit components or soda lime should not hinder induction of or recovery from anesthesia.     

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.     

Cardiovascular safety and actions of high concentrations of I-653 and isoflurane in swine

The ratio of lethal-to-anesthetic concentration can be used to define the margin of safety of an inhaled anesthetic. In mechanically ventilated swine the fatal concentration of I-653, a new inhaled anesthetic, was 23.9 +/- 0.06% (mean +/- SE), and of isoflurane, 6.22 +/- 0.23%. The ratio of fatal anesthetic concentration-to-MAC for I-653 (2.45 +/- 0.11) was less than that determined for isoflurane (3.02 +/- 0.13; P less than 0.01) but relatively greater than that reported previously for other inhaled anesthetics. As with other inhaled anesthetics, the concentration of I-653 causing cardiovascular collapse exceeds that producing apnea, making cardiovascular collapse during spontaneous ventilation unlikely. Mean aortic blood pressure and cardiac output decreased as linear functions of anesthetic concentration. Values for these variables for isoflurane were greater than those for I-653 at concentrations exceeding 1.5 MAC. Heart rate, blood lactate concentration, and base-deficit did not change with anesthetic depth. Mixed venous PO2, mixed venous oxyhemoglobin saturation, and the ratio of oxygen transport to oxygen consumption remained at or above values in conscious swine but decreased similarly with both anesthetics when anesthetic concentration increased to within 0.5 MAC of the fatal concentration. Thus, the latter three variables, reflecting the fraction of delivered oxygen that is consumed, and "mean" tissue PO2 appear to be useful indices of anesthetic concentrations approaching those producing cardiovascular collapse.(ABSTRACT TRUNCATED AT 250 WORDS)     

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。     

Minimum alveolar anesthetic concentration of fluorinated alkanols in rats: relevance to theories of narcosis

The Meyer-Overton hypothesis predicts that the potency of conventional inhaled anesthetics correlates inversely with lipophilicity: minimum alveolar anesthetic concentration (MAC) x the olive oil/gas partition coefficient equals a constant of approximately 1.82 +/- 0.56 atm (mean +/- SD), whereas MAC x the octanol/gas partition coefficient equals a constant of approximately 2.55 +/- 0.65 atm. MAC is the minimum alveolar concentration of anesthetic required to eliminate movement in response to a noxious stimulus in 50% of subjects. Although MAC x the olive oil/gas partition coefficient also equals a constant for normal alkanols from methanol through octanol, the constant (0.156 +/- 0.072 atm) is one-tenth that found for conventional anesthetics, whereas the product for MAC x the octanol/gas partition coefficient (1.72 +/- 1.19) is similar to that for conventional anesthetics. These normal alkanols also have much greater affinities for water (saline/gas partition coefficients equaling 708 [octanol] to 3780 [methanol]) than do conventional anesthetics. In the present study, we examined whether fluorination lowers alkanol saline/gas partition coefficients (i.e., decreases polarity) while sustaining or increasing lipid/gas partition coefficients, and whether alkanols with lower saline/gas partition coefficients had products of MAC x olive oil or octanol/gas partition coefficients that approached or exceeded those of conventional anesthetics. Fluorination decreased saline/gas partition coefficients to as low as 0.60 +/- 0.08 (CF3[CF2]6CH2OH) and, as hypothesized, increased the product of MAC x the olive oil or octanol/gas partition coefficients to values equaling or exceeding those found for conventional anesthetics. We conclude that the greater potency of many alkanols (greater than would be predicted from conventional inhaled anesthetics and the Meyer-Overton hypothesis) is associated with their greater polarity. Implications: Inhaled anesthetic potency correlates with lipophilicity, but potency of common alkanols is greater than their lipophilicity indicates, in part because alkanols have a greater hydrophilicity--i.e., a greater polarity.     

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.     

Some characteristics of an exceptionally potent inhaled anesthetic: thiomethoxyflurane

The authors sought to test whether a deviation existed for the correlation between anesthetic potency and the oil/gas partition coefficient at an extreme of lipid solubility. For thiomethoxyflurane, the sulfur analog of methoxyflurane, the oil/gas partition coefficient was 7230 +/- 50 SEM, and MAC (minimum alveolar concentration of thiomethoxyflurane required for anesthesia) in 4 dogs was 0.035 +/- 0.008 percent of 1 atm. This agrees with the potency predicted by the lipid solubility, although thiomethoxyflurane is 7 1/2 times more potent than methoxyflurane, to date the most potent available anesthetic. Thiomethoxyflurane water/gas and blood/gas partition coefficients were 5.4 +/- 0.3 and 68.1 +/- 1.5, respectively. The latter coefficient accords with the prolonged recovery associated with this agent. Renal and hepatic blood chemistries measured on the 1st and 7th days following anesthesia showed only small changes from preanesthetic values.     

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.     

MAC of I-653 in beagle dogs and New Zealand white rabbits

The minimum alveolar concentration (MAC) of I-653 was determined in six beagle dogs and four New Zealand white rabbits. The MAC values (+/- SD) were 7.2 +/- 1.0 atm % for dogs and 8.9 +/- 0.3 atm % for rabbits. Comparison of these results with published MAC values for other anesthetics indicate that I-653 is one-third to one-eighth as potent as currently available volatile anesthetics (enflurane, isoflurane, and halothane). From these data and previous reports, human MAC was projected to be approximately 5.1 atm %.     

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.