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.     

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 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.     

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.     

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.     

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.     

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.     

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.     

Mechanistic Aspects of Carbon Monoxide Formation from Volatile Anesthetics

Background: Desflurane, enflurane and isoflurane can be degraded to carbon monoxide (CO) by carbon dioxide absorbents, whereas sevoflurane and halothane form negligible amounts of CO. Carbon monoxide formation is greater with drier absorbent, and with barium hydroxide, than with soda lime. The mechanism, role of absorbent composition and water, and anesthetic structures determining CO formation are unknown. This investigation examined sequential steps in anesthetic degradation to CO.

Methods: Carbon monoxide formation from anesthetics and desiccated barium hydroxide lime or soda lime was determined at equimole from deuterium-substituted anesthetics was also quantified. Proton abstraction from anesthetics by strong base was determined by deuterium isotope exchange. A reactive chemical intermediate was trapped and identified by gas chromatography-mass spectrometry. The source of the oxygen in CO was identified by18 O incorporation.

Results: Desflurane, enflurane, and isoflurane (difluoromethylethyl ethers), but not sevoflurane (monofluoromethyl ether), methoxyflurane (methyl-ethyl ether), or halothane (alkane) were degraded to CO. The amount of CO formed was desflurane >or= to enflurane > isoflurane at equiMAC and enflurane > desflurane > isoflurane at equimole concentrations. Proton abstraction from the difluoromethoxy carbon was greater with potassium than with sodium hydroxide, but unmeasurable with barium hydroxide. Carbon monoxide formation was correlated (r = 0.95-1.00) with difluoromethoxy (enflurane > desflurane > isoflurane >or= to methoxyflurane = sevoflurane = 0) but not ethyl carbon proton abstraction. Deuterium substitution on enflurane and desflurane diminished CO formation. Chemical trapping showed formation of a difluorocarbene intermediate from enflurane and desflurane. Incorporation of H218 O in barium hydroxide lime resulted in C18 O formation from unlabeled enflurane and desflurane.     

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.     

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.     

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.     

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.     

Carbon monoxide production from desflurane, enflurane, halothane, isoflurane, and sevoflurane with dry soda lime.

BACKGROUND: Previous studies in which volatile anesthetics were exposed to small amounts of dry soda lime, generally controlled at or close to ambient temperatures, have demonstrated a large carbon monoxide (CO) production from desflurane and enflurane, less from isoflurane, and none from halothane and sevoflurane. However, there is a report of increased CO hemoglobin in children who had been induced with sevoflurane that had passed through dry soda lime. Because this clinical report appears to be inconsistent with existing laboratory work, the authors investigated CO production from volatile anesthetics more realistically simulating conditions in clinical absorbers. METHODS: Each agent, 2.5 or 5% in 2 l/min oxygen, were passed for 2 h through a Dr?ger absorber canister (bottom to top) filled with dried soda lime (Dr?gersorb 800). CO concentrations were continuously measured at the absorber outlet. CO production was calculated. Experiments were performed in ambient air (19-20 degrees C). The absorbent temperature was not controlled. RESULTS: Carbon monoxide production peaked initially and was highest with desflurane (507 +/- 70, 656 +/- 59 ml CO), followed by enflurane (460 +/- 41, 475 +/- 99 ml CO), isoflurane (176 +/- 2.8, 227 +/- 21 ml CO), sevoflurane (34 +/- 1, 104 +/- 4 ml CO), and halothane (22 +/- 3, 20 +/- 1 ml CO) (mean +/- SD at 2.5 and 5%, respectively). CONCLUSIONS: The absorbent temperature increased with all anesthetics but was highest for sevoflurane. The reported magnitude of CO formation from desflurane, enflurane, and isoflurane was confirmed. In contrast, a smaller but significant CO formation from sevoflurane was found, which may account for the CO hemoglobin concentrations reported in infants. With all agents, CO formation appears to be self-limited.     

The efficacy and safety of intravenous emulsified isoflurane in rats

Although direct IV injection of liquid volatile anesthetics is usually lethal, anesthesia using emulsified halothane and isoflurane without adverse effects has been safely induced in animals. We identified the safe concentration of emulsified volatile anesthetic preparations and determined the dose-response relationship of IV emulsified isoflurane and propofol in rats. Liquid/gas partition coefficients of desflurane, sevoflurane, isoflurane, enflurane, and halothane in 20% and 30% Intralipid were measured and used to calculate their saturated concentrations. Unsaturated emulsified isoflurane was prepared by adding liquid isoflurane to 30% Intralipid. The loss of forepaw righting reflex was taken as induction of anesthesia, and disappearance of electrocardiogram was taken as death. The median effective induction dose (ED50) and median lethal dose (LD50) of emulsified isoflurane were 0.072 and 0.216 mL/kg liquid isoflurane, respectively. The ED50 and LD50 of propofol were 5.89 mg/kg and 18.19 mg/kg, respectively. Time to return of forepaw righting reflex after injection of emulsified isoflurane (38 +/- 18 s) was significantly shorter than with propofol (101 +/- 62 s; P < 0.05). Anesthesia was successfully induced in rats by IV emulsified isoflurane with a comparable safety index and certain safety factor as propofol. Recovery of anesthesia after IV emulsified isoflurane was faster than with propofol.     

Interaction of Volatile Anesthetics with Human Kv Channels in Relation to Clinical Concentrations

Background: Recent evidence shows that inhibition of human Kv3 channels by intravenous anesthetics occurs at clinical concentrations. The effects of volatile anesthetics on these human ion channels are unknown. This study was designed to establish whether minimum alveolar concentrations (MAC) of halothane, enflurane, isoflurane, and desflurane exhibit effects on Kv3 channels. To obtain an indication whether these findings may be specific to Kv3 channels, the effects of enflurane and isoflurane on human Kv1.1 channels were also investigated.

Methods: Kv3 channels natively expressed in SH-SY5Y cells and Kv1.1 channels expressed in HEK293 cells were measured with the whole cell patch clamp technique by standard protocols. Concentrations of volatile anesthetics were determined by gas chromatography.

Results: Halothane, enflurane, isoflurane, and desflurane reversibly inhibited Kv3 channels in a concentration-dependent manner. Concentrations at half-maximal effect (IC50 values) ranged between 1,800 and 4,600 [mu]m. Hill coefficients were between 1.7 and 2.5. IC50 values for inhibition of Kv1.1 channels were 2,800 and 5,200 [mu]m, and Hill coefficients were 3.9 and 5.6 for enflurane and isoflurane, respectively.     

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.     

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.     

Carbon Monoxide Production from Desflurane, Enflurane, Halothane, Isoflurane, and Sevoflurane with Dry Soda Lime

Background : Previous studies in which volatile anesthetics were exposed to small amounts of dry soda lime, generally controlled at or close to ambient temperatures, have demonstrated a large carbon monoxide (CO) production from desflurane and enflurane, less from isoflurane, and none from halothane and sevoflurane. However, there is a report of increased CO hemoglobin in children who had been induced with sevoflurane that had passed through dry soda lime. Because this clinical report appears to be inconsistent with existing laboratory work, the authors investigated CO production from volatile anesthetics more realistically simulating conditions in clinical absorbers.

Methods : Each agent, 2.5 or 5% in 2 l/min oxygen, were passed for 2 h through a Drager absorber canister (bottom to top) filled with dried soda lime (Dragersorb 800). CO concentrations were continuously measured at the absorber outlet. CO production was calculated. Experiments were performed in ambient air (19-20[degrees]C). The absorbent temperature was not controlled.

Results : Carbon monoxide production peaked initially and was highest with desflurane (507 +/- 70, 656 +/- 59 ml CO), followed by enflurane (460 +/- 41, 475 +/- 99 ml CO), isoflurane (176 +/- 2.8, 227 +/- 21 ml CO), sevoflurane (34 +/- 1, 104 +/- 4 ml CO), and halothane (22 +/- 3, 20 +/- 1 ml CO) (mean +/- SD at 2.5 and 5%, respectively).