The Effect of Temperature on Solubility of Volatile Anesthetics in Human Tissues<?xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" /> Jian-Xin Zhou, M.D., Jin Liu M.D. Department of Anesthesiology, Fuwai Hospital and Cardiovascular Institute,Chinese Academy of Medical Sciences and Peking Union Medical College.
Beijing, 100037, P. R. China.
Supported by a grant from the National Research Foundation of Nature Sciences, Beijing, P. R.
China and a grant from the Research Foundation of National Education, Beijing, P. R. China. Presented in part at the annual meeting of the ASA, Orlando, FL,U.S.A., 20/10/1998. Running Head: Hypothermia and Anesthetics Solubility in Human Tissues Volatile anesthetics are often used during hypothermic condition, and tissue solubility of volatile anesthetic is an important determinant for the wash-in and wash-out of the anesthetics in tissue. Tissue/gas partition coefficients during hypothermia have implications for understanding the pharmacokinetics of volatile anesthetics at hypothermic condition.
Hypothermia often occurs during surgical anesthesia, and certain surgical procedures, such as complex cardiac repairs and giant intracerebral aneurysms may require profound hypothermia. Tissue solubility of volatile anesthetics influences the rate of tissue anesthetic wash-in and wash-out. Han and Helrich (1) measured the effects of temperature on halothane’s solubility in brain, but the relationship between temperature and tissue/gas partition coefficient for volatile anesthetics has not been systemically studied. Furthermore, data for tissue solubility in young adults are limited. No such data exist for the two newest agents, sevoflurane and desflurane. In present study, we measured the tissue/gas partition coefficients for desflurane, sevoflurane, enflurane, isoflurane, and halothane in the brains, hearts, livers, muscles, and fat of young adults, and determined the effect of temperature on solubility. |
Methods<?xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" /> Approval was given by the Committee of Scientific Research in Fuwai Hospital, and informed consents were obtained from the relatives of tissue donors. Brain, heart, liver, muscle (quadriceps femoris), and subcutaneous fat tissue specimens from 10 deceased adult male (27±8 yr., cause of death was traffic accident) were obtained within 6 hours of death, but not all tissues were obtained from all patients. We prepared tissue specimens within 3 hr. of tissue collection and within 10 hr. of death. Fascial structures and visible fat were removed from muscle. Left-ventricular muscle was collected from heart after discarding pericardial and endocardial membranes. The capsule, large vessels, and ducts of liver were removed. We stripped arachnoid and pial membranes from brain. Vascular structures were removed from fat. Each tissue specimen was sliced into small cubes and the total volume of tissue was measured by saline volume displacement. Each specimen was then homogenized (12000 rpm, 3 min.) in saline which volume was 2 to 3 times (6-8 times for fat) the volume of specimen. The homogenate was filtered through a 4-mm2 stainless steel mesh to remove extraneous fascia. The net volume of tissue presented in the homogenates was determined as the difference between the volume of the tissue specimen and the volume of extraneous fascia (also measured by saline volume displacement). The percentage of the volume of this discarded extraneous fascia in total tissue volume was 1% to 6%, which represented different fascia content in different tissues.
Immediately after tissue preparation, homogenate/gas partition coefficients were determined as follows. A 20-ml gas-tight glass syringe (50-ml syringe was used for fat) capped with a three-way stopcock, whose internal volume of 4-ml and 20-ml scale had been calibrated precisely by water displacement, was sealed by coating the plunger with a thin layer silicone grease. The tightness and non-absorbent of anesthetics of these grease-sealed syringes was tested before the study: the concentrations of anesthetic vapors in the syringes decreased by no more than 2% over 8 hours. Approximately 7 ml of homogenate was added to syringe and anesthetic gas mixture (containing 0.48% desflurane, 0.27% sevoflurane, and 0.41% enflurane; or 0.44% isoflurane and 0.6% halothane) was added to 18-ml mark, and the stopcock was closed. The syringe was shaken vigorously and immersed in a waterbath at one of six temperatures (37℃, 33℃, 29℃, 25℃, 21℃, and 17℃). Every 15 min for 2 hr, the syringe was shaken vigorously for 5-10 seconds. After the third shaking, the plunger of the syringe was withdrawn to the 20-ml scale with stopcock closed, thereby creating a slightly negative pressure. The stopcock was then opened briefly, allowing entry of and equilibration with ambient pressure. After this 2 hr period (the first equilibration period), the concentrations of anesthetic in the gas phase of the syringe were analyzed by gas chromatography. All gas in the syringe was expelled, and the homogenate in the syringe was expelled to the 4-ml mark. Then vapor?free air was drawn to 18-ml scale. The syringe was shaken vigorously and immersed in the waterbath at the same temperature as in the first equilibration period. The second equilibration followed the same sequence of shaking, volume adjustment to 20 ml, and timing as in the first equilibration. At the end of second equilibration period, the concentrations of anesthetics in gas phase were analyzed by gas chromatography.
The total amount of anesthetic (ml in liquid plus gas phase) at the end of the second equilibration equals that in the liquid phase retained in syringe at the end of the first equilibration. This relationship can be expressed as:
C2×VG+CH2×VH=CH1×VH (Equation 1)
where C2 is the anesthetic concentration in the gas phase of the syringe at the end of the second equilibration; VG and VH are the gas volume and homogenate volume retained in the syringe for the second equilibration, respectively; CH1 and CH2 are the anesthetic concentrations in homogenate samples at the end of the first and second equilibration, respectively. Homogenate/gas partition coefficient (λH/G) is defined as the ratio of anesthetic concentration (vol%) in homogenate phase to that in gas phase (vol%), e.g., CH1= λH/G×C1 and CH2= λH/G×C2. Substituting these into equation 1 yields:
C2×VG+λH/G×C2×VH=λH/G×C1×VH (Equation 2)
Rearranging equation 2 yields:
λH/G =( VG/VH) ×[C2/(C1-C2)] (Equation 3)
where C1 and C2 were the anesthetic concentration in the gas phase of the syringe at the end of the first and second equilibration period, respectively; VG and VH were the gas volume and the homogenate volume in the syringe for the second equilibration period, respectively. Equation 3 was used to calculate λH/G.
Anesthetic concentrations were measured with a GOW-MAC 580 gas chromatography, equipped with a 6-meter-long stainless steel column (0.32 cm in internal diameter) packed with chromosorb-P 60/80 Mesh maintained at 75℃. A 10 ml/min nitrogen carrier stream flow was delivered through the column to a flame ionization detector supplied by hydrogen at 35 ml/min and by air at 300 ml/min. Output from gas chromatography was collected by a TAI-SSC922 integrator, and peak areas were calculated automatically. Under these conditions, the peaks for desflurane, sevoflurane and enflurane were separated completely, and the peaks for isoflurane and halothane were separated completely.
Primary and secondary (compressed gas tank) standards were used to calibrate the gas chromatography. Primary standards were produced by injection of aliquots of each volatile anesthetics (from a syringe) into a glass flask of known volume. To ensure that no desflurane (given the high saturated vapor pressure) was lost when producing the primary and secondary standards, liquid desflurane and the syringe were kept at 4 ℃ in a refrigerator before use. Liquid desflurane was drawn into the cool syringe at 4 ℃ in the refrigerator and was transferred into the flask or tank immediately. The primary standards (glass flask) were used to calibrate the secondary standards and the secondary standards (tank) were used to calibrate the gas chromatography during each day. All R2 for the linear regression between concentration of anesthetics and peak area of gas chromatography output exceeded 0.9995. The regression equation was used to convert peak area to agent concentration, and peak areas were proportional to concentrations over the entire range of the concentrations tested.
The tissue/gas partition coefficient (λT/G) at each temperature was calculated as follows:
λT/G=λH/G＋(VS/VT)×(λH/G－λS/G)
where VS and VT were the volume of saline and tissue in the homogenate, respectively. λS/G was saline/gas partition coefficient which was taken from our previous study (2).
We measured tissue/gas partition coefficient for each tissue from a given patient at six temperatures simultaneously. For each given tissue, we averaged tissue/gas partition coefficients from six patients.
Tissue/gas partition coefficients of each tissue at 37℃ were compared across agent using analysis of variance and Student-Newman-Keuls method of multiple comparisons. Regression was performed to examine whether the tissue/gas partition coefficients of the five anesthetics for each tissue correlated with temperature. A P value of less than 0.05 was considered statistically significant. Results For each given tissue, the order of tissue/gas partition coefficient was halothane >enflurane >isoflurane >sevoflurane >desflurane. All tissue/gas partition coefficients at 37℃ were significantly different across agents (P<0.05), except that the liver/gas partition coefficients for isoflurane and enflurane did not differ (Table 1).
As temperature decreased, the logarithm of tissue/gas partition coefficients of five anesthetics increased linearly (Table 1). Slopes of the regression lines were also shown in Table 1, and their absolute values represented the percentage increase in solubility per ℃ decrease. |
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