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Effects of pregnancy on the solubility of halogenated volatile anaesthetics in rat blood and tissues.

Pregnancy is associated with many physiological changes that may affect the pharmacological profile of drugs given to the mother. Several studies have shown a decreased maternal minimum alveolar concentration (MAC) for inhalational agents during pregnancy (1-3). The dynamic distribution of any drug within the body is determined largely by its solubility in the various body parts. Knowledge of these solubilities is a prerequisite for understanding drug uptake and distribution, and hence the rational use of that drug. To date, little information is available concerning the solubility of volatile anaesthetics during pregnancy. Therefore, the purpose of this study in rats was to determine blood/gas, heart/gas, liver/gas, kidney/gas and brain/gas partition coefficients for halothane, sevoflurane and isoflurane and to evaluate the effects of pregnancy on the solubility of the halogenated volatile anaesthetics.

MATERIALS AND METHODS

Approval was given by the Committee of Scientific Research and the Institutional Animal Care and Use Committee of Sichuan University. Ten pregnant adult Sprague Dawley (SD) rats at 18 to 22 days' gestation and 10 non-pregnant adult female SD rats were exsanguinated by bleeding from the femoral artery under pentobarbitone anaesthesia. Tissue samples from the brain, liver, kidney and heart (ventricle) were obtained, washed three times with sterile 0.9% saline and stored at 4[degrees]C. After the capsule and fascia were carefully removed, each tissue specimen was sliced into small cubes and the total volume of tissue was measured by saline volume displacement. Each specimen was then homogenised (12,000 rpm, 35 minutes) in saline (DY89-1, XinZhi Technology Ltd Co., Ningbo, China). The volume of saline was five to 10 times the volume of the specimen. The homogenate was filtered through a 4 [mm.sup.2] 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) (4).

Saline/gas and homogenate/gas partition coefficients ([[lambda].sub.S/G] and [[lambda].sub.H/G]) were determined by a method of two-stage headspace equilibration by gas chromatography (4). Twenty millilitre gas-tight glass syringes capped with three-way stopcocks were precisely calibrated by water displacement to internal volumes of 4 ml and 20 ml (including the stopcock) and then sealed by coating the plunger with a thin layer of silicone grease. The tightness and non-absorbency of anaesthetics in these grease-sealed syringes were tested before the study. The concentration of anaesthetic vapour in the syringes decreased by no more than 2% over eight hours. Approximately 7 ml of saline or homogenate was added to the syringe and anaesthetic gas mixture (containing 5% halothane, 2.5% sevoflurane and 5% isoflurane) to the 18 ml mark and the stopcock was closed. The syringe was shaken vigorously and immersed in a water bath at 37[degrees]C. After one hour, the plunger of the syringe was withdrawn to the 20 ml mark with the stopcock closed, thereby creating a slightly negative pressure. The stopcock was then opened briefly, allowing entry of room air and equilibration with ambient pressure. After a two-hour period (the first equilibration period), peak areas of anaesthetics in the gas phase of the syringe were analysed by gas chromatography. All gas in the syringe was expelled, and the homogenate in the syringe was expelled to the 4 ml mark. Then vapour-free air was drawn to the 18 ml mark. The syringe was shaken vigorously and immersed in the water bath at the same temperature as for the first equilibration period. The second equilibration followed the same shaking, volume adjustment to 20 ml and timing as per the first equilibration. At the end of the second equilibration period, peak areas of anaesthetics in gas phase were analysed by gas chromatography (4) (Figure 1).

[FIGURE 1 OMITTED]

Primary and secondary (compressed gas tank) standards were used to calibrate the gas chromatography. 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 [R.sup.2] values for the linear regression between concentration of anaesthetics and peak area of gas chromatography output exceeded 0.9995. The regression equation was used to convert peak area to drug concentration, and peak areas were proportional to concentrations over the entire range of the concentrations tested (4).

Then [[lambda].sub.S/G] and [[lambda].sub.H/G] were obtained with the following equation:

[[lambda].sub.S/G] or [[lambda].sub.H/G] = ([V.sub.20]-[V.sub.4])/[V.sub.4] x [C.sub.2]/([C.sub.1]-[C.sub.2])

where [[lambda].sub.S/G] and [[lambda].sub.H/G] represent saline/gas and homogenate/gas partition coefficient respectively; [V.sub.4] and [V.sub.20] are internal volumes of 4 ml and 20 ml of each glass syringe, precisely calibrated by water displacement; [C.sub.1] and [C.sub.2] are the anaesthetic concentrations in the gas phase of the syringe at the end of the first and second equilibration, respectively.

Then tissue/gas partition coefficients ([[lambda].sub.T/G]) were obtained with the following equation:

[[lambda].sub.T/G] = [[lambda].sub.H/G] + ([V.sub.S]/[V.sub.T]) x ([[lambda].sub.H/G] - [[lambda].sub.S/G])

where [[lambda].sub.T/G], [[lambda].sub.H/G] and [[lambda].sub.S/G] represent tissue/gas, homogenate/gas and saline/gas partition coefficient, respectively; while [V.sub.S] and [V.sub.T] are the volumes of saline and tissue in the homogenate, respectively.

Anaesthetic concentrations were measured with a gas chromatograph (GOW-MAC, Bethlehem, USA) equipped with a 6 m stainless steel column (0.32 cm internal diameter) packed with Chromosorb[R] P-60/80 mesh (Qi-Lu, Ji-Lan City, Shandong, China) maintained at 75[degrees]C. Carrier stream flow at 17 ml/minute of nitrogen was delivered through the column to a flame ionisation detector supplied with hydrogen at 40 ml/minute and air at 200 ml/minute. The output from the gas chroma-tography was collected by a TAI-SSC922 integrator and peak areas were automatically calculated. Under these conditions, the peaks for sevoflurane, isoflurane and halothane were completely separated.

Statistical analysis

All data were presented as mean [+ or -] standard deviation (SD). For each anaesthetic (halothane, sevoflurane and isoflurane), a comparison was made between pregnant and non-pregnant rats for the blood/gas and tissue/gas partition coefficient for each of the tissues (brain, liver, kidney and heart), testing with the unpaired-samples t-test and corrected for multiple comparisons by the Bonferroni method. In addition, a one-way analysis of variance (ANOVA) compared tissue/gas partition coefficients between each of the tissues. When this analysis resulted in a significant difference, the Student-Newman-Keuls test determined which tissues were different from each other. This system of analysis was repeated for each type of anaesthetic and rat pregnancy type. These ANOVAs were corrected for multiple comparisons by the Bonferroni method. Values were considered statistically different when the Bonferroni corrected value was P <0.05.

RESULTS

Effects of pregnancy on blood/gas and tissue/gas partition coefficients of halothane

The solubility within blood and brain for halothane in the pregnant group (2.90 [+ or -] 0.44, 5.55 [+ or -] 0.73) was significantly lower than that of the non-pregnant group (3.42 [+ or -] 0.23, 6.33 [+ or -] 0.64; P <0.05). However, there was no significant difference between the two groups in other tissue solubility (liver, kidney and heart) of halothone (P >0.05) (Table 1).

Effects of pregnancy on blood/gas and tissue/gas partition coefficients of sevoflurane and isoflurane

For sevoflurane and isoflurane, no significant difference between pregnant and non-pregnant groups was found for either blood/gas partition or tissue/gas partition coefficients (P >0.05) (Tables 2 and 3).

Comparison of each tissue/gas partition coefficient within the three volatile anaesthetics

In pregnant rats, when tissue/gas partition coefficients were compared it was found that there were no significant differences in the brain/gas, liver/gas, kidney/gas and heart/gas partition coefficients. This result was the same regardless of which anaesthetic drug was compared and was also the case when non-pregnant rats were compared (P >0.05). On review the brain tissue/gas partition coefficients in pregnant rats for each anaesthetic drug showed that halothane was greater than isoflurane which was greater than sevoflurane for the brain tissue/gas partition coefficient. Similar results were found with the other tissues (liver, kidney or heart) and within non-pregnant rats.

DISCUSSION

Previous studies have demonstrated that many factors affected blood/gas and tissue/gas partition coefficients, including the anaesthetic drug itself, blood/tissue composition, age and temperature (4-9). Zhou and Liu found that coefficients progressively increased as temperature decreased (4). Therefore 37[degrees] was selected in this study to reflect the solubility at a normal body temperature in rats of 36.5 to 38.5[degrees]. This study found that the saline/gas partition coefficients of isoflurane and halothane and the blood/gas partition coefficient of halothane measured at 37[degrees] (0.56, 0.71 and 3.42, respectively) were similar to those reported by Lerman and Duncan (0.59, 0.82 and 3.6, respectively) (10,11), verifying that this method was reliable and repeatable.

Induction and recovery from halogenated volatile anaesthetics are more rapid in pregnant women than in non-pregnant women. The more rapid recovery has been attributed to a higher ratio of alveolar ventilation to functional residual capacity, a higher fraction of the cardiac output perfusing the vessel-rich tissues, and a higher ratio of alveolar ventilation to cardiac output per kilogram body mass (12,13). Another possible explanation however, is the lower solubility of volatile anaesthetics in the blood and tissues (especially brain) of pregnant women.

As predicted from their low tissue solubility during pregnancy, each of the tissue/gas partition coefficients of halothane, isoflurane and sevoflurane in the pregnant groups was lower than its corresponding value in non-pregnant groups. However, only the blood/gas and brain/gas partition coefficient for halothane was significantly different between pregnant and non-pregnant rats.

When a constant alveolar concentration is maintained, the product of tissue volume (Vt, ml) and tissue/gas partition coefficient ([[lambda].sub.T/G]) determines the capacity for a tissue to store anaesthetic drug (tissue capacity, Ct), (i.e. Ct = Vt x [[lambda].sub.T/G]). Based on the data in Table 1, the blood/gas and brain/gas partition coefficients in pregnant groups were lower than their corresponding value in non-pregnant groups for halothane (decreasing 18% for the blood and 14% for the brain), indicating a lower Ct in pregnant groups. Such lower capacity will accelerate the induction and recovery from inhaled anaesthetics and may increase patient safety. However, given our results were based on a rat model, further studies in other animals or human beings are required.

Knowing the partition coefficient of a volatile anaesthetic in the blood and body tissues allows prediction of the rate of increase of anaesthetic concentration in the lungs and other tissues. Because lower solubility accelerates induction and recovery, the order of induction and recovery from fast to slow would be sevoflurane, then isoflurane, then halothane. The representative tissues such as the brain, liver, renal and heart were selected to reflect the uptake and distribution of anaesthetics drugs into the main organs and tissues. We found no significant differences in tissue/gas partition coefficients of brain, liver, kidney and heart between pregnant and non-pregnant rats (P >0.05). The two results above indicate that pregnancy does not alter the distribution rule for volatile anaesthetics.

In conclusion, our study demonstrated that pregnancy decreased blood/gas and brain/gas partition coefficients for halothane. However, pregnancy did not affect liver/gas, kidney/gas and heart/gas partition coefficients of halothane or blood/gas and tissue/gas partition coefficients of sevoflurane and isoflurane. Further studies are required to elucidate the mechanism responsible for this decrease in coefficients for halothane during pregnancy.

REFERENCES

(1.) Chan MT, Mainland P, Gin T. Minimum alveolar concentration of halothane and enflurane are decreased in early pregnancy. Anesthesiology 1996; 85:782-786.

(2.) Zhou HH, Norman P, DeLima LG, Mehta M, Bass D. The minimum alveolar concentration of isoflurane in patients undergoing bilateral tubal ligation in the postpartum period. Anesthesiology 1995; 82:1364-1368.

(3.) Gin T, Chan MT. Decreased minimum alveolar concentration of isoflurane in pregnant humans. Anesthesiology 1994; 81:829-832.

(4.) Zhou JX, Liu J. The effect of temperature on solubility of volatile anesthetics in human tissues. Anesth Analg 2001; 93:234238.

(5.) Larson CP, Eager EI 2nd, Severing JW. Ostwald solubility coefficients for anesthetic gases in various fluids and tissues. Anesthesiology 1962; 23:686-689.

(6.) Weaver BWQ, Webb AI. Tissue composition and halothane solubility in the horse. Br J Anaesth 1981; 53:487-493.

(7.) Lerman J, Gregory GA, Willis MM, Schmitt BI, Eager EI 2nd. Age and the solubility of volatile anesthetics in ovine tissues. Anesth Analg 1985; 64:1097-1100.

(8.) Lerman J, Schmitt-Bantel BI, Gregory GA, Willis MM, Eager EI 2nd. Effect of age on the solubility of volatile anesthetics in human tissues. Anesthesiology 1986; 65:307-311.

(9.) Yasuda N, Targ AG, Eager EI 2nd. Solubility of I-653, sevoflurane, isoflurane, and halothane in human tissues. Anesth Analg 1989; 69:370-373.

(10.) Lerman J, Willis MM, Gregory GA, Eager EI 2nd. Osmolarity determines the solubility of anesthetics in aqueous solutions at 37[degrees]C. Anesthesiology 1983; 59:554-558.

(11.) Duncan WAM, Raventos J. The pharmacokinetics of halothane (fluothane) anaesthesia. Br J Anaesth 1959; 31:302-315.

(12.) Theunissen I, Parer J. Fluid and electrolytes in pregnancy. Clin Obstet gynecol 1994; 37:3-15.

(13.) Ross A. Physiologic changes of pregnancy. In Birnbach DJ, Gatt SP, Datta S, eds. Textbook of Obstetric Anesthesia. New York: Churchill Livingstone 2000. p. 31-45.

Y. RAO *, Y.-L. WANG [[dagger]], H. LI [[double dagger]], W. ZHANG [[section]], J. LIU **

Department of Anesthesiology, Zhongnan Hospital, Wuhan University, Hubei, PR China

Supported by a grant from the National Research Foundation of Nature Sciences China (No. 30271259) and a grant from 973 program (No. 2005CB522601), Beijing, PR China.

* M.D., Anesthetist.

[[dagger]] M.B., Professor.

[[double dagger]] M.D., Anesthetist, Department of Anesthesiology, State Key Laboratory of Biotherapy of Cancer, West China Hospital, Sichuan University, Sichuan.

[[section]] M.D., Associate Professor, Department of Anesthesiology, State Key Laboratory of Biotherapy of Cancer, West China Hospital, Sichuan University, Sichuan.

** M.D., Professor, Department of Anesthesiology, State Key Laboratory of Biotherapy of Cancer, West China Hospital, Sichuan University, Sichuan.

Address for reprints: Dr Yan-Lin Wang, Department of Anesthesiology, Zhongnan Hospital, Wuhan University, Wuhan 430071, Hubei, PR China.

Accepted for publication on June 26, 2008.
TABLE 1
Effects of pregnancy on [[lambda].sub.B/G] and [[lambda].sub.T/G] of
halothane in rats

 Pregnant

[[lambda].sub.B/G] 2.90 [+ or -] 0.44 (7)

[[lambda].sub.T/G]
Brain 5.55 [+ or -] 0.73 (9)
Liver 7.62 [+ or -] 2.45 (10)
Kidney 4.10 [+ or -] 0.94 (9)
Heart 6.08 [+ or -] 1.75 (9)

 Non-pregnant t value P value

[[lambda].sub.B/G] 3.42 [+ or -] 0.23 (6 ) (a) 2.60 0.025

[[lambda].sub.T/G]
Brain 6.33 [+ or -] 0.64 (10) (6) 2.45 0.025
Liver 7.90 [+ or -] 1.45 (9) 0.30 0.769
Kidney 4.44 [+ or -] 0.76 (9) 0.85 0.408
Heart 7.60 [+ or -] 2.50 (9) 1.50 0.154

(a) at = 2.6, P <0.05, (b) t = 2.45, P <0.05, vs. pregnant group.
Data are presented as mean [+ or -] SD and the number in
parentheses indicates the number of specimens studied. P values
shown are after Bonferroni correction. [[lambda].sub.B/G] =
blood/gas partition coefficients, [[lambda].sub.T/G] = tissue/gas
partition coefficients.

TABLE 2
Effects of pregnancy on [[lambda].sub.B/G] and [[lambda].sub.T/G] of
sevoflurane in rats

 Pregnant

[[lambda].sub.B/G] 0.81 [+ or -] 0.07 (7)

[[lambda].sub.T/G]
Brain 1.66 [+ or -] 0.31 (9)
Liver 2.43 [+ or -] 0.80 (10)
Kidney 1.32 [+ or -] 0.40 (9)
Heart 2.04 [+ or -] 0.81 (9)

 Non-pregnant t value P value

[[lambda].sub.B/G] 0.81 [+ or -] 0.04 (6) 0.07 0.946

[[lambda].sub.T/G]
Brain 1.78 [+ or -] 0.23 (10) 0.92 0.368
Liver 2.44 [+ or -] 0.43 (9) 0.02 0.984
Kidney 1.56 [+ or -] 0.37 (9) 1.28 0.219
Heart 2.07 [+ or -] 0.66 (9) 0.08 0.937

Data are presented as mean [+ or -] SD and the number in
parentheses indicates the number of specimens studied. P values
shown are after Bonferroni correction. [[lambda].sub.B/G] =
blood/gas partition coefficients, [[lambda].sub.T/G] = tissue/gas
partition coefficients.

TABLE 3
Effects of pregnancy on [[lambda].sub.B/G] and [[lambda].sub.T/G] of
isoflurane in rats

 Pregnant

[[lambda].sub.B/G] 1.50 [+ or -] 0.16 (7)

[[lambda].sub.T/G]
Brain 2.93 [+ or -] 0.44 (9)
Liver 4.00 [+ or -] 1.17 (10)
Kidney 2.31 [+ or -] 0.66 (9)
Heart 3.55 [+ or -] 1.21 (9)

 Non-pregnant t value P value

[[lambda].sub.B/G] 1.56 [+ or -] 0.08 (6) 0.71 0.491

[[lambda].sub.T/G]
Brain 3.12 [+ or -] 0.33 (10) 1.13 0.276
Liver 4.20 [+ or -] 0.69 (9) 0.43 0.672
Kidney 2.64 [+ or -] 0.31 (9) 1.21 0.243
Heart 3.69 [+ or -] 1.07 (9) 0.26 0.801

Data are presented as mean [+ or -] SD and the number in
parentheses indicates the number of specimens studied. P values
shown are after Bonferroni correction. [[lambda].sub.B/G] =
blood/gas partition coefficients, [[lambda].sub.T/G] = tissue/gas
partition coefficient.
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Author:Rao, Y.; Wang, Y.-L.; Li, H.; Zhang, W.; Liu, J.
Publication:Anaesthesia and Intensive Care
Article Type:Report
Geographic Code:9CHIN
Date:Nov 1, 2008
Words:2970
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