The Minimum Alveolar Concentration of Isoflurane in Patients Undergoing Bilateral Tubal Ligation in the Postpartum Period

This study was approved by the University of Mississippi Medical Center Institutional Review Board. Twenty-four patients, American Society of Anesthesiologists (ASA) physical status 1 or 2, aged 21-38 yr, undergoing elective bilateral tubal ligation during general anesthesia were studied after written informed consent. The patients were divided into three groups according to the duration between delivery and surgery: control group (n = 8): at least 6 weeks postpartum; early postpartum group (n = 8): less than 12 h postpartum; and late postpartum group (n = 8): 12-25 h postpartum. Exclusion criteria were a history of alcohol or drug abuse; severe anemia (hematocrit < 10%); abnormal body temperature (< 36 degrees Celsius or > 38 degrees Celsius); hypotension (mean blood pressure < 50 mmHg); abnormal serum electrolyte concentrations; impaired renal or liver function; cardiopulmonary disease; or exposure to clonidine, methyldopa, reserpine, verapamil, lithium, benzodiazepines, or progesterone within the preceding 3 weeks.

All patients received ranitidine (150 mg, oral) and metoclopramide (10 mg, oral) 60-90 rain before surgery. Anesthesia was induced with lidocaine (20 mg, intravenous) and propofol (2 mg/kg, intravenous), and the trachea was intubated after administration of succinylcholine (1.5 mg/kg, intravenous).

After tracheal intubation, isoflurane in oxygen was administered to achieve an end-tidal concentration of 2.0 vol% for 10 min with a total gas flow of 10 l/min. Ventilation was controlled with tidal volume of 8-10 ml/kg at a rate of 8-12 breaths/min to keep end-tidal carbon dioxide tension between 26 and 32 mmHg. The end-tidal isoflurane concentration was decreased to 0.7 vol% [10]and then was adjusted to maintain a steady concentration of 1.0 vol% in control subjects and patients in the late postpartum period and of 0.8 vol% in patients in the early postpartum period for 10 min. The difference between inspiratory and end-tidal concentration of isoflurane was maintained at about 0.1 vol%. Respiratory gases were continuously monitored by an infrared gas analyzer (Ohmeda 5250 RGM, British Oxygen Company Health Care, Louisville, CO) in all patients.

A painful electric stimulus (60 mA, 50 Hz, 5 s, in 0.20-ms square-wave pulses) was delivered by a peripheral nerve stimulator (750 digital, Dakkmed, Buffalo, NY) though two electrocardiographic electrodes placed on the volar surface of the dominant forearm, 5 and 13 cm below the skin fold in the cubital fossa and 1 cm to the ulnar side from the midline of the forearm, with the positive electrode placed proximally. [10]A positive response was considered to be gross movement of head or extremity. A delayed movement of extremity within 1 min after stimulation also was considered a positive result. However, the movement of the arm on the stimulated side during the tetanic stimulation and the movement caused by endotracheal tube, including coughing and swallowing, were not considered as positive reactions. If a positive response was observed, the concentration of isoflurane was increased by 0.10 vol%. If no response to stimulation occurred, the concentration was decreased by 0.10 vol%. The stimulation was repeated after at least 10 min of establishing a steady end-tidal concentration.

The bracketing technique was used to achieve a pattern of positive-negative-positive or negative-positive-negative responses. [3,10]The anesthetic concentration midway between that allowing and that preventing movement was the individual MAC value. In each patient the surgical procedure began after determination of isoflurane MAC. Each patient was interviewed within 24 h after surgery for awareness of intraoperative events.

In patients in the early or late postpartum period, 15 min before induction, a venous blood sample (3 ml) was collected from each patient. The plasma concentrations of progesterone were assayed with a radioimmunoactivity technique with a sensitivity of 0.1 ng/ml and interassay coefficients of variation of 11.8% at 1.1 ng/ml and 15.9% at 19.9 ng/ml. [11]The plasma concentrations of beta-endorphin were assayed by a radioimmunoactivity technique with a sensitivity of 14 pg/ml and interassay coefficients of variation of 9% at 190 pg/ml and 7.7% at 892 pg/ml. [12].

Data were analyzed with a statistical program (Systat, Evanston, IL). Student's unpaired t test and Dunnett's test were used for analysis of variance among the groups. The effects of independent variables (progesterone or beta-endorphin) on a dependent variable (MAC) and the effect of progesterone or beta-endorphin versus MAC were analyzed with linear regression. P values less than 0.05 were considered significant.

The demographic data were not significantly different between the three groups (Table 1). The durations (mean plus/minus SD) between induction and MAC determination in the control, early postpartum, and late postpartum groups were 63.8 plus/minus 13.0, 64.4 plus/minus 7.8, and 75.0 plus/minus 17.3 min respectively. The body temperature (mean plus/minus SD) at MAC determination in these groups were 36.1 plus/minus 0.6, 36.0 plus/minus 0.5, and 35.6 plus/minus 0.1 degree, respectively. They were not significantly different from each other (Table 1).

The MAC (mean plus/minus SD) of isoflurane in patients in the early postpartum period (0.75 plus/minus 0.17 vol%) was significantly different from MAC values in control subjects (P < 0.01) and in patients in the late postpartum period (P < 0.05), whereas the MAC in the late postpartum period (0.95 plus/minus 0.20 vol%) was not significantly different from that in the control group (1.04 plus/minus 0.12 vol%) by Student's unpaired t test and Dunnett's test. The MAC value in the early postpartum period at 7.3 h (range 4.5-11 h) after delivery was 28% less than that in the control group. Seven (88%) of eight patients in the early postpartum period and four (50%) of eight patients in the late postpartum period had MAC values less than the mean value of the control group. The lowest MAC value was 0.45 vol%, which was 57% less than the MAC in control patients.

By linear regression, there was an inverse correlation (Figure 1(A)) between progesterone concentration postpartum and time after delivery (r = -0.527; P = 0.036) but no relation between beta-endorphin concentration and time after delivery (Figure 1(B)) (r = 0.089; P = 0.744). Linear regression analysis of plasma progesterone (r = 0.005; P = 0.985) or beta-endorphin (r = 0.154; P = 0.568) against MAC showed no correlation (Figure 1(C and D)), a result confirmed by multiple regression (r = 0.166; P = 0.950).

Previous studies have demonstrated that MAC during pregnancy is decreased by 28% (isoflurane) in humans, [6]by 40% (isoflurane) in ewes, [4]and by 19% (halothane) in rats. [5]In this study the MAC of isoflurane was decreased by 28% in the 1st 12 h of the postpartum period.

Traditionally, MAC determination in humans has involved inhalation anesthetics to eliminate the synergistic effect of intravenous anesthetic agents given during induction of anesthesia. [13,14]However, in the postpartum period, the risk of aspiration of gastric contents is well recognized, [15,16]prompting us to use propofol, a short-acting induction agent, [17]with application of Sellick's maneuver to intubate the trachea rapidly. After a single bolus injection of 2 mg/kg propofol, the concentration in blood at 1 h decreases to 0.28 micro gram/ml in patients postpartum and 0.3 micro gram/ml in pregnant patients, [18]concentrations comparable with those in non-pregnant women (0.34 micro gram/ml). [19]These blood propofol concentrations are less than the concentration (0.7 micro gram/ml) at the time of awakening, [20]suggesting that the residual concentration of propofol 1 h after induction may have minimal effects on the central nervous system. Furthermore, the MAC of isoflurane in our control group (64 min after propofol injection) was similar to the isoflurane MAC obtained by others using inhalation induction of anesthesia. [6,21]This finding suggests that an induction dose (2 mg/kg) of propofol may have minimal effect on MAC after 1 h.

Patients' lungs were ventilated to keep end-tidal carbon dioxide tension between 26 and 32 mmHg, a level that would produce normocapnia in patients in the postpartum period and hypocapnia in the control group. However, MAC is unaffected by hyperventilation when arterial carbon dioxide tension is reduced from 42 to 14 mmHg. [22].

Recently, the electric tetanic stimulation technique with cutaneous electrodes has been used to determine the MAC value in humans. [6,10,21,23]This noninvasive method has the advantage of determining MAC in individual subjects and observing the change of MAC over a period of time. Our study shows that the MAC of isoflurane in healthy nonpregnant women (1.04 plus/minus 0.12 vol%) is similar to the isoflurane MAC of 1.03 vol% (adjusted to sea level) [21]determined by the same method in ASA physical status 1 or 2 adult patients, verifying that this method is reliable and repeatable. The MAC for isoflurane with tetanic stimulation (1.04 vol%) appears to be less than the MAC with skin incision (1.15 vol%). This discrepancy has been attributed to the difficulty in evaluation of movements of a stimulated arm or by the different intensities of stimulation. [21].

The anesthetic-sparing effect of opioids is well known. [24,25]Large doses of butorphanol (greater than or equal to 0.1 mg/kg, intravenous) decrease the MAC for enflurane by 11%, [25]but smaller doses of butorphanol (22 micro gram and 44 micro gram/kg, intravenous) have no significant effect on MAC. [26]In our study, even smaller doses of intravenous butorphanol (about 13 micro gram/kg) were administered for pain control 5-28 h before induction of anesthesia. Five hours after a single intravenous injection (2 mg), the plasma concentration of butorphanol decreases 29 times (from 20 to 0.7 ng/ml) [27]; therefore, the MAC value in this study is unlikely to have been affected by residual serum butorphanol.

The mechanism explaining the decrease in MAC during pregnancy and early postpartum period is unclear. Selye was the first to report that steroids such as progesterone possessed anesthetic activity. [28]Intravenous progesterone can induce sleep in women [29]and decrease halothane MAC in nonpregnant rabbits. [9]Also, the increase in beta-endorphin during pregnancy may decrease anesthetic requirements. [30,31]However, a recent study shows no correlation between serum progesterone and MAC in pregnant women at 8-12 weeks' gestation. [6]Similarly, our study shows no correlation between serum progesterone or beta-endorphin and isoflurane MAC in the postpartum period. Alternatively, MAC may be affected by other factors. Putative candidates as 5 alpha-dehydroprogesterone and 3 alpha-hydroxy-allopregnane-20-one (metabolites of progesterone), potent inhibitors of the central nervous system [32]; beta-lipotropin, the precursor of beta-endorphin [33]; and serotonin. [34]In addition, whether MAC is directly influenced by the substance in the plasma or in the cerebrospinal fluid has not been determined. It is recognized that plasma concentrations of beta-endorphin do not correlate with the concentrations in the cerebrospinal fluid. [33,35].

In conclusion, our study demonstrates that the MAC of isoflurane is 28% less than normal within the 1st 12 h postpartum and returns to normal at 12-25 h after delivery. Further studies are required to elucidate the mechanism responsible for the decrease in isoflurane MAC during early postpartum period.