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Anesth Analg 2001;93:1565-1569
© 2001 International Anesthesia Research Society

OBSTETRIC ANESTHESIA

Early Pregnancy Does Not Reduce the C50 of Propofol for Loss of Consciousness

Hideyuki Higuchi, MD*, Yushi Adachi, MD{dagger}, Shinya Arimura, MD*, Masuyuki Kanno, MD*, and Tetsuo Satoh, MD{dagger}

*Department of Anesthesia, Self Defense Force Central Hospital, Tokyo; and {dagger}Department of Anesthesiology, National Defense Medical College, Saitama, Japan

Address correspondence to Hideyuki Higuchi, MD, Department of Anesthesia, Self Defense Force Hanshin Hospital, 4-1-50 Kushiro, Kawanishi, Hyogo 666-0024, Japan. Address e-mail to higu-chi@ ka2.so-net.ne.jp.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Requirements for inhaled anesthetics decrease during pregnancy. There are no published data, however, regarding propofol requirements in these patients. Because propofol is often used for induction of general anesthesia when surgery is necessary in early pregnancy, we investigated whether early pregnancy reduces the requirement of propofol for loss of consciousness using a computer-assisted target-controlled infusion (TCI). Propofol was administered using TCI to provide stable concentrations and to allow equilibration between blood and effect-site (central compartment) concentrations. Randomly selected target concentrations of propofol (1.5–4.5 µg/mL) were administered to both pregnant women (n = 36) who were scheduled for pregnancy termination and nonpregnant women (n = 36) who were scheduled for elective orthopedic or otorhinolaryngologic surgery. The median gestation of the pregnant women was 8 wk (range, 6–12 wk). Venous blood samples for analysis of the serum propofol concentration were taken at 3 min and 8 min after equilibration of the propofol concentration. After a 10-min equilibration period of the predetermined propofol blood concentration, a verbal command to open their eyes was given to the patients twice, accompanied by rubbing of their shoulders. Serum propofol concentrations at which 50% of the patients did not respond to verbal commands (C50 for loss of consciousness) were determined by logistic regression. There was no significant difference in C50 ± SE of propofol for loss of consciousness between the Nonpregnant (2.1 ± 0.2 µg/mL) and Pregnant (2.0 ± 0.2 µg/mL) groups. These results indicate that early pregnancy does not decrease the concentration of propofol required for loss of consciousness.

IMPLICATIONS: The C50 of propofol for loss of consciousness in early pregnancy did not differ from that in nonpregnant women, indicating that there is no need to decrease the propofol concentration for loss of consciousness when inducing general anesthesia for termination of pregnancy.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Many studies have reported that minimum alveolar concentration is decreased in pregnant animals (1–3), pregnant women of 8–12 wk gestation (4,5), and women 24–36 h postpartum (6,7). In contrast, few studies have investigated the requirement for IV anesthetics during pregnancy. Gin et al. (8) reported that the dose of thiopental required for hypnosis was 17% less and that required for anesthesia was 18% less in pregnant women of 7–13 wk gestation compared with nonpregnant women. There was, however, a limitation in their study in that the effect-site (central compartment) concentrations of thiopental might have been different between pregnant and nonpregnant patients at the time of testing for hypnosis and anesthesia because the responses were investigated after a bolus dose of thiopental. Such a confounding factor can be eliminated by maintaining stable effect-site concentrations of the IV anesthetic using computer-assisted target-controlled infusion (TCI). Further, there is no published information on the propofol requirement during pregnancy. Therefore, the aim of the present study was to investigate whether early pregnancy reduces the requirement of propofol for loss of consciousness using TCI. We evaluated the C50 of propofol for loss of consciousness (the propofol blood concentration at which 50% of the patients did not respond to verbal commands) in patients having elective terminations of pregnancy at 6–12 wk gestation compared with nonpregnant healthy women undergoing elective surgery.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Written informed consent was obtained from each patient after explanation of the study, which was approved by the Local Clinical Research Ethics Committee. Seventy-two female patients (36 nonpregnant and 36 pregnant) were recruited. Patients were eligible for the study if they were classified as ASA physical status I, ages 19–39 yr, and had no known contraindication to using propofol. The sample size of the current study was determined by power analysis ({alpha} = 0.05, ß = 0.20) to reveal a significant difference in the C50. Power analysis indicated that 31 patients per group were required to obtain a significant difference, assuming that the SDs were 0.7 and the difference between the groups was 0.5 µg/mL. Based on the preliminary and previous studies (1–8), the difference of 0.5 µg/mL was estimated by the assumption that the C50 value of the pregnant patients was approximately 75% of that of the controls, 2.1 µg/mL. Patients were excluded if they were taking any medications, including oral contraceptives, or were obese (body mass index >30). Nonpregnant patients had a negative result on pregnancy testing, reported menstruation in the previous 4 wk, and were scheduled for elective orthopedic or otorhinolaryngologic surgery. Pregnant patients had a positive result on pregnancy testing, ultrasonic confirmation of pregnancy, and were 6–12 wk gestation and scheduled for termination of pregnancy by dilation and suction curettage.

No preanesthetic medication was given. On arrival of the patient in the operating room, two 18-gauge IV cannulae were inserted, one in the left forearm for drug infusion, and another in the right forearm for blood sampling. Heart rate, blood pressure, and oxyhemoglobin saturation were monitored continuously during the study. After preoxygenation, 0.5 mg/kg IV lidocaine was administered, and computer-controlled TCI was started, targeting the effect-site concentration. Propofol was administered via a Graseby 3500syringe pump (SIMS Graseby Ltd., Herts, England) by using the infusion program RUGLOOP (T. De Smet and M. Struys, Ghent University, Gent, Belgium) (9) and pharmacokinetics data of Marsh et al. (10) (Table 1). We used the program to incorporate an effect-site equilibration constant (ke0) of 0.25/min (11).


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  		Table 1. Pharmacokinetics Values Used for the Administration of Propofol
 
Within each group, patients were randomized to receive predetermined target concentrations of propofol ranging from 1.5 to 4.5 µg/mL in 0.5 µg/mL steps (Table 2). These values and the randomization method used in the present study were selected on the basis of our preliminary research and other studies of propofol C50 for loss of consciousness (12–15). To ensure equilibration between blood and effect-site, the predetermined target concentration (Table 2) was maintained for 10 min before administering the verbal command, as previously reported by Kazama et al. (12). All patients breathed spontaneously, or with manual assistance when necessary, and received oxygen via a face mask. Venous blood samples for analysis of the serum propofol concentration were taken at 3 min and 8 min after equilibration between the blood and effect-site concentrations. After a 10-min equilibration period of the predetermined propofol serum concentration (set by TCI), a verbal command to open their eyes was given to the patients twice, accompanied by rubbing their shoulders (12). Patients who did not open their eyes were recorded as "unresponsive" (loss of consciousness), and patients who opened their eyes were recorded as "responsive." The responses were identified by one of the authors (S. A.), who was blinded to the predetermined propofol serum concentration. For determination of the C50 for loss of consciousness, only paired samples with concentrations within 35% of each other were analyzed (14). From these samples, only the postassessment propofol concentrations were used for analysis (15). The response-nonresponse data overlapped and were related to the propofol concentration according to following equation (15):


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  		Table 2. Target Concentrations of Propofol to Which Patients were Randomized for Assessment of Response
 
equation


where C is the measured propofol concentration in the serum, C50 is the serum concentration of propofol that results in a 50% probability of no response, and {gamma} is a dimensionless power function that determines the steepness of the slope of the probability versus the concentration curve. The C50 for loss of consciousness was calculated by logistic regression (STATISTICA for Macintosh, StatSoft, Tulsa, OK).

The blood samples were allowed to clot and then centrifuged at 3000 rpm for 10 min, and the serum was frozen at -4°C until assayed. The serum concentration of propofol was determined using a high-performance liquid chromatograph with a fluorescence detection wavelength of 310 nm and excitation wavelength of 276 nm (RF550; Shimadzu, Kyoto, Japan), as described previously (16). The area under the chromatographic peak was measured using an integrator (PowerChrom, ADInstrument, Tokyo, Japan). The propofol concentration was estimated from a peak-area ratio to the internal standard, thymol. Linear relationships were obtained between propofol and the internal standard peak-area ratios. The correlation coefficient was greater than 0.997 in the range of 50 ng/mL to 10 µg/mL. The detection limit of propofol was 10 ng/mL using this assay. The repeatability coefficients of the variation in serum were 4.6 and 2.1% at the concentrations of 1 and 10 µg/mL, and 2.2% between days (10 µg/mL).

For each pair of predicted and measured values, the prediction error (PE) and absolute prediction error ( PE ) were calculated according to the formula (17):

equation


Data were compared between groups using the Mann-Whitney test. A Pvalue of <0.05 was considered statistically significant. Results are presented as median (range) or C50±SE (95% confidence interval).


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
All 72 patients completed the study without adverse effects, such as bradycardia, or hypotension. Of the 72 patients, 5 patients (2 nonpregnant, 3 pregnant) were excluded from analysis because pre- and postassessment paired samples did not give concentrations within 35% of each other; the data from 67 patients were analyzed. There were no significant differences in age, weight, or height between the groups. The pregnant patients were on average 8 wk pregnant by dates (range, 6–12 wk) (Table 3), and pathologic examination confirmed a fetus in all pregnant women.


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  		Table 3. Patient Demographics, C50 of Propofol with 95% Confidence Intervals (CI) for Loss of Consciousness in Nonpregnant and Pregnant Women
 
Mean and absolute prediction error for TCI administration of propofol in the Nonpregnant group were -31.5% and 34.7%, respectively. Corresponding values in the Pregnant group were -32.3% and 33.2%, respectively. The concentration-response to verbal command curve is shown in Figure 1. The C50 ± SE (95% confidence interval) of propofol for loss of consciousness in the Nonpregnant women was 2.1 ± 0.2 (1.8–2.4) µg/mL, whereas the corresponding value in the Pregnant women was 2.0 ± 0.2 (1.6–2.4) µg/mL (Table 3). No difference was found in C50 of propofol for loss of consciousness between the Nonpregnant and Pregnant women (Table 3).



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  		Figure 1. Relation between the serum concentration and response to verbal command and tactile stimuli in both groups. The diagrams show the propofol serum concentration of every patient associated with (unfilled circles = positive response) or without (filled circles = negative response) the response. The concentration-effect curves were defined from the data shown in the upper diagrams of both groups using logistic regression. Straight line indicates ± SE of C50.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
In the present study, the mean absolute prediction error in the nonpregnant women, which indicates the precision of the TCI, was 34.7%, consistent with the findings of Coetzee et al. (18), who investigated the mean absolute prediction error in venous serum with the use of the pharmacokinetics data of Marsh et al. (10). The C50 for loss of consciousness in the Nonpregnant group was 2.1 µg/mL, which was less than that reported in previous studies (12–15). Vuyk et al. (13) reported that the C50 for loss of consciousness in women aged 20–48 years was 3.4 µg/mL. There are other reports that the C50 for loss of consciousness in female and male patients is 2.2–4.4 µg/mL (12–15). The smaller concentration of C50 for loss of consciousness in the present study might be because of differences in the sites of blood sampling for measurement of the propofol concentration. Venous serum propofol concentration was measured in the present study, whereas previous studies measured arterial whole-blood or plasma propofol concentrations. Venous propofol concentrations are generally smaller than arterial values by approximately 0.5 -1 µg/mL (18). In addition, the propofol concentrations in whole blood are larger by approximately 0.5 µg/mL than those in plasma and serum (18).

To optimally control blood concentration, the pharmacokinetics variable provided to the computer model should match the pharmacokinetics of the patients (12). Although the absolute prediction error in pregnant women in this study was similar to that in nonpregnant women, we cannot exclude the possibility that the application of the pharmacokinetics data of Marsh et al. (10) might not be appropriate because many physiologic changes that might affect the pharmacokinetics of the drug occur in early pregnancy (19).

We did not investigate the C50 of propofol for noxious stimuli, such as dilation of the uterine cervix, in the pregnant women because the noxious stimuli by dilation of uterine cervix might not be accurate for the assessment of the depth of anesthesia (20). Dilation of the uterine cervix is no more intense a stimulus than tetanic stimulation or skin incision and is not a constant stimulus (20).

Our finding that the C50 for loss of consciousness in women in early pregnancy did not differ from that in nonpregnant women is consistent with a preliminary study by Mainland et al.,1 who also investigated the propofol concentration for hypnosis in pregnant women of <10 weeks’ gestation. However, these results are inconsistent with those reported by Gin et al. (8), who found that the dose of thiopental for hypnosis was 17% less in pregnant women compared with nonpregnant women. Possible explanations for the discrepancy between the present studies and those of Mainland et al., and the results by Gin et al. (8) are a difference of IV anesthetics (thiopental versus propofol) and a difference in the gestational age of the pregnant women. The median gestational age in the present study was 8 weeks, whereas in the study by Gin et al. (8), the median was 11. Furthermore, the median gestational age in other studies that reported a decreased minimum alveolar concentration of volatile anesthetics in early pregnancy was 10–11 weeks (4,5). Although the underlying mechanism for the decreased anesthetic requirements during pregnancy is unclear, it might not be fully engaged at 8 weeks of gestation. There is a gradual increase in the pain threshold between 16 days before parturition and 4 days before parturition and a more abrupt increase 1–2 days before the event (21). Iwasaki et al. (22) also reported that there was no significant difference in the pain threshold between pregnant rats and nonpregnant rats on day 7 of gestation, whereas a significant difference existed on day 21 of gestation.

There are some limitations in our study. First, we used lidocaine (0.5 mg/kg) before propofol injection to reduce the pain from IV propofol. One might argue that the administration of lidocaine, which has central nervous system effects, affected the results. We believe, however, that this is not the case because it has been previously reported that a small dose of lidocaine (1 mg/kg) did not affect the dose of propofol required for loss of consciousness (23). Second, the venous blood samples were not taken immediately before or after the assessment of loss of consciousness. Therefore, it is possible that the correlation between the propofol concentration and response might not be accurate. A final and critical limitation of the present study is that it lacks the power to adequately address the question regarding different anesthetic sensitivity between pregnant and nonpregnant women and whether the methods used in the present study might be inaccurate to detect the small difference of anesthetic sensitivity between the two groups. Power analysis indicated that the statistical power of the present study is only 6% and approximately 1600 additional patients per group were required to obtain a power of 80% with the same SDs and structural results as the current sample. Although the step between the selected target concentrations was 0.5 µg/mL (12), the step size should have been smaller than 0.5 µg/mL to characterize the propofol concentration-response relationship more accurately and to detect small differences between pregnant and nonpregnant women. Further study with a large sample size, a smaller step size between the selected target concentrations, and an arterial blood sample would be necessary to investigate more precisely whether there is different anesthetic sensitivity between pregnant and nonpregnant women.

In summary, the C50 of propofol for loss of consciousness under the conditions of this study design was not decreased in early pregnant women compared with nonpregnant women, suggesting that there is no need to decrease the concentration of propofol for induction of loss of consciousness for termination of pregnancy being performed at an early gestational age.


   Footnotes
 
1Mainland P, Chan MT, Gin T. Pharmacokinetic/pharmacodynamic study of propofol requirements in pregnancy [abstract]. Anesthesiology 1997; 87:A380. Back


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication August 1, 2001.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2001 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press