Pregnancy alters many physiologic functions that may be associated with the pharmacologic profile of anesthetics. Pregnancy affects the minimum alveolar concentration (MAC) of volatile anesthetics. In experimental animals, the MAC values of volatile anesthetics were reduced by 25% to 40% in pregnant ewes1 and by 16% to 19% in pregnant rats.2 In a human study, the isoflurane MAC of pregnant women at early gestational age was approximately 72% that of nonpregnant women.3 In clinical practice, cesarean deliveries in pregnant women require less volatile anesthetic drugs than lower abdominal surgery in nonpregnant women. However, the mechanism of the low anesthetic requirement of pregnant patients is not fully understood.
Possible causes of decreased anesthetic requirements have been postulated. Many theories involve changes in female hormones and the endogenous opioid system that occur during pregnancy.1,4 Progesterone has generally been assumed to have anesthetic properties,5 and exogenously administered progesterone can reduce anesthetic requirements in animals.6 The increased plasma concentration of progesterone during gestation may trigger activation of the spinal cord opioid system,7,8 which may be responsible for decreased sensitivity to pain.9 Although increased progesterone level might contribute to these changes, the correlation between anesthetic or analgesic requirements and plasma concentration of progesterone in full-term women has not been studied.
The purpose of this prospective, observational study was to test the hypothesis that serum concentrations of progesterone affect the anesthetic and analgesic requirements of pregnant women undergoing cesarean delivery.
This study was approved by the IRB of Chonbuk National University Hospital, and written informed consent was obtained from all participants. The study included 100 pregnant women with an ASA physical status of I or II between the ages of 20 and 45 years over 36 weeks’ singleton gestation, who were scheduled for planned cesarean delivery under general anesthesia. The study excluded patients who used analgesics, sedatives, or antidepressants within 48 hours of surgery. It also excluded patients with hypertension, gastrointestinal disease, documented history of difficult intubation, or potentially difficult airway management as suggested by physical examination.
Venous blood was collected from patients just before the induction of anesthesia to measure the serum concentration of progesterone. Serum concentration of progesterone was measured by electrochemiluminescence immunoassay (Progesterone II, Modular Analytics E170 analyzer, Roche Diagnostics, Mannheim, Germany). The measuring range is 0.03 to 60 ng/mL. If the progesterone concentration exceeded 60 ng/mL, the serum was diluted 5 and 10 times. The upper limit of serum progesterone was 400 ng/mL in this study.
All patients received oral ranitidine 150 mg the night before and on the morning of surgery. Patients were monitored with electrocardiograph, temperature, pulse oximetry, capnography, bispectral index (BIS), and noninvasive arterial blood pressure on the left arm. A 15° left lateral tilt was maintained for uteroplacental displacement until delivery. After BIS and vital signs were measured at baseline, patients were administered 100% oxygen for 3 minutes. Neuromuscular blockade was monitored by a peripheral nerve stimulator (TOF-Watch®, Organon Ltd., Dublin, Ireland). All patients were warmed by a forced-air warming system (Bair Hugger Model 505, Arizant Healthcare Inc., Eden Prairie, MN). Patients were given thiopental sodium 4 to 5 mg/kg and rocuronium 0.8 mg/kg with 6 L/min of fresh gas flow, using a rapid-sequence induction protocol with cricoid pressure. The incision was made immediately after tracheal intubation. Initially, patients’ lungs were mechanically ventilated with sevoflurane 3.0 vol%, 50% nitrous oxide, and 6 L/min of fresh gas until the end-tidal sevoflurane concentration reached 2.0%. Fresh gas flow rate was decreased to 3 L/min after reaching an end-tidal sevoflurane concentration of 2%. Tidal volume was set at 8 mL/kg, and the respiratory rate was adjusted to maintain end-tidal carbon dioxide tension between 30 and 35 mm Hg. Mean arterial blood pressure and heart rate were maintained within 20% of baseline values. The BIS value was maintained between 60 and 40. Immediately after delivery, 5 IU IV oxytocin (mixed with 50 mL normal saline) was administered over 5 minutes. The end-tidal sevoflurane concentration was maintained between 0.5% and 2.0%, titrated to arterial blood pressure, heart rate, and BIS value to prevent intraoperative awareness and uterine relaxation. Vital signs and BIS value were monitored every 5 minutes. The values were recorded at baseline; just before tracheal intubation; just before delivery; at 10, 20, 30, and 40 minutes after delivery; and at the end of surgery. No patients received opioids during anesthesia induction and maintenance. The patients received an additional dose of rocuronium 10 mg, if the train-of-four count was >2 twitches. Anesthesia was managed by 1 anesthesiologist who was blinded to progesterone concentration, and the operation was standardized by 2 obstetricians using a Pfannenstiel incision and in situ repair of the uterus.
Cumulative sevoflurane consumption was recorded by direct injection of a volatile drug (DIVA™, Dräger Medical AG & Co., Lübeck, Germany) system of an anesthesia workstation (Zeus®, Dräger Medical AG & Co.). The system specifically records the consumption of liquid volatile anesthetic drugs in milliliters. The consumption of volatile anesthetics depends on inspired anesthetic concentration (vaporizer setting) and the fresh gas flow rate. Sevoflurane volume per hour of anesthesia was calculated.
Patients were treated with IV ephedrine or labetalol, if mean arterial blood pressure was lower than 60 mm Hg or higher than 120 mm Hg for 5 minutes with inhaled sevoflurane concentration adjusted down to 0.5% or up to 2.0%, respectively. For all patients, a 5-mg bolus of ondansetron (Zofran™, GlaxoSmithKline, Verona, Italy) was administered approximately 30 minutes before the end of surgery, and each patient was equipped with a patient-controlled analgesia device (Walkmed™, Medex, FL). The analgesic solution contained 40 mg morphine, 180 mg ketorolac, and 8 mg ondansetron in 60 mL of normal saline. All patients received a 3-mL bolus of the analgesic solution at skin closure. The demand dose was 1.0 mL with no background infusion and an 8-minute lockout interval. After skin closure, sevoflurane and nitrous oxide administration was discontinued. Patients received pyridostigmine 10 to 15 mg and glycopyrrolate 0.4 mg to reverse the neuromuscular blockade. The patients were transported to the postanesthesia care unit (PACU) when they opened their eyes and breathed spontaneously.
All patients were monitored with electrocardiograph, temperature, pulse oximetry, and noninvasive arterial blood pressure and were warmed by a forced-air warming system in the PACU. To assess postoperative pain intensities at rest and during forced expiration, patients were evaluated with visual analog scale (VAS; where 0 cm = no pain and 10 cm = worst possible pain) scores at postoperative hours 2, 24, and 48. The VAS scores were assessed by 1 anesthesiologist to exclude interrater bias. Patients were transferred to the postpartum ward at 2 hours. The cumulative postoperative analgesic consumption and VAS scores were recorded at 24 and 48 hours postoperatively. All patients were interviewed using the Brice questionnaire to assess intraoperative awareness at 6 to 8 hours after PACU discharge and the following day.10
In this study, the primary outcome was the relationship between serum concentration of progesterone and sevoflurane consumption. We assumed the correlation coefficient between the variables was 0.3. It was then calculated that 85 patients were required to differentiate between correlation coefficient 0.3 and 0 with a significance level of 0.05 (α = 0.05) and a power of 80% (β = 0.20). To allow for attrition, the sample size was enlarged to 100.
The normality of serum concentration of progesterone, sevoflurane consumption, and cumulative analgesic consumption was tested using the Shapiro-Wilk test. The null hypothesis for this test is that the data are normally distributed. Sevoflurane consumption (P = 0.36) passed the test, but progesterone concentration (P < 0.01) and 48-hour cumulative analgesic consumption (P < 0.01) did not pass. The correlations between serum concentration of progesterone and sevoflurane consumption or cumulative analgesic consumption were tested using a Pearson correlation test after the log transformation of the data (Shapiro-Wilk test with the transformation; progesterone concentrations P = 0.16, 48-hour cumulative analgesic consumption P = 0.96). For further analysis, women were divided into 2 groups based on the progesterone concentration: a high group with progesterone values higher than the median value and a low group with values below the median value. Comparisons of continuous demographic data, sevoflurane and analgesic consumption, VAS scores, and vital signs between the high and low groups were analyzed by the Student t test (normal data with equal variance) or Mann-Whitney rank test by the results of Shapiro-Wilk normality test. Categorical data were analyzed with the χ2 test. The values were expressed as mean ± SD. Statistical significance was set at P < 0.05.
One hundred patients were enrolled in the trial from November 2011 to March 2013. Ten of the 100 patients were excluded and the data from 90 patients were analyzed (Fig. 1). Patient characteristics are shown in Table 1. The mean serum progesterone concentration was 128.8 ± 84.2 ng/mL (range, 23–400 ng/mL). Sevoflurane consumption was 12.0 ± 1.9 mL/h and had a significant negative correlation with serum progesterone concentration (Pearson correlation r = −0.26; 95% confidence interval [CI], −0.44 to −0.05, P = 0.01; Fig. 2). Postoperative VAS pain scores at rest and during deep breathing and cumulative postoperative analgesic consumption are presented in Table 2. There were significant negative correlations between progesterone concentration and cumulative analgesic consumption at postoperative hours 2 (r = −0.20; 95% CI, −0.39 to −0.01, P = 0.05), 24 (r = −0.25; 95% CI, −0.44 to −0.05, P = 0.02), and 48 (r = −0.28; 95% CI, −0.46 to −0.08, P = 0.01) (Fig. 3).
The median value of serum progesterone was 102.1 ng/mL. Forty-five subjects composed the low group (serum progesterone below the median value) and 45 subjects the high group (above the median value). The groups were similar in parity, age, height, weight, operation duration, gestational age, and VAS scores (Table 3). The high group had less sevoflurane consumption per hour than the low group (P = 0.02) and less 48-hour cumulative postoperative analgesic consumption (P = 0.02). There were no significant differences in mean arterial blood pressure, heart rate, and BIS between the low and high groups (Table 4).
No patient was treated for hypotension or hypertension during the operation. No patient had BIS values higher than 65 for 2 minutes during surgery or intraoperative awareness.
Most anesthesiologists have known that patients undergoing cesarean delivery have lower anesthetic requirements for general anesthesia than nonpregnant women. Although many clinical and experimental studies have demonstrated the relationship between progesterone and anesthetic requirements, the relationship in full-term women has not been studied. In the current study, maternal serum concentration of progesterone was found to correlate inversely with anesthetic sevoflurane requirements and postoperative analgesic requirements in patients undergoing cesarean delivery under general anesthesia.
Several underlying hypotheses have been postulated to explain the decreased anesthetic requirements observed during pregnancy, although the mechanisms are not fully understood. The MAC value of isoflurane in early gestation patients with high progesterone levels was significantly lower than in nonpregnant patients.3 In women undergoing postpartum tubal ligation between 24 and 120 hours after delivery, the MAC of isoflurane was directly related to the delivery-anesthetic interval and the progesterone concentration.11 In nonpregnant women, the sevoflurane requirement in women in the follicular phase of the menstrual cycle with low progesterone levels was significantly higher than in the luteal group with high progesterone levels.12 In contrast, other studies have found no correlation between plasma progesterone and anesthetic requirements.13,14
Most clinical studies with positive and negative results have examined anesthetic requirements during early pregnancy or after delivery, and the studies were relatively small. The progesterone concentration in early pregnancy is lower than term pregnancy. The concentration declines rapidly after delivery.13 These differences may explain the discrepancy in the results.
Many animal studies demonstrated that female hormones have antinociceptive effects.15–17 However, it is controversial whether female hormones modulate pain in humans.18–21 The plasma concentrations of progesterone are <1 ng/mL in the follicular phase of the menstrual cycle, in postmenopausal women, and in men, while it ranges between 3.3 and 25.6 ng/mL in the luteal phase of the menstrual cycle. Studies have examined pain threshold relative to the progesterone concentration, the phase of the menstrual cycle, or sex.18–22 Although individual serum progesterone concentrations are variable, the differences in progesterone concentration by phase of the menstrual cycle and sex are much smaller than the range in our current study. This small difference may explain the negative results in these studies. We found that increases in progesterone concentration influence anesthetic depth and antinociception, resulting in decreased anesthetic and analgesic consumption.
In the current study, anesthetic depth was titrated using vital signs and BIS values. Unlike previous studies, anesthetic consumption was measured using liquid sevoflurane consumption per hour of anesthesia. Anesthetic requirement is related to surgical stimuli. In the current study, surgical techniques were standardized by 2 obstetricians, and anesthetic depth was managed by 1 anesthesiologist who was blinded to progesterone concentration. Although anesthetic and analgesic requirements were significantly related to progesterone concentration and the requirements were lower in the high progesterone group, the clinical significance of the finding is not clear. The focus of the current study was on the mechanism of decreased anesthetic and analgesic requirements in pregnant women.
This study has several limitations. First, the study did not consider diurnal fluctuation of progesterone concentration. However, the surgical procedure took place in the morning for most study participants, and the progesterone concentrations were very high. Second, pregnancy involves many hormonal changes, including changes in estrogen, human chorionic gonadotropin, and endogenous opioids, and these substances were not studied.
In conclusion, the sevoflurane and postoperative analgesic requirements of parturients undergoing cesarean delivery might depend, in part, on serum progesterone concentration. Further studies are required to identify the effects of other female hormones and endogenous opioids on anesthetic requirements in pregnancy and the interactions between female hormones and endogenous opioids.
Name: Jeongwoo Lee, MD, PhD.
Contribution: This author helped conduct the study, analyzed the data, and prepared the manuscript.
Attestation: Jeongwoo Lee has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Junho Lee, MD.
Contribution: This author collected the data.
Attestation: Junho Lee has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Seonghoon Ko, MD, PhD.
Contribution: This author designed the study, analyzed the data, and wrote the manuscript.
Attestation: Seonghoon Ko has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
This manuscript was handled by: Cynthia A. Wong, MD.
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