Intraoperative awareness and subsequent recall associated with general anesthesia may be a disturbing experience in pregnant women undergoing cesarean delivery.1 For many years, the standard general anesthetic for cesarean delivery consisted of 0.5 minimum alveolar concentration (MAC) of a volatile anesthetic in 50% nitrous oxide (N2O). Opioids were withheld until after delivery.2,3 However, the incidence of awareness during cesarean delivery appears to be higher than that reported in a general surgical population.4,5 Indeed, Lyons and MacDonald4 demonstrated a frequent incidence (1.3%) of awareness when 0.5 MAC volatile anesthetics were used in 50% N2O during cesarean delivery. It is likely that 0.5 MAC of volatile anesthetic may not provide adequate depth of anesthesia for cesarean delivery.
The bispectral index (BIS) is an empirically derived electroencephalographic parameter measuring the hypnotic component of anesthesia that guides the administration of volatile anesthetics.6 BIS values below 60 indicate a low probability of recall and intraoperative awareness.7,8 During cesarean delivery, Yeo and Lo9 found that an end-tidal concentration of 1% sevoflurane (1% ETSEVO, approximately 0.5 MAC) in 50% N2O did not reliably result in BIS values <60.
Animal studies have shown that noxious stimulation activates spinal antinociceptive pathways in which, not only endogenous opioids, but also biogenic amines (serotonin and norepinephrine), are implicated as neurotransmitters.10 The activation of these pathways may reduce the painful sensation to a second noxious stimulus.10 In humans, β-endorphin, an endogenous opioid, is released under conditions of labor pain and other stresses.11,12 Pregnant women who had experienced painful labor tended to have greater cerebrospinal fluid concentrations of norepinephrine and consumed less analgesics after cesarean delivery than those who had not.13 Labor pain may activate the spinal inhibitory noradrenergic pathways to elicit antinociception during subsequent cesarean delivery and the immediate postoperative period.
We hypothesized that ETSEVO 1% and N2O general anesthesia for cesarean delivery would be associated with lower BIS values and stress hormone responses in pregnant women who had prior labor, and were therefore in pain, compared with those without prior labor, and designed and executed an observational study to test this hypothesis.
ASA physical status I or II women at term with uncomplicated pregnancies, undergoing elective or urgent cesarean delivery under general anesthesia, were enrolled in the study. In Korea, general anesthesia is still the most common form of anesthesia for cesarean delivery, and women commonly labor without analgesia. There were two groups according to the absence or presence of labor before the surgery. The labor group (n = 20) had a minimum of 4 h painful labor defined by the presence of cervical dilation of 3 cm or more with uterine contractions occurring at least 3 every 10 min before surgery, and the control group (n = 20) had an elective cesarean birth without prior labor.
The study was approved by the IRB for Human Studies, and all patients provided written informed consent. In the labor group, 124 patients were informed of the study and their consent was obtained in the antenatal period. In the control group, the consent was obtained before the surgery in the ward. All patients in both groups were informed of the risk of intraoperative recall when using the anesthesia method specified in the protocol. Exclusion criteria included women with preexisting or pregnancy-induced hypertension, cardiovascular or cerebrovascular disease, known fetal abnormalities, preterm or multiple gestation, or analgesic medication use before delivery. Pain immediately before surgery was assessed in both groups using a 10-cm visual analog scale (VAS) for pain, in which 0 = no pain and 10 = worst possible pain.
All patients received 30 mL of 0.3 M sodium citrate, 15–20 min before induction of anesthesia. Upon arrival in the operating room, routine monitoring devices were applied and the patient was positioned supine with left lateral tilt. A 20-gauge catheter was placed into a radial artery and connected to a pressure transducer (Deltran; UT Medical Products, Midvale, UT) to measure arterial blood pressure and to collect blood samples. A standard BIS electrode montage (BIS Sensor-Aspect Medical Systems, Inc., Natick, MA) was applied to the forehead before induction of anesthesia, and BIS was measured continuously throughout the surgery using a BISXP monitor (model A-2000; 3.31 software version; Aspect Medical Systems Inc.). The anesthesiologist controlling the sevoflurane concentration was blinded to the BIS value.
After determination of baseline values for the BIS and hemodynamic variables, we performed rapid-sequence induction using IV sodium thiopental 4 mg/kg and succinylcholine 1.5 mg/kg. Tracheal intubation was performed using direct laryngoscopy. Anesthesia was maintained with sevoflurane, adjusted to maintain an end-tidal concentration of 1.0%, and 50% N2O in oxygen using a circle circuit with a fresh gas flow of 6 L/min until the time of delivery. After connection of the circuit to the endotracheal tube, 5% sevoflurane (vaporizer dial concentration) was administered for the first 60 s, and then adjusted to maintain end-tidal concentration at 1%. The steady-state targeted concentration was maintained throughout the operation. After delivery, fresh gas flow was reduced to 4 L/min until the end of surgery. Muscle relaxation was maintained with vecuronium given as an initial bolus of 0.12 mg/kg within a few minutes of succinylcholine administration, and the lungs were mechanically ventilated to maintain an end-tidal carbon dioxide tension between 35 and 40 mm Hg. Neuromuscular blockade was controlled by train-of-four monitoring, and additional boluses of vecuronium 1 mg were administered to maintain one twitch response during the surgical procedure. Throughout the study, the ETSEVO, N2O, and carbon dioxide were measured using a gas analyzer (Capnomac Ultima; Datex-Ohmeda, Helsinki, Finland) and recorded at 1-min intervals. We also recorded the time of skin incision, uterine incision, and delivery.
Immediately after delivery of the neonate, IV oxytocin (20 IU in 500 mL) was administered as an infusion. Intraoperative hypotension, defined as systolic arterial blood pressure (SBP) <90 mm Hg, was treated initially by increasing IV crystalloid infusion, followed by ephedrine 8 mg boluses if SBP decreased below 85 mm Hg. At completion of surgery, sevoflurane was discontinued, and residual neuromuscular block was reversed using neostigmine and atropine.
BIS values, SBP, and heart rate (HR) were recorded by an independent investigator at 1-min intervals in the period between induction of anesthesia to delivery, and at 1, 3, 5, and 10 min thereafter. BIS values corresponding to an intraoperative event (e.g., induction, tracheal intubation, skin incision, uterine incision, and delivery) were recorded as the maximum value displayed within 1 min of each event. These values were confirmed by down-loading data from the electronic memory of the monitor at the end of surgery. Neonatal Apgar scores, ephedrine requirements, and estimated blood loss were also recorded.
Postoperative pain was treated with patient-controlled IV analgesia (PCIA) using fentanyl and propacetamol. The postoperative analgesia device (Abbott Pain Management Provider: Abbott Laboratories, North Chicago, IL) was set to deliver a bolus (fentanyl 15 μg plus propacetamol 120 mg), with a lockout interval 10 min, 4-h limit (300 μg plus 2400 mg/h, respectively) and background infusion (15 μg plus 120 mg/h, respectively). PCIA was continued for 24 h. Each patient was visited by one of the investigators 8, 16, and 24 h after surgery. VAS pain scores at rest were recorded at each assessment and cumulative consumption of analgesics recorded by downloading data from the electronic memory of the PCIA device at the 24-h visit.
Arterial blood samples were drawn before the induction of anesthesia (baseline) and at the time of delivery for measurements of plasma catecholamines, arginine vasopressin, and cortisol. The samples were collected into prechilled tubes containing EDTA-Na and immediately centrifuged at 3000 rpm for 10 min at 4°C. The plasma was stored at −70°C until assayed. Plasma concentrations of norepinephrine and epinephrine were measured in duplicate by using high-pressure liquid chromatography.14 The assay sensitivity was 10 pg/mL, and within-run precision coefficients of variation were 13.5% and 14.2% for norepinephrine and epinephrine, respectively. Plasma concentrations of arginine vasopressin (NEN-DuPont, Boston, MA) and cortisol (DSL-2000 SP Aktive® Cortisol; Diagnostic System Laboratories, Sinsheim, Germany) were measured by radioimmunoassay.
The sample size calculation was based on the primary end-point of BIS value at skin incision. A power analysis suggested a sample size of 17 patients in each group should be adequate to detect a 15% difference in BIS at skin incision with a two-sided significance level α of 0.05 and a power of 0.8. Both between and within group comparisons of BIS and hemodynamic data were analyzed using two-way repeated measures analysis of variance followed by Scheffé post hoc testing as required. Normal distribution was determined using the Kolmogorov–Smirnov test. Categorical data were analyzed using Fisher’s exact test. Other data were compared between the groups using paired Student’s t-test. All analyses were performed using StatView software version 4.0 (Abacus Concepts, Berkeley, CA). A P value <0.05 was considered significant.
Forty parturients were enrolled into the study, 20 in each group. There were no differences between groups with respect to age, weight, height, or gestational age. Blood loss and surgical characteristics did not differ between the groups (Table 1). The duration of painful labor was 5.4 ± 1.9 h in the labor group.
The BIS values during significant intraoperative events are illustrated in Figure 1. Baseline BIS values were similar between groups. In the control group, the BIS values decreased after induction of anesthesia and then increased after tracheal intubation to 64 ± 10 (mean ± sd) and further increased to maximum value of 70 ± 6 at skin incision. In the labor group, the BIS values decreased similarly after anesthetic induction and then increased to 47 ± 14 after tracheal intubation and further to the maximum value of 55 ± 12 at skin incision. The increases in BIS from the postinduction to tracheal intubation values (19 ± 11 vs 8 ± 13, P < 0.01) and postinduction to skin incision values (24 ± 10 vs 15 ± 15, P < 0.05) were larger in the control than in the labor group. BIS values in the labor group continued to be lower than the control group in the period between skin incision and 10 min after delivery. Sevoflurane concentrations were approximately 1.0% in both groups throughout the study.
There were no differences in SBP and HR between groups during the whole study period (data not shown). No patient required ephedrine for the treatment of hypotension. The incidence of 1-min and 5-min Apgar scores ≤7 was 20% and 0% in the labor group and 5% and 0% in the control group and was not different between groups.
Maternal plasma concentrations of stress hormones are shown in Table 2. The concentrations of norepinephrine were increased at delivery compared with those at baseline in both groups. Additionally, norepinephrine levels at baseline and delivery were higher in the labor group compared with the control. Plasma concentrations of epinephrine did not differ between the groups at baseline. However, they increased compared with baseline in the control, and remained unchanged in the labor group, at delivery. Epinephrine levels were higher at delivery in the control compared with the labor group. Neither plasma vasopressin nor cortisol concentrations were significantly different within and between groups at any time.
The preoperative pain score was 6.7 ± 0.6 cm in the labor group, whereas there was no continuing pain (0 ± 0) in the control. Twenty-four hour analgesic consumption was significantly less in the labor group (fentanyl 403 ± 131 μg [range 216–648] plus propacetamol 3.1 ± 1.8 g), than in the control (fentanyl 634 ± 199 μg [range 350–993] plus propacetamol 5.1 ± 2.1 g, P < 0.01). However, the VAS scores at rest did not differ between the groups (3.2 ± 0.5 cm vs 3.5 ± 0.4 cm) at 24 h.
The present study demonstrated that laboring women undergoing urgent cesarean delivery had lower intraoperative BIS values and required less analgesia postoperatively than patients undergoing elective cesarean delivery without prior labor given equivalent doses of anesthetics. Induction of anesthesia with thiopental and maintenance with 1% ETSEVO combined with 50% N2O during the period between tracheal intubation and delivery resulted in mean BIS values >60 in the control group, consistent with those reported previously.9 In contrast, in women who had experienced active labor, mean BIS values were <60, consistent with adequate depth of hypnosis to prevent recall.7,8 These findings suggest that maternal physical and psychological stresses associated with labor reduce the afferent nociceptive signals in response to painful stimuli during surgery and increase the tolerance to pain postoperatively. The difference in BIS values between groups was observed before (at tracheal intubation) and after the administration of sevoflurane, suggesting that labor affects the BIS response to both thiopental and sevoflurane anesthesia.
Labor pain, one of the most intense pains experienced by women,15 induces the pituitary release of β-endorphin.11,12 Opioids have been shown to produce analgesia by direct effects. In a sheep model, they were also shown to activate the spinal descending noradrenergic inhibitory pathway.16 Another animal study demonstrated that noxious stimuli cause activation of spinal antinociceptive systems, release of antinociceptive mediators (norepinephrine, enkephalins, and others) in cerebrospinal fluid, and result in an increase in the pain threshold.10 In pregnant women, it was found that these systems may not be tonically active, but may be activated by labor pain. Eisenach et al.13 observed the doubling of cerebrospinal fluid norepinephrine concentrations during painful labor compared with that without labor pain (1240 ± 300 vs 570 ± 160 pmol/L, P = 0.056). Although the data were inconclusive, they hypothesized that activation of descending spinal noradrenergic pain inhibitory pathways during labor might explain the observation.
Surgical stimulation has been shown to induce changes in brain electrical activity during general anesthesia.17 The increase in BIS due to noxious stimulation was suppressed in a concentration-dependent manner by remifentanil.18 Our study demonstrated that the increases in BIS after tracheal intubation and skin incision were lower in the labor group than in the control (P < 0.05). A possible explanation is that β-endorphin released during painful labor may suppress afferent nociceptive inputs during painful stimuli by direct effects and/or by activating the spinal descending noradrenergic inhibitory pathway, resulting in an attenuated BIS response. Furthermore, this antinociceptive effect may extend into the postoperative period, as evidenced by the reduced postoperative analgesic requirements observed in the current study, and by Eisenach et al.13
Stress conditions can cause hormonal responses, such as increased secretion of catecholamines, β-endorphin, cortisol, and vasopressin.11,12,19,20 As 1% ETSEVO in 50% N2O may induce relatively light anesthesia in women undergoing elective cesarean delivery9 compared with those who had prior labor, we postulated that the stress hormone responses would be decreased in the latter. Indeed, epinephrine levels remained unchanged at delivery from the baseline values in the labor group, although they increased in the control group. In contrast, the plasma norepinephrine concentrations were higher at both baseline and delivery in the labor group compared with the control group. Since spinal norepinephrine is an antinoceptive mediator,10 and α2 agonists have a profound effect on BIS values,21 it is tempting to postulate an inverse relationship between plasma norepinephrine concentrations and BIS values. However, several lines of evidence argue against a simple relationship between labor, plasma norepinephrine, and BIS values. Plasma norepinephrine levels were unrelated to cerebrospinal fluid levels in a study of term pregnant women.22 Moreover, subjects given diazepam demonstrated an inverse relationship between BIS and plasma norepinephrine levels.23 Finally, in the current study, baseline BIS values did not differ before induction of anesthesia between the groups, although plasma norepinephrine levels did.
BIS values were above 60 in the control group, which is considered at risk for awareness. One may thus argue that the use of 0.5 MAC volatile anesthetics in 50% N2O during elective cesarean delivery is inadequate. However, this small-dose anesthetic technique is still popular in Korea, and we are not aware of any claims of awareness during cesarean delivery in our practice. We generally titrate the analgesic component of general anesthesia on the basis of changes in SBP and/or HR rather than BIS values. However, because of the frequent incidence of awareness associated with this technique in women in the United Kingdom,4 and reports that the technique is associated with BIS values >60 in many women,9,24 anesthesiologists from Western countries are using volatile anesthetics at higher than 0.5 MAC concentrations before delivery, and supplementing inhaled anesthesia with IV sedative-hypnotics and analgesics after delivery.
The BIS values in the current study appear to be slightly higher (5–10 BIS units) than those in the previous study done by Chin and Yeo,24 both at skin incision and subsequent times. However, the induction to skin incision time in the current study was shorter than in their study24 and this may have resulted in lower brain concentrations of sevoflurane and hence higher BIS values at the time of skin incision.25 Furthermore, Chin and Yeo did not specify whether or not laboring women were included in their study, and this may have influenced the BIS values.
Our study has several limitations. First, we could not standardize all of the surgical and other factors that may have influenced the stress responses. Apart from the prolonged painful labor of at least 4 h, the labor group differed from the control group in many aspects, including the presence of anxiety, exhaustion, and nonreassuring fetal status, exposure to various medications, acid–base status, and others. By unknown mechanisms, these differences may also have contributed to the altered BIS response to general anesthesia and painful stimuli observed in this study. Second, norepinephrine is released in a paracrine fashion from sympathetic nerve terminals, and its plasma levels may not reflect central nervous system levels.22 Third, β-endorphin is released during labor,11,12 and opioids reduce the BIS response to a painful stimulus18; therefore, measurement of endogenous opioids may have provided additional information. Finally, data collection was not performed in a blinded fashion, since it was clear to investigators which patients were laboring and which were not. Ideally, the investigator who recorded the data would not have known the group assignment. However, since many of the observations are objective (e.g., BIS value, SBP, HR), and the investigator was not involved in the intraoperative care, a lack of intraoperative blinding is unlikely to have influenced our results.
In conclusion, intraoperative BIS values during 1% sevoflurane/50% N2O general anesthesia were lower, and postoperative analgesic consumption was reduced, in women with prior labor undergoing cesarean delivery compared with women without prior labor. Further studies are needed to elucidate the underlying mechanisms, which may be multifactorial.
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