Remifentanil is a potent, short-acting μ-opioid agonist related chemically to fentanyl (1). Its major advantage over other opioids stems from its rapid onset of action and rapid clearance rate by red blood cells and tissue esterase to an inactive metabolite, with a T½ keo of 1.3 min (2). Consequently, prolonged administration does not cause accumulation of the drug. Previous reports have shown remifentanil to be effective when used as an adjunct to general anesthesia in parturients requiring cesarean delivery (3–6). However, clinical studies on the use of remifentanil for labor pain have been restricted to case reports or small series with contradictory and inconclusive results regarding maternal and fetal side effects, appropriate dosing, and mode of administration (7–15). The main objective of this investigation was to compare the analgesic effect of remifentanil administered as patient-controlled IV analgesia (PCIA) with the effect of an IV infusion of meperidine for labor pain. Additionally, effects of treatment methods on labor, delivery, and fetal outcomes were assessed.
In this randomized, controlled trial, every parturient who requested analgesia other than epidural analgesia and agreed to receive systemic analgesia was invited to participate in the study. Approximately 30% of our parturients requested analgesia other than epidural analgesia. Randomization was based on computer-generated codes kept in sequentially numbered opaque envelopes until just before use. After we obtained institutional and Ministry of Health approval for human studies and patients’ written informed consent, 88 term parturients with singleton cephalic presentation requesting systemic analgesia (ASA physical status I or II) were recruited. All women were in active labor (cervical dilation of 3–6 cm). After randomization, the parturients received either PCIA with remifentanil (n = 43) or an IV infusion of meperidine (n = 45) throughout labor. For blinding, PCIA remifentanil parturients were connected to a dummy IV saline bag, and IV meperidine parturients were connected to a dummy saline PCIA. We chose this mode of administration of meperidine because of its different pharmacokinetic and pharmacodynamic characteristics, which could have led to overdose and neonatal respiratory depression, as was observed in our pilot study. The specific dosing scheme for remifentanil was based on previous studies and our pilot study. Exclusion criteria were an ASA physical status of III or more, obesity (more than 100 kg or body mass index >40 kg/m2), history of drug (including analgesic chronic use or large doses) or alcohol abuse, smoking more than 10 cigarettes per day, and abnormal liver, renal, or hematologic function. After admission to the delivery room, patients were placed in a left lateral tilt, lactated Ringer’s solution 150 mL/h was infused, and fetal heart rate and uterine activity were recorded by using external monitoring. Fetal invasive monitoring—i.e., scalp electrode, intrauterine pressure recording, or fetal scalp blood samples—was used as warranted for obstetrical indications. Maternal monitoring included noninvasive arterial blood pressure, heart rate, respiratory rate, and pulse oximetry. Each patient’s pain score was assessed with the visual analog scale (VAS) by using a horizontal line of 100 mm with 2 anchors (1 at each end; no pain to worst pain) (16). The VAS was recorded before analgesia, 1 h after analgesic administration, and at the end of the first stage of labor. A senior anesthesiologist, not involved in data recording, attended each parturient throughout labor. Patients randomized to receive remifentanil were connected to PCIA by a one-way infusion line (PCAM Syringe Pump Model P500; IVAC Medical Systems, NH) with patient-controlled boluses of 20 μg each as a starting dose, regardless of parturient weight, and a 3-min lockout interval without basal infusion. The dose was increased by the attending anesthesiologist every 15 to 20 min by 5-μg increments, on patient request, to a maximum dose limit of 1500 μg/h. If any parturient had reached the maximum dose, a single bolus would have had 70 μg (0.93 μg/kg). For inadequate analgesia, adverse effects due to opioids, or failure of the technique (VAS >40), epidural analgesia was offered. The decision to cross over from systemic opioids to epidural analgesia was made by the parturient in corroboration with the anesthesiologist and after an additional trial of increasing the dose of the analgesic and a repeat VAS score of ≥40. Although satisfactory analgesia is often considered a VAS of <30, in our study group the VAS before the administration of analgesic was more than 80, and a VAS of <40 was satisfactory in most of our patients. A VAS of 40 was considered an indication for crossover to epidural analgesia.
Parturients in the control group received 75 mg of meperidine in 100 mL of normal saline over 30 min (approximately 1 mg/kg in a single bolus), as applied routinely in our labor and delivery ward. In case of insufficient analgesia, another dose of 75 mg, followed by 50 mg when necessary, was administered, to a maximum dose of 200 mg of meperidine. Reduced fetal heart rate variability and reactivity after opioid administration is a well known side effect of opioids that causes fetal heart rate tracing changes. Therefore, this was not regarded as a contraindication for continuation of treatment. Parturients from both groups were also assessed every 30 min until delivery for maternal hemodynamic and respiratory variables. The amount of drug used was recorded, as were the Ramsey sedation score (graded between 1 [anxious] and 6 [unarousable]), nausea and vomiting, mode of delivery, and patient cooperation (the ability to push and follow instructions during delivery). The ability to push was not quantified (graded). To avoid possible hypoxemia, supplemental oxygen was administered to the parturients whenever Spo2 decreased to less than 95%. Fetal heart rate during labor and fetal outcome—including Apgar score, umbilical artery pH, problems with breast-feeding, and serum bilirubin level—were also recorded. Patient satisfaction (Grade 1, poor; Grade 2, fair; Grade 3, good; Grade 4, excellent) was assessed 24 h after delivery by an anesthesiologist blinded to the mode of labor analgesia.
Data analysis was performed with SPSS 9.0 for Windows (SPSS Inc., Chicago, IL). This double-blind, randomized, controlled clinical trial enrolled 88 parturients, which provided 80% power to detect a reduction of 15% in the VAS scores reported by participants in the remifentanil group compared with the meperidine group. On the basis of experience with VAS scores in meperidine-treated parturients in a pilot investigation, it was assumed that a mean score of 50 ± 11 points would be observed. Furthermore, it was assumed that to be clinically meaningful a difference in VAS score of at least 15% was required. Sample-size calculation was based on the aforementioned assumptions by using the equation for sample-size determination for the Student’s t-test for independent samples (two sided). The ratio of the expected difference in the two means to the sd was 0.65. Continuous variables, such as maternal and fetal weight and age, were reported as mean ± sd. The distribution of continuous variables for normalcy was tested with the Kolmogorov-Smirnov test. Hypothesis testing for normally distributed data was done with the Student’s t-test for independent samples, and the treatment group was used as the categorical variable. Data with distributions differing significantly from normal were tested with the Mann-Whitney U-test or median tests. Categorical data were described with frequency counts and percentages and were compared by treatment group by using the χ2 test (with the Yates correction as appropriate) or Fisher’s exact test as needed. All differences in data were considered significant at P < 0.05.
Eighty-eight parturients were enrolled and completed the study: 43 received remifentanil, and 45 received meperidine. Eight parturients were excluded from the study before enrollment because of obesity (n = 4), heavy smoking (n = 3), and drug abuse (n = 1). The groups did not differ demographically (Table 1), either in proportion to primiparity or to the cervical dilation at which analgesia was initiated. The duration of labor (active phase and second stage) and oxytocin use did not differ between groups. In the remifentanil group, 93% of deliveries were spontaneous, versus 84.4% in the meperidine group. The instrumental-delivery ratio (vacuum extraction) was not different between groups (2.3% versus 4.4%). Low or outlet forceps were not used in either group. The cesarean delivery rate was not significantly different: two cases (4.6%) in the remifentanil group versus five cases (11.1%) in the meperidine group. The indications for cesarean delivery in the remifentanil group were acute fetal distress in one patient (versus one case with meperidine) and arrest of descent in the other (versus four cases with meperidine). In all patients with a nonreassuring fetal heart rate pattern, arterial cord blood pH values were ≥7.28, and Apgar scores were ≥8 at 1 and 5 min in both groups.
The VAS scores in labor and delivery during remifentanil administration (Table 2) were lower than with meperidine (P < 0.001). All patients receiving remifentanil were cooperative during delivery, versus 82% in the meperidine group. The need to cross over to epidural analgesia occurred only because of unsatisfactory pain control. This happened more frequently in the meperidine group than in the remifentanil group (38.8% versus 10.8%, respectively; P < 0.007). The time interval for crossover to epidural analgesia was not longer in the meperidine group as compared with the remifentanil group (428.5 ± 188.4 min versus 309.8 ± 180.2 min, respectively). All crossovers to epidural analgesia occurred during the first stage of labor. Patient satisfaction was higher (3.9 ± 0.6 versus 1.9 ± 0.4; P < 0.001) in the remifentanil group as compared with the meperidine group. With respect to analgesic requirements (Table 3), the mean starting PCIA dose of remifentanil (per bolus) was 0.27 μg/kg. The maximal PCIA dose of remifentanil (per bolus) was 0.93 ± 0.10 μg/kg. The median (range) total dose of remifentanil per hour was 270 μg/kg (89–1018 μg/kg). For meperidine, the median total dose required per patient was 150 mg (75–200 mg).
There were no differences between groups with respect to systolic and diastolic blood pressure, heart rate, and respiratory rate at each stage of labor (Table 4). The decrease in oxygen saturation during meperidine administration was significant as compared with remifentanil (94.2% ± 1.5 versus 97.5% ± 1.0; P < 0.001). The values recorded were the lowest values measured. Eight patients (17.7%) in the meperidine group and none in the remifentanil group had decreases in Spo2 to less than 95%. Meperidine produced more sedation (2.8 ± 0.1 versus 1.2 ± 0.1; P < 0.001) compared with remifentanil.
Table 5 lists the fetal and neonatal variables. Variable fetal heart rate decelerations were more frequent in parturients treated with meperidine (P < 0.001). More parturients receiving meperidine had abnormal fetal heart rate patterns compared with those in the remifentanil group. Variable deceleration at the end of the second stage of labor was seen in 2.4% of the remifentanil group and in none of the meperidine group. There were no differences between infant outcome variables (Table 5).
Nausea, vomiting, or pruritus was not observed with remifentanil administration, even with increased doses. In the meperidine group, nausea and vomiting occurred in 5% of the parturients (P < 0.001) and were treated satisfactorily by IV metoclopramide 10 mg.
The results of this study indicate that PCIA with remifentanil during labor and delivery is associated with improved VAS scores, higher patient satisfaction, and less need to cross over to epidural analgesia compared with IV meperidine. Although our protocol allowed for increasing the dose of remifentanil on demand throughout labor, there was a small rate of sedation and minimal respiratory or cardiovascular depression. With respect to fetal or neonatal side effects, remifentanil was associated with fewer abnormalities of the fetal heart rate tracing. Neonatal outcome was similar in both groups.
Meperidine, the most widely used systemic opioid for labor pain relief (17,18), is more sedative than analgesic (17–19) and has well documented neonate side effects when given in large doses (13,18,20,21). In two studies (13,15), the efficacy of PCIA remifentanil during labor was compared with that of PCIA meperidine (13) or with IM meperidine (15). PCIA with meperidine caused low Apgar scores and led to the termination of the study after the incorporation of 17 subjects (13). When PCIA remifentanil was compared with IM meperidine (15), the pain scores were lower in the remifentanil group, and the respiratory depressant effect was greater. In this study, we administered remifentanil as PCIA or meperidine (given in a limited dose—up to 200 mg—to avoid excessive sedation and other negative effects). We were convinced after a pilot study that repeated small doses of remifentanil were not causing maternal and neonatal side effects.
Remifentanil is a potent, ultra-short-acting opioid with a rapid onset and offset of action regardless of the duration of administration and with no active metabolites (1–3). Beneficial analgesic effects and a lack of significant maternal and neonatal side effects have been reported with the use of remifentanil as an adjunct to epidural or general anesthesia for cesarean delivery and in parturients with preeclampsia and cardiomyopathy (3–6). The effect of remifentanil as a systemic analgesic for labor was noted in a few case reports and small series, with contradictory results with respect to maternal and neonatal adverse effects with various doses and modes of administration (8–10). Lavand’homme et al. (11) and Dhileepan and Stacey (12), in a Letter to the Editor, responding to the study of Olufolabi et al. (10), suggested other explanations for remifentanil failure, i.e., too-small doses, rather than a tolerance to the effects of remifentanil. In another study comparing 18 parturients receiving PCIA remifentanil with a control group receiving IM meperidine, those who received remifentanil had better pain relief (15), but had more respiratory depression as compared with the treatment with meperidine. Remifentanil, when administered without background infusion, provided safe but incomplete analgesia (14). Because painful contractions in labor are normally intermittent (every three to five minutes) and because remifentanil is an ultra-short-acting drug, we deemed it inappropriate to apply continuous analgesia. Rather, providing an intermittent incremental regimen with starting boluses of 20 μg each, irrespective of the parturient’s weight, and increasing the bolus dose slowly over time, may be more effective and have fewer side effects. In this manner, we tried to reduce the sedative effect of remifentanil and keep the parturients alert most of the time, with minimal respiratory depression. Most parturients had satisfactory analgesia with boluses of 25–40 μg; rarely was the bolus dose increased to 70 μg (0.93 μg/kg), although the possibility of further increasing the dose was not limited.
The effect of remifentanil on fetal heart rate was less pronounced than that of meperidine. Fetal heart rate in the remifentanil group remained reactive (89.8% versus 38.2%) with meperidine even with an increased dosage of remifentanil. This could be explained by the gradual increase of the dose and the shorter duration of the drug action. In this context, the potential adverse effect of meperidine on the fetus should be mentioned. When epidural analgesia is contraindicated or refused by the patient and meperidine is used instead, the dose may need to be increased more than once or twice. This may be problematic because of the adverse effects of meperidine, including nausea, vomiting, drowsiness, and neonatal respiratory depression (20–24); thus, the use of remifentanil in patients in whom epidural analgesia is contraindicated may be more advantageous. The relatively infrequent neonatal side effects seen in the meperidine group were probably related to the following two factors: only 45% received more than 75 mg of meperidine, and 38.8% of parturients requested to cross over from meperidine to epidural analgesia because of unsatisfactory analgesia. Another interesting finding is that stable hemodynamics were seen with both drugs (Table 4): this may suggest that fetal heart rate changes were not caused by the hemodynamic side effects of the drugs themselves.
The cesarean delivery rate was not significantly different between groups. Neonatal outcome was comparable in both groups studied; it was satisfactory, with infrequent adverse effects regardless of the dose of remifentanil used. In our series, which is the largest to date, we did not observe any adverse effects of this drug.
In conclusion, PCIA remifentanil appears to provide better analgesia than meperidine throughout labor and delivery and has minimal maternal or neonatal side effects. These findings may justify the use of remifentanil as a systemic opioid in labor and delivery whenever there is a contraindication to neuraxial analgesia. A large study is still necessary to investigate the maternal and fetal side effects. To decrease the likelihood of maternal and neonatal hypoxemia, continuous monitoring of the oxyhemoglobin saturation of the parturient is recommended.
We wish to extend our appreciation to Judy Brandt for her English editing and word-processing expertise and contributions.
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