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OBSTETRIC ANESTHESIA

Remifentanil in Obstetric Analgesia: A Dose-Finding Study

Petri Volmanen, MD^*, Ethem I. Akural, MD, Tytti Raudaskoski, MD, PhD, and Seppo Alahuhta, MD, PhD

*Lapland Central Hospital, Rovaniemi, Finland; and Departments of Anaesthesiology and Obstetrics and Gynaecology, University of Oulu, Oulu, Finland

Address correspondence and reprint requests to Petri Volmanen, MD, Lapland Central Hospital, PL 8041, 96101 Rovaniemi, Finland. Address e-mail to petri.volmanen{at}lshp.fi

	Abstract

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IV patient-controlled analgesia (PCA) with remifentanil is a new approach in systemic opioid analgesia during labor. We determined the minimum effective dose of IV remifentanil by increasing the PCA bolus from 0.2 µg/kg with 0.2 µg/kg increments during a 60-min study period until the analgesia was considered adequate by the parturient. Twenty healthy parturients with singleton pregnancies participated in the study during the first stage of labor. Remifentanil hydrochloride was given IV via PCA over 1 min with a lockout time of 1 min. The parturient started the PCA bolus at the first subjective sign of uterine contraction. All 17 patients who completed the study reached adequate pain relief. The median effective PCA bolus was 0.4 µg/kg and consumption was 0.066 µg · kg^-1 · min^-1, with wide individual variation (0.2–0.8 µg/kg and 0.027–0.207 µg · kg^-1 · min^-1, respectively). The pain scores were reduced by a median of 4.2 (25th–75th percentiles, 3.1–5.2; P < 0.001) on an 11-point numeric scale. Although there was a wide individual variation in the dose required, remifentanil seems effective for labor analgesia. However, maternal oxygen desaturation, sedation, and reduced fetal heart rate beat-to-beat variability were observed frequently. There was wide individual variation in the dose required for effective labor analgesia. Potentially serious side effects, which were observed frequently during remifentanil analgesia, may limit remifentanil’s use in obstetrics.

IMPLICATIONS: We determined the minimum effective dose of patient-controlled IV remifentanil for labor analgesia. There was wide individual variation in the dose required for effective labor analgesia. Potentially serious side effects, which were observed frequently during remifentanil analgesia, may limit its use in obstetrics.

	Introduction

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Remifentanil is a new ultrashort-acting µ-receptor agonist with a rapid onset of action after an IV dose and a context-sensitive half-time of approximately 3 min. Remifentanil crosses the placenta but is metabolized rapidly in the neonate (1). Because of these features, remifentanil may be a safer and more effective alternative for obstetric analgesia than the parenteral opioids currently being administered to parturients not receiving neuraxial analgesia.

Remifentanil is not currently indicated for obstetric use. However, five cases of effective IV patient-controlled (PCA) remifentanil analgesia during labor have been reported (2,3). In these reports, a bolus dose of 0.2–1.0 µg/kg in <20 s with a lockout time of 2–3 min was used. In one case, the initial PCA bolus of 75 µg (approximately 1.0 µg/kg) was noted to cause maternal sedation and fetal heart rate (FHR) tracing decelerations. These side effects subsided when the PCA bolus was reduced to 0.5 µg/kg (2). Six cases of successful IV remifentanil labor analgesia have been reported, in which a continuous infusion of 0.05 µg · kg^-1 · min^-1 was combined with 25-µg PCA boluses (4). A rapid manual bolus of 0.5 µg/kg was used in a preliminary study, which attempted to determine a suitable dosage regimen for remifentanil used to treat labor pain. That study, however, was terminated because of significant maternal side effects in the absence of effective pain control (5).

Experience is limited regarding the dose requirements and safety of remifentanil analgesia during labor. We designed a study to evaluate the minimum effective analgesic dose of remifentanil and to assess the safety of short-term remifentanil when it is administered for pain relief during the first stage of labor.

	Methods

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The study protocol was accepted by the ethical committee of Oulu University Hospital and the National Agency for Medicines. After written informed consent was obtained, we studied 20 healthy term parturients with uncomplicated singleton pregnancies. The patients were recruited during the first stage of labor (<7 cm cervical dilatation) if the fetus was in a normal cephalic presentation and there was no prior administration of regional or opioid analgesia.

Before the administration of drug, the patients were introduced to the PCA pump and carefully instructed in its use. The PCA device was set to deliver 0.2 µg/kg (the smallest PCA bolus used in earlier studies) of Ultiva^® (remifentanil hydrochloride; Glaxo Operations UK Ltd., Durham, UK) as a bolus infused during a period of 1 min with a lockout time of 1 min to an IV catheter attached to a continuous infusion of saline at approximately 100 mL/h. During the study, the PCA bolus was increased by 0.2 µg/kg increments every 10 min until the parturient did not want more analgesia, until a maximum dose of 0.8 µg/kg was achieved, until there was a sign of a serious side effect (arterial oxygen saturation [SaO₂] <92%, respiratory rate <8 breaths/min, FHR <80 bpm), or until the total exposure time exceeded 60 min. The parturient was advised to start the PCA bolus at the first subjective sign of a forthcoming uterine contraction. To mimic a normal clinical situation, the subjective signs anticipating uterine contraction were not specified, and no attempts were made to train the parturient in early recognition of the onset of contractions. The decision as to whether to start the PCA bolus was left solely to the patient. Remifentanil hydrochloride was diluted with saline and given as a solution of 25 µg/mL. There was no background infusion or limit for the total dose.

The parturients assessed their pain scores on an 11-point numeric rating scale (0 = no pain, 10 = worst pain imaginable) and assessed the pain relief on a ranked categorical verbal rating scale (4 = complete, 3 = good, 2 = moderate, 1 = slight, 0 = no relief). They assessed side effects and desire for more effective analgesia every 10 min. SaO₂ and heart rate were monitored continuously and recorded at 1- and 5-min intervals, respectively. Noninvasive blood pressure was recorded at 5-min intervals. After the experiment, patient satisfaction was assessed, and each parturient was asked whether she would have liked to continue with remifentanil PCA if this had been available for routine clinical use.

FHR tracings were monitored with an HP 8040A cardiotocogram recorder (Hewlett-Packard, Böblingen, Germany) by using an external ultrasound transducer, or a scalp electrode if membranes were ruptured. Parturients labored in the lateral recumbent position or sitting in a rocking chair to prevent supine hypotension. The FHR tracings were analyzed by an obstetrician blinded to the dose used by the patient. The Apgar scores were given by midwives blinded to the dose used by the patient, and the umbilical artery pH of the newborns was recorded.

The patients scored the presence and intensity of side effects as follows: sedation (four-point rank score: awake and alert, awake but drowsy, drowsy but arousable, and unarousable), nausea, and itching (four-point rank score: none, slight, moderate, or severe). Respiratory rate, hemoglobin oxygen saturation, and blood pressure were monitored noninvasively with a Datex-Ohmeda Light monitor (Instrumentarium Corp., Helsinki, Finland). Hemoglobin oxygen saturation was recorded at 1-min intervals. Oxygen saturation of <94% during two or more subsequent recordings was considered as an episode of desaturation.

An individual effective dose was defined as the largest bolus dose during which the patient did not want to have more analgesia. Because pain intensity tends to increase during labor, the mean of the pain scores at 0 and 80 min was chosen as the reference value (i.e., the pain intensity when no analgesic effect was assumed). The pain intensity difference was calculated for each parturient as follows: the reference value subtracted by the mean of the pain scores given during the time the parturient used the effective dose. SPSS 9.0 (SPSS Inc., Chicago, IL) was used for statistical analysis. Wilcoxon’s signed-rank test was used for the comparison of pain and pain relief scores. The Mann-Whitney U-test was used for the comparison of remifentanil consumption during the effective dose among three dichotomous pairs of subgroups (primipara/multipara, desaturation <94%/no desaturation <94%, and FHR changes/no FHR changes). The Spearman test was used for correlation. P values <0.05 were considered statistically significant. Continuous variables are expressed as median and 25th–75th percentiles.

	Results

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Three women entered the second stage of labor during the study period and were excluded. Twelve primiparous and five multiparous mothers completed the study. The main characteristics of the women are listed in Table 1. One woman was started at a PCA bolus dose of 0.4 µg/kg because of a calculation error. However, she was included in the sample because her individual effective dose was higher than the initial dose.

The median pain intensity difference was 4.2 (3.1–5.2, P < 0.001). The pain scores recorded during the experiment are shown in Figure 1. The median difference in the pain relief scores was 2.7 (1.7–3.6, P < 0.001) when the pain relief scores given during the time the parturients used the effective PCA doses were compared with the ones recorded at the end of the 20-min follow-up time, when no analgesics were given. All 17 women who completed the study would have liked to continue with IV PCA remifentanil if this had been available. The dose (total dose, consumption of remifentanil at the effective dose, and the effective PCA bolus dose) did not correlate with age, weight, cervical dilatation, speed of cervical dilation, average contraction interval, or the pain intensity and the pain relief differences mentioned previously.

View larger version (17K): [in this window] [in a new window]   Figure 1. Median pain scores (±25th and 75th percentiles) during the 60 min when remifentanil was administered and the 20-min follow-up period when no analgesics were given.

Twelve patients had normal FHR recordings. Four patients had reduced beat-to-beat variability alone or combined with early decelerations, and one patient had early decelerations during remifentanil administration. These changes were observed within 30 min of the first remifentanil dose and disappeared within 15 min after the last remifentanil dose. The median consumption of remifentanil at the effective dose of the patients with changes in FHR tracings was 0.10 (0.07–0.18) µg · kg^-1 · min^-1, whereas that of the patients with normal FHR tracings was 0.06 (0.03–0.08) µg · kg^-1 · min^-1 (P = 0.03).

All newborns had Apgar scores of 8 to 10, except one, who had lower Apgar scores of 6, 7, and 7 at 1, 5, and 15 min, respectively. The umbilical artery pH was higher than 7.1 in all cases except two, one of which was the baby with low Apgar scores. This baby was delivered 6 h 15 min after the study period. The mother had fever at the end of the first stage of labor and had antibiotic treatment started immediately after the delivery for suspected chorioamnionitis.

The three mothers who did not complete the study because of entering into the second stage of labor delivered in 13–31 min after the administration of the last dose of remifentanil. The umbilical artery pH was more than 7.1 in all of these cases. The babies were all vigorously breathing and had Apgar scores of 8 or more.

Two parturients spontaneously reported difficulty in reading and visual focusing, and one of them reported difficulty in swallowing toward the end of remifentanil administration. Another spontaneous observation was that most of the mothers shivered during the 20-min follow-up period after withdrawal of remifentanil.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
It seems that it is relatively easy to titrate the IV PCA bolus of remifentanil according to individual needs during labor. With the dose escalation scheme used in this study, most parturients were satisfied with their analgesia within 30 minutes.

The average dose of remifentanil needed to relieve pain was within the same range as that reported in the previously published case reports of successful labor analgesia (2,3). We used a bolus duration of one minute instead of the infusion time of <20 seconds used in the previous cases. According to computer simulations and pharmacodynamic studies of ventilatory responses in nonobstetric populations, the peak central nervous system effect of a remifentanil bolus is estimated to occur 1–2.9 minutes after a fast IV bolus (6–8). Hence, a single bolus given at the beginning of the uterine contraction will probably not give the peak analgesic effect for the contraction for which it was demanded. Depending on the interval of contractions, the peak effect is likely to occur before or during the next contraction. It is possible that the longer duration of the bolus used in our study resulted in a better timing of the maximal effect on the contraction compared with the rapid manual boluses given in the previous study, in which no analgesic effect could be noted (5). The repetition of the PCA dose at every contraction may have resulted in some accumulation of the analgesic effect. However, the analgesic effect disappeared within 20 minutes after the last dose.

There was wide individual variation in the effective doses, which may have been because the sample of parturients was not homogeneous. We included both primiparae and multiparae in the sample, and there was also wide variation between the phase of the first stage at which the parturients were enrolled into the study. A study with more uniform inclusion criteria may yield a narrower dose range. It is also possible that the wide range in the effective doses observed in this study is due to differences in the individual perceptions of ideal labor pain.

The use of parenteral narcotic analgesics for labor pain has been criticized for the lack of evidence of their effects (9). In this study, there was a consistent pain-relieving effect, which was reflected in the pain scores and the pain relief scores. This suggests that remifentanil may have a true analgesic effect on labor pain. This finding is consistent with the recent comparative study showing that remifentanil provided better analgesia than meperidine when IV PCA was used for both opioids (10).

All patients in this study had an initial hemoglobin oxygen saturation of 95% or more, which is in agreement with an earlier study of nonmedicated labor (11). During the administration of remifentanil, most of the patients had periods of oxygen desaturation. The incidence of desaturation increased toward the end of the study and decreased after the discontinuation of the drug. With respect to oxygen saturation, however, short periods of remifentanil analgesia may be no worse than other forms of analgesia. Hemoglobin oxygen desaturation has also been reported during nonmedicated labor, labor with epidural analgesia or IV opioids, and combined analgesia with IM meperidine and nitrous oxide (12,13). There were only minor differences in the consumption of remifentanil between the parturients with and without desaturation periods during the time the parturients were using the effective doses. This suggests that titration of the dose according to individual needs may reduce the risk of this potentially serious side effect. It is also possible to reduce the remifentanil PCA bolus if excessive side effects are noted, as was suggested in the previous report, in which an initial PCA bolus of 1.0 µg/kg caused maternal sedation and deceleration in the FHR (2). Because of the limited number of patients in our study, it is premature to suggest that remifentanil is safe for labor analgesia. The respiratory depression associated with remifentanil may be hazardous in routine clinical use, especially if continuous monitoring of the respiratory function cannot be maintained.

Five patients showed changes in the FHR tracings during the study. The fact that the changes were observed soon after the first remifentanil dose and that they normalized soon after the completion of the last PCA dose of remifentanil suggests a causal relationship. The observed changes were similar to those reported during systemic use of other opioids (14). None of these changes required fetal scalp blood sampling or discontinuation of the study. All these babies had normal arterial blood pH values and high Apgar scores when they were born. It is possible, however, that these FHR changes may be unacceptable to obstetricians, especially in the high-risk patient population.

Remifentanil analgesia did not seem to increase the incidence of nausea during the period of administration. There was, however, an increase in the incidence of nausea after termination of the remifentanil administration. This increase could have been caused by the recurrence of more intense pain. Another explanation could be that at the same time that they were experiencing nausea, many of the parturients began to move around. However, the small number of women experiencing nausea hinders us from making any conclusions.

In summary, remifentanil seems to be potentially effective for obstetric analgesia. Side effects, however, may limit its use. There is wide variation in the individual doses required to achieve pain relief, and it is difficult to find a single dose suitable for all parturients with the administration regimen used in this study. Because of the depressant effect of remifentanil on respiration, continuous monitoring of respiratory function is mandatory, and supplemental oxygen should be given to the parturients receiving remifentanil. The clinician should also expect reduced variability of the FHR after the administration of remifentanil. Further studies to more fully evaluate the safety of remifentanil in labor are recommended.

	References

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999