The activation of the sympathetic system during caesarean section is associated with an increase in maternal plasma catecholamine concentrations and results in umbilical arterial vasoconstriction with reduced oxygen delivery to the neonate.1 Adjuvant drugs that decrease maternal sympathetic nervous system activity would be a favourable addition to anaesthesia induction, and opioids are the most preferred adjuvant agents for this purpose. In the obstetric population, the preferred opioid should provide rapid recovery and reduce the risk of prolonged neonatal respiratory depression to a negligible amount.2 Remifentanil with its short context-sensitive half-life has been shown to be suitable during caesarean section in high-risk parturients by providing excellent intraoperative haemodynamic stability and causing no adverse effects in the neonates.3
The potential benefits of remifentanil on marked haemodynamic response during caesarean section has been demonstrated even in healthy parturients. However, remifentanil administration at induction of general anaesthesia was the cause of respiratory depression in neonates with an incidence of 5–7.5%.4,5 To balance the overall effects of remifentanil on both the parturient and the neonate, a dose range should be determined in this highly specific group of patients. In our study, we aimed to describe a dose range and compared the effects of different remifentanil dose regimens on Apgar scores in healthy parturients.
Sixty ASA I or II parturients who opted for general anaesthesia were randomly allocated into four groups by the sealed envelope technique and participated in this prospective, double-blind study after the local ethics committee approved the study protocol and written informed consent was obtained. The demographic data of the patients were noted and standard monitoring for heart rate, mean arterial pressure and oxygen saturation was carried out and measurements were recorded at induction, intubation and at 1, 3 and 5 min after intubation. The remifentanil bolus and infusion doses were calculated according to the patient's lean body mass (LBM) values with the following equation: LBM = 1.07 × weight − 148 × (weight/height)2. The infusion solution was prepared as a 5 μg ml−1 concentration of remifentanil and was given by means of an infusion pump by an anaesthesiologist who did not participate in the study.
A 1 μg kg−1 remifentanil bolus calculated according to LBM was given and calculated infusion doses were started with the infusion pump immediately after the bolus dose. Group I received a saline infusion following the bolus remifentanil to provide blinding and the remifentanil infusion doses were 0.0625, 0.125 and 0.25 μg kg−1 min−1 in groups II, III and IV, respectively. Induction was sustained with 5 mg kg−1 thiopental and 1 mg kg−1 rocuronium. Tracheal intubations were performed 1 min after anaesthesia induction. Anaesthesia was maintained with 1% inspired sevoflurane and 50% O2 in air until delivery and sevoflurane was increased to a concentration of 2–3% after clamping of the umbilical cord. At the end of the surgery, residual neuromuscular block was antagonized using neostigmine and atropine. Total remifentanil consumption until delivery, induction–delivery time, duration of surgery and anaesthesia were also recorded.
Following delivery of the fetus, a paediatrician evaluated the neonates and recorded Apgar scores at 1 and 5 min. The paediatrician was informed about the study but was unaware of the group assignment. The resuscitation of neonates with low Apgar scores was also performed by the same paediatrician. The systematic resuscitation process for those neonates included tactile stimulation, mask ventilation, naloxone administration and intubations. The newborns who did not recover following mask ventilation in 60 s were treated with naloxone. The resuscitated neonates were admitted to the neonatal intensive care unit for clinical observation. The need for tactile stimulation, mask ventilation, the necessity for intubations and treatment with naloxone were also recorded.
The primary outcome parameter of this study was the Apgar score at 1 min. A power analysis indicated that 15 patients per group were required to detect a true difference of 1 unit between Apgar scores at 1 min where the standard deviation was 0.94 (α = 0.05 and β = 0.20). SPSS 10.0 (Statistical Package for the Social Sciences, version 10.0, SSPS Inc., Chicago, Illinois, USA) was used to analyse the data. Statistical analyses were performed using a one-way analysis of variance (ANOVA) for repeated measures. Data were expressed as mean value ± standard deviation and a P value less than 0.05 was considered to be statistically significant.
The study groups were similar with respect to demographic data, that is, age, weight, height, gestational week, ASA physical status and LBM values. Heart rate and mean arterial pressure were not significantly different between the groups, although intubations resulted in a similar increase in heart rate in all groups. Induction–delivery time, duration of anaesthesia and surgery were also similar between groups. Remifentanil consumption from induction to delivery was 47.6 ± 3.7 μg in group I, 61.8 ± 6.7 μg in group II, 82.2 ± 12 μg in group III and 78.4 ± 32 μg in group IV.
Apgar scores were similar between groups recorded at 1 and 5 min. Two neonates in group I had Apgar scores of 5 or less at 1 min. One of these neonates was born apneic with chest wall rigidity and had Apgar scores of 3 and 7 at 1 and 5 min, respectively. He was treated with naloxone and required assisted ventilation. Two neonates in group II and one neonate in group IV required brief mask ventilation because of the absence of breathing. Within 5 min, one neonate in group II resumed spontaneous ventilation, whereas the other was treated with naloxone. In group III, one of the neonates presented with brief respiratory depression and required respiratory support by face mask (Table 1).
Remifentanil as an adjuvant agent during general anaesthesia induction has been reserved to maintain an alternative anaesthesia strategy for high-risk parturients, and it has been demonstrated that remifentanil administration prevented maternal haemodynamic response adequately and provides acceptable Apgar scores in neonates.3 In healthy parturients, knowledge of the safety profile for remifentanil as demonstrated by Apgar scores can also provide an option for opioid-based general anaesthesia for caesarean section.
In our study, we chose to use a 1 μg kg−1 remifentanil bolus dose according to a study in nonobstetric patients. In that study, a bolus dose of 0.5 μg kg−1 was demonstrated to be ineffective in controlling stimulus-related haemodynamic and stress response, whereas the use of a 1.25 μg kg−1 dose was associated with cardiovascular depression which might be intolerable in obstetric patients.6 The infusion dose was determined to be less than 0.5 μg kg−1 min−1 according to a case series where respiratory depression was observed in 50% of healthy newborns.7 Therefore, we preferred to investigate the favoured remifentanil dose regimen for healthy parturients of 0.0625, 0.125 and 0.25 μg kg−1 min−1 infusion doses. The results demonstrated that the incidence of low Apgar scores at 1 min was only 10% with the use of each infusion regime following a preceding bolus dose of 1 μg kg−1. Furthermore, the theoretical consideration that any respiratory depression would be transitory as remifentanil rapidly clears from the neonate was also confirmed with high Apgar scores at 5 min.
In our study, remifentanil was administered at lower bolus and infusion doses than in previous reports because we calculated remifentanil doses according to the patients' lean body mass values. Independent of the remifentanil dose, brief respiratory depression and low Apgar scores were observed at 1 min and, with the advantage of the lack of remifentanil accumulation in neonates, rapid spontaneous respiration and full recovery was established within 5 min. Although remifentanil has the potential to cause a degree of neonatal respiratory depression, as mentioned above, our results did not support the assumption that maternal remifentanil doses used in the study cause neonatal respiratory depression because of the absence of a control group without remifentanil. The lack of a control group means that it is difficult to determine the most suitable dose of remifentanil and implies that adding remifentanil to general anaesthetics for caesarean section needs to be assessed in subsequent trials.
In conclusion, we planned to determine an effective remifentanil dose range for opioid-based general anaesthesia with favourable Apgar scores in healthy parturients who prefer general anaesthesia despite a regional technique possibly being superior. The calculated remifentanil bolus and infusion doses according to LBM values were preferred and suggested that the remifentanil dose regimens up to 0.25 μg kg−1 min−1 following a 1 μg kg−1 bolus would be acceptable in healthy parturients when opioid-based general anaesthesia is preferred or chosen for clinical reasons because of the unique properties of remifentanil. However, one should keep in mind that brief respiratory depressions and transient low Apgar scores might occur independently from the investigated remifentanil dose regimens in our study and paediatricians who deal with any problems in neonates arising after general anaesthesia should also be aware of remifentanil administration.
1 Conklin KA, Backus AM. In: Chestnut DH, editor. Physiologic changes of pregnancy
. 2nd ed. Tennessee: Mosby; 1999; chapter 2.
2 Buerkle H, Wilhelm W. Remifentanil for gynaecological and obstetric procedures. Curr Opin Anaesthesiol 2000; 13:271–275.
3 Michelsen LG, Hug CC Jr. The pharmacokinetics of remifentanil. J Clin Anesth 1996; 8:679–682.
4 Ngan Kee WD, Khaw KS, Ma KC, et al
. Maternal and neonatal effects of remifentanil at induction of general anesthesia for cesarean delivery: a randomized, double-blind, controlled trial. Anesthesiology 2006; 104:14–20.
5 Kolsi K, Sow A, Derbel M, et al
. Neonatal effects of a remifentanil-based technique in general anesthesia for planned cesarean section. Eur J Anaesthesiol 2006; 23:178–179.
6 O'Hare R, McAtamney D, Mirakhur RK, et al
. Bolus dose remifentanil for control of hemodynamic response to tracheal intubations during rapid sequence induction of anaesthesia. Br J Anaesth 1999; 82:283–285.
7 Alexander R. Hemodynamic changes with administration of remifentanil following intubations for caesarean section. Eur J Anaesthesiol 2002; 19(Suppl 24):A571.