|Year : 2015 | Volume
| Issue : 2 | Page : 211-216
Neostigmine versus Fentanyl administration with Ropivacaine by patient-controlled epidural analgesia for the management of labor pain
Ahmed A Khalaf MD
Department of Anesthesia, Dubai Hospital, Dubai Health Authority, Dubai, UAE; Department of Anesthesia, ICU and Pain Relief, National Cancer Institute, Cairo University, Cairo, Egypt
|Date of Submission||22-May-2014|
|Date of Acceptance||18-Jun-2014|
|Date of Web Publication||8-May-2015|
Ahmed A Khalaf
Department of Anesthesia, Dubai Hospital, Dubai Health Authority, Dubai (POB 7272 Dubai)
Source of Support: None, Conflict of Interest: None
The aim of this study was to evaluate the use of epidural Neostigmine (4 mcg/ml) in patient-controlled epidural anesthesia (PCEA) in the management of labor pain.
Patients and methods
This randomized double-blind controlled prospective study was designed to compare PCEA Ropivacaine 0.15%+Fentanyl 2 mcg/ml (F group) with PCEA Ropivacaine 0.15%+Neostigmine 4 mcg/ml (N group). The study included 60 ASA I-II laboring mothers. Pain, sedation, nausea, maternal vital signs, motor power, and fetal heart rate were evaluated every 5 min after epidural bolus for the first 30 min, and then every 2 h until delivery. The incidence of shivering was documented. Apgar scores at 1 and 5 min were documented.
There were no differences in maternal and labor characteristics between groups. Progress of labor and modes of delivery were the same (P = 0.47). Pain scores were significantly reduced 20 min after initiation of analgesia compared with baseline in both groups (P < 0.001) and did not differ between groups at any time during the study (P = 0.21-0.43). Addition of Neostigmine reduced the mean hourly epidural dose of Ropivacaine by 11% compared with the Fentanyl group (P = 0.003). There were no differences in maternal vital signs between groups. The sedation score increased compared with baseline through the first 20 min after initiation of analgesia in both groups (Fentanyl P = 0.043 - Neostigmine P = 0.04). There was no significant difference in sedation scores between groups at any time or compared with baseline (P = 0.23-0.46). The incidence of nausea, shivering, pruritus, and motor block was similar in both groups.
Neostigmine 4 mcg/ml can be used as a safe adjuvant with Ropivacaine 0.15% by PCEA for the management of labor pain. Its analgesic properties are comparable to that of epidural Fentanyl. It causes temporary sedation within the first 20 min. This sedation is comparable to that of Fentanyl. Epidural low-dose Neostigmine infusion did not increase the risk for nausea during labor.
Keywords: epidural analgesia, fentanyl, neostigmine, ropivacaine
|How to cite this article:|
Khalaf AA. Neostigmine versus Fentanyl administration with Ropivacaine by patient-controlled epidural analgesia for the management of labor pain. Ain-Shams J Anaesthesiol 2015;8:211-6
|How to cite this URL:|
Khalaf AA. Neostigmine versus Fentanyl administration with Ropivacaine by patient-controlled epidural analgesia for the management of labor pain. Ain-Shams J Anaesthesiol [serial online] 2015 [cited 2021 Apr 17];8:211-6. Available from: http://www.asja.eg.net/text.asp?2015/8/2/211/156689
| Introduction|| |
Ropivacaine is a newly introduced amide local anesthetic that has effects similar to Bupivacaine. It is believed to be less toxic to the central nervous and cardiovascular systems with less motor blockade , . Although local anesthetics alone can provide effective epidural labor analgesia, their use can be complicated by maternal hypotension and motor block, particularly with prolonged infusions. Adjuvant opioids are added to improve the quality of analgesia, decrease local anesthetic use, and minimize motor block. Neuraxial opioids produce pruritus, increase the incidence of respiratory depression, and decrease fetal heart rate (FHR), in addition to the extra time required to document the use of a controlled drug , .
Intrathecal injection of the cholinesterase inhibitor Neostigmine increases extracellular acetylcholine concentrations within the spinal cord. Neuraxial acetylcholine increases the stimulation of spinal muscarinic and possibly nicotinic receptors to produce analgesia  . Intrathecal Neostigmine entered clinical trials, including use in laboring mothers, in whom it demonstrated efficacy but also severe nausea and vomiting , . However, more recent studies of single epidural bolus administration of Neostigmine have shown it to produce effective analgesia without severe nausea or vomiting ,, , and a few studies have examined the safety and efficacy of epidural Neostigmine in obstetrics, which demonstrated an analgesic effect associated with mild sedation, nausea, or vomiting ,, .
The aim of this study was to evaluate the efficacy of Neostigmine 4 mcg/ml added to Ropivacaine 0.15% compared with Fentanyl 2 mcg/ml added to the same Ropivacaine concentration in patient-controlled epidural analgesia (PCEA) for the management of labor pain.
| Patients and methods|| |
After approval of the Dubai Hospital Ethics Committee, written informed consent for study participation was obtained from 60 mothers who requested epidural labor analgesia. All mothers were of American Society of Anesthesiologists (ASA) physical status I or II, weighing less than 115 kg, with a single fetus in active labor and cervical dilation of 6 cm or less. Epidural analgesia was initiated at the mothers' request and they had a minimum verbal pain score of 4.
Five hundred milliliters of lactated Ringer's solution was administered intravenously before the epidural initial bolus. With the mother in the sitting position, an epidural catheter was inserted into the L3-L4 or L4-L5 intervertebral space using normal saline loss-of-resistance technique; then 3-4 cm of catheter was threaded into the epidural space. With the mother in the supine position, a test dose of local anesthetic (3 ml of 1% lidocaine) was administered through the catheter, and the study drugs were then administered through it. All mothers were randomized into two groups (by means of drawing lots and sealed envelopes). When the mother requested for epidural labor analgesia, an attending anesthesiologist (who was familiar with the study protocol but not involved with the care of the mother or with data collection) opened the sealed envelope indicating group assignment and prepared the study solution. The mothers, the investigators, and the research personnel involved in the data collection, as well as the midwife involved in the medical care of the mothers, were all blinded to the assignment and study drug.
Mothers were randomized to receive 15 ml (in 5 ml increments) of Ropivacaine 1.5 mg/ml with Fentanyl 2 mcg/ml (F group) or Ropivacaine 1.5 mg/ml with Neostigmine 4 mcg/ml (N group). If the mother failed to achieve analgesia (verbal pain score > 3) 20 min after this injection, she was excluded from the study and the epidural catheter was either manipulated or replaced. For both groups, PCEA was initiated with continuous infusion at a rate of 6 ml/h, a bolus of 6 ml, lock-out period of 10 min and maximum hourly dose of 24 ml of the same solution prepared for each group.
Mothers who had contraindication to neuraxial blockade, those who received systemic opioids within 30 min before request for epidural labor analgesia, those who presented with a history of hypersensitivity to local anesthetics Fentanyl or Neostigmine, or whose fetus showed signs of possible intrauterine suffering (nonreassuring heart rate tracing) were excluded from the study.
Pain was assessed (using a 0-10 verbal rating scale: 0 being no pain and 10 being worst pain ever) before epidural catheter insertion, at 5 min after the test dose, every 5 min for the first 30 min after the initial study drug administration, and then every 2 h until delivery.
Maternal vital signs and degree of motor block (using a 0-3 Bromage scale: 0 = free lower limb movement; 1 = mother can move knee; 2 = mother can move ankle; and 3 = no movement) were recorded at the same time with pain assessment, or more frequently if indicated.
Maternal sedation (using a 0-10 rating scale assessed by an instructed midwife: 0 being fully awake and not feeling sleepy at all, and 10 being asleep) were recorded at the same time as pain assessment.
Nausea was rated by the mother on a scale of 0-10 (0 being no nausea to 10 being worst experience of nausea) after delivery. Nausea was treated with Metoclopramide 10 mg given intramuscularly.
Maternal hypotension was defined as a decrease of 20% from the average systolic blood pressure obtained from the time of admission until epidural administration. Treatment for maternal hypotension included rapid infusion of 500 ml of normal saline and boluses of 5 mg Ephedrine. The presence of maternal hypotension, shivering (as per mother's self-assessment), mode of delivery, 1 and 5 min Apgar scores, total volume of study solution, and FHR for the duration of labor after initiation of epidural analgesia were evaluated by an obstetrician , blinded to mother's group assignment.
Sample size calculation
On the basis of our previous observations, the total hourly volume consumed during labor was calculated to be equivalent to 13.5 ml of Ropivacaine 1.5 mg/ml+Fentanyl 2 mcg/ml, with a SD of 3.5 ml. According to this assumption, we have to study 20 patients in each group to be able to reject the null hypothesis that the population means of the experimental and control groups are equal with a probability (power) of 0.8. The type I error probability associated with this null hypothesis was 0.05. However, to enhance the power and reliability of study, and to cover for any failure of epidural analgesia or missed data throughout the study, we have selected 30 patients in each group, which is statistically not a small sample.
The hourly Ropivacaine use was analyzed with a two-tailed t-test. Nonparametric data were analyzed with the Mann-Whitney U-test. Change in continuous measures over time within each group was determined using one-way analysis of variance for repeated measures and two-way analysis of variance for comparison between groups. Incidence and proportion were compared between groups using Fisher's exact test or the χ2 -test. Sedation, shivering, pruritus, nausea, and motor block were considered present if the score was greater than 0. Data are presented as mean ± SD or incidence (%), and P values less than 0.05 were considered significant.
| Results|| |
Sixty women were recruited: 12 were excluded from the study because of no block and inadequate analgesia from the initial epidural dose (four in the F group and four in the N group), recognition of breech presentation after insertion of the epidural catheter (one in the F group), protocol violation due to intramuscular Pethidine administration within 30 min before epidural catheter placement (two excluded before randomization for group assignment), and epidural catheter dislodgement (one in the N group). The remaining 48 women (24 in each group) who completed the study did not differ in maternal ([Table 1]) or labor characteristics ([Table 2]).
Pain scores were significantly reduced 20 min after initiation of analgesia compared with baseline in both groups (P < 0.001), and did not differ between groups at any time during the study (P = 0.21-0.43) ([Figure 1]).
|Figure 1: Pain scores. Data presented as median (IQR) , Verbal Rating Scale (VRS).|
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The mean dose of the epidural solution was 13.6 ± 4.6 ml/h in the F group (Ropivacaine+Fenanyl) versus 12.1 ± 3.2 ml/h in the N group (Ropivacaine+Neostigmine). Addition of Neostigmine in the N group reduced the mean hourly epidural dose of Ropivacaine by 11% compared with the F group (P = 0.003). Groups did not differ in relation to satisfaction with pain control (P = 0.58).
Maternal arterial blood pressure was similar in the two groups before initiation of analgesia and was reduced to a similar degree after initiation of epidural analgesia (P = 0.06-0.16) ([Figure 2]). Seven patients in the F group and five in the N group received treatment for hypotension (P = 0.52). Maternal heart rate between contractions before and after epidural analgesia was similar between groups and was not affected by epidural analgesia (P = 0.09-0.13).
FHR was similar in the two groups (P = 0.11) before and after epidural analgesia (P = 0.09). Groups did not differ in Apgar scores at 1 and 5 min (P = 0.18 and 0.22, respectively).
Progress of labor was not affected by the use of Neostigmine. Cervical dilation was similar between groups at the time of initiation of analgesia and 2 h later (P = 0.81 and 0.92, respectively). Time until complete cervical dilation did not differ between groups (P = 0.89). No statistically significant difference was observed in modes of delivery between the two groups (P = 0.47) ([Table 2]).
Maternal sedation scores was increased compared with baseline through the first 20 min after initiation of analgesia in both groups (Fentanyl: P = 0.043; Neostigmine: P = 0.04)([Figure 3]). There was no significant difference in sedation scores between groups at any time or compared with baseline (P = 0.23-0.46). Mothers who experienced prolonged labor (>4 h) showed increased sedation rates in both groups compared with baseline but it was statistically nonsignificant (P = 0.061)
The groups did not differ in the incidence of shivering (P = 0.27) or degree of motor block at any time during the entire study period (P = 0.89).
Although the incidence of nausea and pruritus was higher in the F group compared with the N group, this increase was statistically nonsignificant (nausea P = 0.25 - pruritus P = 0.31). Two cases in the F group received treatment for nausea.
| Discussion|| |
Effect of PCEA settings on PCEA efficacy, such as the volume of the PCEA bolus, lock-out interval, and the use of background infusion, has yielded conflicting results , . We decided to use our standard clinical protocol to set PCEA. The newer amide local anesthetic Ropivacaine, alone or combined with adjuvant, is mostly used for epidural labor analgesia. Several authors studied the use of Ropivacaine in combination with Fentanyl for labor analgesia and postoperative pain control. They concluded that such combination is associated with better pain control, lower Ropivacaine dosage, and improvement in patients' satisfaction ,,, . Neostigmine was tried as a neuraxial adjuvant to local anesthetics. Intrathecal Neostigmine had been found to reduce the amount of local anesthetic with prolonged analgesic effect. Several studies have shown that intrathecal Neostigmine was associated with severe sedation, nausea, and vomiting , . Few studies have examined the analgesic properties of epidural Neostigmine in obstetrics, and these are limited to single bolus studies. These studies have demonstrated an analgesic effect with mild sedation and without severe nausea or vomiting , . Ross et al.  are the first to study the use of low-dose epidural Neostigmine (4 mcg/ml) infusion for the control of labor pain, and they concluded that it reduces epidural Bupivacaine requirement up to 25% during labor without significant side effects on the mother, baby, or on the progress of labor.
Results of the current study showed that pain score is significantly reduced in both groups 20 min after initiation of epidural labor analgesia. This significant pain control was mainly due to exclusion of any case that did not express pain score less than 3 after 20 min from initiation of epidural analgesia. Pain scores were similar between the two groups throughout the study period. Neostigmine use showed significant reduction in the dose of Ropivacaine required, with maintenance of the same satisfaction rate in relation to pain control. This reflects that the analgesic properties of epidural Neostigmine can be compared with epidural Fentanyl. These results were similar to previous observations , .
Epidural Neostigmine can stimulate spinal cholinergic receptors, which can lead to increase in sympathetic nervous system outflow  . This may lead to increase in maternal blood pressure and heart rate, and decrease in uteroplacental blood perfusion. The current study showed no evidence of this effect with Neostigmine at the doses studied, and there were no differences in comparison with the Fentanyl group in maternal arterial blood pressure or heart rate. These results may be due to the use of a low dose of Neostigmine. These results coincide with those of Ross et al.  . In contrast, there was a significant incidence of hypotension in both groups, which happened at the start of epidural labor analgesia. This hypotension may have been due to the use of epidural Ropivacaine and the prevalence of prolonged starvation and hypovolemia between laboring mothers.
The fetus did not show any signs of suffering due to the use of epidural Neostigmine; there were no significant FHR abnormalities or increased rates of cesarean section due to fetal distress. Systemic absorption of neostigmine can result in increase in uterine activities  , and if absorbed into the baby can cause fetal bradycardia  . The absence of these effects in the current study may be due to the low dose of epidural Neostigmine and its insignificant systemic absorption. Another cause of fetal distress may be related to stimulation of spinal cholinergic receptors and reduction of uteroplacental blood perfusion. This effect is not significant here because the mother did not show any signs of sympathetic stimulation. Thus, the fetus mostly will not be affected by the use of low epidural Neostigmine dose. This conclusion failed to be proved in this study as well as in previous studies ,,, . These effects have to be clarified during further investigations with emphasis on the effect of epidural Neostigmine on uteroplacental blood flow.
The current study did not show any effect of epidural Neostigmine on the progress of labor (oxytocine use, cervical dilatation progress, and mode of delivery). This can be explained by the absence of any significant motor block related to epidural Neostigmine use with low-dose Ropivacaine.
The results of the current study, like previous studies, showed that the use of epidural Neostigmine can cause sedation. This sedation can be compared with sedation caused by epidural Fentanyl ,, . Significant sedation was temporary and was related to the initial epidural dose. It may be related to the initial epidural bolus of either Fentanyl (30 mcg) or Neostigmine (60 mcg) in different groups. After that, no significant sedation was observed, neither between groups nor compared with baseline. Only mothers who experienced prolonged labor (>4 h) showed nonsignificantly higher sedation scores in both groups. This can be related to maternal exhaustion.
Epidural Fentanyl may increase the incidence of pruritus and reduce the incidence of shivering  . Pruritus can affect 20% of pregnant mothers without the use of epidural opioids  . Incidence of shivering during labor is variable and can be related to variable factors. It can occur with or without epidural labor analgesia  . There is no proven relationship between the use of epidural Neostigmine and the incidence of pruritus or shivering. Results of the current study showed that the incidence of pruritus is high in the Fentanyl group, but this difference was insignificant. This can be due to the use of epidural Fentanyl or due to pregnancy itself. There was no difference in the incidence of shivering between groups in the current study.
| Conclusion|| |
Neostigmine 4 mcg/ml can be used as a safe adjuvant with Ropivacaine 0.15% in PCEA for the management of labor pains. Its analgesic properties are comparable to that of epidural Fentanyl. Use of Neostigmine reduced the mean hourly epidural dose of Ropivacaine by 11% compared with the Fentanyl group. It causes temporary sedation stat within 20 min after injection of bolus dose. This sedation is comparable to that of Fentanyl and may be related to the initial bolus Neostigmine dose (60 mcg). Epidural low-dose Neostigmine infusion did not increase the risk of nausea during labor. It did not increase the density of motor block or risk of pruritus and shivering. Epidural Neostigmine did not affect the FHR or Apgar score at 1 and 5 min, but further studies to investigate its effect on uteroplacental blood flow are required.
| Acknowledgements|| |
The authors thank Eng. Amr Khalaf for statistics consultation.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]