Introduction
Although epidural analgesia is the reference standard for labor pain relief owing to its superior efficacy and safety, many parturients have no access to this modality, have contraindications to its use, or prefer less invasive analgesic options. In these parturients, patient-controlled intravenous analgesia (PCIA) remifentanil may be a feasible option for labor pain relief. Remifentanil is a potent opioid with pharmacokinetic properties that convey unique advantages when used for labor analgesia. For instance, remifentanil has a quick onset of 20–30 s with maximum effect achieved in 80–90 s,[ 1 ] followed by rapid elimination to non-active metabolites within 3 min.[ 2 ] In theory, these properties allow parturients to receive efficacious analgesia during uterine contractions, while its rapid elimination constitutes an important safety feature that minimizes the risk of maternal and fetal adverse effects.[ 3 ]
Despite these theoretical advantages, the use of PCIA remifentanil for labor analgesia has been implicated in cases of rare but potentially significant adverse effects, including respiratory or cardiac arrest.[ 4 , 5 ] Furthermore, numerous studies have associated remifentanil with maternal oxygen desaturation, pruritus, sedation, nausea and vomiting, reduced fetal bradycardia or heart rate (HR) variability, and neonatal acidosis.[ 3 , 6 ] In terms of efficacy, several open label studies have estimated that remifentanil is capable of reducing labor pain scores by two to four points (based on an 11-point numerical rating scale, 0: no pain to 10: worst pain imaginable).[ 7-11 ] When compared to other forms of labor analgesia, a recent review reported that remifentanil provided superior analgesia than nitrous oxide and pethidine, but was less effective than epidural analgesia.[ 3 ]
PCIA remifentanil has been in use in our institution since year 2011, and a standardized protocol was implemented in year 2014 to guide its usage and improve safety and monitoring. The aims of this retrospective observational study were to identify parturient or clinical factors associated with high versus low maternal satisfaction (primary outcome), describe the trend of PCIA remifentanil utilization, and assess the incidence of adverse maternal and fetal outcomes.
Materials and Methods
This single center retrospective observational study was approved by relevant ethical board. The need for written informed consent was waived due to the retrospective nature of the study. This work was conducted in accordance with the Declaration of Helsinki, and adheres to the relevant Strengthening the Reporting of Observational Studies in Epidemiology guidelines.
Data of parturients who utilized PCIA remifentanil for labor analgesia between January 1, 2014 and December 31, 2020 were extracted from a hospital database from a specialist obstetrics and gynecology center in Singapore. This database was specifically created to investigate outcomes associated with PCIA remifentanil for labor analgesia. Veracity of the data was ensured via cross-checking by a dedicated research team, and missing data were obtained from review of the clinical record, if available. Parturients with missing data pertaining to the primary outcome were excluded from the study.
As per institutional practice, PCIA remifentanil for labor analgesia was offered to parturients who refused epidural analgesia or had contraindication to neuraxial procedures (e.g. thrombocytopenia or previous spinal instrumentation). PCIA remifentanil was not offered to parturients who were unable to self-administer PCIA boluses, or those with hypersensitivity to remifentanil, severe respiratory disease, history of drug dependence or abuse, or fetal bradycardia. In addition, parturients who participated in trials evaluating a novel remifentanil vital signs-integrated system were excluded from this study.[ 12-14 ]
PCIA remifentanil was administered using a CADD-Solis® Infusion System (Smiths Medical, St. Paul, Minnesota). Patient-controlled boluses of 20–40 μg were delivered over 12–22 s, followed by a lock-out period of 1 or 2 min, without background infusion. Continuous pulse oximetry was instituted before starting PCIA remifentanil and supplemental oxygen via nasal cannulae was provided to all parturients. PCIA remifentanil was stopped if the parturient requested for conversion to epidural analgesia, or if significant opioid-related adverse effects occurred, such as parturient or fetal bradycardia, recurrent SpO2 < 95%, excessive nausea despite antiemetics, and severe hypotension. Concomitant use of 50% nitrous oxide with oxygen was permitted.
The primary outcome was parturient satisfaction with labor analgesia from PCIA remifentanil, assessed at 24 h postpartum using a numerical rating scale of 0: very dissatisfied to 100: very satisfied. Additionally, we included data on parturient age, weight, body mass index (BMI), gestational age, and mode of labor onset. Before the initiation of PCIA remifentanil, data on cervical dilatation, dose of oxytocin for labor augmentation, and pain score (0: no pain, 10: worst pain imaginable) were included. After initiation of PCIA remifentanil, remifentanil bolus dose, lock-out period, duration of PCIA utilization, remifentanil consumption, number of demand and successful boluses, oxygen supplementation, use of nitrous oxide, and conversion to epidural analgesia were obtained. Adverse effects associated with remifentanil were recorded, including oxygen desaturation (SpO2 < 95%), bradypnea (respiratory rate < 8 per min), sedation (score of ≥2 assessed using 0: awake, 1: occasionally drowsy but easy to rouse and responds to calling, 2: often drowsy and difficult to rouse, responds to shaking only, and 3: unresponsive and unarousable), bradycardia (HR < 50 per min), hypotension (systolic blood pressure < 90 mmHg), nausea/vomiting, fetal bradycardia (sustained fetal HR < 110 per min), and inadequate analgesia (parturient complaints of pain requiring intervention by an anesthetist). Clinical management of the above adverse effects were also recorded, such as additional oxygen supplementation, use of naloxone, atropine, ephedrine, antiemetics, terbutaline, emergency cesarean delivery, and conversion to epidural analgesia. Immediately postpartum, parturients were inquired about the average pain score at the time of fetal delivery. Obstetric and fetal outcomes such as duration of second stage of labor, mode of delivery, birth weight, Apgar scores, and umbilical venous and arterial pH were analyzed.
The primary outcome of parturient satisfaction was treated as a binary data with categories “high satisfaction ” (satisfaction score ≥ 80) or “low satisfaction ” (satisfaction score < 80). These cut-offs were used as audit standards by our institution, and in previous studies investigating parturient satisfaction with labor analgesia.[ 15 ] All demographic and clinical variables were summarized based on satisfaction status. Categorical and continuous variables were summarized as frequency (percentages) or mean ± standard deviation (SD) or median (interquartile range (IQR)), respectively. Differences between satisfaction categories were tested using two sample t -test or χ 2 test for continuous and categorical variables, respectively. Univariate and multivariable logistic regression analyses were performed to identify associated variables with low satisfaction. Results were expressed as odds ratio (OR) with 95% confidence intervals (95% CI). No multivariable model was identified. All tests were two-sided, and P -values < 0.05 were considered statistically significant. Analyses were performed using SAS version 9.4 (SAS Institute, Cary, North Carolina).
Results
Over the seven-year study period, 177 parturients received PCIA remifentanil for labor analgesia with increasing year-on-year utilization [Table 1 ]. Data from 146 parturients were analyzed after excluding 31 parturients due to missing primary outcome data. The overall study cohort had a mean ± SD satisfaction score of 79.9 ± 17.5. Of the 146 parturients analyzed, 99 (67.8%) parturients reported “high satisfaction” with a mean ± SD satisfaction score of 89.5 ± 8.9, while 47 (32.2%) parturients were in the “low satisfaction” group with a mean ± SD satisfaction score of 59.7 ± 13.2.
Table 1:: Utilization of patient-controlled intravenous analgesia (PCIA) remifentanil between 2014 and 2020
Before the initiation of PCIA remifentanil, there were no significant differences in terms of baseline parturient and clinical characteristics between the high and low satisfaction groups [Table 2 ]. At the time of fetal delivery, parturients in the high satisfaction group had significantly lower pain scores (8.3 ± 2.2), compared to those in the low satisfaction group (9.2 ± 1.4, unadjusted OR = 1.39, 95% CI 1.02–1.88, P = 0.035). No significant differences were noted in PCIA settings, duration of PCIA remifentanil utilization, number of demand and successful boluses, oxygen supplementation, and use of nitrous oxide between the high and low satisfaction groups [Table 3 ].
Table 2:: Baseline parturient and clinical characteristics before initiation of patient-controlled intravenous analgesia (PCIA) remifentanil
Table 3:: Analgesic characteristics after initiation of patient-controlled intravenous analgesia (PCIA) remifentanil
Adverse effects associated with PCIA remifentanil utilization are summarized in Table 4 , with no significant differences noted between the high and low satisfaction groups. Overall, 16 parturients (11.0%) reported inadequate analgesia, of whom two requested for conversion to epidural analgesia and both reported low satisfaction. Fifteen (10.3%) parturients experienced at least one episode of desaturation (SpO2 < 95%), with a mean ± SD SpO2 of 92.3 ± 1.4% and lowest SpO2 of 90%. The oxygen saturation in these parturients improved spontaneously, and none required ventilatory support. A total of 15 (10.3%) parturients experienced nausea or vomiting, and were administered either intravenous ondansetron (n = 6) or metoclopramide (n = 7). Eight patients experienced hypotension, of whom two required intravenous ephedrine 3 mg. Fetal bradycardia occurred in three parturients with one requiring emergency cesarean delivery, and three had increased sedation scores. None of the parturients experienced significant bradycardia, or required treatment with naloxone. Obstetric and fetal outcomes were similar between the high and low satisfaction groups [Table 5 ].
Table 4:: Adverse events during patient-controlled intravenous analgesia (PCIA) remifentanil usage
Table 5:: Obstetric and fetal outcomes
Discussion
Over the seven-year study period, we noted increasing year-on-year utilization of PCIA remifentanil, with approximately 68% of parturients reporting high satisfaction scores regarding their labor analgesia. We also found that PCIA remifentanil was associated with a low incidence of conversion to epidural analgesia, and infrequent minor adverse effects that either resolved spontaneously or with minimal clinical intervention. Of the variables studied, lower pain scores at fetal delivery were univariately associated with high satisfaction scores.
Our results show that PCIA remifentanil provided adequate satisfaction in the majority of parturients, which seemingly contradicts our findings of high mean pain scores recorded at fetal delivery and the association between high pain scores and lower satisfaction. However, previous studies have reported that remifentanil was associated with similar satisfaction scores compared to epidural analgesia, despite higher pain scores in parturients receiving the former.[ 16 , 17 ] Hence, it is possible that pain severity is just one of several factors contributing to parturient satisfaction with labor analgesia. In fact, a systematic review investigating the role of pain in satisfaction with childbirth showed that personal expectations, caregiver support, quality of caregiver-parturient relationship, and involvement in decision making had much larger influence on satisfaction than labor pain.[ 18 ] Nonetheless, our findings of high pain scores at fetal delivery are consistent with prior studies demonstrating that remifentanil is most effective in early labor, after which pain scores increase in conjunction with labor progression.[ 3 ] Hence, future research should focus on optimizing the analgesic efficacy of PCIA remifentanil, such as matching the peak analgesic effect with uterine contractions, especially with increased frequency of uterine contractions as labor progresses.
We also showed that PCIA remifentanil was associated with infrequent adverse effects that resolved spontaneously or with minimal clinical intervention. One of the most concerning risks associated with PCIA remifentanil is respiratory depression. In this study, approximately 10% of parturients experienced oxygen desaturation and only one had bradypnea, with none requiring mechanical ventilation. In comparison, Van de Velde and Carvalho[ 19 ] estimated that respiratory depression occurs in 32% of parturients, while Douma et al .[ 16 ] reported that 48% of parturients receiving PCIA remifentanil had oxygen desaturation below 90%. We postulate that the low incidence of respiratory depression noted in our study compared to prior studies may be in part due to the low prevalence of respiratory comorbidities and obesity in our parturient population. Also, Stocki et al .[ 20 ] noted that apnea (>20 s of respiratory arrest) occurred in 26% of parturients receiving remifentanil, many of whom resumed breathing upon verbal or physical stimulation. Given that parturients receiving PCIA remifentanil in our institution also receive continuous one-to-one nursing care, it is possible that the resultant increase in monitoring and verbal stimulation may have reduced the incidence of significant respiratory depression. It should also be noted that oxygen supplementation was routinely administered to all parturients on PCIA remifentanil, which may have helped prevent oxygen desaturation. We also noted that 10% of our parturients experienced nausea or vomiting, which may have been contributed by nitrous oxide use in 14% of parturients.
Standard practice for PCIA remifentanil in our institution involves starting with 20 μg boluses followed by a 2-min lockout, which can be stepped up to 40 μg boluses and lockout of 1 min. This practice is in line with current literature indicating that boluses over 40 μg may increase the risk of maternal adverse effects.[ 3-5 , 11 ] Although it was suggested that routine capnography may facilitate timely detection of respiratory depression,[ 3 ] this was not adopted within the study period. However, we are in the process of incorporating capnography into the PCIA remifentanil protocol, although this may raise concerns such as poor compliance, challenges with detecting apneic episodes, variations in respiratory patterns, dilution of exhaled carbon dioxide with nitrous oxide or supplemental oxygen, alarm fatigue, and desensitization.[ 21 ]
We acknowledge several limitations with this study. First, this is a retrospective observational study from a single center, which may increase the risk of bias and limit generalizability. Second, the retrospective nature of the study precludes analysis of other possible factors associated with low satisfaction such as sociodemographic and psychological characteristics. Third, the data collected as part of the routine clinical practice may be incomplete in some patients and lead to missing data that may affect the accuracy of our findings; however, our dataset was verified by a dedicated research team and efforts were made to obtain missing data from the clinical record.
Conclusions
Our findings suggest that PCIA remifentanil for labor analgesia resulted in high satisfaction with no severe adverse events noted. Standardized protocols for PCIA settings and close monitoring may help improve parturient and fetal safety. Future research should focus on improving the analgesic efficacy of PCIA remifentanil and monitoring practices to reduce the risk of severe adverse events.
Acknowledgments
The authors would like to thank the senior clinical research coordinator (Miss Agnes Teo) and the staff of the delivery suites at KK Women’s and Children’s Hospital, Singapore, for their support in this study. This study received approval by SingHealth Centralized Institutional Review Board (references 2017/2023 and 2021/2286) on January 31, 2017 and May 27, 2021 respectively. The need for written informed consent was waived by SingHealth Centralized Institutional Review Board due to the retrospective nature of the study.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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