Abstract
Background
This study aimed to explore the ED90 of programmed intermittent epidural bolus (PIEB) volume for labor analgesia with different concentrations of ropivacaine when combining with dural puncture epidural (DPE) techniques.
Methods
Ninety patients were randomized to three groups (n=30 each) to receive an initial 12-mL bolus of ropivacaine (0.075%, 0.1%, or 0.125%) with 0.3 μg/mL sufentanil. PIEB began at 60 min after the initial bolus, with 45-min intervals; the first patient in each group received 10 mL ropivacaine‑sufentanil solution, and subsequent volumes were adjusted by ± 2 mL via sequential allocation based on effective labor analgesia (no epidural bolus intervention administered). The primary and secondary outcomes were, respectively, the ED90 of PIEB volume at different ropivacaine concentrations for effective labor analgesia, and maternal analgesia quality and neonatal outcomes.
Results
The ED90 of PIEB volume for achieving effective labor analgesia was 13.2 mL (95% CI, 11.9–14.5), 11.1 mL (95% CI, 10.0–12.2), and 9.4 mL (95% CI, 8.4–10.3) in the 0.075%, 0.1%, and 0.125% groups, respectively. No statistically significant differences in maternal analgesia quality and neonatal outcomes were identified among groups.
Conclusion
When the combined DPE and PIEB technique is applied for effective labor analgesia, the ED90 of PIEB volume at concentrations of 0.075%, 0.1%, and 0.125% is 13.2 mL, 11.1 mL, and 9.4 mL respectively. Since higher concentration corresponds to a higher administered dose of ropivacaine, the ED90 of PIEB volume decreases as concentration increases.
Keywords: programmed intermittent epidural bolus, dural puncture epidural, concentration, ropivacaine, labor analgesia
Introduction
Epidural analgesia stands as the most prevalently utilized and favored approach for pain alleviation during childbirth.1,2 Among these methods, programmed intermittent epidural bolus (PIEB) serve as a significant technique for labor analgesia.3,4 It provides analgesic efficacy comparable to continuous epidural infusion, while concurrently reducing the dosage of analgesic drugs and minimizing risks, such as lower - limb motor block.5 Additionally, in comparison with conventional epidural labor analgesia, dural puncture epidural (DPE) can effectively shorten the onset time of analgesia and enhance the initial quality of analgesia.6,7
At present, the combined application of PIEB and DPE has been extensively employed in epidural labor analgesia.8–10 Halliday et al11 conducted a comparison of three concentrations of local anesthetics applied in labor analgesia, namely ultra-low (≤ 0.08%), low (> 0.08% to ≤ 0.1%), and high (> 0.1%); among these, 0.1% is the most widely adopted concentration in clinical practice, while the application of 0.075%12 and 0.125%13 has also been documented in existing literature. Additionally, our research group previously investigated the ED90 of initial ropivacaine dose and determined the ED90 of interval time of PIEB for labor analgesia across three different concentrations,14,15 yet the ED90 of PIEB volume with different concentrations of ropivacaine under this combined technique lacks evidence.
Different concentrations correspond to different doses of local anesthetic administered at an equal injection volume, therefore further investigation into the ED90 of PIEB volume provides guiding value for the selection of appropriate administration volumes in clinical practice. We hypothesize that the ED90 of PIEB volume decreases with an increase in its corresponding concentration. This study utilizes a randomized sequential allocation study to explore the ED90 of PIEB volume for labor analgesia with different concentrations of ropivacaine for effective analgesia, defined as no interventions from patients or anesthesiologists for epidural bolus prior to delivery when PIEB combining with DPE techniques.
Materials and Methods
Study Design
This study was approved by the Ethics Committee of the Huai’an Hospital Affiliated to Yangzhou University (The Fifth People’s Hospital of Huai’an) (No. KY-P-2024-011-01) and registered in the Chinese Clinical Trials Registry (ChiCTR2500095945). It was conducted from June 2025 to June 2026. This study complied with the CONSORT guidelines and the Declaration of Helsinki, and written informed consent was obtained from all patients.
Participants
Patients aged 18–40 years with singleton term gestation, admitted for spontaneous or induced vaginal delivery, who had labor analgesia administered following multidisciplinary consensus among obstetric, anesthetic, and midwifery staff; presented with cervical dilatation < 5 cm, a visual analog scale (VAS) pain score > 5, and American Society of Anesthesiologists (ASA) physical status classification II—were enrolled. Patients were ineligible for participation if they had any contraindications that precluded epidural labor analgesia, such as epidural puncture contraindications or drug hypersensitivity to ropivacaine and sufentanil. Additional exclusion conditions included severe gestational hypertension, uncontrolled gestational diabetes mellitus, fetal overgrowth (macrosomia), fetal distress during labor, and the simultaneous use of any other analgesic treatments.
Monitor
After a multidisciplinary consensus determined that the patient was eligible for epidural analgesia during labor, the patient was administered a standard labor analgesia regimen, accompanied by standardized maternal and neonatal care. During the observation period, patients underwent continuous physiological monitoring, including real-time electrocardiogram (ECG), non-invasive blood pressure (NBP), and percutaneous oxygen saturation (SpO2). A peripheral intravenous access of 18-gauge size was established for fluid infusion. Fetal heart rates were monitored before and after the initiation of labor analgesia.
Randomization and Masking
Based on the randomization sequence generated by SPSS, patients were randomly assigned to receive one of three concentrations of ropivacaine (0.075%, 0.1%, or 0.125%) for labor analgesia and were correspondingly assigned to the 0.075% group, 0.1% group, or 0.125% group. Responsible obstetric anesthesiologists and patients were blinded to the concentrations of ropivacaine used for labor analgesia. An independent obstetric anesthesiologist, who served as an evaluator not involved in analgesia management, was responsible for group allocation for each patient using a sealed envelope and prepared different concentrations of ropivacaine diluted with normal saline for labor analgesia administration. Different concentrations of ropivacaine solutions were labeled only with local anesthetics.
Implementation of Labor Analgesia
Labor analgesia was carried out at the estimated L2–3 interspace. A 25G needle was inserted to puncture the dura, and it was confirmed that clear cerebrospinal fluid was flowing without the administration of any local anesthetic (DPE technique). Subsequently, an epidural catheter was inserted into the epidural space to a depth of 4 cm. Upon completion of the aforementioned steps, it was verified that there was no outflow of cerebrospinal fluid or blood from the epidural catheter. Subsequently, a test dose of 3 mL of 1% lidocaine was administered, and monitoring was carried out for 5 to 8 minutes. If no significant elevation in sensory level occurred, the initial volume of 12 mL of ropivacaine combined with sufentanil at a concentration of 0.3 μg/mL for labor analgesia was administered via the same catheter according to group assignment.
Intervention
60 minutes subsequent to the initial epidural injection, programmed intermittent epidural bolus (PIEB) was commenced at 45‑minute intervals. According to the algorithm of sequential allocation method, the first patient in each group received 10 mL of ropivacaine combined with sufentanil at a concentration of 0.3 μg/mL. The primary endpoint was a prespecified binary outcome: effective versus ineffective labor analgesia. For subsequent patients, the PIEB volume was adjusted by an increment or decrement of 2 mL (of the same ropivacaine‑sufentanil solution) according to whether effective analgesia was achieved (no interventions from patients or anesthesiologists for epidural bolus prior to delivery). If an epidural bolus intervention was administered prior to fetal delivery, the volume for the subsequent patient was increased; otherwise, the volume was decreased.
We did not define the allocation probabilities or the minimum dose of PIEB, but the maximum upper limit was set at 16 mL. If effective analgesia was not achieved when this upper limit was reached, subsequent patients would still receive the same maximum dose. The trial will be terminated if inadequate analgesia is documented in three consecutive patients who have reached the maximum dose limit, or in five consecutive patients at any dose level. If the patient’s VAS score remains ≥ 3 during labor analgesia, patient-controlled epidural analgesia (PCEA) or manual epidural bolus administered by anesthesiologists can be initiated as necessary, utilizing a mixture of 8 mL ropivacaine combined with sufentanil at a concentration of 0.3 μg/mL.
If effective analgesia remained unachieved following two consecutive interventions, or if any other unanticipated events occurred (such as patient withdrawal or severe adverse complications), this would be identified as a protocol deviation. The patient would be discontinued from the trial, and the next enrolled participant would receive the currently assigned dose in accordance with the pre - specified randomization scheme. The observation period terminated upon the fetal delivery. Throughout the process of labor analgesia, sensory block should be maintained at a level above T10 and should not reach or exceed T6.
Outcomes
The primary outcome was the ED90 of PIEB volume with different concentrations of ropivacaine for achieving effective labor analgesia, which was determined based on no interventions from patients or anesthesiologists for epidural bolus prior to delivery. Secondary outcomes encompassed the duration of labor analgesia, the baseline VAS score, and the time needed to reach a VAS score of ≤ 1. Other outcomes included the highest sensory block level, the incidence of a sensory block level of ≥ T6, and the proportion of asymmetric blocks; the use of rescue bolus, PCEA, a Bromage score of ≥ 1, cesarean delivery, and the patients with satisfaction scores of ≥ 4 (on a scale from 1 to 5, where 1 indicates the least satisfaction and 5 indicates the most satisfaction); as well as the neonatal Apgar scores at 1 minute and 5 minutes.
Statistical Analysis
According to Pace et al’s assessment of the sample size for the up-and-down study design, a sample size ranging from 20 to 40 with more than six reversals is deemed sufficient.16 In our study, a sample size of 30 cases per group was adopted.
The Kolmogorov–Smirnov test was used to assess the normality of continuous variables. Continuous variables that followed a normal distribution were analyzed using one-way analysis of variance (ANOVA), and Bonferroni post hoc tests were performed for pairwise comparisons following significant ANOVA results. Continuous variables that did not follow a normal distribution were analyzed using the Kruskal–Wallis test, and Dunn’s post hoc test was conducted for pairwise comparisons following significant Kruskal–Wallis results. Categorical data were analyzed using chi-square tests, and pairwise post hoc comparisons were performed for significant overall tests.
Isotonic regression using the pool-adjacent-violators algorithm (PAVA) was applied to estimate the ED90 of PIEB volume for each ropivacaine concentration, enforcing a monotonic non-decreasing dose–response relationship. The ED90 point estimate was obtained by linear interpolation between adjacent dose levels, and its 95% confidence interval was derived via bias-corrected percentile bootstrap with 3000 replications—effectively handling sparse categorical outcomes. Intergroup comparisons were performed using a permutation test based on isotonic regression: the null hypothesis of equal true ED90 across the three groups was tested by randomly permuting outcome labels across pooled subjects for 2000 replicates, with the maximum absolute pairwise ED90 difference as the test statistic to generate a global P value. Pairwise comparisons were then adjusted with Bonferroni correction. Statistical analyses were performed using SPSS version 25.0 and R software version 4.2.1, and a two-sided P value < 0.05 was considered statistically significant.
Results
A total of 103 patients were initially recruited, five of whom did not satisfy the inclusion criteria and eight withdrew consent to participate in the interventions. Ultimately, 90 participants (30 participants per group), without any patient withdrawals, protocol deviations, failed labor analgesia, or missing data were eligible for the final statistical analysis (Figure 1). Table 1 summarizes the maternal baseline and obstetric characteristics. Statistically significant among-group differences were observed in patients’ age (P = 0.001), while no significant among-group differences were identified for the remaining characteristics.
Figure 1.
Study flow diagram.
Table 1.
Maternal Baseline and Obstetric Characteristics
| 0.075% Group (n=30) | 0.1% Group (n=30) | 0.125% Group (n=30) | P value | |
|---|---|---|---|---|
| Age, years | 30.4 ± 5.3 | 25.5 ± 4.8 | 27.2 ± 5.1 | 0.001 |
| Body mass index, kg/m2 | 27.7 ± 3.5 | 28.0 ± 2.9 | 27.8 ± 3.1 | 0.912 |
| Gestational age, (weeks) | 39 [38, 40] | 39 [38, 39] | 39 [38, 39] | 0.595 |
| Parity | 0 [0, 1] | 0 [0, 1] | 0 [0, 1] | 0.650 |
| Multipara, n (%) | 10 (33.3%) | 9 (30.0%) | 13 (43.3%) | 0.532 |
| Spontaneous labor, n (%) | 18 (60.0%) | 16 (53.3%) | 14 (46.7%) | 0.585 |
| Baseline systolic blood pressure, mmHg | 118.5 ± 11.5 | 123.0 ± 11.9 | 122.1 ± 9.7 | 0.260 |
| Baseline diastolic blood pressure, mmHg | 79.2 ± 10.2 | 74.6 ± 8.5 | 77.1 ± 7.0 | 0.123 |
| Baseline heart rate, bpm | 86.8 ± 10.3 | 85.2 ± 8.9 | 84.5 ± 9.9 | 0.662 |
| Baseline Fetal heart rate, bpm | 145.1 ± 3.5 | 142.9 ± 6.7 | 144.9 ± 8.9 | 0.373 |
| First stage of labor, min | 420 [307, 472] | 300 [210, 375] | 345 [218, 443] | 0.077 |
| Second stage of labor, min | 39 [17, 62] | 35 [25, 55] | 35 [24, 58] | 0.995 |
| Prolonged second stage of labor, n (%) | 1 (3.3%) | 0 (0.0%) | 0 (0.0%) | 0.364 |
Notes: Data are presented as mean ± SD, median [IQR] and n (%).
The sequential allocation data, observed dose-response counts, and response rates are presented in Table 2. No fewer than six reversals were observed across the three groups over the full sequential course of the procedure, and they had not yet reached the maximum upper limit dose, which guaranteed the robustness of the ED90 estimation. The ED90 of PIEB volume for achieving effective labor analgesia was 13.5 mL (95% CI, 12.3–16.7) in the 0.075% group, 11.3 mL (95% CI, 9.1–11.8) in the 0.1% group, and 9.5 mL (95% CI, 8.6–9.8) in the 0.125% group.
Table 2.
Effective Analgesia Rate Across Three Ropivacaine Concentrations
| Assigned Dose | 0.075% Group (n=30) | 0.1% Group (n=30) | 0.125% Group (n=30) | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Effective Number | Total Number | Effective Rate | Effective Number | Total Number | Effective Rate | Effective Number | Total Number | Effective Rate | |
| 2 mL | – | – | – | – | – | – | 0 | 2 | 0.0% |
| 4 mL | – | – | – | 0 | 6 | 0.0% | 2 | 8 | 25.0% |
| 6 mL | – | – | – | 6 | 8 | 75.0% | 6 | 10 | 60.0% |
| 8 mL | 0 | 4 | 0.0% | 3 | 7 | 42.9% | 4 | 7 | 57.1% |
| 10 mL | 4 | 11 | 36.4% | 5 | 7 | 71.4% | 3 | 3 | 100.0% |
| 12 mL | 7 | 11 | 63.6% | 2 | 2 | 100.0% | – | – | – |
| 14 mL | 4 | 4 | 100.0% | – | – | – | – | – | – |
A significant intergroup difference in age was observed across the three groups (P = 0.002), therefore multivariable logistic regression was adopted to adjust for age as a confounding variable and calculate the ED90 estimate. After adjustment, the ED90 values for the 0.075%, 0.1%, and 0.125% groups were 13.2 mL (95% CI, 11.9–14.5), 11.1 mL (95% CI, 10.0–12.2), and 9.4 mL (95% CI, 8.4–10.3), respectively. The maximum relative change following adjustment was below 5%, and the confidence intervals exhibited substantial overlap, indicating that the study conclusions are of high robustness. The sequences of PIEB volume are presented in Figure 2.
Figure 2.
The sequence of the programmed intermittent epidural bolus volumes under different concentrations. The y-axis indicates the received programmed intermittent epidural bolus (PIEB) volume, and the x-axis indicates the consecutive patient sequence number. Black solid downward-pointing triangles indicate effective doses, which are defined as doses with no epidural bolus administered prior to delivery, while black hollow downward-pointing triangles indicate ineffective doses.
The 0.075% group demonstrated a significantly higher ED90 than the 0.125% group, with a difference of 4.00 mL (95% CI, 1.72–6.28; adjusted P < 0.001). The ED90 of the 0.1% group was higher than that of the 0.125% group by 1.80 mL (95% CI, 0.31–3.29; adjusted P = 0.054); however, this difference did not retain statistical significance after Bonferroni correction. No statistically significant difference was observed between the 0.075% group and the 0.1% group (difference 2.20 mL, 95% CI, 0.39–4.79; adjusted P = 0.288). After adjustment, the 0.075% group demonstrated a significantly higher ED90 than the 0.125% group (difference of 4.0 mL; 95% CI, 1.72–6.28; adjusted P < 0.001). Similarly, no significant difference in ED90 was observed between the 0.075% group and the 0.1% group (difference of 2.1 mL; 95% CI, 0.40–3.0; adjusted P = 0.045), nor between the 0.1% group and the 0.125% group (difference of 1.7 mL; 95% CI, 0.25–3.15; adjusted P = 0.066).
The maternal analgesia quality characteristics and neonatal outcomes are presented in Table 3, and no statistically significant differences were identified among groups. Accordingly, no post-hoc pairwise comparison was further incorporated.
Table 3.
Maternal Analgesia Quality Characteristics and Neonatal Outcomes
| 0.075% Group (n=30) | 0.1% Group (n=30) | 0.125% Group (n=30) | P value | |
|---|---|---|---|---|
| Duration of labor analgesia, min | 265 [206, 460] | 240 [210, 300] | 300 [210, 420] | 0.309 |
| Baseline VAS scores | 8 [7, 8] | 8 [6, 8] | 7 [6, 8] | 0.115 |
| Time from labor analgesia to VAS ≤ 1 | 18 [15, 29] | 17 [13, 30] | 15 [10, 25] | 0.101 |
| Highest sensory block | 8 [7, 8] | 8 [7, 8] | 8 [7, 8] | 0.116 |
| Sensory block ≥ T6, n (%) | 0 (0.0%) | 2 (6.7%) | 0 (0.0%) | 0.129 |
| Asymmetric sensory block, n (%) | 0 (0.0%) | 0 (0.0%) | 1 (3.3%) | 0.364 |
| Rescue bolus, n (%) | 11 (36.7%) | 8 (26.7%) | 10 (33.3%) | 0.700 |
| Patient controlled epidural analgesia, n (%) | 8 (26.7%) | 8 (26.7%) | 6 (20.0%) | 0.786 |
| Bromage score ≥ 1 | 1 (3.3%) | 0 (0.0%) | 0 (0.0%) | 0.364 |
| Cesarean section, n (%) | 2 (6.7%) | 1 (3.3%) | 4 (13.3%) | 0.338 |
| Apgar score at 1 min | 10 [10, 10] | 10 [10, 10] | 10 [10, 10] | 0.795 |
| Apgar score at 5 min | 10 [10, 10] | 10 [10, 10] | 10 [10, 10] | 0.598 |
| Patient Satisfaction ≥ 4 | 30 (100.0%) | 30 (100.0%) | 30 (100.0%) | 1.000 |
Note: Data are presented as median [IQR] and n (%).
Discussion
The results of this study demonstrated that for labor analgesia administered with ropivacaine at concentrations of 0.075%, 0.1%, and 0.125% combined with 0.3 μg/mL sufentanil, the ED90 of PIEB volume for achieving effective labor analgesia after adjustment was 13.2 mL (95% CI, 11.9–14.5), 11.1 mL (95% CI, 10.0–12.2), and 9.4 mL (95% CI, 8.4–10.3), respectively.
Song et al,17 conducted a sequential allocation design combining DPE and PIEB with an initial 12 mL of 0.08% ropivacaine combined with sufentanil at a concentration of 0.3 μg/mL followed by PIEB administered at 40-minute intervals over a volume range of 7–12 mL, determined the ED90 of PIEB volume for 6-h effective labor analgesia as 9.2 mL (95% CI: 8.5–9.9 mL) using the truncated Dixon and Mood method. Subsequently, Zhang et al18 extended the application of this method to patients with gestational hypertension, and their findings obtained via isotonic regression indicated that the ED90 was 9.95 mL (95% CI: 9.52–10.38). The discrepancy in ED90 values from the aforementioned results with ours may be attributable to the use of PIEB doses in the 7–12 range and the 45-minute interval. Furthermore, although the 0.075% and 0.08% concentrations are numerically close, this minor difference can also contribute to the observed discrepancy in ED90 outcomes.
A random-allocation graded dose-response study, Xiao et al,19 combined the DPE and PIEB techniques, using an initial loading dose of 15 mL of 0.1% ropivacaine with sufentanil at a concentration of 0.5 μg/mL, and a fixed 40-minute PIEB interval, while testing four different PIEB volumes (6, 8, 10, and 12 mL). The ED90 of the PIEB volume for achieving 6-hour effective labor analgesia, defined as the absence of any PCEA or manual clinician interventions, was determined to be 11.3 mL (95% CI: 9.9–15.2 mL) by probit regression analysis. Our results were unexpectedly consistent with the aforementioned result, despite our using isotonic regression analyses rather than their using probit regression analyses.
Currently, no research outcomes regarding the PIEB volume are available for the combined application of DPE and PIEB techniques with 0.125% ropivacaine. While 0.125% ropivacaine concentration has been reported for use in labor analgesia,13,20 expert consensus and meta-analyses recommend using local anesthetics at concentrations below 0.1% to reduce the risk of motor block and its associated adverse events, as well as to achieve higher vaginal delivery rates.11,21 In our study, patients in the 0.125% concentration group received higher doses of local anesthetics over the same analgesia period, and prolonged labor duration was correlated with increased local anesthetic dosage. Nevertheless, the 0.125% concentration group did not exhibit an elevated risk of motor block. Furthermore, no statistically significant differences were observed among the three groups in terms of analgesic efficacy, delivery outcomes, and neonatal Apgar scores. These results indicate that all three commonly utilized concentrations are clinically effective, further underscoring the clinical significance of determining the ED90 of PIEB volume.
This study presents several limitations. First, ultra-low concentrations such as 0.0625% ropivacaine were not further investigated, even though existing meta-analyses indicate that such concentrations offer potential benefits for labor analgesia.11 Second, the failure to stratify nulliparous and multiparous women separately may have biased the estimation of the ED90 values. Third, a statistically significant among-group difference in patients’ age was observed across the three groups despite random allocation. Although the maximum differences in ED90 among the three groups after the sensitivity analysis were all below 5%, since age is correlated with pain tolerance and delivery outcomes, it may act as a confounding factor in the estimation of ED90 values. Fourth, this study is a single-center investigation, which inherently limits the generalizability of our findings. Finally, given the limited overall and each subgroup sample size of this study, secondary outcomes including safety could not be subjected to adequately powered comparative analysis.
In conclusion, under the specific DPE–PIEB regimen studied, the estimated ED90 of PIEB volumes was 13.2 mL for 0.075% ropivacaine, 11.1 mL for 0.1% ropivacaine, and 9.4 mL for 0.125% ropivacaine. The estimates suggest that the required bolus volume decreases as ropivacaine concentration increases. No statistically significant differences were detected in the measured maternal analgesia and immediate neonatal outcomes; however, the study was not designed to establish equivalence or comparative safety. These findings should be interpreted within the context of the specific protocol, the population studied, the regimen-specific nature of the treatment, and the differing precision of the estimates; thus, they require confirmation in larger, multicenter trials.
Funding Statement
This work was supported by the Jiangsu Health System Fund for Scientific Research (No. Z2025071) and the Science and Education Integration Research Development Foundation of Jiangsu College of Nursing (No. SH202510250313).
Data Sharing Statement
The data that support the study findings are available from the corresponding author upon reasonable request.
Disclosure
The authors report no conflicts of interest in this work.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the study findings are available from the corresponding author upon reasonable request.