Intermittent Epidural Bolus Compared with Continuous Epidural Infusions for Labor Analgesia: A Systematic Review and Meta-Analysis

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1 Intermittent Epidural Bolus Compared with Continuous Epidural Infusions for Labor Analgesia: A Systematic Review and Meta-Analysis Ronald B. George, MD, FRCPC, * Terrence K. Allen, MBBS, FRCA, and Ashraf S. Habib, MB, ChB, MSc, MHS, FRCA BACKGROUND: The current standard labor epidural analgesic regimens consist of a local anesthetic in combination with an opioid delivered via continuous epidural infusion (CEI). With CEI local anesthetic, doses may be large with resulting profound motor blockade potentially affecting the incidence of instrumental deliveries. In this systematic review of randomized controlled trials (RCTs), we compared the effect of intermittent epidural bolus (IEB) to standard CEI dosing with or without patient-controlled epidural analgesia on patient satisfaction, the need for manual anesthesia interventions, labor progression, and mode of delivery in healthy women receiving labor epidural analgesia. METHODS: A systematic review of RCTs that compared CEI with IEB for labor analgesia was performed. The articles were evaluated for validity, and data were extracted by the authors and summarized using odds ratios (ORs), mean differences (MDs), and 95% confidence intervals (CIs). RESULTS: Nine RCTs were included in this systematic review. Three hundred forty-four subjects received CEI, whereas 350 subjects received IEB labor analgesia. All 9 studies were deemed to be low risk of bias. There was no statistical difference detected between IEB and CEI in the rate of cesarean delivery (OR, 0.87; 95% CI, ), duration of labor (MD, 17 minutes; 95% CI, 42 to 7), or the need for anesthetic intervention (OR, 0.56; 95% CI, ). IEB did result in a small but statistically significant reduction in local anesthetic usage (MD, 1.2 mg bupivacaine equivalent per hour; 95% CI, 2.2 to 0.3). Maternal satisfaction score (100-mm visual analog scale) was higher with IEB (MD, 7.0 mm; 95% CI, ). CONCLUSIONS: IEB is an appealing concept; current evidence suggests IEB slightly reduces local anesthetic usage and improves maternal satisfaction. Given the wide CIs of the pooled results for many outcomes, definite conclusions cannot be drawn for those outcomes, but there is also a potential that IEB improves instrumental delivery rate and need of anesthesia interventions. More study is required to conceptualize the ideal IEB regimen and investigate its effect on labor analgesia and obstetric outcomes. (Anesth Analg 2013;116:133 44) Childbirth is arguably one of the most painful experiences a woman can undergo. 1 The degree of pain experienced and the quality of pain relief affect patients satisfaction with the birthing process and may have long-term emotional and psychological effects. 2 The quality of labor neuraxial analgesia has surpassed parenteral opioids, nitrous oxide, and nonpharmacologic measures, with limited effect on the mode of delivery and maternal and neonatal outcomes. 3 From the *IWK Health Centre, Dalhousie University, Halifax, Nova Scotia, Canada; Division of Women s Anesthesia, Duke University Medical Center, Durham; and Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina. Accepted for publication August 14, Reprints will not be available from the authors. Dr. George acknowledges the Canadian Anesthesiologists Research Foundation for the 2011 CAS Career Scientist Award in Anesthesia. The authors declare no conflicts of interest. This report was previously presented, in part, at the Society of Obstetric Anesthesia and Perinatology Annual Meeting 2011, Canadian Anesthesiologists Society Annual Meeting Address correspondence to Ronald B. George, MD, FRCPC, Department of Women and Obstetric Anesthesia, IWK Health Centre, Dalhousie University, 5850/5980 University Avenue, PO Box 9700, Halifax, NS, Canada B3K 6R8. Address to rbgeorge@dal.ca. Copyright 2012 International Anesthesia Research Society DOI: /ANE.0b013e b26 The current standard labor epidural analgesic regimens in many institutions in North America and Europe consist of a local anesthetic in combination with an opioid delivered via continuous epidural infusion (CEI) with or without patient-controlled epidural analgesia (PCEA) boluses. Despite improved analgesia with CEI with or without PCEA compared with nonneuraxial analgesia, local anesthetic doses may be large with resulting profound motor blockade. 4 This reduces mobility, pelvic muscle tone, and may impair the ability to bear down during the second stage of labor, potentially resulting in increased rates of dystocia and instrumental deliveries. 5 In the continuing evolution of labor analgesia, rather than delivering the local anesthetic continuously, small regularly spaced intermittent boluses may lead to a more extensive spread of local anesthetic in the epidural space. 6 Therefore, the same dose of local anesthetic given via intermittent epidural bolus (IEB) may provide improved analgesia. Research into IEB is growing, and medical devices are in development. A shift in current practice from CEI (with or without PCEA) to IEB (with or without PCEA) will require enhanced pump technology and acceptance by obstetric anesthesiologists to justify the cost of pump replacement to hospital administration. Previous systematic reviews have addressed labor epidural analgesia versus no analgesia and alternate forms of neuraxial analgesia. 7 9 van der Vyver January 2013 Volume 116 Number

2 Intermittent Epidural Bolus: A Systematic Review et al. 10 systematically reviewed traditional PCEA versus CEI; however, their study was published in 2002, before the use of IEB dosing. We, therefore, performed this systematic review of randomized controlled trials (RCTs) to compare the effects of IEB to standard CEI dosing with or without PCEA in healthy women receiving labor epidural analgesia. Specifically, we investigated whether IEB compared with CEI affects patient satisfaction, the need for manual anesthesia interventions, labor progression, and mode of delivery. METHODS The current meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for reporting meta-analyses. 11 The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (PubMed), Excerpta Medica Database (EMBASE), Cumulative Index to Nursing and Allied Health Literature (CINAHL), and the Web of Science (Science Citation Index/ Social Science Citation Index [SCI/SSCI]) were searched. CENTRAL, EMBASE, CINAHL, and SCI/SSCI were last searched in July The PubMed search was last updated on July 4, MeSH terms relating to labor analgesia and neuraxial anesthetic techniques (analgesia, epidural; anesthesia, obstetrical; pregnancy; analgesia, patient-controlled) were combined with text searches for intermittent and automated and relevant synonyms. The results of these searches were combined with a sensitive methodologic filter for RCTs found in Section of the Cochrane Handbook for Systematic Reviews of Interventions. 12 No restrictions, other than those intrinsic to the database being searched, were placed on the dates of publication. The reference lists from retrieved RCTs were screened to identify additional trials, as were recent tables of contents for the leading anesthesia journals. a A search by author for any individual who appears as an author on 2 or more relevant articles was completed. Using PubMed s See related articles function with relevant trials, additional references were sought. In addition, citation records for all relevant RCTs were searched and reviewed with SCI/SSCI. No restrictions with respect to language were included. Unpublished meeting abstracts were not searched, only published RCTs were sought. An attempt was made to contact authors regarding any clarification of primary outcome measures; unpublished data were not requested. Study Identification The types of studies considered for this review included all published RCTs involving a comparison of IEB dosing for maintenance of labor epidural analgesia compared with traditional CEI dosing with or without PCEA. Specifically, participants were healthy laboring women (nulliparous and parous) with lumbar epidural catheters placed for labor analgesia (induced or spontaneous). Primary outcomes analyzed included patient satisfaction, anesthesia interventions, labor progression, and mode of delivery (vaginal, a January 1, 2012, to July 4, 2012 International Journal of Obstetric Anesthesia, Anesthesia & Analgesia, Anesthesiology, Canadian Journal of Anesthesia, Anaesthesia, and British Journal of Anaesthesia. instrumental vaginal, or cesarean delivery [CD]). Secondary outcomes included degree of motor blockade, degree of sensory blockade, time to first anesthetic intervention, local anesthetic dose delivered per hour, presence of pruritus, shivering, maternal fever, nausea and vomiting, neonatal Apgar scores at 1 minute and 5 minutes, and umbilical artery and vein ph. Studies were included if they reported any of the primary outcomes. Disagreements regarding inclusion of potentially eligible trials were resolved by discussion and, if necessary, arbitration by a third reviewer. Data Extraction and Assessment Data were extracted independently by 2 authors (RG and AH). No predesigned data sheet was used. When data were presented as medians, ranges, and confidence intervals (CIs), the mean and standard deviations were calculated as per Hozo et al. 13 Two reviewers (RG and TA) independently assessed the quality (i.e., risk of bias) of all included studies using criteria adapted from Furlan et al. 14 Each of the 12 criteria were scored as yes, no, or unclear. Studies that met 6 of the criteria were rated as having a low risk of bias. In the event that discussion was unable to solve a disagreement between the 2 reviewers, the opinion of the third reviewer (AH) was sought. An a priori sensitivity analysis was planned excluding studies with high risk of bias. Epidural dose calculations were calculated from summarized data by dividing total dose delivered by the mean duration of labor or duration of analgesia delivery reported in each study. Local anesthetic doses were converted to milligram equivalents of bupivacaine per hour of anesthesia delivery. Ropivacaine and levobupivacaine were assumed to be approximately 60% as potent as bupivacaine All data pertaining to the predetermined outcome measures were transcribed to RevMan 5 for meta-analysis (Version 5.1. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2011). If meta-analytic methods were not possible, the data were simply presented qualitatively. All data were analyzed using a random-effects model due to clinical or methodologic heterogeneity. Continuous variables were reported as mean difference (MD) with 95% CI, while dichotomous data were reported as odds ratios (OR) with 95% CI. Heterogeneity was assessed with the I 2 statistic that describes the percentage of variation across studies that is due to heterogeneity rather than chance. 18 A P < 0.1 was considered statistically significant heterogeneity, and I 2 > 50% was considered to indicate significant heterogeneity. Heterogeneity was explored by performing a sensitivity analysis excluding outlier studies if they were methodologically different from other studies. Publication bias was formally assessed with the Egger test. 19 RESULTS The results of the literature search are outlined in Figure 1. After screening, 21 articles were selected for in-depth fulltext review, from which 9 articles were deemed eligible for inclusion in this systematic review The 12 excluded citations clearly did not include a randomized comparison of IEB dosing of a labor epidural compared with standard CEI Three hundred forty-four subjects received CEI, while 350 subjects received IEB labor analgesia. Study characteristics and risk of bias assessment are included in ANESTHESIA & ANALGESIA

3 Figure 1. Manuscript selection flow diagram. Tables 1 and 2. All 9 studies were deemed low risk of bias. Spontaneous onset of labor was an inclusion criteria in 4 studies. 20,21,24,27 However, 3 of the 4 studies reported a percentage of women who received preanalgesia oxytocin. 21,24,27 Two studies reported the portion of women whose labor was induced. 22,26 Wong et al. 28 only recruited parous women for induction of labor. Two studies reported the preanalgesia use of oxytocin. 23,25 Mode of Delivery Of the 9 included trials, 8 reported data on the mode of delivery. These 8 studies included 652 subjects. 20,22 28 None of the studies reported a significant difference in the CD rate. Pooled results also did not show a difference in the rate of CD (OR, 0.87; 95% CI, ; Fig. 2). Similarly, none of the studies reported a reduction in instrumental delivery rate except the study by Capogna et al. 20 This was the only study designed and powered to detect a difference in instrumental delivery rates and reported a significant reduction with IEB compared with CEI (7% vs 20%; P = 0.03). 20 The pooled results for these 8 studies approached but did not achieve statistical significance with reduction of instrumental delivery rate with IEB (OR, 0.59; 95% CI, ; Fig. 3). Wong et al. 28 recruited only parous women, while the other studies contained only nulliparous women. Excluding the study by Wong et al. 28 had no effect on pooled results (cesarean delivery OR, 0.85; 95% CI, ; instrumental delivery OR, 0.57; 95% CI, ). There was no publication bias for CD (P = 0.27) or instrumental delivery (P = 0.48). Duration of Labor Of the 9 included studies, 8 reported the total duration of labor or duration of labor analgesia (n = 652), 20,22 28 while only 5 reported the duration of the second stage of labor (n = 321) ,26,27 There was no statistically significant difference in total duration of labor between IEB and CEI (Fig. 4A). The duration of second stage of labor was statistically significantly shortened in the IEB group (MD, 12 minutes; 95% CI, 23 to 0; Fig. 4B). There was no publication bias for duration of labor (P = 0.06) or second stage of labor (P = 0.82). Anesthesia Interventions Of the 9 included trials, 8 reported data on the need for manual boluses of local anesthetic by the anesthesia caregiver ,27,28 These 8 studies included 567 subjects (Fig. 5). Capogna et al. 20 reported that no subjects in either group required an anesthetic intervention. There was no statistically significant reduction in the need for additional anesthetic intervention (OR, 0.56; 95% CI, ). The time to a subject s first anesthetic intervention was not significantly January 2013 Volume 116 Number

4 Intermittent Epidural Bolus: A Systematic Review Table 1. Study Characteristics and Risk of Bias Assessment of Included Studies Study n Parity Combined spinal epidural subarachnoid medications Epidural solution CEI regimen IEB regimen Capogna et al Nulliparous N/A Levobupivacaine, % 0.125%; sufentanil, 0.5 µg/ml Chua and Sia Nulliparous Fentanyl, 25 µg Ropivacaine, 0.1%; fentanyl, 2 µg/ml Fettes et al Nulliparous N/A Ropivacaine, 0.2%; fentanyl, 2 µg/ml Leo et al Nulliparous Ropivacaine, 2 mg; fentanyl, 15 µg Ropivacaine 0.1%; fentanyl 2 µcg/ml Lim et al Nulliparous Fentanyl, 25 µg Levobupivacaine, 0.1%; fentanyl, 2 µg/ml Lim et al Nulliparous Ropivacaine, 2 mg; fentanyl, 15 µg Ropivacaine, 0.1%; fentanyl, 2 µg/ml Salim et al Nulliparous N/A Bupivacaine, 0.125% 0.25%; fentanyl, 2 µg/ml Sia et al Nulliparous Ropivacaine, 2 mg; fentanyl, 15 µg Wong et al Parous Bupivacaine, 1.25 mg; fentanyl, 15 µg Ropivacaine, 0.1%; fentanyl, 2 µg/ml Bupivacaine, 0.625%; fentanyl 2, µg/ml 10 ml/h (0.0625%) + PCEA (5 ml bolus, 10 minute lockout, 0.125%) (n = 70) 10 ml (0.0625%) bolus every hour + PCEA (5 ml bolus, 10 minute lockout, 0.125%) (n = 75) Spontaneous/induced labor, n (%) Spontaneous labor a ; oxytocin use not reported 5 ml/h (n = 21) 5 ml bolus every hour (n = 21) Spontaneous labor a ; preanalgesia oxytocin; CEI, 8 (38); IEB, 9 (43) 10 ml/h (n = 20) 10 ml bolus every hour (n = 20) Induction of labor; CEI, 12 (60); IEB, 14 (70) 5 ml/h + PCEA (5 ml bolus, 10 minute lockout) (n = 31) 5 ml bolus every hour (or 30 minutes after successful PCEA dose) + PCEA (5 ml bolus, 10 minute lockout) (n = 31) 10 ml/h (n = 30) 5 ml bolus every 30 minutes (n = 30) 10 ml/h (n = 25) 2.5 ml bolus every 15 minutes 8 ml/h (0.125%) + PCEA (3 ml bolus, 20 minute lockout) (n = 63) 5 ml/h + PCEA (5 ml bolus, 10 minute lockout) (n = 21) 12 ml/h + PCEA (5 ml bolus, 10 minute lockout) (n = 63) (initiated 7.5 minutes after SA dose) (n = 25) 10 ml bolus every hour (0.25%) (n = 64) 5 ml bolus every hour (or 1 hour after successful PCEA dose) (n = 21) 6 ml bolus every 30 minutes + PCEA (5 ml bolus, 10 minute lockout) (n = 63) Preanalgesia oxytocin; CEI, 10 (32); IEB, 15 (48) Preanalgesia oxytocin; CEI, 4 (13); IEB, 9 (30) Spontaneous labor a ; preanalgesia oxytocin; CEI, 10 (40); IEB, 5 (20) Induction of labor; CEI, 17 (27); IEB, 14 (22) Spontaneous labor a ; preanalgesia oxytocin; CEI, 5 (24); IEB, 7 (33) Induction of labor a ; CEI, 63 (100); IEB; 63 (100) CEI = continuous epidural infusion; IEB = intermittent epidural bolus; PCEA = patient-controlled epidural analgesia; SA = subarachnoid. a Reported as an inclusion criteria. Risk of bias assessment ANESTHESIA & ANALGESIA

5 Table 2. The Risk of Bias of Included Studies 14 Capogna et al. 20 Chua and Sia 21 Fettes et al. 22 Leo et al. 23 Lim et al. 25 Lim et al. 24 Salim et al. 26 Sia et al. 27 Wong et al. 28 Was the method of randomization adequate? Yes No Yes No No Yes Yes Yes Yes Was the treatment allocation concealed? Yes Yes Yes Yes No Yes Yes Yes Yes Was the patient blinded to the intervention? Yes Yes Yes Yes No Yes Unsure Yes Yes Was the care provider blinded to the intervention? Yes Yes Yes Yes Unsure Yes Unsure Yes Yes Yes Yes Yes Yes Yes Yes Unsure Yes Yes Was the outcome assessor blinded to the intervention? Was the dropout rate described and acceptable? Yes Yes Yes Yes Yes Yes Yes Yes Yes Were all randomized participants analyzed in their Yes Yes Yes Yes Yes Yes Yes Yes Yes allocated group? Are reports of the study free of suggestion of Yes Yes Yes Yes Yes Yes No Yes Yes selective outcome reporting? Were the groups similar at baseline? Yes Yes Yes Yes Yes Yes Yes Yes Yes Were cointerventions avoided or similar? Yes Yes Yes Yes Yes Yes Yes Yes Yes Was the compliance acceptable in all groups? Yes Yes No Yes Yes Yes Yes Yes No Was the timing of the outcome assessment similar? Yes Yes Yes Yes Yes Yes Yes Yes Yes different between groups (MD, 17 minutes; 95% CI, 28 to 62; Fig. 6). Significant heterogeneity was observed for the time to first interventions outcome (I 2 = 74%). Chua et al. 21 appear to add significant heterogeneity to this analysis. Removing this study abolishes this heterogeneity (I 2 = 0%) with no effect on pooled results (MD, 7 minutes; 95% CI, 37 to 24). Wong et al. 28 and Sia et al. 27 did not report time to first anesthesia intervention. Sia et al., 27 reported no significant difference in the pain-free interval between CEI and IEB. Wong et al. 28 did report the time to first PCEA usage, and this was not significantly different between the IEB and CEI groups. There was no publication bias for manual interventions (P = 0.57) or time to intervention (P = 0.15). Dose of Local Anesthetic The specific regimens and local anesthetic concentrations are listed in Table 1. Of the 9 included studies, 3 published data regarding the total dose of local anesthetic per hour during the study period. 23,24,28 Five other studies 20,22,25 27 reported the total dose given. The study of Chua et al. 21 was not included in this analysis because the study concluded with the first need for anesthetic intervention. With these 8 studies (n = 652) there was a statistically significant reduction in total local anesthetic delivered with IEB (MD, 1.2 mg bupivacaine equivalents per hour; 95% CI, 2.2 and 0.3; I 2 = 83%; Fig. 7A). Salim et al. 26 used a concentrated local anesthetic mixture for their IEB group, different from their CEI group; therefore, we performed a sensitivity analysis excluding this study. The effect was smaller but still statistically significant in favor of IEB with less heterogeneity (MD, 0.7 mg/h; 95% CI, 1.2 to 0.2; I 2 = 40%; Fig. 7B). There was no publication bias for local anesthetic consumption (P = 0.26). Maternal Satisfaction Overall maternal satisfaction with labor analgesia was reported in 5 of the included studies ,27,28 Four studies reported maternal satisfaction with a verbal rating scale (VRS) where 0 is very dissatisfied and 100 is extremely satisfied ,27 Wong et al. 28 reported maternal satisfaction with a 100-mm visual analog scale (VAS) score. Pooled data from the 5 studies showed greater maternal satisfaction in the IEB groups (MD, 7.0 mm; 95% CI, ; Fig. 8). Exclusion of the study by Wong et al. 28 did not have a significant effect on the pooled results (MD, 7.1 mm; 95% CI, ). There was no publication bias for maternal satisfaction (P = 0.84). Subgroup Analysis of Primary Outcomes Each of the primary outcomes had a subgroup analysis completed based on: (1) the use of a combined spinal epidural (CSE) technique to initiate labor analgesia and (2) the use of PCEA during maintenance of labor analgesia. Five studies initiated analgesia with a CSE. 21,23 25,27 The initiation of labor analgesia with a CSE did not have a significant effect on any of the primary outcomes. The use of PCEA for maintenance of labor analgesia made a noteworthy effect on the duration of the first stage of labor and the total duration of labor. When PCEA was used for maintenance of labor, the duration of first stage was longer with IEB 23,26,27 (MD, 20 minutes; 95% CI, 22 to 61). However, when PCEA was not used for maintenance of labor, the duration of first stage January 2013 Volume 116 Number

6 Intermittent Epidural Bolus: A Systematic Review Figure 2. Forest plot for mode of delivery (cesarean). CEI = continuous epidural infusion; IEB = intermittent epidural bolus. Figure 3. Forest plot for mode of delivery (instrumental). CEI = continuous epidural infusion; IEB = intermittent epidural bolus. was shorter with IEB 22,24 (MD, 61 minutes; 95% CI, 129 to 6; Fig. 9). The total duration of labor was reduced with IEB when PCEA was not used 22,24,25 (MD, 86 minutes; 95% CI, 146 to 27), but not when it was used 20,23,26 28 (MD, 4 minutes; 95% CI, 26 to 17; Fig. 4A). Additional Outcomes Other than dose of local anesthetic, most of the secondary outcomes were infrequently reported. A meta-analysis was completed on specific outcomes that contained data from more than 1 study. There were no significant differences between the groups with respect to these outcomes. The results are summarized in Table 3. Umbilical ph values and 1-minute Apgar scores were only reported in 1 study (no significant difference). 22 The 5-minute Apgar was reported in 4 studies, in which the MD was 0.04 with a 95% CI of 0.2 to 0.1. The degree of sensory block was quantified in 4 studies. Leo et al. 23 and Lim et al. 24 reported the sensory block level at the first request for additional analgesia. Chua et al. 21 reported the maximal sensory block level within the first 3 hours of analgesia, while Sia et al. 27 reported the maximal sensory block during the entire study period. Within these studies, there was no significant difference between CEI and IEB with respect to sensory blockade. Capogna et al. 20 designed their study to detect a clinically significant degree of motor blockade measured with the Bromage score modified by Breen et al. 41 In their study, the incidence of motor block (defined as modified Bromage score 41 <6, i.e., the inability to stand and complete a partial knee bend) at least once during labor was significantly increased in the CEI group compared with the IEB group (26/70 vs 2/75, P < 0.001). Assuming the modified Bromage score <6 20 is equivalent to a traditional Bromage score >1, 21,27,28 then the pooled results are not statistically significant (Table 3). DISCUSSION Nine high-quality low risk of bias RCTs have evaluated IEB versus CEI in laboring women. In healthy women requesting labor epidural analgesia, the mode of maintenance of epidural analgesia may not affect the mode of delivery. However, intermittent bolus dosing of local anesthetic may be associated with reduced local anesthetic consumption, decreased anesthetic interventions, and an improvement in maternal satisfaction when compared with those women receiving CEI. The 2 techniques of local anesthesia delivery appear to be comparable in terms of total duration of labor, but there was a statistically significant reduction in the length of the second stage of labor with IEB. The duration of the second stage was a much as 22 minutes shorter with IEB. Arguably, this may enter the realm of clinically significant, ANESTHESIA & ANALGESIA

7 Figure 4. A, Forest plot for the total duration (minutes) of labor and the subgroup analysis for patient-controlled epidural analgesia (PCEA) maintenance of labor analgesia. B, Forest plot for the duration (minutes) of second stage of labor. CEI = continuous epidural infusion; IEB = intermittent epidural bolus. Figure 5. Forest plot for required anesthetic interventions. CEI = continuous epidural infusion; IEB = intermittent epidural bolus. and IEB may positively affect labor progression. Although there was no statistically significant difference between the 2 groups with regard to the incidence of adverse events (Table 3), the wide CIs of the pooled results preclude us from making any conclusions. Despite not reaching statistical significance, several outcomes should be considered potentially clinically significant. The pooled results for instrumental delivery rate, rate of anesthetic interventions, and duration of labor each have wide CIs that contain clinically significant end points, therefore precluding us from drawing conclusions from the pooled data for those outcomes. For instance the lower end CI for the OR for instrumental delivery is 0.35, a clinically significant possibility with IEB. With a January 2013 Volume 116 Number

8 Intermittent Epidural Bolus: A Systematic Review Figure 6. Forest plot for time (minutes) to first required anesthetic intervention. CEI = continuous epidural infusion; IEB = intermittent epidural bolus. Figure 7. A and B, Forest plot for milligrams per hour of local anesthetic (bupivacaine equivalents) delivered. CEI = continuous epidural infusion; IEB = intermittent epidural bolus. Figure 8. Forest plot for maternal satisfaction (visual analog scale [VAS] mm; verbal rating scale [VRS] 23 25, ; 0 = very dissatisfied, 100 = extremely satisfied). CEI = continuous epidural infusion; IEB = intermittent epidural bolus ANESTHESIA & ANALGESIA

9 Figure 9. Forest plot for the duration (minutes) of first stage of labor and the subgroup analysis for patient-controlled epidural analgesia (PCEA) maintenance of labor analgesia. CEI = continuous epidural infusion; IEB = intermittent epidural bolus. Table 3. Secondary Outcomes Outcome Studies Nausea Lim et al. 24,25 Sia et al. 27 Leo et al. 23 Vomiting Lim et al. 24,25 Sia et al. 27 Leo et al. 23 Pruritus Lim et al. 24,25 Sia et al. 27 Leo et al. 23 Hypotension Lim et al. 24,25 Sia et al. 27 Fettes et al. 22 Chua et al. 21 Leo et al. 23 Motor blockade Chua et al. 21 Sia et al. 27 Wong et al. 28 Capogna et al. 20 Number of events/total in intermittent epidural bolus group Number of events/total in continuous epidural infusion group Odds ratio (95% confidence interval) 10/107 (9.3%) 3/107 (2.8%) 2.83 ( ) 9/107 (8.4%) 3/107 (2.8%) 3.21 ( ) 62/107 (57.9%) 62/107 (57.9%) 1.00 ( ) 7/148 (4.7%) 3/148 (2.0%) 1.70 ( ) 5/180 (2.8%) 28/175 (16.0%) 0.47 ( ) heterogeneity measure of zero, 8 studies contributing to a very close statistical significance (P = 0.05) and an absolute risk difference of 5.2% suggest a number-needed-to-treat of 20 to prevent 1 instrumental delivery. The effect size of 0.59 suggests that future trials of IEB should include approximately 486 participants (G-Power v , Mannheim, Germany) to show a statistically significant reduction in the instrumental delivery rate compared with standard CEI. 42 Induced versus spontaneous labor is a potential factor in these important outcomes; however, not all studies restricted the inclusion criteria nor specifically reported this event; therefore, a subgroup analysis was not possible. Interference with normal labor progression leading to instrumental deliveries is a potentially unfavorable outcome of labor analgesia. However, modern labor analgesia with low concentrations of local anesthetics can be administered without adversely affecting labor outcomes. 42 In the Comparative Obstetric Mobile Epidural Trial (COMET) conducted in the United Kingdom, Wilson et al. 43 demonstrated that despite improved analgesia and lower doses of local anesthetic in the CSE analgesia arm of the study, this technique did not alter delivery modality or duration of labor. Despite the lack of statistical significance to alter labor outcomes with IEB delivery of epidural analgesia, the improvement in maternal satisfaction, which may loosely reflect improved analgesia, is still an important goal for labor analgesia research. Satisfaction with labor analgesia is an important outcome of the quality of care given to women. It is a complex measure commonly used to describe overall adequacy of pain relief. However, maternal satisfaction involves many factors maternal involvement in decision making, perception of emotional control, maternal expectations, and labor pain Furthermore, labor pain is more than a simple physiological process; it is a complex reaction for which inadequately validated measures of maternal satisfaction, such as VAS and VRS measures, may or may not necessarily correlate to the effectiveness of pain relief. 47,48 Given the complexity January 2013 Volume 116 Number

10 Intermittent Epidural Bolus: A Systematic Review of measuring satisfaction, the different scales used, and the timing of such a measure, the lack of heterogeneity (I 2 = 0%) should be interpreted with caution. All of the studies had small sample sizes reflecting the difference in the outcomes they were powered to detect. Two trials were powered to detect a difference in the dose of local anesthetic delivered. 27,28 A single study was powered to detect a difference in the duration of labor. 26 Fettes et al. 22 powered their study to detect a difference in VAS score at an arbitrary time, 4 hours after the intervention. Four studies were powered to detect a difference in need for anesthesia interventions. 21,23 25 Other than Capogna et al., 20 none of the included trials was powered to detect a difference in the side effects of labor analgesia. No studies were powered to detect a difference in maternal satisfaction. Capogna et al. 20 published the largest and most recent trial, which was powered to detect a difference in the incidence of motor blockade (primary outcome) and instrumental deliveries (secondary outcome). They reported a greater incidence of motor blockade with CEI using the modified Bromage score, which may be more sensitive than the traditional Bromage score. 41 The authors suggested that the greater incidence of motor blockade and subsequent higher instrumental delivery rate in the CEI group compared with other similar trials was due to the longer duration of observation in their study. However, the duration of labor was not significantly longer in this trial and was likely shorter than average. The dramatic decrease in instrumental delivery rate is likely related to the reduced motor blockade. Perhaps the CEI infusion that was started immediately after induction of analgesia or the increased number of patients who used the higher concentration 0.125% levobupivacaine PCEA option in the CEI group added significantly to the cumulative dose of levobupivacaine and subsequent increased motor blockade. The ultralow dose regimen for epidural analgesia based on the study by Capogna et al. 20 and the reduced PCEA use in the IEB group and subsequent reduced motor blockade appear to eloquently display a potential benefit of IEB. Whether it was the higher PCEA use in the CEI group or the characteristics of IEB with % levobupivacaine, they both seem to deliver appropriate analgesia, as neither group required a manual anesthetic intervention. This came at the cost of increased motor blockade and instrumental delivery in the CEI group. This review has several limitations. There was significant inconsistency with regard to reporting of outcomes. Each of the included studies reported at least 1 primary outcome, but none of the included studies included all primary outcomes reported in this systematic review. Each study, except Sia et al., 27 found at least 1 significant difference in a primary outcome measure. Measures of analgesia such as pain scores reported using VAS, VRS, or numeric rating scales were not measured at standard intervals. In contrast, maternal satisfaction was nearly consistently reported and may represent a surrogate measure of analgesia. The study by Wong et al. 28 was the only study to recruit parous subjects; in fact, they only included parturients with at least 1 previous vaginal delivery (126 subjects). The remaining studies only included uncomplicated nulliparous women. This likely limits our ability to extrapolate our conclusions to women presenting with multiple gestations and parous women. Because of the small number of studies, a metaregression was not conducted to control for factors known to affect the outcomes of interest. There was significant clinical heterogeneity among studies with regard to labor analgesia initiation, specific local anesthetic and concentration, and drug delivery regimens. A subgroup analysis of the effect of PCEA maintenance and CSE analgesia initiation yielded only a potential interaction between PCEA, IEB, and the duration of labor. Because of the small number of studies, the relatively youthful field of IEB, and the variety of analgesia regimens, sensitivity analysis of these dosing variables was not part of this analysis. Currently, because of IEB with PCEA equipment not being readily available, standardization of equipment among institutions is nearly impossible. Specifically, the dosing volumes and intervals varied among the studies, and it is unknown whether this influenced the reported outcomes. Much like the debates regarding the ideal regimen of CEI combined with PCEA, the search for the ideal IEB regimen is sure to inspire future studies. Wong et al. 49 have initiated this avenue of research. They recently compared 3 regimens of IEB and PCEA: 2.5 ml every 15 minutes, 5 ml every 30 minutes, and 10 ml every 60 minutes of mg/ml bupivacaine with 1.95 µg/ml of fentanyl. The 10/60 group did consume less bupivacaine, and the 2.5/15 group appeared to require more interventions for poor analgesia, but otherwise all 3 groups were very similar with respect to mode of delivery, PCEA usage, manual anesthesia interventions, pain scores, and motor blockade. Future studies will need to be powered to detect the small differences that may exist between the extremes of bolus size. Accepting that the lowdose epidural regimens of Wong et al. 49 and Capogna et al. 20 are likely near the ideal concentration, the trends suggest that larger volume boluses may be required. In summary, IEB may be associated with reduced local anesthetic consumption, shorter second stage of labor, and higher maternal satisfaction but possibly no difference in mode of delivery or required anesthetic interventions compared with CEI. As previously noted, the wide CIs for the pooled results of some of the reported outcomes do contain clinically significant differences, such as the potential for a clinically significant reduction in the instrumental delivery rate with IEB. Further research of IEB for labor analgesia is necessary before definite conclusions can be made. Current epidural pump technology does not allow using IEB with PCEA, and changing current practice would require a significant financial influx to labor wards for the required pump technology and education. On the basis of the findings of this systematic review and metaanalysis, current evidence suggests that there may be potential improvements in instrumental delivery rates and rates of anesthesia interventions, so more studies are required to conceptualize the ideal IEB/PCEA regimen and then consistently show an improvement in labor analgesia and a greater effect on obstetric outcomes. The new pump technology required for this new technique and the cost that this entails could easily be justified by improved outcomes. E ANESTHESIA & ANALGESIA

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