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Hyperbaric Versus Isobaric Bupivacaine for Spinal Anesthesia

Systematic Review and Meta-analysis for Adult Patients Undergoing Noncesarean Delivery Surgery

Uppal, Vishal, FRCA*; Retter, Susanne, MD*; Shanthanna, Harsha, MD; Prabhakar, Christopher, FRCPC; McKeen, Dolores M., FRCRC*

doi: 10.1213/ANE.0000000000002254
Regional Anesthesia and Acute Pain Medicine: Meta-Analysis
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BACKGROUND: It is widely believed that the choice between isobaric bupivacaine and hyperbaric bupivacaine formulations alters the block characteristics for the conduct of surgery under spinal anesthesia. The aim of this study was to systematically review the comparative evidence regarding the effectiveness and safety of the 2 formulations when used for spinal anesthesia for adult noncesarean delivery surgery.

METHODS: Key electronic databases were searched for randomized controlled trials, excluding cesarean delivery surgeries under spinal anesthesia, without any language or date restrictions. The primary outcome measure for this review was the failure of spinal anesthesia. Two independent reviewers selected the studies and extracted the data. Results were expressed as relative risk (RR) or mean differences (MDs) with 95% confidence intervals (CIs).

RESULTS: Seven hundred fifty-one studies were identified between 1946 and 2016. After screening, there were 16 randomized controlled clinical trials, including 724 participants, that provided data for the meta-analysis. The methodological reporting of most studies was poor, and appropriate judgment of their individual risk of bias elements was not possible. There was no difference between the 2 drugs regarding the need for conversion to general anesthesia (RR, 0.60; 95% CI, 0.08–4.41; P = .62; I2 = 0%), incidence of hypotension (RR, 1.15; 95% CI, 0.69–1.92; P = .58; I2 = 0%), nausea/vomiting (RR, 0.29; 95% CI, 0.06–1.32; P = .11; I2 = 7%), or onset of sensory block (MD = 1.7 minutes; 95% CI, −3.5 to 0.1; P = .07; I2 = 0%). The onset of motor block (MD = 4.6 minutes; 95% CI, 7.5–1.7; P = .002; I2 = 78%) was significantly faster with hyperbaric bupivacaine. Conversely, the duration of motor (MD = 45.2 minutes; 95% CI, 66.3–24.2; P < .001; I2 = 87%) and sensory (MD = 29.4 minutes; 95% CI, 15.5–43.3; P < .001; I2 = 73%) block was longer with isobaric bupivacaine.

CONCLUSIONS: Both hyperbaric bupivacaine and isobaric bupivacaine provided effective anesthesia with no difference in the failure rate or adverse effects. The hyperbaric formulation allows for a relatively rapid motor block onset, with shorter duration of motor and sensory block. The isobaric formulation has a slower onset and provides a longer duration of both sensory and motor block. Nevertheless, the small sample size and high heterogeneity involving these outcomes suggest that all the results should be treated with caution.

Published ahead of print July 13, 2017.

From the *Department of Anesthesia, Perioperative Medicine and Pain Management, Dalhousie University, Nova Scotia Health Authority and IWK (Izaak Walton Killam) Health Centre, Halifax, Nova Scotia, Canada; Department of Anesthesia, McMaster University, St Joseph’s Health Care, Hamilton, Ontario, Canada; and Department of Anesthesiology, Pharmacology, and Therapeutics, University of British Columbia, St Paul’s Hospital, Vancouver, British Columbia, Canada.

Accepted for publication April 21, 2017.

Published ahead of print July 13, 2017.

Funding: None.

Conflicts of Interest: See Disclosures at the end of the article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website.

The abstract of this report was presented as a podium presentation at the European Society of Regional Anesthesia Annual Meeting, Maastricht, the Netherlands, in September 2016.

Reprints will not be available from the authors.

Address correspondence to Vishal Uppal, FRCA, Department of Anesthesia, Perioperative Medicine and Pain Management, Dalhousie University, Nova Scotia Health Authority and IWK Health Centre, Halifax, Nova Scotia, B3H2Y9 Canada. Address e-mail to v.uppal@dal.ca.

More than 300 million surgical procedures are performed worldwide each year.1 Approximately 5%, or 15 million, surgical procedures are performed under spinal anesthesia (SA).2 Bupivacaine hydrochloride is an aminoacyl local anesthetic and is the most commonly used local anesthetic medication for SA. There are 2 forms of commercially available bupivacaine: isobaric bupivacaine (IB), with a density equal to that of cerebrospinal fluid (CSF), and hyperbaric bupivacaine (HB), with a density heavier than CSF. The difference in densities of the 2 available preparations is believed to affect their diffusion patterns and thus determine the effectiveness, spread (dermatome height or block height), and side-effect profile of the drug.3

Anesthesiologists, on a daily basis, when performing SA, must choose between the 2 most commonly available HB or IB preparations. Despite the 2 formulations being used for >30 years, there is still disagreement regarding the choice of the formulation. This decision is often based on personal experience, training, local institutional practices, and drug preparation availability. Looking at the literature to guide choice (HB versus IB) revealed multiple studies, yet little has been synthesized into clear practice guidance to help anesthesiologists make evidence-informed decisions.

A recent Cochrane Review compared these formulations for cesarean delivery anesthesia.4 There are various well-known physiological and pharmacological changes in women during pregnancy that significantly impact SA characteristics and that limit the generalizability of this review to their nonpregnant counterparts.5

Publications that have compared IB and HB in the nonpregnant population have not provided evidence for guidance on formulation choice. Vernhiet et al6 suggested that the use of HB for SA is associated with a lower failure rate compared with IB; however, there was a lower incidence of hypotension with IB. Some studies have reported a higher incidence of hypotension with the use of HB for SA.7–11 To the contrary, others have reported similar incidences of hypotension or even a lower incidence of hypotension with the use of HB compared with IB.12–16 Similarly, there is conflicting evidence related to the time of onset of the block, maximum dermatomal spread, time to block regression, and the duration of motor block.7,17–21 Limitations of existing studies include small sample size and differences in the actual direction of outcomes, leading to difficulties in the obvious application of existing knowledge.

We are unaware of any previously published systematic review addressing this question in noncesarean delivery surgery. This systematic review summarizes the best available evidence regarding the effectiveness and the safety profile including block characteristics of HB compared with IB when used to provide SA for surgery. The results of this review will enable clinicians to make an evidence-based choice on the type of bupivacaine formulation they should use while performing SA for noncesarean delivery surgery.

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METHODS

Registration and Protocol

This meta-analysis was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).22 The study protocol was registered with PROSPERO (registration number PROSPERO 2015: CRD42015017672) and published in BMJ Open.23

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Eligibility Criteria

We included randomized controlled clinical trials (RCTs), published in any language that included adult patients (>18 years of age) undergoing SA for elective surgical procedures on the lower abdomen, pelvis, or the lower extremity. We excluded patients undergoing emergency surgery or cesarean delivery. Included studies compared HB with IB administered as part of single injection SA. We included only studies that had used standard glucose formulations for HB (ie, bupivacaine with glucose 80 mg/mL). Studies using additives in the form of opioids or mixtures of local anesthetics were excluded to reduce heterogeneity. A study was excluded if it compared different dosages of local anesthetics between each arm, if patients received planned general anesthesia (GA) along with SA, or any other modality of regional analgesia (nerve block or epidural) techniques.

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Information Sources

An electronic literature search was conducted in MEDLINE (using PubMed platform), EMBASE, and the Cochrane Central Register of Controlled Trials (April 2015) by a professional librarian. This search was repeated before submission for publication (September 2016). The search strategy was modified slightly to suit each particular database. The search strategy is shown in Supplemental Digital Content 1, Appendix 1, http://links.lww.com/AA/B819.

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Study Selection

Study selection was performed in 2 stages, by 2 independent reviewers (V.U. and C.P.). During the first stage, we screened the title and abstracts followed by the full-text screening at the second stage. The details of our selection criteria have been published and are also shown in Supplemental Digital Content 2, Appendix 2, http://links.lww.com/AA/B820. In brief, we included RCTs of adults (>18 years of age) having SA for noncesarean delivery surgeries in which bupivacaine was used as either a hyperbaric or an isobaric formulation in at least 2 of the study groups. Any discrepancy between reviewers was settled by mutual agreement or by an arbitrator (D.M.M.).

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Data Collection Process

Two reviewers (V.U. and S.R.) independently extracted the data using a standardized electronic form. Extracted items included study characteristics, the risk of bias (RoB) domains, as per modified Cochrane RoB, participant disposition, and study outcomes.24

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Data Items (Outcome Measures Extracted)

Primary Outcomes.

  1. The failure rate of spinal anesthesia, assessed as either the need for conversion to GA or by the cancellation of surgery, or the need for frequent analgesic supplementation during surgery.
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Secondary Outcomes.

  1. The incidence of intraoperative hypotension: defined as the need for the use of vasopressors.
  2. The incidence of intraoperative nausea and vomiting: defined as the number of patients requiring treatment. The unit of measurement was considered “a patient” and not episodes of nausea and vomiting.
  3. Onset time of block (motor and sensory): defined as the time from the performance of SA to the time when patients were deemed suitable for the start of surgery.
  4. Duration of anesthesia: defined as the time from insertion of SA to regression of sensory and motor block by the authors in each publication. Examples include 2 to 3 dermatome regression or motor recovery on Bromage scale.
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Data Synthesis and Analysis of Outcomes

Data analysis and synthesis were performed using Review Manager (RevMan computer program) version 5.3 (The Nordic Cochrane Centre, the Cochrane Collaboration, 2014, Copenhagen, Denmark) and Microsoft Excel (Microsoft Corporation, Redmond, WA). Pooling of outcomes was performed whenever there were 3 or more studies for a particular outcome. Pooling was done using a fixed-effects model. However, if the I2 for a pooled outcome was >25%, indicative of significant inconsistency, a random-effects model was used for analysis. Dichotomous outcomes are reported as relative risks (RRs), and continuous outcomes are reported as weighted mean differences for the time of onset and duration of anesthesia. Outcomes are reported with their effect estimates, along with 95% confidence interval (CI). The trials that used 10 mg or a lower dose of bupivacaine were classified as low-dose studies. Sensitivity or subgroup analysis was performed to explore differences in outcomes for low-dose studies versus standard (higher) dose studies. We also report the findings with measures of RR reduction and absolute risk reduction. Rating of the quality of evidence with confidence in effect estimates is reported using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach.

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RESULTS

Results of Literature Search (Study Selection)

Figure 1

Figure 1

The results of the search are shown in a PRISMA flowchart (Figure 1). Of 751 citations, 611 records were screened in the first stage of selection after removing duplicates. After the full-text screening, 18 studies met the inclusion criteria. As one of the studies did not have any of the outcomes of interest and a second one used levobupivacaine instead of bupivacaine, 16 studies (including 724 participants) were included in the meta-analysis.

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Study Characteristics

Table 1

Table 1

Table 2

Table 2

Table 1 shows the patient/population characteristics for the included studies. Most studies were conducted in patients undergoing urological, gynecology, or lower limb orthopedic procedures. The median dose of bupivacaine administered was 15 mg with a range of 6–25 mg. All spinal anesthetics were performed either in a sitting or lateral position, and the final position was either supine or lithotomy. We also included 3 studies28–30 that intended to produce a unilateral block by using a dose <10 mg bupivacaine and keeping that patient in a lateral position for 20 minutes after the spinal injection. The studies were small with total sample size ranging from 20 to 100 participants. Most studies assessed outcomes related to blood pressure, side effects, onset time, and duration of anesthesia. There was no consistency in definition of outcomes between studies (Table 2). Three studies25,26,33 did not report a measure of variance for duration of block. This was imputed using the approach described in the Cochrane handbook.39

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RoB Within Studies

Figure 2

Figure 2

The RoB in the included studies is shown in Figure 2. As most of the studies included in the review were conducted before the development of the CONSORT guidelines (2010), the reporting was variable, and therefore, the RoB was unclear for most domains.

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Synthesis of Results

Spinal Failure/Conversion to GA.

Figure 3

Figure 3

Six RCTs with a total population of 320 subjects reported data regarding our primary outcome of “conversion to GA.” Only 2 studies observed conversion to GA (Figure 3) with only 3 events, resulting in no significant difference between the 2 drug formulations (RR, 0.60; 95% CI, 0.08–4.41; P = .62; I2 = 0%). One of the 6 included studies used low-dose (ie, <10 mg) bupivacaine.28 A sensitivity analysis was performed excluding this study (see Supplemental Digital Content 3, Figure 1, http://links.lww.com/AA/B821). The risk of conversion to GA remained similar between the 2 groups (RR, 0.59; 95% CI, 0.08–4.61; P = .62; I2 = 0%). Similarly, sensitivity analysis by excluding 2 studies21,28 that were judged “high” RoB showed no difference between the 2 formulations for risk of conversion to GA (RR, 0.60; 95% CI, 0.08–4.41; P = .62; I2 = 0%; see Supplemental Digital Content 4, Figure 2, http://links.lww.com/AA/B822). The quality of evidence was low due to low event rate and unclear RoB in most included studies.

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The Incidence of Hypotension.

Figure 4

Figure 4

Pooled data from 8 studies with a total of 364 subjects showed that there was no difference between the 2 formulations regarding the incidence of hypotension (RR, 1.15; 95% CI, 0.69–1.92; P = .58; I2 = 0%). Subgroup analysis was conducted for the studies that used fluid preloading versus study that did not (Figure 4). Fluid preloading did not change the risk of hypotension between the 2 groups. Sensitivity analysis by excluding 2 studies28,30 that used low bupivacaine did not affect the incidence of hypotension for the 2 formulations (RR, 1.38; 95% CI, 0.81–2.34; P = .24; I2 = 0%; see Supplemental Digital Content 5, Figure 3, http://links.lww.com/AA/B823). The quality of evidence was moderate due to an unclear RoB for most included studies.

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The Incidence of Intraoperative Nausea and Vomiting.

Like incidence of hypotension, no difference was observed in the incidence of the number of patients with “nausea/vomiting needing treatment” (RR, 0.29; 95% CI, 0.06–1.32; P = .11; I2 = 7%). The quality of evidence was low due to few studies and unclear RoB.

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Onset Time for the Motor Block.

Based on 6 studies that included 219 participants, the onset of the motor block was significantly faster with HB (MD = 4.6 minutes; 95% CI, 7.5 to 1.7; P = .002; I2 = 78%). Sensitivity analysis was performed by excluding one low-dose study29 that lead to a reduction in the heterogeneity of the finding with onset remaining faster with HB (MD = 3.0 minutes; 95% CI, 0.8–5.2; P = .008; I2 = 44%; see Supplemental Digital Content 6, Figure 4, http://links.lww.com/AA/B824). The quality of evidence was low due to moderate to high heterogeneity and unclear RoB.

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Onset Time for the Sensory Block.

The onset of the sensory block was similar between the 2 groups (MD = 1.7 minutes; 95% CI, −3.5 to 0.1; P = .07; I2 = 0%). The quality of evidence was moderate due to an unclear RoB.

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Duration of Motor Block.

Pooled data from 7 studies with a total of 279 participants showed that the duration of the motor block was longer in IB group (MD = 45.2 minutes; 95% CI, 66.3–24.2; P < .001; I2 = 87%). Sensitivity analysis by excluding a low-dose study29 showed some reduction in heterogeneity, with motor duration remaining longer for the IB group (MD = 56.3 minutes; 95% CI, 35.4–77.3; P < .001; I2 = 67%; see Supplemental Digital Content 7, Figure 5, http://links.lww.com/AA/B825). The quality of evidence was low due to high heterogeneity and unclear RoB.

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Duration of Sensory Block.

Figure 5

Figure 5

Similarly, pooled data from 9 studies including 420 participants showed that the duration of the sensory block was also longer in IB (MD = 29.4 minutes; 95% CI, 15.5–43.3; P < .001; I2 = 73%; Figure 5). The results of 2 subgroups (low dose and standard dose) can be seen in the forest plot (Figure 5). The mean duration of sensory block was similar in both the subgroups, however; the low-dose group was less heterogeneous. The quality of evidence was low due to high heterogeneity and unclear RoB.

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Additional Analysis

Funnel plots to address any publication bias were not done as there were <10 studies for each outcome.40 The Cochrane guidelines (Cochrane Handbook, section 16.7.2) were followed to deal with the issue of multiple outcome testing. The primary and secondary outcomes and the analysis plan were decided a priori. Statistical adjustments for multiple tests were not used as we conducted a restricted number of preplanned comparisons.41

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DISCUSSION

Summary of Evidence

Main Findings.

The primary finding of this study showed no difference between IB and HB regarding failure rate. Furthermore, no significant differences were observed in the adverse events such as the incidence of hypotension or incidence of nausea/vomiting requiring intervention or treatment. However, when assessing duration of anesthesia, there was a clear indication for a longer duration of the motor (45.2 minutes) and sensory block (29.4 minutes) with IB compared with HB. With regard to onset time, evidence suggests a more rapid onset of a motor block (4.6 minutes), with no difference in the onset of the sensory block for HB. Nevertheless, the small sample size and high heterogeneity involving these outcomes suggest that these results should be treated with caution.

For most studies included in this review (Table 1), the SA was performed in a sitting or lateral position, and the subjects were repositioned to supine or lithotomy positions immediately following the procedure. These studies used 15–25 mg bupivacaine (mode = 15 mg). We believe that our review summarizes the evidence about this population group.

Three included studies attempted to compare the 2 formulations for producing a unilateral SA by using low-dose bupivacaine (5–8 mg), performing the procedure in a lateral position, and keeping the patient in a lateral position for 20 minutes.28–30 All of them observed that HB provides a consistently higher incidence of a unilateral block.

Some studies also performed the SA procedure in a sitting position and kept the patient sitting for 2–3 minutes to observe any differing clinical effects.21,25,35,38 Alston21 and Axelsson et al25 found that both IB and HB were equally effective. However, a longer duration of the motor block was seen with IB. Furthermore, Streiner and Norman41 and Visentin et al38 observed no difference in the cephalad spread achieved by the 2 formulations using this approach.

Our findings are in agreement with the recent Cochrane Review (Sng et al)4 that addressed the same question in cesarean delivery surgery. That is, despite the anatomical, physiological, and pharmacological differences of the nonpregnant population.42 Sng et al4 did not observe any differences between the 2 groups regarding “conversion to GA,” “incidence of hypotension,” or “incidence of nausea/vomiting.” However, they showed that the time for the sensory block to the thoracic fourth (T4) spinal level was shorter with HB (MD = 1.06 minutes; 95% CI, −1.80 to −0.31). This trend toward a faster onset of adequate anesthesia with HB was also observed by a more rapid onset of a motor block in our review. Although one could argue that the faster onset time by a few minutes may not be as clinically relevant, in a noncesarean delivery population.

Perhaps more relevant is our observation of longer duration of sensory and motor block with IB. There are multiple studies in cesarean delivery population, assessing the motor and sensory duration of anesthesia.43–47 Punshi and Afshan43 and Richardson et al44 found the longer duration of both sensory and motor block with IB. Russell and Holmqvist45 and Sarvela et al46 showed a longer duration of motor block, and Vichitvejpaisal et al47 showed longer sensory duration with IB. All these studies are consistently in agreement with our finding of increased duration of sensory and motor block with IB. In general surgical population, the surgeries such as revision arthroplasty of major lower limb joints could take longer than 2 hours. Thus, this clinically significant finding is relevant for the anesthesiologist to inform the choice of formulation that would allow the sufficiently prolonged duration of action.

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Strength of Evidence for Outcomes.

The methodological reporting of most studies was poor, and proper judgment of their individual RoB elements was not possible. Allocation concealment was reported in only 1 of the 16 studies; method of random sequence generation was reported in only 3 of the 16 studies, and 9 studies indicated that the outcome assessors were blinded. Even though most studies were described as double-blinded, accurate details regarding blinding of patients, anesthesiologists, and outcome assessors were not clear. It is more than likely that the patients were blinded as the spinal injection is performed behind them on their back. Thus, while possible that they would be able to identify the formulation, this makes it unlikely that patients would have been able to see the drug during the procedure. Six studies stated that the anesthesiologists were not blinded and therefore were assessed as high risk of performer bias. The rest were assessed as unclear risk of performer bias. We did not suspect much attrition bias as the outcomes were assessed immediately after the procedure with no possibility of loss to follow-up. Selective outcome reporting could not be identified in the absence of the published study protocols; therefore, these were assessed as having an unclear RoB. The evidence was summarized using the GRADE approach for individual outcomes. The evidence for most outcomes was rated as being of low quality, except for the risk of hypotension and onset of the sensory block, which was rated as being of moderate quality.

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Relevance to Anesthesiologists.

There is no compelling evidence to favor HB or IB regarding the effectiveness or adverse effects in general surgical population. The decision to use one over the other should be based on the needs of the surgical procedure, especially about the required onset and duration of the block. The HB formulation allows for a relatively rapid onset, with shorter duration of motor and sensory block. Two studies concluded that HB is also more effective in producing a unilateral spinal block. Therefore, it would be suitable for shorter procedures to allow early mobilization. On the other hand, IB provides a longer duration of both sensory and motor blocks, making it suitable for longer surgical procedures. This is an important point for clinical practice as it is challenging to perform a rescue GA for a spinal that is regressing during an ongoing surgical procedure. This is especially when surgery is being performed in a lateral position (eg, total hip replacement procedure). Furthermore, the need to convert to a GA exposes the patient to the inherent risks of an urgent unplanned anesthetic intervention, as well as that of 2 independent GA and SA interventions. Since the type of preparation chosen influences the duration of the motor and sensory duration, this makes this review relevant. One of the theories for a longer duration of action of IB is that the injected drug reaches a higher concentration at the point of injection, as it does not spread extensively in CSF. Whereas HB, because of its baricity, quickly spreads caudad and cephalad due to lumbar lordosis leading to faster onset. However, the onset and duration data from these studies should be interpreted with caution because of high heterogeneity.

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Limitations

Opioids are commonly added to bupivacaine to improve the quality of anesthesia and prolong the duration of analgesia.48 Pöpping et al49 reviewed the effect of adding opioids to local anesthetics for single-shot intrathecal anesthesia. They found that different authors have studied several opioids and combinations as additives to local anesthetic for spinal anesthesia. These include morphine, fentanyl, sufentanil, diamorphine and buprenorphine, tramadol, and meperidine, pentazocine, methadone, and hydromorphone. The current review excluded studies that used intrathecal opioids and this may reduce the generalizability of this review; however, including these studies would have confounded our aim of teasing out the difference of efficacy and safety between the preparations. Pöpping et al49 state that the opioids are not expected to have any impact on one of these end points; “time to onset of sensory block,” “time to maximal level of sensory block,” “duration of sensory block,” “time to onset of motor block,” and “duration of motor block.” However, Hamber and Viscomi,50 in a review of intrathecal opioids as an adjuvant to SA in obstetric population, state that “synergistic drug interactions between LA and lipophilic opioids may lead to faster block onset and improved intraoperative conditions but, little to no change in motor/sensory block.”

Despite both the formulations being available for >30 years, there is a lack of clear evidence on this topic to guide selection. Most trials included in the review were small and not adequately powered to detect failure rate or even adverse events, given such low event rates. Additionally, limited numbers of recent trials are available in this area, and the older trials have poorly reported important methodological details, such as randomization, blinding, and complete outcome data assessment. Methods used to measure the duration of the motor or sensory block or regression of SA were varied between studies. We think this could be a significant contributor to the observed inconsistency. Attempts to produce unilateral anesthesia by keeping the patient lateral for 20 minutes may be another source of heterogeneity across the studies. However, we attempted to account for this by using subgroup analysis.

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CONCLUSIONS

Our review demonstrates that there is no difference in the primary outcome of SA block efficacy/failure when choosing HB or IB (moderate- to low-quality evidence). Results show that the duration of anesthesia is prolonged with IB (low-quality evidence) and provides useful estimates of differences in motor and sensory block that are clinically meaningful. The review has several limitations, which result from the quality, size, and heterogeneity of included studies. A well-designed, adequately powered RCT might produce further results that would inform clinical decision-making.

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ACKNOWLEDGMENTS

We thank Darlene Chapman (Manager, Library Services) and Pamela Parker (Library Assistant) from IWK Health Centre (Halifax) for helping us with the literature search. We also thank Lorraine Chiasson, Research Manager, Women’s and Obstetric Anesthesia, IWK Health Centre, for proofreading our manuscript.

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DISCLOSURES

Name: Vishal Uppal, FRCA.

Contribution: This author helped conceive the study, design the study, draft the protocol, screen the studies, draft the manuscript, revise the submission, and approve the publication of the manuscript.

Conflicts of Interest: Vishal Uppal has conducted a clinical trial that was funded by Recro Pharma (Devault, PA). However, this does not directly impact the contents of this report.

Name: Susanne Retter, MD.

Contribution: This author helped design the study, screen the studies, and approve the publication of the manuscript.

Conflicts of Interest: None.

Name: Harsha Shanthanna, MD.

Contribution: This author helped design the study, draft the protocol, draft the manuscript, revised the submission, and approve the publication of the manuscript.

Conflicts of Interest: None.

Name: Christopher Prabhakar, FRCPC.

Contribution: This author helped conceive the study, design the study, screen the studies, and approve the publication of the manuscript.

Conflicts of Interest: None.

Name: Dolores M. McKeen, FRCRC.

Contribution: This author helped design the study, draft the protocol, screen the studies, draft the manuscript, revise the submission, and approve the publication of the manuscript.

Conflicts of Interest: Dolores M. McKeen has received payments and travel funding for lectures from Merck Canada, Inc. She has conducted a clinical trial that was funded by Merck Canada, with total funding of approximately $130,000 CAD. She has acted as a consultant for Merck Canada, Inc.

This manuscript was handled by: Richard Brull, MD, FRCPC.

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