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
RoB Within Studies
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.
Synthesis of Results
Spinal Failure/Conversion to GA.
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.
The Incidence of Hypotension.
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.
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.
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.
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.
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.
Duration of Sensory Block.
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.
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
Summary of Evidence
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.
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.
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.
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.
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.
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.
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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