The MEDLINE, CENTRAL, and Embase databases were searched for articles published between January 2011 and March 2016. In addition, the Cochrane Pregnancy and Childbirth Group Trials Register was searched. All randomized, controlled trials involving healthy women undergoing spinal anesthesia for elective cesarean delivery were included in the systematic review and meta-analysis. The primary outcomes analyzed were conversion to general anesthesia and inadequate pain control requiring the use of supplemental analgesics during surgery. The secondary outcomes included: the use and dose of ephedrine; the time taken for the sensory block to reach the fourth thoracic dermatome; the prevalence of high sensory block (above the eighth cervical dermatome); the incidence of nausea and vomiting; and the incidence of headache within 7 days of spinal anesthesia. Risk ratios were determined for binary outcomes, and mean differences were calculated for continuous outcomes. In addition, trial sequential analysis was performed for the primary outcomes.
Nine articles involving 10 studies were included in the systematic review with data available from 614 patients. The rate of conversion to general anesthesia was reported as similar for hyperbaric and isobaric bupivacaine. However, in 7 of the 10 studies no conversions to general anesthesia were reported, and the quality of evidence for this outcome was deemed very low. Of note, when trial sequential analysis was performed, statistical significance favoring hyperbaric bupivacaine was found. The need for supplemental analgesia was also similar for hyperbaric and isobaric bupivacaine. However, there were few events reported among the studies, resulting in wide confidence intervals (0.26-1.41). In addition, the investigators also rated the evidence as very low quality. Trial sequential analysis did not find statistical significance favoring one formulation.
For secondary outcomes, no differences were noted in the use of ephedrine, the amount of ephedrine used, incidence of nausea and vomiting, and incidence of headache. The time required to reach a T4 level was shorter for hyperbaric bupivacaine, with a mean difference of –1.06 (95% confidence interval, –1.80 to –0.31).
In conclusion, these investigators determined there was no compelling evidence to consider hyperbaric or isobaric spinal bupivacaine as superior to the other formulation in terms of the rate of conversion to general anesthesia or the need for supplemental analgesia. Because hyperbaric bupivacaine provided a faster onset to achieve a T4 sensory block, it may have some clinical advantages, although the mean difference was small. The authors recommended that an adequately powered randomized controlled trial be performed to further investigate the primary outcomes analyzed in this systematic review and meta-analysis.
In the United States, the most common anesthetic technique for elective cesarean deliveries is spinal anesthesia using hyperbaric bupivacaine (0.75%), often combined with both a lipid-soluble opioid (fentanyl or sufentanil) and morphine. The publication of this meta-analysis by Sng and colleagues is timely because this past summer (2018) hyperbaric bupivacaine became completely unavailable in the United States for a 4- to 5-month period and anesthesia providers were forced to use plain bupivacaine for cesarean delivery anesthesia, a formulation that many of us had never used for this purpose. This was very uncomfortable, because long experience with hyperbaric bupivacaine has taught us what to expect, how to modify the dose/technique for different patients, and how to manage complications. This broad knowledge was almost completely useless with the “new” drug formulation, plain (nondextrose-containing) bupivacaine.
Of note, the so-called “isobaric bupivacaine” (bupivacaine dissolved in normal saline) is not isobaric in most patients. In fact, it is hypobaric. Baricity is defined as ratio of the density of the spinal anesthetic solution relative to cerebrospinal fluid (CSF) density.1 Density varies inversely with temperature. The density of CSF varies among individual patients and patient populations. On average, the CSF density of pregnant women is slightly lower than premenopausal nonpregnant women. Because of the variability in CSF density among individual patients, hyperbaric and hypobaric anesthetic solutions must have a density that is at least 3 SD above or below, respectively, the mean CSF density, for the solution to reliably behave as a hyperbaric or hypobaric solution.
The temperature-dependence of density is particularly important when using plain bupivacaine. This drug formulation (with and without opioids) acts as an isobaric drug at room temperature, but hypobaric at body temperature.1,2 Thus, as presumably used in the studies included in the meta-analysis by Sng et al3, plain bupivacaine may behave as a hypobaric drug in many women. This concern was expressed in a letter-to-the-editor by Wildsmith4 in response to the Sng and colleagues meta-analysis.
Why is this important? A drug solution that is not definitively hypobaric or hyperbaric will behave less predictably than a solution that is definitely hypobaric or hyperbaric.5 The drug solution (0.5% or 0.75% plain bupivacaine with opioids) that US anesthesiologists were forced to use this past summer was likely hypobaric in most women. Thus, the position of the patient during and after the intrathecal injection may be important when comparing the 2 drugs. Sng et al3 did not control for this potentially important variable in the meta-analysis.
The studies included in the meta-analysis were heterogeneous with regard to several other potentially important variables. These include the actual dose of local anesthetic (the results of a comparison study between plain and hyperbaric bupivacaine might be dose-dependent, for example, no difference with a high-dose technique, but a difference with a low-dose technique), anesthetic technique (single-shot spinal vs. combined spinal-epidural anesthesia (CSE)—the duration of time a sitting patient remains sitting is longer with a CSE technique, which will influence spread of both hypobaric and hyperbaric drugs), addition of opioids (the meta-analysis included studies using only bupivacaine, bupivacaine with fentanyl or sufentanil, and bupivacaine with morphine—no studies used bupivacaine with morphine and a lipid-soluble opioid, which is the most common solution used in the United States), and surgical technique (eg, exteriorization of the uterus, which requires more dense anesthesia for patient comfort).
Of note, the authors performed a sensitivity analysis on their initial meta-analysis because the trial data did not satisfy all criteria for analysis for the Mantel-Haenszel method. Only one of the 3 methods returned a positive result for the outcome “conversion to general anesthesia” although the confidence intervals were wide and included clinically significant differences for both the “conversion to general anesthesia” and “need for supplemental analgesia” outcomes. The trial sequential analysis for conversion to general anesthesia favored hyperbaric bupivacaine. Trial sequential analysis is a tool for quantifying the statistical reliability of data in the cumulative meta-analysis that adjusts for significance levels for sparse data and repetitive tests on accumulating data (www.ctu.dk/tools-and-links/trial-sequential-analysis.aspx, accessed December 16, 2018).
The authors of the Sng and colleagues study concluded that there is “no compelling evidence in favor of isobaric over hyperbaric bupivacaine, or vice versa, for spinal anaesthesia for cesarean section.” While I agree with this statement, it is not because the data show no difference, but rather that the data are inadequate to answer the question. After my 5-month forced trial of using plain bupivacaine this summer, and at the risk of being accused of practicing anecdotal medicine, I continue to prefer hyperbaric bupivacaine. The results of the meta-analysis support the premise that both drugs provide satisfactory anesthesia in most women, and whether one is better than the other may depend on comfort and experience of the anesthesiologist more than any other factor. I have made hyperbaric bupivacaine work for me for many years and given the choice, will continue to use it rather than plain bupivacaine.
Comment by Cynthia A. Wong, MD
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