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Hyperbaric Versus Plain Bupivacaine for Spinal Anesthesia for Cesarean Delivery

Heng Sia, Alex Tiong MBBS, MMed, FAMS*†; Tan, Kok Hian MBBS, MMed, MRCOG*‡; Sng, Ban Leong MBBS, MMed, FANZCA, FFPMANZCA, MCI; Lim, Yvonne MBBS, MMed§; Chan, Edwin S. Y. PhD*‖; Siddiqui, Fahad Javaid MBBS, MSc*‖

doi: 10.1213/ANE.0000000000000443
Obstetric Anesthesiology: Research Report

BACKGROUND: Bupivacaine is an amide local anesthetic used in hyperbaric and plain forms administered as spinal anesthesia for cesarean delivery. In this systematic review, we summarized the effectiveness and safety of hyperbaric versus plain bupivacaine in providing anesthesia for cesarean delivery. We considered the adequacy of anesthesia for completion of cesarean delivery and the need for interventions to treat complications.

METHODS: We searched the CENTRAL, MEDLINE, and EMBASE databases. We imposed no language restriction. We included all randomized controlled trials involving patients undergoing spinal anesthesia for elective cesarean delivery that compared the use of hyperbaric bupivacaine with plain bupivacaine.

RESULTS: We included 6 studies with a total of 394 patients in this review. These studies have small sample size, few observed events, differences in methodology, and insufficient information pertaining to assessment of risk of bias. This prevented us from calculating pooled estimates. Results show that there is no compelling evidence in favor of the use of intrathecal plain or hyperbaric bupivacaine for spinal anesthesia for cesarean delivery.

CONCLUSIONS: There is a lack of clear evidence regarding the superiority of hyperbaric compared with plain bupivacaine for spinal anesthesia for cesarean delivery. The need for conversion to general anesthesia because of failed spinal anesthesia is an important clinical outcome, but current data are insufficient to compare spinal anesthesia induced with hyperbaric compared with plain bupivacaine for this outcome. Further research is required.

Published ahead of print October 1, 2014.Supplemental Digital Content is available in the text.

From the *Duke-NUS Graduate Medical School, Singapore, Singapore; Medical Board, Obstetrics and Gynaecology, and §Women’s Anaesthesia, KK Women’s and Children’s Hospital, Singapore, Singapore; and Clinical Research Institute, Singapore, Singapore.

Accepted for publication July 19, 2014.

Published ahead of print October 1, 2014.

Funding: This study did not receive funding.

The authors declare no conflicts of interest.

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.

Reprints will not be available from the authors.

This article is based on a Cochrane Review published in the Cochrane Database of Systematic Reviews (CDSR) 2013, Issue 5, DOI: 10.1002/14651858. CD005143.pub2 (see http://www.thecochranelibrary.com/ for information).29 Cochrane Reviews are regularly updated as new evidence emerges and in response to feedback, and the CDSR should be consulted for the most recent version of the review.

Address correspondence to Ban Leong Sng, MBBS, MMed, FANZCA, FFPMANZCA, MCI, Senior Consultant, 100 Bukit Timah Rd., Singapore 229899. Address e-mail to blsngdr@yahoo.com.sg.

The incidence of cesarean delivery is reported to be 27.3% in an Asian global study1 and ranges from 15% in Sweden to 48% in Thailand.2,3 For nonemergency cesarean delivery, neuraxial anesthesia generally is preferred to general anesthesia. In some tertiary centers, the use of neuraxial anesthesia for cesarean delivery is as high as 96.4%.4

Bupivacaine is the most commonly used local anesthetic in neuraxial anesthesia for cesarean delivery.5 It is available in 2 forms, the plain form that is dextrose free and a hyperbaric form derived by the addition of glucose (80 mg/mL) to plain bupivacaine. Both forms have been widely used intrathecally to provide anesthesia for cesarean delivery.6 Opioids such as fentanyl, sufentanil, and morphine often are coadministered to supplement the effect of the local anesthetic.

Several trials have compared hyperbaric bupivacaine and plain bupivacaine, but none have conclusively shown one to be better than the other.6,7 Several trials have suggested that hyperbaric bupivacaine appears to result in more predictable sensory blockade than plain bupivacaine.6,8 Hyperbaric and plain bupivacaine also appear to differ in their motor blockade pattern and duration of action.7 This systematic review summarizes the best-available evidence regarding the effectiveness and safety of hyperbaric bupivacaine compared with plain bupivacaine when used to provide spinal anesthesia for cesarean delivery. This review was undertaken to determine whether there is currently sufficient evidence to guide the decision between using these 2 formulations in spinal anesthesia for cesarean delivery.

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METHODS

We included only randomized controlled clinical trials that recruited women undergoing spinal anesthesia for elective cesarean delivery and compared the use of hyperbaric bupivacaine and plain bupivacaine. We excluded studies that included patients with underlying morbidities, undergoing emergency cesarean delivery, or women who were in preterm labor.

We included studies that used bupivacaine in combination with spinal opioids (fentanyl, sufentanil, morphine) and those using the combined spinal-epidural (CSE) technique with the initial bupivacaine administered only in the intrathecal space. We excluded studies using the sequential CSE technique, other local anesthetics concomitantly, or any other form of anesthesia for cesarean delivery. Primary outcomes were: (a) inadequate anesthesia requiring conversion to general anesthesia and (b) inadequate anesthesia requiring use of supplemental analgesics. Secondary outcomes included: (a) requirement for ephedrine, (b) incidence of nausea and vomiting, (c) incidence of headache within 7 days of spinal anesthesia, (d) time to sensory blockade at the T4 dermatome, (e) incidence of high dermatomal sensory block (above the C8 dermatome), and (f) ephedrine dose. All outcomes were dichotomous except outcomes time to T4 sensory blockade and ephedrine dose.

We searched the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2011, Issue 4), MEDLINE (January 1966 to May 2011), and EMBASE (January 1980 to May 2011). Our search strategies are found in the appendices (CENTRAL, Appendix 1; MEDLINE, Appendix 2; EMBASE, Appendix 3). We also searched the Cochrane Pregnancy and Childbirth Group Trials Register with the Highly Sensitive Search Strategy found in the Cochrane Handbook for Systematic Reviews of Interventions9 with the help of their Trials Search Coordinator. The Cochrane Pregnancy and Childbirth Group Trials Register is maintained by the Trials Search Co-ordinator and contains trials identified from quarterly searches of CENTRAL, monthly searches of MEDLINE, hand searches of 30 journals (including the International Journal of Obstetric Anesthesia), the proceedings of major conferences, and a weekly current awareness search of a further 37 journals. We placed no language restrictions on our searches.

Two authors independently collected data on a standardized data-collection form, reviewed the titles and abstracts from the searches, extracted the data using a standardized form, and assessed trial quality. A third author resolved any disagreements at any stage. We extracted information pertaining to the study design, method of randomization, use of allocation concealment, reporting of the study setting and participants, inclusion and exclusion criteria, sample size, interventions, and outcomes listed previously. Based on the Cochrane “Risk of bias” tool in Revman 5.1,9,10 we considered the following: (1) random sequence generation; (2) allocation; concealment; (3) blinding of participants and personnel; (4) blinding of outcome assessment; (5) Incomplete outcome data; (6) selective reporting; and (7) other bias (Table 1). We graded each of the aforementioned dimensions of trial quality as low-risk, high-risk, or unclear risk of bias and also gave supporting judgment for the decisions.

We summarized the treatment effect for dichotomous outcomes by using risk ratios and their 95% confidence intervals (CIs). For continuous outcomes such as time to dermatomal block at the T4 level and amount of ephedrine used (mg/person), the mean difference (MD) and 95% CI were reported. The patient was the unit of analysis in all of the studies.

We evaluated clinical heterogeneity by qualitatively appraising differences in study characteristics such as participants, interventions, outcomes assessed, and study methodology and refrained from pooling results if there was significant clinical heterogeneity. Quantitative pooling of the data was first justified by a consensus clinical judgment of sufficient clinical homogeneity. We informally evaluated and investigated the degree of statistical heterogeneity by visual inspection of forest plots and more formally by the I2 statistic.11 We refrained from quantitative synthesis if there was a high degree of statistical heterogeneity, that is, I2 > 75%.

Risk ratios (RRs) were reported for binary outcomes in included studies; hence, we reported summary results using the same effect measure. We used MD to pool the results of the continuous outcomes as all included studies measured outcomes on the same scale. We also report the 95% CI of each outcome.

We did not anticipate any subgroup analysis because there were only 6 studies and not all studies provided information for all the outcomes. The patient characteristics were restricted to pregnant women requiring elective cesarean delivery. We planned to consider other methodologic differences by using the random-effects model.

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RESULTS

Search Results

We identified 192 citations from the database searches (Fig. 1). After screening by title and abstract, we obtained full texts for 15 citations that were judged potentially eligible for inclusion in the review. Of these, 9 did not fulfill our inclusion criteria and were excluded (Table 2). a,1,8,12–18 We included 6 studies.6,7,19–22 All 6 studies enrolled women at term and excluded women with complicated pregnancies (Table 3). Sarvela et al.7 and Vercauteren et al.6 used the CSE technique with intrathecal injection, whereas the rest of the studies19–22 used a spinal anesthesia technique. We did not present a funnel plot because there were only 6 studies. We did not perform sensitivity analysis because no studies were judged as having a high risk of bias.

Figure 1

Figure 1

Table 1

Table 1

Table 2

Table 2

Table 3

Table 3

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Risk of Bias in Included Studies

Only 1 study described the method of randomization,7 and none described the method of allocation concealment. Four studies reported that randomization resulted in intervention groups that were balanced at baseline6,19–21 (Supplemental Digital Content, http://links.lww.com/AA/A1000).

All 6 studies were described as double-blinded, but exactly which parties were blinded was not explicitly stated. We deduced that the patients were all blinded because of the nature of the study. The spinal injections were performed on the patient’s back. The attending anesthesiologists who were also outcome assessors were blinded to group assignment in 5 of the studies.6,7,19–21 A blinded assessor was involved in the study by Richardson et al.,22 because the attending anesthesiologists prepared the injections and followed the study protocol. The amount of ephedrine administered, however, was up to the discretion of the attending anesthesiologist. All 6 studies were judged as having low risk of performance bias and detection bias.6,7,19–22 Patients who were blinded were the outcome assessors for nausea, vomiting, and headache.

All 6 studies had a low risk of attrition bias because all outcome data (recruitment and attrition data) had been reported with no missing data. Analyses were performed using the intention-to-treat principle.6,7,19–22 All 6 studies6,7,19–22 reported all prespecified outcomes. All 6 studies6,7,19–22 appeared to be free of other bias.

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Primary Outcomes

Conversion to General Anesthesia

Six studies with a total of 394 patients reported the need for conversion to general anesthesia with significant clinical heterogeneity (Fig. 2, A).6,7,19–22 Two studies had conversion to general anesthesia. das Neves et al.19 with 1 of 30 in the plain bupivacaine group and Vichitvejpaisal et al.20 with 1 of 10 in the hyperbaric bupivacaine group and 7 of 48 in the plain bupivacaine group. Four of the 6 studies reported no conversions in either treatment group.6,19,21,22 The I2 value was 0%. Pooled results are not reported because of clinical heterogeneity.

Figure 2

Figure 2

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Requiring Supplemental Analgesia

Six studies with a total of 394 patients reported the need for supplemental analgesics with significant clinical heterogeneity (Fig. 2, B).6,7,19–22 Vichitvejpaisal et al.20 had no need for supplemental anesthesia in either arm, and the rest had a very low number of events.6,7,19,21,22 In most studies, no more than 1 event was observed, with less need occurring in the hyperbaric bupivacaine group. Richardson et al.22 reported 1 subject who required IV supplementation with fentanyl 50 µg in the plain bupivacaine group. Russell and Holmqvist21 reported 1 subject in the plain bupivacaine group who required supplemental analgesia that included the use of nitrous oxide and trichloroethylene. One subject reported by das Neves et al.19 who received hyperbaric bupivacaine had partial motor block and pain on incision that required epidural anesthesia supplementation after initial spinal anesthesia.

The CSE technique was used in 2 studies.6,7 Using the CSE technique, Sarvela et al.7 used a greater dose of bupivacaine (intrathecal injection containing bupivacaine 9 mg and fentanyl 20 µg) compared with Vercauteren et al.6 One subject in the plain bupivacaine group required epidural supplementation, although no additional details were given. Vercauteren et al.6 had more events of supplemental analgesia required compared with Sarvela et al.7 because a lower dose of bupivacaine (intrathecal injection containing bupivacaine 6.6 mg and sufentanil 3.3 µg) using the CSE technique was used. Five of 49 subjects in the hyperbaric groups and 8 of 48 subjects in the plain bupivacaine group required supplemental analgesia in the form of epidural medications (RR 0.61; 95% CI: 0.22−1.74). Epidural supplementation using plain lidocaine 2% was administered in incremental doses of 2 mL per unblocked segment if the upper sensory level did not reach the T6 level 10 minutes after intrathecal injection. The observed I2 value was 0%. Pooled results are not reported because of clinical heterogeneity.

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Secondary Outcomes

Requirement for Ephedrine

Three studies with a total of 196 patients reported the need for ephedrine (Fig. 2, C).6,7,22 Different criteria were used to judge the need for ephedrine among studies. The need for hyperbaric bupivacaine was less than plain bupivacaine in 1 study with 97 patients.6 In the study by Richardson et al.,22 the need for ephedrine was left to the discretion of the attending anesthesiologist. In the study by Sarvela et al.,7 ephedrine was administered when the systolic blood pressure decreased below 95 mm Hg or decreased >20% below the baseline value. Ephedrine was administered when the systolic blood pressure decreased <100 mm Hg or decreased >25% from the baseline value in the study by Vercauteren et al.,6 in which the authors used low-dose bupivacaine with a CSE technique, possibly leading to less use of ephedrine in both the hyperbaric and plain bupivacaine groups. The observed I2 value was 75%. Pooled results are not reported because of clinical heterogeneity.

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Nausea and Vomiting

Five studies with a total of 333 patients reported the incidence of nausea and vomiting (Fig. 2, D).6,7,20–22 Vercauteren et al.6 showed a statistical difference in favor of hyperbaric bupivacaine (RR 0.59; 95% CI: 0.36−0.97), and Vichitvejpaisal et al.20 showed a statistical difference in favor of plain bupivacaine (RR 2.30; 95% CI: 1.24−4.29) in decreasing the incidence of nausea and vomiting. The observed I2 value was 66%. Pooled results are not reported because of clinical heterogeneity.

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Headache

Three studies with a total of 234 patients reported the incidence of headaches (Fig. 2, E).6,20,21 Two studies20,21 with 137 patients reported no difference in the incidence of headache. The third study did not report any subject with headache.6 The observed I2 value was 3%. Pooled results are not reported because of clinical heterogeneity.

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Time to T4 Dermatomal Block

Two studies with a total of 128 patients reported the time until the sensory block reached the T4 level (Fig. 2, F).20,22 This interval was considerably shorter for hyperbaric bupivacaine in the study by Vichitvejpaisal et al.20 (MD −1.10; 95% CI: −2.09 to −0.11). There was no difference in this outcome in the study by Richardson et al.22 (MD −1.00; 95% CI: −2.13 to 0.13), although the CI is wide. The observed I2 value was 0%. Pooled results are not reported because of clinical heterogeneity.

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High Dermatomal Sensory Block

Three studies with a total of 205 patients reported the incidence of undesirably high sensory block (greater than the C8 dermatome; (Fig. 2, G).6,7,21 No differences were reported between groups. Vercauteren et al.6 used low-dose bupivacaine with a CSE technique; 5 of 48 patients in the plain bupivacaine group had a high block compared with no patients in the hyperbaric group (RR 0.09; 95% CI: 0.01−1.5). The observed I2 value was 59%. Pooled results are not reported because of clinical heterogeneity.

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Ephedrine Dose

Three studies with a total of 226 patients reported the ephedrine dose (Fig. 2, H).6,7,19 In the study by Vercauteren et al.,6 women in the hyperbaric bupivacaine group received less ephedrine than women in the plain bupivacaine group (MD −1.80; 95% CI: −3.49 to −0.11); however, the difference may not be clinically significant. The other 2 studies showed no difference in the ephedrine dose between groups.7,19 The observed I2 value was 33%. Pooled results are not reported because of clinical heterogeneity.

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DISCUSSION

Out of 6 included studies, only 2 studies19,20 contributed to the result of less conversion to general anesthesia, with only that of Vichitvejpaisal et al.20 showing a difference. Furthermore, only 2 studies20,22 contributed to the result of a more rapid onset of sensory block at the T4 level with hyperbaric bupivacaine, with only that of Vichitvejpaisal et al.20 showing a difference. All other analyses did not show any differences. In addition, the small sample sizes of the included studies suggest that larger studies should be conducted. Pooling was not performed because of clinical heterogeneity.

In nonobstetric patients, some studies have shown that hyperbaric bupivacaine has a greater cephalad spread compared with plain bupivacaine.23–26 The wider distribution of hyperbaric bupivacaine within the intrathecal space may induce a lower degree of motor block compared with plain bupivacaine.6 Furthermore, hyperbaric bupivacaine is associated with increased risk of hypotension compared with plain bupivacaine.23–26 In obstetric studies using spinal anesthesia for cesarean delivery, the baricity of bupivacaine does not significantly influence the onset or duration of the sensory block,7,21,22 except for 1 study by Vercauteren et al.,6 in which the block level was more predictable when hyperbaric bupivacaine was used.

Conversion to general anesthesia was a rare event in the 6 studies. Most studies did not report any conversions to general anesthesia.6,7,21,22 das Neves et al.19 did not find any significant differences in the rate of conversion to general anesthesia; thus, evidence for the superiority of hyperbaric bupivacaine for this outcome comes from Vichitvejpaisal et al.20 There was a lack of information regarding the criterion used for conversion to general anesthesia in this study. Conversion to general anesthesia occurred in 9.2% of subjects in the study when the analgesic level was deemed inadequate by the attending anesthesiologist. The study did not mention the use of sensory-level examination or the position in which spinal anesthesia was administered. The use of supplemental analgesia was dominated by a single study by Vercauteren et al.6 because this study reported more events and was significantly larger than the other studies. The larger number of events might be attributable to the use of the CSE technique with low-dose hyperbaric and plain bupivacaine leading to a greater event rate for supplemental analgesia.

For cesarean delivery, an anesthetic level of T4 has been widely deemed as the standard to allow pain-free delivery of the infant. Therefore, we reviewed the mean time to onset of T4 sensory blockade, which was reported in 2 studies.20,22 Both studies used the loss of sensation to pinprick as the test for sensory level. We could not investigate the maximal sensory level achieved during intrathecal block or recession of sensory blockade due to the different methods used to test sensory level. There was no apparent reason to explain the heterogeneity found for nausea and vomiting.6,7,20–22 Furthermore, the studies had small sample sizes, and the differences found in individual studies could have been due to chance. The measurement of nausea and vomiting was subjective with differing definitions of nausea and vomiting among studies.

There was significant clinical heterogeneity in the studies. There is evidence that bupivacaine dose is directly related to the incidence of hypotension. The dose of bupivacaine used in the 6 studies varied from 6.6 to 15 mg.6,7,19–22 The presence of short-acting opioids decreases the incidence of nausea and vomiting. Some studies included intrathecal opioids such as morphine,22 sufentanil,6 and fentanyl,7 whereas others did not use adjuvant intrathecal drugs.19–21 There was also variability in the technique of regional block with 2 studies performing the CSE technique to administer intrathecal drugs.6,7 Patient position may have affected clinical outcomes; 3 studies included right lateral, left lateral in 1 study, lateral position that was unspecified in 1 study, and sitting in 1 study.6,7,19–22 Using hyperbaric bupivacaine in the sitting position may slow the onset of the block and thus may limit the spread of bupivacaine when compared to plain bupivacaine.27,28 Other potentially relevant outcomes not reported in most studies were pain on injection and recovery, duration of anesthesia after delivery, pain with delivery of spinal anesthesia, pain after delivery, and ability to ambulate.

Intrathecal drug dose, adjuvant drugs, and technique of administration may affect the spread of local anesthetic in the intrathecal space; however, because the methodology has not been standardized, it is difficult to draw a definitive conclusion from the studies in this review. It may be necessary to conduct a large randomized trial to confirm these findings and to examine the economic impact before a switch from plain bupivacaine to hyperbaric bupivacaine can be recommended.

There is a lack of clear evidence regarding the superiority of hyperbaric compared with plain bupivacaine for spinal anesthesia for cesarean delivery. Thus, no change in practice is indicated at the present time. Adequately powered randomized clinical trials are required in which the definitions, criteria, and assessment methodology of the important outcomes, including conversion to general anesthesia, requirement for supplemental analgesia, nausea, vomiting, and sensory testing, should be clearly stated. All clinically relevant side effects should be evaluated, and reporting standards should adhere to the CONSORT guidelines.

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APPENDIX 1

Search strategy for CENTRAL, The Cochrane Library

#1 MeSH descriptor Cesarean Section explode all trees #2 (cesarea* or caesarea* or cesaria* or caesaria*) #3 (#1 OR #2) #4 MeSH descriptor Bupivacaine explode all trees #5 bupivacain* and (hyperbaric or heavy or dextrose or glucose or isobaric or plain or hypobaric or isotonic) #6 (#4 OR #5) #7 (#3 AND #6)

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APPENDIX 2

Search strategy for MEDLINE (OvidSP)

1. exp CESAREAN-SECTION/ or (cesarea* or caesarea* or cesaria* or caesaria*).mp. 2. exp BUPIVACAINE/ or (bupivacain* and (hyperbaric or heavy or dextrose or glucose or isobaric or plain or hypobaric or isotonic)).mp. 3. 1 and 2 4. ((randomized controlled trial or controlled clinical trial).pt. or randomized.ab. or placebo.ab. or clinical trials as topic.sh. or randomly.ab. or trial.ti.) not (animals not (humans and animals)).sh. 5. 4 and 3

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APPENDIX 3

Search strategy for EMBASE (OvidSP)

1. exp CESAREAN-SECTION/ or (cesarea* or caesarea* or cesaria* or caesaria*).mp. 2. exp BUPIVACAINE/ or (bupivacain* and (hyperbaric or heavy or dextrose or glucose or isobaric or plain or hypobaric or isotonic)).mp. 3. 1 and 2 4. (RANDOMIZED-CONTROLLED-TRIAL/ or RANDOMIZATION/ or CONTROLLED-STUDY/ or MULTICENTER-STUDY/ or PHASE-3-CLINICAL-TRIAL/ or PHASE-4-CLINICAL-TRIAL/ or DOUBLE-BLIND-PROCEDURE/ or SINGLE-BLIND-PROCEDURE/ or (RANDOM* or CROSS?OVER* or FACTORIAL* or PLACEBO* or VOLUNTEER* or ((SINGL* or DOUBL* or TREBL* or TRIPL*) adj3 (BLIND* or MASK*))).ti,ab.) not (animals not (humans and animals)).sh. 5. 4 and 3

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DISCLOSURES

Name: Alex Tiong Heng Sia, MBBS, MMed.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Alex Tiong Heng Sia has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Kok Hian Tan, MBBS.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Kok Hian Tan has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Ban Leong Sng, MBBS, MMed, FANZCA, FFPMANZCA, MCI.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Ban Leong Sng has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.

Name: Yvonne Lim, MBBS, MMed.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Yvonne Lim has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Edwin S. Y. Chan, PhD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Edwin S. Y. Chan has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Fahad Javaid Siddiqui, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Fahad Javaid Siddiqui has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

This manuscript was handled by: Cynthia A. Wong, MD.

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