Society for Obstetric Anesthesia and Perinatology

Section Editor: Cynthia A. Wong

Hyperbaric Versus Plain Bupivacaine for Spinal

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

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 summa-
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rized the effectiveness and safety of hyperbaric versus plain bupivacaine in providing anesthe-
sia 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 bupiva-
caine 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 informa-
tion pertaining to assessment of risk of bias. This prevented us from calculating pooled esti-
mates. 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 com-
pared with plain bupivacaine for spinal anesthesia for cesarean delivery. The need for con-
version 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.  (Anesth Analg
2015;120:132–40)

T
he 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 cesar-
ean delivery, neuraxial anesthesia generally is preferred to
general anesthesia. In some tertiary centers, the use of neur-
axial 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 hyper-
baric form derived by the addition of glucose (80 mg/mL)
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.
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 (www.anesthesia-analgesia.org).
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, FFP-
MANZCA, MCI, Senior Consultant, 100 Bukit Timah Rd., Singapore 229899.
Address e-mail to blsngdr@yahoo.com.sg.
Copyright © 2014 International Anesthesia Research Society
DOI: 10.1213/ANE.0000000000000443
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 predict-
able 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 regard-
ing 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 suffi-
cient evidence to guide the decision between using these 2
formulations in spinal anesthesia for cesarean delivery.
METHODS
We included only randomized controlled clinical trials that
recruited women undergoing spinal anesthesia for elective
cesarean delivery and compared the use of hyperbaric bupiva-
caine 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 combina-
tion with spinal opioids (fentanyl, sufentanil, morphine)

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and those using the combined spinal-epidural (CSE) tech- data was first justified by a consensus clinical judgment of
nique with the initial bupivacaine administered only in the sufficient clinical homogeneity. We informally evaluated and
intrathecal space. We excluded studies using the sequential investigated the degree of statistical heterogeneity by visual
CSE technique, other local anesthetics concomitantly, or any inspection of forest plots and more formally by the I2 statis-
other form of anesthesia for cesarean delivery. Primary out- tic.11 We refrained from quantitative synthesis if there was a
comes were: (a) inadequate anesthesia requiring conversion high degree of statistical heterogeneity, that is, I2 > 75%.
to general anesthesia and (b) inadequate anesthesia requir- Risk ratios (RRs) were reported for binary outcomes in
ing use of supplemental analgesics. Secondary outcomes included studies; hence, we reported summary results using
included: (a) requirement for ephedrine, (b) incidence of the same effect measure. We used MD to pool the results of
nausea and vomiting, (c) incidence of headache within 7 the continuous outcomes as all included studies measured
days of spinal anesthesia, (d) time to sensory blockade at outcomes on the same scale. We also report the 95% CI of
the T4 dermatome, (e) incidence of high dermatomal sen- each outcome.
sory block (above the C8 dermatome), and (f) ephedrine We did not anticipate any subgroup analysis because
dose. All outcomes were dichotomous except outcomes there were only 6 studies and not all studies provided infor-
time to T4 sensory blockade and ephedrine dose. mation for all the outcomes. The patient characteristics were
We searched the Cochrane Central Register of Controlled restricted to pregnant women requiring elective cesarean
Trials (CENTRAL; The Cochrane Library 2011, Issue 4), delivery. We planned to consider other methodologic differ-
MEDLINE (January 1966 to May 2011), and EMBASE ences by using the random-effects model.
(January 1980 to May 2011). Our search strategies are found
in the appendices (CENTRAL, Appendix 1; MEDLINE, RESULTS
Appendix 2; EMBASE, Appendix 3). We also searched the Search Results
Cochrane Pregnancy and Childbirth Group Trials Register We identified 192 citations from the database searches
with the Highly Sensitive Search Strategy found in the (Fig.  1). After screening by title and abstract, we obtained
Cochrane Handbook for Systematic Reviews of Interventions9 full texts for 15 citations that were judged potentially eli-
with the help of their Trials Search Coordinator. The gible for inclusion in the review. Of these, 9 did not fulfill
Cochrane Pregnancy and Childbirth Group Trials Register
is maintained by the Trials Search Co-ordinator and con-
tains 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 lan-
guage restrictions on our searches.
Two authors independently collected data on a standard-
ized 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 per-
taining 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 con-
sidered the following: (1) random sequence generation; (2)
allocation; concealment; (3) blinding of participants and per-
sonnel; (4) blinding of outcome assessment; (5) Incomplete
outcome data; (6) selective reporting; and (7) other bias
(Table 1). We graded each of the aforementioned dimen-
sions 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 out-
comes 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/per-
son), 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 par-
ticipants, interventions, outcomes assessed, and study meth-
odology and refrained from pooling results if there was
significant clinical heterogeneity. Quantitative pooling of the Figure 1. Study flow diagram.

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Hyperbaric Versus Isobaric Bupivacaine for Cesarean

Table 1.  Risk of Bias Table

Blinding of Blinding of Incomplete
Random sequence Allocation participants outcome outcome Selective Other
Study generation concealment and personnel assessment data reporting bias
das Neves et al.19 Low Uncertain Low Low Low Low Low
Richardson et al.22 Low Uncertain Low Low Low Low Low
Russell and Holmqvist21 Low Uncertain Low Low Low Low Low
Sarvella et al.7 Low Uncertain Low Low Low Low Low
Vercauteren et al.6 Low Uncertain Low Low Low Low Low
Vichitvejpaisal et al.20 Low Uncertain Low Low Low Low Low

Table 2.  Characteristics of Excluded Studies

Connolly et al.12 Inclusion and exclusion criteria were not clearly defined. Treatment and control groups were not adequately described
at entry of study. Comparison of 8 mg/mL glucose versus 80 mg/mL glucose, both of which were hyperbaric to
cerebrospinal fluid. No plain bupivacaine used.
Connolly et al.13 Inclusion and exclusion criteria were not clearly defined. Treatment and control groups were not adequately described
at entry of study. Comparison of 8 mg/mL glucose versus 80 mg/mL glucose, both of which were hyperbaric to
cerebrospinal fluid. No plain bupivacaine used.
Connolly et al.14 Comparison of 8 mg/mL glucose versus 80 mg/mL glucose, both of which were hyperbaric to cerebrospinal fluid. No plain
bupivacaine used.
Echevarría et al.8 Comparison of hyperbaric bupivacaine with plain mepivacaine and plain bupivacaine with adrenaline.
King et al.15 Comparison of 0.5% tetracaine in 10% dextrose and 0.5% tetracaine.
King et al.16 Comparison of 0.5% tetracaine in 5% dextrose and 0.5% tetracaine.
Lew et al.17 Comparison of epidural volume extension with combined spinal-epidural with spinal anesthesia using hyperbaric bupivacaine.
The comparisons are not using plain solution. The study investigated the effect of epidural volume extension.
Sodhi et al.18 Comparison of hyperbaric, isobaric, and hypobaric bupivacaine with fentanyl using combined spinal epidural technique.
Study outcome on spread of intrathecal bupivacaine in the prolonged sitting position.
Sudarshan et al.a Sequential administration and not comparison of hyperbaric versus plain bupivacaine.
a
Sudarshan G, Kokri MS, Kumar CM. Evaluation of sequential administration of plain and hyperbaric bupivacaine for spinal anesthesia for lower segment
Caesarean section. Paper presented at: American Society of Regional Anesthesia & Pain Medicine Annual Meeting Abstracts. http://journals.lww.com/rapm/
Citation/1994/19021/Evaluation_of_sequential_administration_of_plain.23.aspx. Accessed March 26, 2014.

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 pregnan-
cies (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.
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 discre-
tion of the attending anesthesiologist. All 6 studies were
judged as having low risk of performance bias and detec-
tion bias.6,7,19–22 Patients who were blinded were the out-
come 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 stud-
ies6,7,19–22 reported all prespecified outcomes. All 6 stud-
ies6,7,19–22 appeared to be free of other bias.
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.
Requiring Supplemental Analgesia
Six studies with a total of 394 patients reported the need for
supplemental analgesics with significant clinical heteroge-
neity (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 hyper-
baric 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 sup-
plemental analgesia that included the use of nitrous oxide

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Table 3.  Characteristics of Included Studies
das Neves et al.19 Prospective, randomized, and double-blinded study.
N = 60 spinal anesthesia
Inclusion criteria: term pregnant women undergoing spinal anesthesia for elective cesarean delivery
Study groups:
30: 0.5% hyperbaric bupivacaine 12.5 mg with morphine 100 µg
30: 0.5% plain bupivacaine 12.5 mg with morphine 100 µg
Left lateral position, paramedian approach, L3-4 interspace, 27-gauge Quincke needle. Preload and co-load
with lactated Ringer’s solution.
1 subject in the plain group had referred pain at hysterotomy converted to general anesthesia. 1 subject in the
hyperbaric group had partial motor block and pain at incision, which was converted to epidural anesthesia.
The only outcomes were supplemental analgesia and ephedrine use.
Richardson et al.22 Prospective, randomized, and double-blinded study.
N = 30 spinal anesthesia
Inclusion criteria: American Society of Anesthesiologists Physical Status I and II, nonlaboring parturients
scheduled for elective cesarean delivery with spinal anesthesia
Exclusion criteria: history of chronic opioid use, allergy to any of the study drugs
Study groups:
15: hyperbaric bupivacaine 15 mg with morphine 200 µg
15: hypobaric bupivacaine 15 mg with morphine 200 µg
Sitting position, L3-4 interspace, 25-gauge Quincke needle. Preloaded with lactated Ringer’s solution.
Russell and Holmqvist21 Prospective, randomized, double-blinded study.
N = 40 spinal anesthesia
Study groups:
19: 0.5% hyperbaric bupivacaine 12.5 mg
20: 0.5% plain bupivacaine 12.5 mg
Right lateral position, midline approach, L2-3 or L3-4 interspace, 25-gauge needle. Preload with lactated
Ringer’s solution.
1 hyperbaric group excluded from analysis: result of deviation from design of the study (had wedge placed
under left hip). N = 39.
Sarvela et al.7 Prospective, randomized, double-blinded study.
N = 76 CSE anesthesia
CSE needle through needle technique with 16-gauge Tuohy needle and 26-gauge Whitacre needle. Epidural
catheter insertion.
Inclusion criteria: healthy, full-term (gestational age 37−42 weeks) singleton parturients undergoing elective
cesarean delivery
Study groups:
36: hyperbaric bupivacaine 9 mg with fentanyl 20 µg
34: plain bupivacaine 9 mg with fentanyl 20 µg
Right lateral position, midline approach, L2-3 interspace, CSE technique. Preload and colloid with lactated
Ringer’s solution and ephedrine 15 mg. Uniform surgical technique with exteriorization of uterus.
7 excluded. 1 inability of the observer to follow the protocol, 1 premature birth, 4 no backflow of cerebrospinal
fluid after spinal anesthesia and conversion of anesthesia to epidural. 1 patient in the plain bupivacaine group
required epidural supplementation although backflow was seen after spinal anesthesia and therefore was not
included in the spinal block data and side effects during caesarean delivery. n = 70.
Vercauteren et al.6 Prospective, randomized, double-blinded study.
N = 98 CSE anesthesia
CSE BD-Durasafe Adjustable tray
Inclusion criteria: scheduled for elective or semiurgent cesarean delivery
Exclusion criteria: urgent cesarean delivery, parturients in active labor, those presenting with a pregnancy
duration of <35 weeks’ gestation, initial systolic blood pressure ≥150 mm Hg
Study groups:
49: hyperbaric bupivacaine 6.6 mg with 3.3 µg sufentanil
48: plain bupivacaine 6.6 mg with 3.3 µg sufentanil
Right lateral position, CSE technique. Preload with lactated Ringer’s solution and hydroxyethyl starch 6%.
1 in the plain bupivacaine group was excluded because of an unintentional dural puncture with the Tuohy
needle.
Vichitvejpaisal et al.20 Prospective, randomized study.
N = 98 spinal anesthesia
Inclusion criteria: cesarean delivery (cephalopelvic disproportion, elderly primigravidarum, previous cesarean
delivery, premature rupture of membrane)
Exclusion criteria: deformity of spinal column, skin infection near puncture site, coagulopathy
Study groups:
50: hyperbaric bupivacaine 2 mL 0.5%
48: plain bupivacaine 2 mL 0.5%
Lateral position, midline approach, 24-gauge spinal needle via 18-gauge introducer needle. Preload with
lactated Ringer’s solution.
The number in front of the study group refers to N for the group.
CSE = combined spinal epidural.

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Hyperbaric Versus Isobaric Bupivacaine for Cesarean

and trichloroethylene. One subject reported by das Neves et The CSE technique was used in 2 studies.6,7 Using the
al.19 who received hyperbaric bupivacaine had partial motor CSE technique, Sarvela et al.7 used a greater dose of bupi-
block and pain on incision that required epidural anesthesia vacaine (intrathecal injection containing bupivacaine 9 mg
supplementation after initial spinal anesthesia. and fentanyl 20 µg) compared with Vercauteren et al.6 One

Figure 2. (Continued)

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 G
Figure 2. Characteristics of excluded studies. A, Conversion to general anesthesia. B, Supplemental analgesia. C, Ephedrine requirement. D,
Nausea and vomiting. E, Headache. F, Time to dermatomal block T4 (minutes). G, High block C8. H, Amount of ephedrine used (mg/person).
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 contain-
ing bupivacaine 6.6 mg and sufentanil 3.3 µg) using the
CSE technique was used. Five of 49 subjects in the hyper-
baric groups and 8 of 48 subjects in the plain bupivacaine
group required supplemental analgesia in the form of epi-
dural medications (RR 0.61; 95% CI: 0.22−1.74). Epidural
supplementation using plain lidocaine 2% was adminis-
tered 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.
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 pres-
sure 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.
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
January 2015 • Volume 120 • Number 1 www.anesthesia-analgesia.org 137
showed a statistical difference in favor of hyperbaric bupiva-
caine (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.
Headache
Three studies with a total of 234 patients reported the inci-
dence of headaches (Fig. 2, E).6,20,21 Two studies20,21 with 137
patients reported no difference in the incidence of head-
ache. The third study did not report any subject with head-
ache.6 The observed I2 value was 3%. Pooled results are not
reported because of clinical heterogeneity.
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 inter-
val 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.
High Dermatomal Sensory Block
Three studies with a total of 205 patients reported the inci-
dence 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 bupi-
vacaine 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.
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
Hyperbaric Versus Isobaric Bupivacaine for Cesarean
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.
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 bupi-
vacaine, 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 com-
pared 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 asso-
ciated with increased risk of hypotension compared with
plain bupivacaine.23–26 In obstetric studies using spinal anes-
thesia for cesarean delivery, the baricity of bupivacaine does
not significantly influence the onset or duration of the sen-
sory 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 crite-
rion 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 sig-
nificantly 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 hetero-
geneity 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
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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 vari-
ability in the technique of regional block with 2 studies per-
forming the CSE technique to administer intrathecal drugs.6,7
Patient position may have affected clinical outcomes; 3 stud-
ies 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 defini-
tive 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 prac-
tice is indicated at the present time. Adequately powered
randomized clinical trials are required in which the defini-
tions, criteria, and assessment methodology of the impor-
tant 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. E
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 bupi-
vacain* and (hyperbaric or heavy or dextrose or glucose or
isobaric or plain or hypobaric or isotonic) #6 (#4 OR #5) #7
(#3 AND #6)
APPENDIX 2
Search strategy for MEDLINE (OvidSP)
1. exp CESAREAN-SECTION/ or (cesarea* or caesarea* or
cesaria* or caesaria*).mp. 2. exp BUPIVACAINE/ or (bupi-
vacain* 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.
anesthesia & analgesia
sh. or randomly.ab. or trial.ti.) not (animals not (humans
and animals)).sh. 5. 4 and 3
APPENDIX 3
Search strategy for EMBASE (OvidSP)
1. exp CESAREAN-SECTION/ or (cesarea* or caesarea* or
cesaria* or caesaria*).mp. 2. exp BUPIVACAINE/ or (bupi-
vacain* 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 RANDOM
IZATION/ 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 VOLU
NTEER* 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
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 manu-
script, 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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