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MINERVA ANESTESIOL 2009;75:185-90

O R I G I N A L A RT I C L E

Does anesthetic induction for Cesarean section with

a combination of ketamine and thiopentone confer
any benefits over thiopentone or ketamine alone?
A prospective randomized study
R. NAYAR, H. SAHAJANAND
Department of Anesthesiology, St Johns Medical College Hospital, Bangalore, Karnataka, India

ABSTRACT
Background. The aim of this study was to evaluate the benefit of a combination of thiopentone and ketamine over
either of these drugs alone as an induction agent for Cesarean section.
Methods. Randomized prospective study of 3 groups of 20 patients (Group I: thiopentone alone; Group II: ketamine alone; Group III thiopentone and ketamine combination).
Results. Systolic blood pressure (BP) (as measured at baseline, after induction, at intubation, and at 5 min, 10 min,
15 min, 20 min, 25 min, 30 min): baseline BP did not differ significantly across groups. However, postinduction values were significantly higher for Group II (ketamine alone) (P>0.001), but these values normalized by 30 min postinduction. Diastolic BP (as measured at baseline, after induction, at intubation, and at 5 min, 10 min, 15 min, 20 min,
25 min, 30 min): baseline BP did not differ significantly across groups. After induction, diastolic BP increased significantly in all groups. In Group I and Group III, these values returned to baseline after 10 min, and in Group II at the
30 min postinduction stage. Heart rate (measured at the same time as BP): at rest, presented no significant difference
in heart rate across groups. At induction, all groups showed a significant rise in heart rate. At intubation, Group I
showed an increase in heart rate, Group II a decrease in heart rate, and Group III no change. These intergroup variations were statistically significant. Apgar scores and umbilical venous gas measurements: although there were intergroup
variations, these were not statistically significant. Postoperative pain assessment (subjective) VAS scores: the VAS
pain scores 3 h after surgery were significantly higher in Group I, both at rest and coughing, at 24 h after surgery the
difference persisted for scores at rest, but equalized during coughing. Postoperative pain assessment (objective) time
to first analgesic demand: the duration of time to demand for first analgesic was significantly longer in Group II (ketamine only). Postoperative pain assessment (objective) total consumption of analgesic: patients of Group I consumed a significantly higher amount of analgesics than the other groups. Intraoperative event recall, awareness: no
patient reported any adverse events of this nature.
Conclusion. We conclude that though there were no adverse events and a significantly lower analgesic requirement,
the use of ketamine alone as an induction agent in Cesarean section should be avoided, as it causes significant maternal hemodynamic changes. The addition of a reduced dose of ketamine to thiopentone in the induction cocktail confers the benefit of reducing analgesic requirement without side effects. The treatment is safe and effective for the mother and child.
Key words: Cesarean section - Ketamine - Thiopental - Ketamine.

he choice of anesthesia for Cesarean section

depends on the indication, the degree of
urgency as assessed by the obstetrician, the judg-

Vol. 75 - No. 4

ment of the anesthesiologist, and the preference

of the patient. While regional anesthesia is currently preferred, general anesthesia with rapid

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KETAMINE AND THIOPENTONE COMBINATION FOR CESAREAN SECTION VS THIOPENTONE OR KETAMINE ALONE

induction, less hypotension and cardiovascular

instability, and better control of airways has also
been widely used.1 However, during general anesthesia there is often a high incidence of maternal
awareness, and inadequate maternal analgesia due
to the need to lessen fetal exposure to anesthetic
drugs.2
Ketamine, when used as an induction agent
during general anesthesia, has been shown to
reduce maternal awareness, and has a potent analgesic effect, both centrally and directly. It has been
combined with thiopentone to reduce the incidence of dysphoria.3 The current study was conducted to assess the potential for use of ketamine
as an induction agent, comparing it to thiopentone alone and to a combination of ketamine and
thiopentone in our setting.
Materials and methods
The study was conducted in the Department
of Anesthesiology at St. Johns Medical College
Hospital, a tertiary referral center in South India,
over a 26-month period from November 2005 to
December 2007 after due approval by the
Institutional Ethical Review Board.
The exclusion criteria were: patients with known
allergy to these induction agents, patients with
pregnancy-induced hypertension, eclampsia, preeclampsic toxemia, diabetes mellitus and other
systemic diseases.
Sixty patients, classified as ASA I and II, who
required general anesthesia for elective Cesarean
section, were included in this study. Informed consent was obtained, following which they were randomly assigned to 3 groups depending on the
induction agent, as either receiving thiopentone
alone (5 mg/kg), or ketamine alone (1 mg/kg), or
ketamine (0.5 mg/kg) and thiopentone (2.5
mg/kg) together. They were all instructed on the
use of the Visual Analogue Scale for pain (from
0, no pain, to 10, extremely painful).
Premedication as per standard protocol was
Ranitidine 150 mg on the night before surgery,
30 mL of 0.3 M sodium citrate 0.5 h before surgery.
After preoxygenation, rapid sequence induction was performed, with the above mentioned
drugs injected over a time period of 20 s. This was

186

followed by Suxamethonium 1.5 mg/kg prior to

intubation, and maintenance with IPPV using
N2O with oxygen and halothane (0.5%). Further
neuromuscular block was achieved using
Vecuronium. After delivery of the fetus, the concentration of Halothane was reduced to 0.25%
and N2O increased to 70%; 10 IU of Oxytocin,
and Pethidine 0.5 mg/kg were also given intravenously. Umbilical venous blood samples were
drawn from a clamped section of the umbilical
cord for ABG analysis, taking care to ensure that
the same machine was used in all cases.
APGAR scores at 1 and 5 min were recorded
by the pediatrician in attendance. Reversal after
anesthesia was obtained by neostigmine (50 g/kg),
and atropine (20 g/kg). Each patient was visited
by an anesthetist blinded to the patient group, 3
h and 24 h postsurgery, to record VAS pain scores
at rest and during coughing, and to estimate recall
of operative events or any other adverse events.
The time in minutes to first analgesic requirement
was noted from the charts in the recovery ward.
The cumulative consumption of analgesics was
also recorded.
Statistical analysis
Descriptive statistics: range, mean, and standard deviation.
Inferential statistics: for comparison of mean
values of three independent groups, one-way
ANOVA.
For identification of pairs of groups which differed significantly when ANOVA F was significant, Students and Newman-Keuls multiple comparison test was applied. When distributions were
significantly abnormal or heterogeneous across
groups, the Kruskal-Wallis test was employed.
For comparison of the means of dependent variables, whose values were obtained from the same
individual at different points in time, repeated
measures of multivariate analysis of variance
(RMANOVA), with Pillais trace.
For calculation of the power of the study, the
power analysis statistical system (PASS) program
was used for 3 groups of 20 subjects each. The
study is estimated to have 98% power to detect
an effect size of 0.59 between groups with 90%
confidence interval (effect size is equal to SD of
group by alternate hypothesis/SD within a group).

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150

100

140

90

DBP (mmHg)

SBP (mmHg)

KETAMINE AND THIOPENTONE COMBINATION FOR CESAREAN SECTION VS THIOPENTONE OR KETAMINE ALONE

130
120
110

Baseline Induction Intubation

10

15

20

80
70
60

25

Baseline Induction Intubation

Time (min)
Group 1

Group 2

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10

15

20

25

Time (min)
Group 3

Figure 1Systolic blood pressure changes across the groups.

SBP: systolic blood pressure.

Group 1

Group 2

Group 3

Figure 2.Diastolic blood pressure changes across the groups.

DBP: diastolic blood pressure.

Results

130
120

There was no significant variation in age and

weight between the groups.
Age (range/mean/SD): Group I (1834/24.6/4.3); Group II (18-30/23.3/4.1); Group
III (18-30/23.1/3.5); one way ANOVA with
df=2.57.
Weight (range/mean/SD): Group I (5075/57.6/5.85); Group II (40-90/57.2/7.17);
Group III (40-71/57.4/8.7); P=0.98, not significant.

110

HR (bpm)

Descriptive statistics

100
90
80
70

Base- Indu- Intu- 5

10 15
line ction bation
Time (min)
Group 1

20

Group 2

25

30

Group 3

Figure 3.Heart rate changes across the groups.

Maternal parameters
Systolic BP (as measured at baseline, after induction, at intubation, and at 5 min, 10 min, 15 min,
20 min, 25 min, 30 min) (Figure 1).
Preoperatively systolic BP did not differ significantly across groups: F=0.73; df=2.57; P=0.049;
not significant.
However, postinduction values were significantly higher for Group II (Ketamine alone) P>0.001,
The difference between the groups was statistically significant (F=7.13; df=2.57; P=0.002). These
values normalized by 30 min postinduction.
Diastolic BP (as measured at baseline, after
induction, at intubation, and at 5 min, 10 min,
15 min, 20 min, 25 min, 30 min) (Figure 2).
Preoperatively, diastolic BP did not differ significantly between groups (F=0.52; df=2.57; P=0.6).
After induction, diastolic BP increased signifi-

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cantly in all three groups. For 30 min, from the

time of induction diastolic BP (at 5 min intervals)
was maximum in Groups 2 and 3, which was statistically significant (F=3.6; df=2.57, P=0.034).
In Groups 1 and 3, the return of DBP to baseline was roughly complete after 10 min. In Group
2, the return of DBP to baseline was slower and
occurred only after 20 min.
Heart rate (measured at the same time as BP)
(Figure 3).
At rest there was no significant difference in
heart rate across groups. At induction all groups
showed a significant rise in heart rate. At intubation, Group I showed an increase in heart rate,
Group II a decrease in heart rate, while Group III
showed no change. These intergroup variations
were statistically significant.

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KETAMINE AND THIOPENTONE COMBINATION FOR CESAREAN SECTION VS THIOPENTONE OR KETAMINE ALONE

TABLE I. Changes in fetal parameters (Values are expressed as range, mean and standard deviation [SD]).
Group 1

Apgar 1 min
Apgar 5 min
Umbilical venous blood gas values
pH
PCO2 (mmHg)
PO2 (mmHg)

1-8
7.2 (1.8)
4-8
7.8 (0.9)
(N.=19)
6.8-7.4
7.2 (0.13)
16.7-63.3
40.2 (12.8)
7.8-46.4
25.9 (9.3)

Group 2

6-8
7.8 (0.5)
8
8 (0)
(N.=18)
7.1-7.3
7.2 (0.1)
19.8-61.4
40.7 (11.74)
9.4-47.7
26.7 (11.1)

Group 3

2-8
6.8 (2.1)
6-8
7.8 (0.5)
(N.=20)
7.2-7.3
7.3 (0.04)
32.3-60
40.4 (6.5)
19.2-40.2
23.2 (4.9)

Significance
Kruskall-Wallis test
with 2 df

2=3.63
P=0.16, NS
2=2.96
P=0.23 NS
Not significant (P=0.28)
Not significant (P=0.99)
Not significant (P=0.43)

TABLE II.Maternal analgesia (Values are expressed as range, mean and standard deviation [SD]).
VAS pain scores

Group 1
(N. 20)

Group 2
(N. 20)

Group 3
(N. 20)

Significance

3h
At rest

3-8
6.4 (1.4)

2-7
4 (1.2)

3-8
4.9 (1.5)

F=15.36
df=2.57
P<0.0001
Gp1>(Gp2=Gp3)

On coughing

6-9
7.8 (1.1)

4-9
6.4 (1.4)

4-9
6.9 (1.4)

F=6.7
df=2.57
P<0.0024
Gp1>(Gp2=Gp3)

2-6
4.3 (1)

2-5
2.8 (0.9)

2-5
3.2 (1)

F=12.26,
df=2.57
P<0.0001
Gp1>(GP2=GP3)

On coughing

2-7
4.7 (1.5)

3-6
5 (1)

4-7
5.3 (1)

F=1.29,
df=2.57
P<0.28
Not significant

Time to first analgesic

demand (min)

94-580
216.3
(154.1)

90-1 200
425.6
(303.9)

45-660
363.4
(182.5)

F=4.64
df=2.57
P=0.014
(Gp2=Gp3)>Gp1

Cumulative consumption
of analgesics in 24 h

2.55 (0.82)

1.55 (0.759)

1.8 (1.005)

F=7.16
df=2-57
P value = s0.0016
Gp1>(Gp2=Gp3)

24 h
At rest

EFFECTS ON THE NEONATE

Apgar scores: the Apgar scores at 1 min and 5
min were similar between groups.
All neonates had scores >7 at 5 min.
Umbilical venous gas measurements: blood sam-

188

ples from 1 patient in Group 1 and 2 patients in

Group 2 could not be analyzed as the samples were
clotted.
Even though the umbilical venous blood pH
was slightly lower in Groups 1 and 2 compared

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KETAMINE AND THIOPENTONE COMBINATION FOR CESAREAN SECTION VS THIOPENTONE OR KETAMINE ALONE

to Group 3, this difference was not statistically

significant (Table I).
POSTOPERATIVE PAIN ASSESSMENT
VAS scores (subjective): 3 h after surgery, they
were significantly higher in Group I, both at rest
and coughing, and at 24 h after surgery the difference persisted for scores at rest.
VAS pain scores on coughing were almost similar in all three groups after 24 h.
Time to first analgesic demand (objective): the
duration of time to demand for first analgesic was
significantly longer in Group II (ketamine alone).
Total consumption of analgesic (objective):
patients of Group I consumed a significantly higher amount of analgesics (Table II).
INTRAOPERATIVE EVENT RECALL, AWARENESS
No patient reported any adverse events.
Discussion
Pain management is the cornerstone of obstetric care. Pain decreases the ability to function and
interferes with maternal care of the newborn.
Severe postoperative pain is also associated with
longer postoperative stay, nausea and vomiting,
reduced cough, sputum retention, atelectasis,
hypoxemia, and increased risk of cardiac events.2
During general anesthesia for Cesarean section,
painful stimuli during surgery are relatively unattenuated as the induction agent thiopentone has
no analgesic effect, and opioid analgesics are avoided until delivery of the fetus. This increases the
potential for central hypersensitization with
increase in postoperative pain and analgesic requirements.4, 5
Ketamine is a potent analgesic which blocks
central hypersensitization 6 and is effective in pain
relief after upper abdominal surgery.7 Though this
effect is dose-dependent, a subanesthetic dose of
ketamine has been reported to be an effective analgesic.8 When used as an induction agent, ketamine resulted in less analgesic requirements than
thiopentone.9 This effect was also noted when ketamine and fentanyl were added to thiopentone
during induction.10 In a study assessing postoperative pain in patients undergoing upper abdom-

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NAYAR

inal surgery when ketamine in low doses was added

to standard general anesthesia, the effect of analgesia lasted longer than the direct analgesic action
of ketamine, evidence of a preemptive analgesic
effect.11
This effect was confirmed in our study by the
significantly later demand for first analgesic use
in the patients who received ketamine alone
(Group II) vs the other groups, and significantly
lower total demand for analgesic in Group II and
Group III, where ketamine was used as an induction agent.
Ketamine, when compared with thiopentone
in the context of Cesarean section, has been shown
to be a superior drug for induction as it shows a
lower incidence of awareness, enhanced postoperative analgesia, no emergence delirium, and also
no significant adverse effects on the fetal Apgar
scores.12 In another similar series, when ketamine
was used as an induction agent, awareness was not
reported, but patients reported pleasant and
unpleasant dreams, though without hallucinations.13
When wakefulness, awareness, responsiveness
and emergent phenomena were compared after
ketamine and thiopentone, and to a combination
of the above drugs (each in reduced concentration), ketamine alone appeared to result in reduced
intraoperative responsiveness, awareness without
any increase in emergent phenomena or any reported unpleasant dreams. There was no significant
advantage of ketamine and thiopentone over
thiopentone alone with respect to intraoperative
awareness; this combination was inferior to ketamine alone.14 Intraoperative awareness was noted to be significantly higher when thiopentone
was used as an induction agent for obstetric anesthesia.15
None of our patients reported intraoperative
awareness or dreams, and circulatory ketamine
levels were probably low enough so as not to cause
emergent phenomena.
In a study, Apgar scores, blood gas values, and
acid-base parameters in 206 neonates delivered by
Cesarean under general anesthesia induced by ketamine or thiopentone, were found to be comparable.16 While assessing the effects of ketamine use
on fetal oxygenation, it was found that, provided
the induction to delivery interval was <10 min

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KETAMINE AND THIOPENTONE COMBINATION FOR CESAREAN SECTION VS THIOPENTONE OR KETAMINE ALONE

and the incision to delivery interval was <90 s,

there was no fetal depression,15 and the values
obtained were not different from those obtained
during thiopentone usage.17
No significant fetal acidosis or changes in the
Apgar score were noted in our study.
Ketamine has been reported to ensure better
hemodynamic stability than thiopentone during
surgery.18 It has been suggested that this is due to
the fact that ketamine has less effect on vascular
tone and myocardial contractility.13
In our study, the effect on the maternal physiology of ketamine alone appeared to be different
from when thiopentone or a combination of ketamine and thiopentone was used. The heart rate
decreased during induction, suggesting a reduction in sympathetic stimulation, possibly because
of the analgesic effects of ketamine.8, 14 However,
BP changes in this group in both systolic BP (rise
after induction) and diastolic BP (time to return
to normal) was significant, offsetting any gains.
The combination of ketamine and thiopentone
did not cause any significant change in heart rate,
and was devoid of widely fluctuant BP changes, suggesting beneficial effects of combining the two drugs.
Conclusions
The use of ketamine, either singly or in an induction cocktail with thiopentone during induction of
general anesthesia for Cesarean section reduced postoperative pain and analgesic requirement. We conclude that, even if there were no adverse events and
a significantly lower analgesic requirement, the use
of ketamine alone as an induction agent in Cesarean
section should be avoided, as it causes significant
maternal hemodynamic changes.
The addition of ketamine to thiopentone in the
induction cocktail in a reduced dose confers the
benefit of reduction of analgesic requirement without side effects and is safe and effective for both
mother and child.

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Received on April 26, 2008 - Accepted for publication on September 2, 2008.

Corresponding author: R. Nayar, MD, Assistant Professor, Department of Anesthesiology, St Johns Medical College Hospital, Bangalore 560034,
India. E-mail: anesthesia62@hotmail.com

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