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British Journal Of Anaesthesia, 117 (5): 61722 (2016)

doi: 10.1093/bja/aew311
Obstetrics

OBSTETRICS

I.V. paracetamol as an adjunct to patient-controlled


epidural analgesia with levobupivacaine and fentanyl
in labour: a randomized controlled study
K. Gupta1, S. Mitra1*, S. Kazal1, R. Saroa1, V. Ahuja1 and P. Goel2
1
Department of Anaesthesia & Intensive Care, Government Medical College & Hospital, Chandigarh, India and
2
Department of Obstetrics & Gynaecology, Government Medical College & Hospital, Chandigarh, India

*Corresponding author. E-mail: drsmitra12@yahoo.com

Abstract
Background: Use of i.v. paracetamol for postoperative pain is well documented, but it is unclear if it can reduce the con-
sumption of opioids during patient-controlled epidural analgesia (PCEA) in labouring parturients.
Methods: In this randomized, double-blind, placebo-controlled clinical trial conducted in a tertiary care hospital, 80parturi-
ents were randomly assigned to two groups of 40 each, to receive either 1000 mg (100 ml) i.v. paracetamol or 100 ml normal
saline as placebo, 30 min before the procedure. After insertion of the epidural catheter, all patients received 10 ml of levobu-
pivacaine 0.1% with 2 lg ml-1 fentanyl, followed by continuous background epidural infusion of 6 ml h-1 with a provision of
patient-controlled bolus 5 ml of same drug with a lock-out interval of 12 min.
The primary outcome was hourly mean consumption of levobupivacaine and fentanyl mixture (ml.h-1). Secondary
outcomes included pain score, sensory and motor block, haemodynamic parameters of mother, duration of second stage of
labour, mode of delivery, Apgar scores, foetal heart rate and adverse effects.
Results: The hourly mean drug consumption in the Paracetamol group was significantly lower as compared with the
Placebo group (7.03 ml.h-1, SD 0.83 vs. 8.12 ml.h-1, SD 1.34; p < 0.001). The mean number of boluses taken were also
significantly less in the paracetamol group (1.00, SD 0.93 vs. 1.43, SD 0.90; p 0.036). Pain scores decreased in both the groups
without significant inter-group differences.
Conclusions: Use of 1000 mg i.v. paracetamol decreases the mean hourly drug consumption through epidural route. Thus
i.v. paracetamol is a safe and effective adjunct to PCEA in labour analgesia.
Clinical trial registration: Clinical Trials RegistryIndia (http://ctri.nic.in/Clinicaltrials/login.php), trial registration number
2013/09/003968.

Key words: administration, intravenous; analgesia; analgesia, epidural; obstetric labour; paracetamol; patient-controlled

Accepted: July 6, 2016


C The Author 2016. Published by Oxford University Press on behalf of the British Journal of Anaesthesia.
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618 | Gupta et al.

Committee. After obtaining written informed consent, women


Editors key points requesting analgesia in the first stage of labour were enrolled in
Multimodal analgesia for labour can be used to optimize this study. The inclusion criteria were: primiparous ASA I and II
parturients aged 1835 yr, spontaneous onset of labour at term
pain control and reduce opioid consumption.
(3742 weeks gestation), with cervical dilatation of 5 cm, and a
The effects on analgesia and labour of i.v. paracetamol
single live foetus in cephalic presentation. The exclusion criteria
before epidural insertion were studied.
were: refusal by parturient, parturients who had received paren-
I.V. paracetamol reduced epidural fentanyl and levobu-
teral opioids in the last four h, any systemic and local sepsis,
pivacaine use with similar pain scores.
deranged coagulation profile, multiple pregnancies, premature
Further studies are needed to explore the role of i.v. par-
labour, obstetric complications (e.g., premature rupture of amni-
acetamol in labour analgesia. otic membranes) and allergy to study drugs (i.e. paracetamol,
levobupivacaine and fentanyl).
Eighty participants were allocated randomly to two groups by
using computer generated random numbers (CONSORT flow
chart shown in Fig. 1). Cervical dilatation and patient character-
The pain of childbirth is arguably the most severe pain most
istic data, including age, weight, height and baseline investiga-
women will endure in their lifetime. Various responses to pain
tions were recorded. The Paracetamol group (n 40) received a
such as marked stimulation of respiration and circulation, acti-
100-ml i.v. infusion containing 1000 mg of paracetamol
vation of neuroendocrine system and pain-related behaviors,
(PerfalganTM, Bristol-Myers Squibb, Mumbai, India) over 15 min,
may produce deleterious consequences to both mother and foe-
while the placebo group (n 40) received an i.v. infusion of 100 ml
tus. Many of these responses are mitigated by effective pain
of normal saline (Denis Chem Lab Limited, Gujarat, India) as pla-
relief.1 Neuraxial techniques are accepted as the gold standard
cebo, 30 min before the procedure. Epidural blocks were sited in a
for intrapartum labour analgesia. It has been refined over the
standard manner in all the patients. After shifting the patient to
past 20 yr to provide higher quality of pain relief, less motor
the clean labour room operation theatre, i.v. access was secured
weakness and more control over the administration of pain
and baseline visual analog pain score (VAS based on a 010 mm
relief medications. Addition of adjunctive agents (opioids, epi-
scale, 0 mm no pain and 10 mm worst pain imagined) was
nephrine or clonidine) in epidural analgesia, may provide a dose
noted. The patient was continuously monitored for HR, NIBP and
sparing effect, increase the duration and quality of analgesia,
SpO2 throughout the study period. With the parturient in the sit-
but the use of narcotics is limited by adverse effects such as
ting position, using a disposable 18 g Touhys needle (MinipackR,
drowsiness, nausea, and vomiting in the mother, and respira-
Smith UK) the epidural space was identified, by using loss of
tory depression in the neonate.24
resistance to saline at either L2-3 or L3-4, using universal aseptic
For over a century, paracetamol has been widely used as an
precautions. After noting the distance between the epidural space
effective antipyretic and analgesic medication with well-
and skin by using the marking on the epidural needle, 3-4 cm of
established tolerability and favorable safety profile, including
20-gauge catheter was inserted in the epidural space from the
more recent evidence of its use through the i.v. route in postop-
skin was noted and. The catheter was into the epidural space.
erative pain.57 Although paracetamol has been used as an
The loading dose of 10 ml of 0.1% levobupivacaine with fentanyl
effective and safe analgesic medication,8 there is a paucity of
2 lg ml-1 was given after negative aspiration for blood and CSF.
studies assessing its intrapartum use. The few recently pub-
Maintenance of PCEA (Master PCA pump, Fresenius Kabi USA)
lished studies have compared i.v. paracetamol with i.v. pethi-
was started after the loading dose, with 6 ml h-1 of 0.1%
dine,9,10 i.m. pethidine,11 i.m. tramadol,12,13 i.v. morphine,14,15 or
Levobupivacaine, with fentanyl 2 lg ml-1 as a continuous back-
with saline during Caesarean section under general anaesthe-
ground infusion and patient controlled boluses of 5 ml of the
sia.1618 To the best of our knowledge, no study has compared
same drug with a lockout interval of 12 min if needed.
the role of i.v. paracetamol as an adjunct analgesic agent, to the
Blinding was done by the following means: the drugs were
well established labour analgesia regimes. The combination of a
contained in similar looking 100-ml glass bottles obtained from
local anaesthetic (levobupivacaine) and an opioid (fentanyl) as
the hospital pharmacy, which were covered by opaque brown
patient controlled epidural analgesia (PCEA), is a standard pro-
papers marked to conceal their identity. The group allocation
cedure for labouring women in many hospitals including ours.
was done by one investigator (S.M.), the paracetamol or saline
It would be of interest to learn if i.v. paracetamol could have an
infusion bottles were covered by opaque brown paper and infu-
opioid sparing effect, which could have implications for both
sion started by another investigator (S.K.), while the assess-
the mother and the baby.
ments were done by a third investigator (K.G.) who was blinded
Thus the present study was designed to evaluate the efficacy
to the group and drug received.
of i.v. infusion of 1000 mg of paracetamol as an adjunct and its
The primary outcome of the study was hourly average con-
sparing effect on total consumption of levobupivacaine and fen-
sumption of levobupivacaine and fentanyl mixture, including
tanyl combination given as patient controlled epidural analge-
both continuous background infusion plus bolus doses (in ml)
sia in labouring parturients.
starting from 1 h after administration of paracetamol or saline,
till delivery. The hourly average consumption was considered
important so as to correct for the variable duration of labour,
Methods and it was calculated as a mean value (ml/h) by dividing the
The study was conducted from June 2013 to June 2014 at a total consumption during the entire course of labour by the
tertiary-care teaching hospital in north India. It was registered duration of labour in h. Secondary outcomes were pain score
with the Clinical Trials Registry of India (the trial was registered (VAS), sensory and motor block characteristics (using moist cold
in May 2013 with the Trial Reference No. Ref/2013/05/005092, wisp of cotton and Bromage score respectively), haemodynamic
final CTRI Registration number 2013/09/003968). Ethical appro- parameters of mother (using multichannel monitor), foetal
val for this study was provided by the Institutional Ethics heart rate (by cardiotochograph) and adverse effects (assessed

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I.V. paracetamol as adjunct in labour analgesia | 619

Assessed for eligibility

(n=92)

Excluded (n=12)

Enrollment Not meeting inclusion


criteria (n=9)
Refused to participate (n=3)
Other reasons (n=0)
Randomized

Group 1: i.v. Paracetamol Group 2: Placebo

Allocated to intervention (n=40) Allocated to intervention (n=40)

Received allocated intervention (n=40) Received allocated intervention (n=40)

Lost to follow-up (n=0) Lost to follow-up (n=0)

Discontinued intervention (n=0) Discontinued intervention (n=0)

Analysed (n=40) Analysed (n=40)

Excluded from analysis (n=0) Excluded from analysis (n=0)

Fig 1 CONSORT flow diagram.

clinically). All these variables were recorded every 5 min for the value of 12.4 ml h-1 as the mean hourly neuraxial drug con-
first 20 min and then every 1 h until delivery. Duration of second sumption in the paracetamol group.
stage of labour, mode of delivery, Apgar scores and maternal Thus, for this study, sample size analysis with the above
satisfaction (VAS) were also recorded at the end of labour. assumption and with b of 0.20 (i.e. power of 80%) and a of 0.05
Women were questioned regarding their satisfaction for analge- demonstrated that a sample size of 36 per group would allow us
sia and future desire to use it in subsequent pregnancies, to detect a 20% difference in total epidural drug combination
12-24 h after delivery, using separate 100 mm visual linear ana- volume required per h. To allow for slight oversampling, it was
logue scales. decided to have a total sample size of 80 patients, with 40
patients per group.

Sample size calculation


We used the primary outcome measure to calculate sample
Statistical analysis
size. From our own previous data on 30 patients undergoing All data were analysed using Statistical Package for Social
labour epidural analgesia with PCEA in our hospital, it was seen Sciences (SPSS Inc., Chicago, IL, version 17.0 for Windows).
that the mean hourly consumption of levobupivacaine and fen- Means were compared using Students t-test for independent
tanyl mixture was 15.5 ml h-1, with SD 4.66. Following the exam- groups if the data were normally distributed and Mann-
ple of Ross and colleagues19 we decided that a 20% reduction in Whitney U-test if the data were not normally distributed.
hourly consumption of neuraxial analgesic combination would Proportions were compared using v2 or Fishers exact test
be considered as clinically meaningful difference, yielding a whichever was applicable. Two-way repeated-measures

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620 | Gupta et al.

Table 1 Comparison of patient characteristics in the two groups Table 3 Comparison of mode of deliveries (MOD) in the two
groups
Characteristics GROUPI GROUPII
(PCM) N 40 (PLACEBO) N 40 MOD Group I Group II P value
(PCM) n40 (PLACEBO) n40
Age (yr) 26.15 25.9
Range 20-35 21-32 Normal n (%) 29 (72.5) 30 (75) 0.799
Height (cm) 157.55 (4.43) 157.6 (5.21) Forceps assisted n (%) 5 (12.5) 3 (7.5) 0.456
Mean (SD) Caesarean n (%) 6 (15) 7 (17.5) 0.762
Weight (kg) 66 (9.89) 69.18 (11.79)
Mean (SD)
ASA I Category 39 (97.5%) 39 (97.5%)
n (%)

Table 4 Comparison of Apgar scores at 5 min in the two groups

Groups Group I Group II


(PCM) n40 (PLACEBO) n40
Table 2 Comparison of clinical parameters in the two groups.
Data are shown as Mean (SD) APGAR SCORE: 9-10 n (%) 38 (95%) 38 (95%)
APGAR SCORE: 6-8 n (%) 2 (5%) 2 (5%)
PARAMETERS GROUPI GROUPII P Value APGAR SCORE: 5 <5 n (%) 0 (0) 0 (0)
(PCM) (PLACEBO)
N 40 N 40

Hb (g dL-1) 11.32 (1.62) 11.00 (1.38) 0.34


Blood sugar (mg dL-1) 93.37 (15.11) 95.15 (12.25) 0.56 both the groups (8.97, SD 0.54 in the paracetamol group and 9.00,
Prothrombin time 98.50 (2.90) 98.17 (3.12) 0.63 SD 0.60 in the placebo group; 95% CI of Difference of Means -
index (%) 0.114 0.829; P 0.89). Compared with the pretreatment score,
Serum Sodium 141.10 (3.37) 141.67 (3.23) 0.43 the mean VAS score was lower at subsequent intervals in both
(mEq L-1) the groups. There was no significant difference in the VAS
Serum Potassium 4.01 (0.44) 3.94 (0.43) 0.52 scores in both the groups during the course of labour.
(mEq L-1)
The mean duration of second stage of labour was compara-
ble in the groups (65.29 min, SD 23.5 vs. 68.24 min, SD 27.6 for
Group I and II respectively; 95% CI of Difference of Means -9.367
11.985; P 0.35). There was no difference in incidence of opera-
ANOVA were conducted with post-hoc Scheffes test to conduct tive delivery and neonatal outcome as measured by Apgar score
pair-wise. Statistical tests were two-sided and performed at a in both the groups (Tables 3 and 4). The changes in mean heart
significance level of a 0.05. rate, systolic and diastolic blood pressure in both groups were
minimal and non-significant between the groups (data not
shown). Similarly, time to sensory and motor blockade was
Results comparable between the groups (data not shown).
A total of 80 parturients were enrolled, 40 in each group. Both No difference in global maternal satisfaction mean score
the groups were similar with respect to patient characteristics was observed between both the groups (91.78, SD 4.22 vs. 90.25,
profile and baseline investigations (Tables 1 and 2). SD 4.56; 95% CI of Difference of Means -0.430 3.480; P 0.12).

Regarding the primary outcome of interest, it was seen that Adverse effects were common but minor in this study and con-
the mean hourly drug consumption was significantly lower in sisted mainly of nausea, vomiting and urinary retention. There
the paracetamol group (7.03 ml, SD 0.83; range 5.77-8.75) as com- were non-significant differences in occurrence of side-effects
pared with the placebo group (8.12 ml, SD 1.34; range 6.00-11.70; between the two groups (Table 5).
P <0.001). The paracetamol group also required significantly less
total number of boluses (mean 1.00, SD 0.93; interquartile range
[IQR] 0-2) than placebo group (mean 1.43, SD 0.90; IQR 1-3;
Discussion
P 0.036). When hourly bolus consumption rate was compared, This randomized, double-blinded, placebo controlled clinical
statistically significant difference in the bolus consumption was trial demonstrated that i.v. paracetamol is a safe and effective
observed at 2 h, with lower bolus consumption in the paraceta- adjunct to PCEA in labour analgesia. A few previous studies
mol group as compared to placebo group. No significant differ- have shown the effective use of i.v. paracetamol during intra-
ence was found in number of boluses taken at the rest of the partum period.918 Elbohoty and colleagues9 showed that use of
time intervals over the study period. i.v. paracetamol, was as effective as pethidine for intrapartum
In our study, time to onset of analgesia was recorded from analgesia during the first stage of labour. In another study done
the time when the bolus drug was injected, to the time when by Abd-El-Maeboud and colleagues10, it was demonstrated that
VAS became less than three. The mean onset time was similar i.v. infusion of paracetamol was associated with significantly
in both groups (11.90 min, SD 2.09 in paracetamol group and lower VAS score and lower incidence of need for rescue medica-
12.00 min, SD 1.93 in placebo group; 95% Confidence Interval [CI] tion as compared with sterile water (placebo) for intrapartum
of Difference of Means -0.998 0.798; P 0.82). The mean VAS analgesia. In both these studies, and in the recently published
score before institution of epidural analgesia was comparable in studies from Iran,11 India12,13 and USA,14,15 i.v. paracetamol was

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I.V. paracetamol as adjunct in labour analgesia | 621

meta-analysis, too reports no adverse neonatal outcome in


Table 5 Comparison of incidence of adverse effects in two labour epidural deliveries.22 Non-reassuring foetal heart tones
groups. Data are shown as n (%)
during labour have been reported in 10% to 20% of patients after
initiation of neuraxial analgesia, although adverse neonatal out-
Side-effects Group I Group II P value
comes have not been reported.24
(PCM) n40 (PLACEBO) n40
Paracetamol is a frequently used painkiller and antipyretic
Pruritus 1 (2.5) 3 (7.5) 0.11 drug in pregnant women. As compared with other analgesics
Nausea 2 (5.0) 1 (2.5) 0.55 including opioids, it has an overall favourable safety profile,
Vomiting 3 (7.5) 2 (5.0) 0.64 though one recent commentary25 and editorial26 have raised
Urinary retention 3 (7.5) 3 (7.5) 1.00 safety concerns regarding the indiscriminate and massive use
Fever 0 (0.00) 2 (5.00) 0.15 of paracetamol. In our study no maternal adverse effects have
Hypotension 0 (0.00) 1 (2.5) 0.31 been recorded in the women who received paracetamol, con-
Foetal bradycardia 2 (5.0) 3 (7.5) 0.64 firming the safety and tolerability of paracetamol reported in
other studies.5,8
In conclusion, providing the perfect combination of effective
and safe analgesia during labour has remained an ongoing chal-
lenge. Thus, addition of a long-established safe and well-
used as the sole intrapartum analgesic. The comparison agents tolerated analgesic such as paracetamol, by the i.v. route to the
were pethidine, tramadol, or morphine. The use of 1000 mg par- intrapartum labour analgesia regime as above, can have a sig-
acetamol in the present study significantly decreased hourly nificant reduction in consumption of the anaesthetic-opioid
mean drug consumption and the number of boluses through combination by the epidural route, thereby allowing the use of
the epidural route, thus proving the epidural drug dose sparing lower doses of each agent, while minimizing undesirable side-
effect of intrapartum paracetamol. The statistically significant effects at the same time.
difference in bolus consumption at 2 h between two groups in
this study, may be because of occurrence of breakthrough pain
in the placebo group, which prompted the patients to take addi- Authors contributions
tional bolus at 2 h.
Study design/planning: S.M.
The combination of a local anaesthetic (levobupivacaine)
Study conduct: K.G., S.M., S.K., R.S., P.G.
and an opioid (fentanyl) as patient controlled epidural analgesia
Data analysis: K.G., S.M., S.K.
(PCEA), is a standard procedure for labouring women in many
Writing paper: K.G., S.K. Revising paper: all authors
hospitals including ours. This study demonstrated that i.v. para-
cetamol has an opioid sparing effect, which could have implica-
tions for both the mother and the baby. A systematic review of
24 trials found that intrathecal opioid in labour, increased the
Declaration of interest
chances of fetal bradycardia (Odds Ratio [OR] 1.8, 95% confi- None declared.
dence interval [CI] 1.0-3.1, number-needed to-harm [NNH] 28). It
also found a very high probability of maternal pruritus (OR 29.6,
95% CI 13.6-64.6, NNH 1.7).20 Incidence of foetal bradycardia has
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