Asian Journal of Anesthesiology xxx (2017) 1e5

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Asian Journal of Anesthesiology

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Research paper

Pre-emptive ketorolac for prevention of intraoperative shoulder pain

in patients undergoing cesarean section: A double blind randomized
clinical trial
Mostafa Samy Abbas a *, Omnia Ahmed Askar b, Ahmed Ali Abdel Aleem c
a
Department of Anesthesia and Intensive Care, Assiut University Hospital, Assiut University, Egypt
b
Department of Anesthesia and Intensive Care, University Hospital Kerry, Tralee, Ireland
c
Department of Obstetrics and Gynecology, Assiut University Hospital, Assiut University, Egypt

a r t i c l e i n f o a b s t r a c t

Article history: Background: Shoulder pain is a commonly observed but mostly neglected consequence of cesarean
Received 4 March 2017 section and little is known as well as explored about intraoperative shoulder pain. We conducted this
Received in revised form randomized prospective double-blinded study to evaluate the efficacy of ketorolac in reducing the
30 May 2017
incidence and severity of intraoperative shoulder pain in patients undergoing cesarean section.
Accepted 4 July 2017
Methods: Two hundred ASA I and II patients scheduled to undergo elective cesarean section under spinal
anesthesia were randomized to receive either intravenous ketorolac 30 mg (ketorolac group) or normal
Keywords:
saline (control group). The primary outcome was the incidence of intraoperative shoulder pain. Sec-
Cesarean section;
Ketorolac;
ondary outcomes were severity of intraoperative shoulder pain, amount of intraoperative blood loss,
Shoulder pain incidence of hypotension, bradycardia and request for intraoperative rescue analgesia.
Results: The incidence of intraoperative shoulder pain in the control group was significantly higher than
the ketorolac group (P ¼ 0.003). Severity of shoulder pain and requests for intraoperative analgesia was
significantly higher in the control group (P ¼ 0.012, P ¼ 0.006 respectively). Patients in the Ketorolac
group experienced significantly higher incidences of bradycardia (P ¼ 0.037).
Conclusion: 30 mg ketorolac administered intravenously just before the operation could decrease inci-
dence and severity of intraoperative shoulder pain in patients undergoing cesarean section.
Clinical trial registration: ClinicalTrial.gov (Registration number: NCT02380898, first registered in 01/03/
2015).
© 2017 Taiwan Society of Anesthesiologists. Published by Elsevier Taiwan LLC. This is an open access
article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction combined spinal epidural anesthesia experience very high in-

Cesarean section (CS) is the most common abdominal surgery
among women worldwide.1 Shoulder pain, is very common but
mostly neglected consequence of CS and little is known about
intraoperative shoulder pain.2
Spinal anesthesia (SA) is most commonly used anesthesia
technique in patients scheduled for CS. There are very well know
complications of SA used during CS, but there are few studies
exploring about intraoperative shoulder pain as one of its compli-
cations. Kikuchi et al reported that women undergoing CS under
* Corresponding author. Second Floor, Department of Anesthesia and Intensive
Care, Faculty of Medicine, Assiut University, Assiut, Egypt. Fax: þ20 882333327.
E-mail: mostafasamy@aun.edu.eg (M.S. Abbas), omnia.askar@gmail.com
(O.A. Askar), aboaliabdelaleem@gmail.com (A.A. Abdel Aleem).
cidences of intraoperative shoulder pain.2
This sharp type of pain noticed intraoperatively during CS is
usually experienced in the shoulder area, and was described by the
patients to originate from deep inside the shoulder. They also at
times complain it to originate this from the right side of chest. The
pain is found to go down to the upper arm and in the neck on right
side sometimes. This pain at times leads muscle spasm. The reason
for this pain is postulated to be due to sub-diaphragmatic clot,
subdiaphragmatic air trapping, or because of peritoneal irritation
resulting from them.3
Preventive analgesia using non-opioid analgesics is aimed to
improve postoperative pain while minimizing side effects of opi-
oids. Ketorolac is a nonsteroidal anti-inflammatory analgesic
(NSAID) used frequently to treat postoperative pain as combined
multimodal analgesia. Single dose ketorolac has been used in labor

https://doi.org/10.1016/j.aja.2017.07.002
2468-824X/© 2017 Taiwan Society of Anesthesiologists. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).

Please cite this article in press as: Abbas MS, et al., Pre-emptive ketorolac for prevention of intraoperative shoulder pain in patients undergoing
cesarean section: A double blind randomized clinical trial, Asian Journal of Anesthesiology (2017), https://doi.org/10.1016/j.aja.2017.07.002
2 M.S. Abbas et al.
analgesia and it is found to be safe and effective both to mother and
fetus.4
Considering this safety profile and efficacy in obstetrics as well
as the opioid sparing role, we decided to use ketorolac to evaluate
its efficacy in reducing intraoperative should pain in patients
scheduled to undergo CS under SA.
2. Methods
After approval from the Medical Ethics Committee of the Faculty
of Medicine of Assiut University, 200 primigravida healthy preg-
nant women (ASA I and II) having singleton pregnancy at term
(more than equal to 37 weeks of gestation) were included in this
study after obtaining their verbal and written informed consent.
This randomized double-blind placebo controlled study was con-
ducted between March to September, 2015.
Patients having allergy to study drug, gestational diabetes, car-
diovascular or biliary disorders, asthma, renal impairment, pre-
eclampsia, any chronic pain condition or trauma in the shoulder,
forearms or upper limbs, history of previous abdominal surgery,
patients with complication in current pregnancy, any contraindi-
cation to SA were excluded from the study.
Patients were randomly allocated using computer-generated
randomization to receive either intravenous ketorolac 30 mg
(ketorolac group) or equal volume of normal saline (control group).
An independent person not involved in managing the patients
perioperatively prepared the study drugs with matching random
numbers to be used in designated patients. Neither the participants
nor the investigators involved in collecting the data and assessing
the outcomes of the study were aware of the identity of the target
drugs used in the study.
All the patients preassessed before undergoing CS. They were fully
explained by the investigator about use of numerical rating scale
(NRS) in describing pain. They were fasted for 6 h before the opera-
tion. They were also premedicated with oral ranitidine (150 mg), oral
sodium citrate (30 mL, 0.3 M) and intramuscular metoclopramide
(10 mg) 1 h before operative as antiaspiration prophylaxis.
In the operating room in all patients a large bore intravenous
access (preferably 18 gauges) was inserted in left dorsum of the
hand and they were preloaded with 15 mL/kg of Ringer's solution
intravenously. All patients were connected to standard routine
monitoring [non-invasive blood pressure (NIBP), ECG and periph-
eral oxygen saturation]. All participants received either 30 mg
Ketorolac intravenously in 4 mL volume (ketorolac group) or
similar volume of normal saline (control group).
They were made to sit upright and spinal anesthesia was
inserted using the midline approach after proper antiseptic clean-
ing and draping in the lumbar vertebral interspace of L3-L4 or a level
below using a 25 gauge Quincke needle. After obtaining free flow of
cerebrospinal fluids, 12 mg of hyperbaric bupivacaine and 0.2 mg
morphine were injected intrathecally. All patients were then made
to lie supine and a wedge was placed below right hip to give a left
lateral tilt. Continuous NIBP monitoring at every 1e3 min interval
was started. Block level was tasted using response to cold. After
attaining a block level of at least up to T6 surgeons were allowed to
proceed with surgery. The surgical technique was similar in both
the groups. To reduce the possibility of chemical peritonitis, both
the surgeon and the assistants washed their gloves with saline just
before proceeding with surgery.
The incidence of intraoperative shoulder pain was noted. To
exclude abdominal or visceral origin of pain, a leading question was
asked patients to indicate the site of that pain after any complain
was received. The severity of that pain was assessed using the
verbal numerical rating scale (0e10) at time of complaint. Based on
the score the pain was categorized for analysis as mild (0e3),
Please cite this article in press as: Abbas MS, et al., Pre-emptive ketorolac for prevention of intraoperative shoulder pain in patients undergoing
cesarean section: A double blind randomized clinical trial, Asian Journal of Anesthesiology (2017), https://doi.org/10.1016/j.aja.2017.07.002
moderate,4e7 and severe.8e10 If the pain was more than mild, rescue
analgesia was provided with intravenous fentanyl (25e50 mcg).
Patients were prescribed to receive regular paracetamol (1 gm) oral
or intravenous for persistent postoperative shoulder pain. Esti-
mated blood loss was calculated using the difference in hematocrit
values taken prior to and 24 h after cesarean delivery, according to
the following formula:
Estimated blood loss ¼ EBV  ½ðPreoperative hematocrit
 Postoperative hematocritÞ
 =Preoperative hematocrit:
where EBV (estimated blood volume) in ml ¼ the woman's weight
in kg  85.5
Hypotension (defined as >20% decrease in systolic blood pres-
sure) was treated with bolus of intravenous fluid and ephedrine
(6 mg). Bradycardia (heart rate< 60/min) was treated with intra-
venous atropine (0.5 mg).
2.1. Statistical analysis
In a pilot study to analyze sample size we found that 88 patients
per group were sufficient to detect a relative difference of at least
20% in the incidence of shoulder pain, with a power of 80%, an alpha
error of 0.05 and an allocation ratio of 1:1. Taking into account of
dropouts, 100 patients were recruited in each group to give suffi-
cient difference. Continuous data were presented as mean with SD
or median with range. These data were analyzed using independent
t-test. Categorical data were expressed as frequency or percentage
and were analyzed using chi-square test. Pain intensity assessed by
verbal numerical rating scale score was analyzed using the Mann
Whitney and U test. All P values were two-sided, and the statistical
significance was defined as a P-value of less than 0.05. All analyses
were performed using SPSS 16.0 (SPSS Inc., Chicago, IL).
3. Results
Total 254 patients from March until September 2015 were
evaluated for eligibility, and 205 were initially included in our
study, and 5 other were excluded as they required general anes-
thesia. Finally we completed the study with 200 patients (Fig. 1).
Patients in both groups were similar in characteristics with regard
to age, height, weight, and gestational age (Table 1). The operative
and analgesic details are shown in (Table 2).
Incidence of shoulder pain was significantly higher in control
group compared to ketorolac group (23% vs. 8%, P ¼ 0.003). There
was significant reduction in requests for intraoperative rescue
analgesia for intolerable shoulder tip pain in the ketorolac group
compared to control group (6% vs. 19%, P ¼ 0.005). Higher incidence
of intraoperative bradycardia was noticed in ketorolac group
compared to control group (12% vs. 4%, P ¼ 0.037). However, there
were no significant differences between both groups with respect
to the incidence of hypotension, time to sensory block, the highest
level to sensory block and estimated blood loss (Table 2).
The overall NRS score for intraoperative shoulder pain at the
time of first complaint was significantly higher in the control group
compared to ketorolac group (P ¼ 0.012) (Fig. 2). Also the severity of
that initial pain was much higher (moderate to severe) in control
group compared to study group (P ¼ 0.031) (Table 3).
4. Discussion
We found in this study that 30 mg of intravenous ketorolac
given before cesarean section can result in significant reduction of
Ketorolac for intraoperative shoulder tip pain in Cesarean section 3

Fig. 1. Consort Recruitment flowchart.

Table 2
Operative data.
Table 1
Preoperative patient characteristics. Ketorolac group Control group P value
(n ¼ 100) (n ¼ 100)
Ketorolac group Control group P value
(n ¼ 100) (n ¼ 100) Shoulder tip pain (n) 8 23 0.003
Women requesting 6 19 0.005
Age (years) 24.10 (3.74) 23.50 (3.18) 0.223 intraoperative
Weight (kg) 75.58 (8.85) 74.28 (7.80) 0.272 Fentanyl for
Height (cm) 161.54 (9.42) 162.64 (9.79) 0.419 shoulder tip pain (n)
Gestational 38 (37e41) 38 (36e41) 0.622 Bradycardia (n) 12 4 0.037
age (weeks) Hypotension (n) 56 46 0.157
Data are presented as mean (SD), or median (range). Time to sensory 6.02 (1.1) 5.87 (1.2) 0.361
block (minutes)
Highest level of
Sensory block (n)
incidence and severity of intraoperative shoulder pain. Shoulder  T4 42 41 0.761
pain, as one of the intraoperative complications of CS, is usually  T3 44 48
neglected in clinical research even though it is very distressing to  T2 14 11
Duration of procedure 57.52 (6.2) 58.90 (6.9) 0.143
patients and is a very common happening. Shoulder pain is com-
(minutes)
mon in CS performed under SA and it commonly demands intra- Estimated blood loss (ml) 600.5 (132.99) 582.8 (135.87) 0.353
operative intervention due to its severity.
Data are presented as means (SD) or number. Statistically significant (P < 0.05),
Our study was first conducted to provide some evidence of n ¼ number of patients, Hypotension ¼ >20% decrease in systolic blood pressure,
possible benefit of ketorolac to provide some preemptive analgesia Bradycardia ¼ heart rate < 60 beats/min.
to reduce intraoperative shoulder pain during CS performed under
SA. To our surprise, we found that preemptive use of ketorolac Concerning our secondary outcomes, preemptive ketorolac also
significantly reduced the incidence of such annoying intraoperative significantly reduced the severity of intraoperative shoulder pain in
pain and also reduced unnecessary intervention and sufferings of those who suffered it. Zirak et al had studied shoulder pain in pa-
our patients. tients undergoing CS, and evaluated the incidence between spinal

Please cite this article in press as: Abbas MS, et al., Pre-emptive ketorolac for prevention of intraoperative shoulder pain in patients undergoing
cesarean section: A double blind randomized clinical trial, Asian Journal of Anesthesiology (2017), https://doi.org/10.1016/j.aja.2017.07.002
4 M.S. Abbas et al.

Fig. 2. Intraoperative shoulder Pain at first complaint shown as box plot. Comparison between ketorolac group (n ¼ 100) and control group (n ¼ 100) (P ¼ 0.012). Notes: The top
and bottom of the boxes indicate the upper and lower quartiles. Whiskers from the box indicate the most extreme value less than or equal to 1.5 interquartile ranges. Outliers
(individual values more than 1.5 interquartile ranges) are shown with stars or circles.

Table 3 phrenic nerve.9 This may be possible mechanism of that severe

Relationship between preemptive analgesia and severity of intraoperative shoulder intraoperative pain. Also peritoneal mopping, visceral manipula-
pain.
tion may paly a role.
Painless Mild Moderate Severe Single dose intravenous ketorolac is an effective adjunct in
pain pain pain multimodal analgesic regimen to reduce postoperative pain and
Ketorolac group (n) 92 4 3 1 opioid requirement, which results in reduction of pain, and opioid
Control group (n) 77 2 8 13 induced side effects.10 30 mg ketorolac given intramuscularly in
Total (n) 169 6 11 14
patients undergoing CS was found to have similar efficacy to
Data are presented as numbers. equivalent doses of opioids, but resulted in fewer adverse effects.11,12

and general anesthesia. They found that the prevalence of shoulder
pain in patients undergoing CS is a very common occurrence
(39.45%) and is more common in patients who received GA than
those who received SA.3 Kikuchi et al had investigated the incidence
of shoulder pain again in patients undergoing CS under combined
spinal-epidural anesthesia and showed that their patients very
frequently experience shoulder-tip pain. They also found that head-
up position during surgery decreases that pain during and after
cesarean delivery.2 But such position will hardly be feasible in CS
patients getting operated under SA as the block level will recede
with time.
The exact mechanism of that shoulder pain is still unknown.
Referred shoulder pain after laparoscopic surgeries is reported to
be between 20 and 25% and is found to result from diaphragmatic
or peritoneal irritation resulting from gas entrapment or perito-
neal stretching.6 Ardalan et al suggested that 5% of peritoneal
dialysis patients suffer left shoulder pain and it takes subsides in
3e4 weeks to subside.7 The fluid used in peritoneal dialysis usu-
ally induces diaphragmatic irritation and the pain is referred to
hand and shoulder through radial, axillary, median or muscu-
locutaneous nerve.8 In patients undergoing CS, retained blood
clots may cause diaphragmatic irritation and stimulate the
4.1. Limitations
There are indeed some limitations in our study.
 We did not evaluate the impact of single dose ketorolac on uterine
tone or neonatal outcome. Use of NSAIDs in the third trimester
may be associated with neonatal renal impairment in premature
infants.13 However, Walker et al, evaluated role of ketorolac and
pethidine in labor analgesia and found no adverse effect in mother
or fetus.4 Also in our study, we included only term babies.
 Also in regard to the significant bradycardia observed in patients
in ketorolac group we do not have any clear explanation. When
we searched literature we found that FDA has reported (Refer-
ence ID: 3281582) bradycardia as one of the occasional adverse
effects (<1%) in patients who take NSAIDs. Also, Foster et al, have
reported for two cases of bradycardia following the intra-
operative use of intravenous ketorolac and attributed it to rapid
intravenous injection.14 We recommend further randomized
controlled trials to assess this effect of ketorolac.
To date, no study has been conducted to selectively investigate
the efficacy of ketorolac to reduce intraoperative shoulder pain in

Please cite this article in press as: Abbas MS, et al., Pre-emptive ketorolac for prevention of intraoperative shoulder pain in patients undergoing
cesarean section: A double blind randomized clinical trial, Asian Journal of Anesthesiology (2017), https://doi.org/10.1016/j.aja.2017.07.002
Ketorolac for intraoperative shoulder tip pain in Cesarean section
patients undergoing CS under SA. Further studies are required to
revalidate our findings in respect to reduced incidence of this
annoying intraoperative pain and to assess the maternal and fetal
impact of a single perioperative dose of intravenous ketorolac.
5. Conclusion
We found that the prevalence of intraoperative shoulder pain in
patients undergoing cesarean section under spinal anesthesia was
31%, which is indeed very high and is being neglected till date. Mere
30 mg of intravenous ketorolac administered just before surgery
decreases incidence and severity of shoulder pain to a significant
instance. We thus highly recommend to study these aspects in
future larger powered randomized controlled trials.
Conflict of interest
The authors have no conflicts of interests to disclose.
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cesarean section: A double blind randomized clinical trial, Asian Journal of Anesthesiology (2017), https://doi.org/10.1016/j.aja.2017.07.002
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