Beneficial effects of adding ketamine to intravenous patient-controlled analgesia with fentanyl after the Nuss procedure in pediatric patients.

Abstract

The aim of this prospective, double-blind, randomized study was to investigate the analgesic effects of low-dose ketamine on intravenous patient-controlled analgesia (IV-PCA) with fentanyl for pain control in pediatric patients following the Nuss procedure for pectus excavatum.
Sixty pediatric patients undergoing the Nuss procedure were randomly assigned to receive fentanyl (Group F, n=30) or fentanyl plus ketamine (Group FK, n=30). Ten minutes before the end of surgery, following the loading dose of each solution, 0.5 μg/kg/hr of fentanyl or 0.5 μg/kg/hr of fentanyl plus 0.15 mg/kg/hr of ketamine was infused via an IV-PCA pump (basal rate, 1 mL/hr; bolus, 0.5 mL; lock out interval, 30 min). Fentanyl consumption, pain score, ketorolac use, nausea/vomiting, ondansetron use, pruritus, respiratory depression, hallucination, dreaming, and parent satisfaction with pain control were measured throughout the 48 hours following surgery.
The pain scores, ketorolac use, and fentanyl consumption of Group FK were significantly lower than in Group F (p<0.05). The incidence of nausea/vomiting and ondansetron use in Group FK was significantly lower than in Group F (p<0.05). There were no reports of respiratory depression, hallucination or dreaming. Parent satisfaction with pain control was similar between the two groups.
We concluded that low-dose ketamine added to IV-PCA with fentanyl after the Nuss procedure in pediatric patients can reduce pain scores, consumption of fentanyl, and incidence of nausea/vomiting without increasing side effects.

Full text

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Yonsei Med J http://www.eymj.org Volume 53 Number 2 March 2012
427
Original Article
http://dx.doi.org/10.3349/ymj.2012.53.2.427
pISSN: 0513-5796, eISSN: 1976-2437
Yonsei Med J 53(2):427-432, 2012
Beneficial Effects of Adding Ketamine to Intravenous Patient-
Controlled Analgesia with Fentanyl after the Nuss Procedure
in Pediatric Patients
Moon Ho Cha, Ji Hye Eom, Yoon Sook Lee, Woon Young Kim, Young Cheol Park,
Sam Hong Min, and Jae Hwan Kim
Department of Anesthesiology and Pain Medicine, Korea University College of Medicine, Seoul, Korea.
Received: March 30, 2011
Revised: May 17, 2011
Accepted: June 21, 2011
Corresponding author: Dr. Jae Hwan Kim,
Department of Anesthesiology and Pain
Medicine, Korea University College
of Medicine, 123 Jeokgeum-ro, Danwon-gu,
Ansan 425-707, Korea.
Tel: 82-31-412-5295, Fax: 82-31-412-5294
E-mail: anejhkim@korea.ac.kr
∙ The authors have no financial conflicts of
interest.
© Copyright:
Yonsei University College of Medicine 2012
This is an Open Access article distributed under the
terms of the Creative Commons Attribution Non-
Commercial License (http://creativecommons.org/
licenses/by-nc/3.0) which permits unrestricted non-
commercial use, distribution, and reproduction in any
medium, provided the original work is properly cited.
Purpose: The aim of this prospective, double-blind, randomized study was to in-
vestigate the analgesic effects of low-dose ketamine on intravenous patient-con-
trolled analgesia (IV-PCA) with fentanyl for pain control in pediatric patients fol-
lowing the Nuss procedure for pectus excavatum. Materials and Methods: Sixty
pediatric patients undergoing the Nuss procedure were randomly assigned to re-
ceive fentanyl (Group F, n=30) or fentanyl plus ketamine (Group FK, n=30). Ten
minutes before the end of surgery, following the loading dose of each solution, 0.5
μg/kg/hr of fentanyl or 0.5 μg/kg/hr of fentanyl plus 0.15 mg/kg/hr of ketamine
was infused via an IV-PCA pump (basal rate, 1 mL/hr; bolus, 0.5 mL; lock out in-
terval, 30 min). Fentanyl consumption, pain score, ketorolac use, nausea/vomiting,
ondansetron use, pruritus, respiratory depression, hallucination, dreaming, and par-
ent satisfaction with pain control were measured throughout the 48 hours follow-
ing surgery. Results: The pain scores, ketorolac use, and fentanyl consumption of
Group FK were significantly lower than in Group F (p<0.05). The incidence of
nausea/vomiting and ondansetron use in Group FK was significantly lower than in
Group F (p<0.05). There were no reports of respiratory depression, hallucination or
dreaming. Parent satisfaction with pain control was similar between the two groups.
Conclusion: We concluded that low-dose ketamine added to IV-PCA with fentanyl
after the Nuss procedure in pediatric patients can reduce pain scores, consumption
of fentanyl, and incidence of nausea/vomiting without increasing side effects.
Key Words: Fentanyl, funnel chest, ketamine, patient-controlled analgesia, pedi-
atrics
INTRODUCTION
Pectus excavatum is a congenital deformity in which the sternum and the inferior
costal cartilage area are depressed. Nuss, et al.1 described the Nuss procedure to
correct pectus excavatum using specially made metal rods fitted to the chest defor-
mity of the patient. Bending of the rod pushes against the depressed costa and ster-
num, thereby restoring the chest to its normal shape. The procedure has excellent

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428
Acemedical, Seoul, Korea) were excluded.
One hour prior to the induction of anesthesia, 0.1 mg/kg
of atropine was injected intramuscularly as premedication.
An IV line was introduced and a dextrose/saline solution
was infused at 4 mL/kg/hr during the operation. Anesthesia
was induced by 5 mg/kg of thiopental sodium and 0.6 mg/
kg of rocuronium. After the trachea was intubated, anesthe-
sia was maintained with 1.5 L/min of oxygen, 1.5 L/min of
nitrous oxide and 1.5-2.5 vol% of sevoflurane. Throughout
the operation, blood pressure, electrocardiogram, end-tidal
carbon dioxide concentration and pulse oximetry saturation
were routinely monitored.
Ten minutes before the end of surgery, a loading dose of
1 μg/kg of IV fentanyl or 1 μg/kg of IV fentanyl plus 0.3
mg/kg of IV ketamine was injected for respective each
group. Subsequently, 0.5 μg/kg/hr of fentanyl or 0.5 μg/kg/
hr of fentanyl plus 0.15 mg/kg/hr of ketamine was infused
via an IV-PCA pump with a basal rate of 1 mL/hr respec-
tively to each group. Drug concentrations were prepared for
each patient according to his/her body weight, totaling 1
mL of drug preparation comprising 0.5 μg/kg of fentanyl or
0.5 μg/kg of fentanyl plus 0.15 mg/kg of ketamine for each
group. When patients experienced pain, they or their guard-
ians pushed the demand button, and, thereafter, a 0.5 mL
drug bolus, comprising 0.25 μg/kg of fentanyl or 0.25 μg/
kg of fentanyl plus 0.075 mg/kg of ketamine for each re-
spective group, was injected. The frequency of bolus injec-
tion was limited to two times per one hour. The total vol-
ume of IV-PCA medication was determined to be 100 mL,
corresponding to 50 μg/kg of fentanyl or 50 μg/kg of fen-
tanyl plus 15 mg/kg of ketamine for each group, i.e. the
maximum dose over 48 hours. The intensity of pain was as-
sessed using a visual analogue scale (VAS) ranging from 0
(no pain) to 10 (worst imaginable pain). VAS and cumula-
tive fentanyl consumption were measured at 1, 6, 12, 24,
and 48 hours after the surgery. For patients who responded
with pain greater than 4 on the VAS, 0.5 mg/kg of IV ketor-
olac was administered and the administration was recorded.
A blinded anesthesiologist assessed and recorded the de-
velopment of side effects including nausea/vomiting, pruri-
tus, respiratory depression, hallucination, and dreaming at
1, 6, 12, 24, and 48 hours after surgery. Nausea was defined
as the subjective sensation of discomfort associated with
the awareness of the urge to vomit. Vomiting was defined as
a forceful expulsion of gastric contents through the mouth.
In cases of severe nausea/vomiting, or nausea/vomiting that
did not resolve, we administered 0.1 mg/kg of IV ondanse-
esthetic results and helps improve lung function. However,
the Nuss procedure can induce severe postsurgical pain due
to the expansion of the thorax. This pain can be controlled
with intravenous patient-controlled analgesia (IV-PCA) us-
ing opioids.2-4
Strong pain stimuli activate N-methyl-D-aspartate (NMDA)
receptors and produce hyperexcitability of dorsal root neu-
rons.5 This trigger induces central sensitization, the wind-up
phenomenon, and pain memory. An NMDA receptor antag-
onist can prevent the induction of central sensitization caused
by stimulation of peripheral nociception as well as by block-
ing the wind-up phenomenon.5 When used in a large dose
for a prolonged period as well as at the very early stage of
therapy, opioids can induce hyperalgesia and tolerance,
which may lead to increased postoperative pain.6,7 Increased
postoperative pain, in turn, leads to the need for higher dos-
es of opioids. Ketamine, by blocking NMDA receptors, can
prevent the development of central sensitization and opioid
resistance.5,7 Therein is the basis for using ketamine as an
adjuvant to opioids in postoperative pain control.
However, clinical trials of ketamine added to IV-PCA with
opioids in postoperative pain control have demonstrated con-
tradictory results.8-11 The effects of ketamine combined with
fentanyl in IV-PCA for postoperative pain control for the
Nuss procedure have not been examined. Therefore, we in-
vestigated the analgesic effects of low-dose ketamine on IV-
PCA with fentanyl for pain control following the Nuss proce-
dure for pectus excavatum repair in pediatric patients.
MATERIALS AND METHODS
　　　
This prospective, double-blind randomized study was ap-
proved by the Institutional Review Board. Written informed
consent for the study was obtained from the parents of all
children enrolled in the study. Sixty children, American So-
ciety of Anesthesiologists physical status I or II, aged 6-16
years, who underwent the Nuss procedure for repair of pec-
tus excavatum were enrolled in this study. The patients were
divided randomly into two groups. Group F was given fen-
tanyl only, and Group FK was given fentanyl plus ketamine.
The equipment and procedure were explained in detail. Pa-
tients with congenital heart disease, lung parenchymal dis-
ease, gastrointestinal disease, psychiatric disease, skin dis-
ease, a history of motion sickness or postoperative nausea/
vomiting, drug contraindications, or who were unable to un-
derstand how to use the IV-PCA device (AutoMed 3200,

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as mean±SD or as the number of patients (%). Statistical
analyses were performed using the statistical software pack-
age SPSS version 12 for Windows (SPSS Inc., Chicago, IL,
USA). For numerical variables, independent t-tests were
employed to compare inter-group differences and chi-square
or Fisher’s exact tests were adopted for categorical vari-
ables. Differences were regarded as statistically significant
when the p value was less than 0.05.

RESULTS

Sixty five patients were assessed for eligibility. Three pa-
tients were not included in the study due to being younger
than 6 years of age. Two patients were excluded due to his-
tory of motion sickness. In total, sixty patients were enrolled
for the study. Thirty patients were randomly allocated to
each group (Fig. 1). Gender, age, weight, and duration of an-
esthesia were not significantly different between the two
groups (Table 1).
The VAS pain scores of Group FK were significantly
lower than those of Group F at 6, 24, and 48 hours after sur-
gery (p<0.05) (Table 2). There were 7 (23%) patients who re-
quired additional analgesic, ketorolac, during the 48 hours
after surgery, in Group FK, significantly lower than the 18
patients (53%) in Group F (p<0.01).
The cumulative fentanyl consumption was significantly
reduced in Group FK compared to Group F, at 24 and 48
hours after surgery (p<0.05) (Table 3).
tron. Pruritus was defined as the subjective sensation of
itching without skin lesions and was treated with 0.1 mg/kg
of IV chlorophenyramine or 1 μg/kg of IV naloxone, in se-
vere cases only. Respiratory depression was defined as pulse
oximetry saturation levels less than 90% at room air or a
respiration rate less than 10/min. Respiratory depression, if
present, was managed with oxygen insufflation via nasal
cannula at 5 L/min. When respiratory depression was not
corrected by oxygen insufflations, 1 μg/kg of IV naloxone
was administered. If the respiratory depression was still not
corrected by these measures, the IV-PCA infusion rate was
to be reduced by 50% every hour, until it was resolved. Res-
piration rate and pulse oximetry saturation were to be moni-
tored throughout these measures until the respiratory depres-
sion was resolved. Hallucination and dreaming were defined
as any sensation that was not caused by an external event,
and if present, the IV-PCA infusion rate would be reduced
by 50% every hour, until symptoms were resolved. Overall
parent satisfaction with pain control was determined at 48
hours after surgery as either satisfactory or unsatisfactory.
Michelet, et al.9 hypothesized a 25% reduction in mor-
phine consumption with an expected standard deviation of
30% in a calculated sample size of 24 subjects per group,
detecting a difference with a power of 0.80 and a 5% risk of
type I error. Based on their study,9 we expected that fentan-
yl plus ketamine IV-PCA could reduce fentanyl consump-
tion by 25% in a sample size of 24 patients per group with
the same statistical power. We planned to enroll enough pa-
tients to obtain 30 patients per group. Values were expressed
Fig. 1. Flow diagram of the progress through the trial. Group F, fentanyl
group; Group FK, fentanyl plus ketamine group.
Table 1. Patient Characteristics

Group F
(n=30)
23/7
10.2±2.9
34.4±9.2
106.0±13.9
Group FK
(n=30)
25/5
9.9±2.7
31.2±8.9
110.2±16.8
Sex (M/F)
Age (yrs)
Weight (kg)
Duration of anesthesia (min)
Group F, fentanyl group; Group FK, fentanyl plus ketamine group.
Values are mean±SD or number of patients.
Table 2. Postoperative Pain Scores Using the Visual Ana-
logue Scale (VAS)
Time after surgeryGroup F (n=30)
1 hr3.3±0.7
6 hrs2.9±0.7
12 hrs2.5±0.7
24 hrs1.9±0.5
48 hrs1.6±0.6
Group F, fentanyl group; Group FK, fentanyl plus ketamine group.
Values are mean±SD.
*p<0.05 versus Group F.
Group FK (n=30)
3.1±0.7
2.5±0.6*
2.2±0.6
1.4±0.5*
1.0±0.5*
Assessed for eligibility
(n=65)
Enrollment, randomization
(n=60)
Allocated to Group F
(n=30)
Allocated to Group FK
(n=30)
Received allocated
intervention (n=30)
Received allocated
intervention (n=30)
Follow up (n=30)Follow up (n=30)
Analysis (n=30) Analysis (n=30)
Excluded (n=5)
-Not meeting inclusion criteria (n=3)
-Meeting exclusion criteria (n=2)

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430
yl in IV-PCA, which has been shown to be effective for pain
control with fewer side effects after the Nuss procedure in
pediatric patients.3
Ketamine has analgesic properties in subanesthetic dos-
es.5,7 Small doses of ketamine act specifically to prevent
opioid tolerance and pain sensitization.7 Low-dose ket-
amine is defined as a single injection of less than 1 mg/kg
or continuous infusion of less than 20 μg/kg/min.12 The in-
cidence of psychomimetic effects and cognitive impairment
is negligible at doses less than 2.5 μg/kg/min and increases
with higher doses of ketamine.12 It has been reported that a
2.5 μg/kg/min infusion of ketamine on IV-PCA can de-
crease morphine consumption and the incidence of nau-
sea.13 Therefore, we decided to test a basal infusion rate of
ketamine at 2.5 μg/kg/min (=0.15 mg/kg/hr).
In review, Subramaniam, et al.14 concluded that a small
dose of ketamine is a safe and useful adjuvant to standard
IV or epidural opioid-analgesia, however, adding ketamine
to IV-PCA with morphine showed no beneficial effect in
postoperative pain control. Subsequently, conflicting results
exist concerning the potential benefits of adding ketamine
to opioids in IV-PCA for postoperative pain control.8-20 The
results can be categorized by several types of surgery.
For thoracic surgery, Nesher, et al.8,15 studied patients un-
dergoing thoracotomy and reported that a bolus of 5 mg of
ketamine plus 1 mg of morphine IV-PCA (lockout 7 min)
resulted in a reduction in pain score and a 45-50% reduc-
tion in morphine consumption with cardiovascular stability
and better respiratory parameters. Michelet, et al.9 studied
patients undergoing thoracic surgery and reported that add-
ing ketamine 1 mg/mL to morphine 1 mg/mL IV-PCA (a
bolus of 0.015 mL/kg per every 10 min) resulted in reduc-
tions in morphine consumption and pain score and a reduc-
tion in nocturnal desaturation.
The benefit of adding ketamine to morphine in IV-PCA
for orthopedic surgery remains unclear. Javery, et al.16 stud-
ied patients undergoing lumbar microdiscectomy and re-
ported that ketamine 1 mg/mL added to morphine 1 mg/mL
IV-PCA (bolus 1 mL, lockout 6 min) reduced pain scores
and halved morphine consumption. Kollender, et al.17 stud-
ied patients undergoing orthopedic-oncological surgery and
found that a bolus of 5 mg ketamine plus 1 mg morphine
IV-PCA (lockout 7 min) resulted in a 60% reduction in
morphine consumption and reductions in pain score and ad-
ditional analgesic use. However, Sveticic, et al.10 studied
patients undergoing major orthopedic surgery and reported
that a bolus of 1.5 mg ketamine plus 1.5 mg morphine in
The incidence of nausea/vomiting was 23% in Group
FK, significantly lower than 53% in Group F (p<0.05) (Ta-
ble 4). The number of patients who required the antiemetic,
ondansetron, during the 48 hours after surgery was 3 (10%)
in Group FK, significantly lower than 11 patients (37%) in
Group F (p<0.05). The degree of pruritus was not severe,
and the incidence of pruritus was not different between the
two groups (Table 4). There were no reports of respiratory
depression, hallucination, or dreaming in either group (Ta-
ble 4). No patients required administration of naloxone or
chlorophenyramine. The number of parents satisfied with
pain control was 25 (83%) in Group F and 28 (93%) in Group
FK, and the difference was not significant.
DISCUSSION
In our study, administration of IV-PCA with fentanyl plus
low-dose ketamine resulted in reductions of the fentanyl
consumption and pain scores as well as a decrease in nau-
sea/vomiting over fentanyl alone.
Opioids in IV-PCA are used widely in the management of
severe postoperative pain after the Nuss procedure.2-4 Control
of severe pain requires more opioids. However, higher doses
of opioids are associated with significant side effects in-
cluding respiratory depression, nausea/vomiting, sedation,
constipation, urinary retention, as well as acute tolerance. In
our study, we infused a basal rate of 0.5 μg/kg/hr of fentan-
Table 3. Cumulative Fentanyl Consumption (μg) after the
Surgery
Time after surgeryGroup F (n=30)
1 hr 31.2±9.6
6 hrs158.8±43.6
12 hrs306.6±87.9
24 hrs565.4±153.6
48 hrs 1138.9±304.2
Group F, fentanyl group; Group FK, fentanyl plus ketamine group.
Values are mean±SD.
*p<0.05 versus Group F.
Group FK (n=30)
27.5±8.1
140.1±38.3
264.3±78.8
481.7±141.3*
886.0±253.6*
Table 4. Incidence of Side Effects
Group F (n=30)
16 (53)
4 (13)
0 (0)
0 (0)
0 (0)
Group FK (n=30)
7 (23)*
2 (7)
0 (0)
0 (0)
0 (0)
Nausea/Vomiting
Pruritus
Respiratory depression
Hallucination
Dreaming
Group F, fentanyl group; Group FK, fentanyl plus ketamine group.
Values are number of patients (%).
*p<0.05 versus Group F.

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431
amine, could induce nausea/vomiting. In our study, 2.5 μg/
kg/min of ketamine, was low enough to avoid emetic ef-
fects. The incidence of patients who used the antiemetic,
ondansetron, during the 48 hours after surgery was 10% in
the fentanyl plus ketamine group and was lower than 37%
in the fentanyl group.
Pruritus is a common side effect of opioid administration,
however, the incidence and severity is lower in the IV route
than in the epidural or intrathecal route.22 The incidence of
pruritus is 0-10% when fentanyl IV-PCA is used after the
Nuss procedure.2,3 In our study, the incidence of pruritus
was 13% in the fentanyl group and 7% in the fentanyl plus
ketamine group. Although, the incidence was almost two
times higher in the fentanyl group than in the fentanyl plus
ketamine group, the incidences of both groups were too
low to differentiate with statistical significance in either
group. There were no instances of severe pruritus which re-
quired treatment in both groups.
Thoracic surgery can lead to respiratory depression due
to severe pain, inhibiting thoracic expansion while breath-
ing. Adequate analgesia to reduce postoperative pain en-
hances the ability to breathe deeply and cough effectively,
alleviating respiratory depression.23 However, opioids in
large doses can worsen respiration rates, oxygenation, and
ventilation. Therefore, a reasonable amount of opioids and
adjuvant to opioids are important to pain control as well as
respiration. High doses of ketamine can have respiratory
depressive effects, but respiratory depression associated
with small doses of ketamine is minimal.8,9,15,21 Ketamine
also sustains the patency of small and large airways, thus
preventing obstruction, including the kind that can occur in
patients under the effect of opioids. In our study, the infu-
sion rates of 0.5 μg/kg/hr of fentanyl and 0.15 mg/kg/hr of
ketamine were low enough to avoid respiratory depression.
These features lead to better respiration and a probable
preservation of more than 90% of pulse oximetry saturation
during the postoperative period.
Ketamine is associated with a risk of psychomimetic ef-
fects, including hallucination, vivid dreaming, sedation, and
dizziness. However, the safety of adding low-dose ketamine
to morphine for postoperative IV-PCA regarding its psy-
chomimetic effects is well established.8,13,15,17,18 Badrinath,
et al.21 investigated the dose-dependent effects of ketamine
and reported that a dose of 24 μg/kg/min can increase psy-
chomimetic effects. Edwards, et al.24 used a dose-finding
approach to study the combination of morphine and ket-
amine in IV-PCA for postoperative pain in elderly patients
IV-PCA (lockout 8 min) failed to demonstrate beneficial ef-
fects in morphine consumption and pain control.
The benefit of adding ketamine to morphine in IV-PCA
for abdominal surgery also remains unclear. Adriaenssens,
et al.13 studied patients undergoing abdominal surgery and
reported that continuous infusion of ketamine 2.5 μg/kg/
min with morphine IV-PVA (loading dose 3 mg, bolus 1
mg, lockout 8 min) reduced pain score and morphine con-
sumption. Unlügenç, et al.18 studied patients after major ab-
dominal surgery and found that ketamine 1 mg/mL added
to tramadol 5 mg/mL IV-PCA (loading dose 1 mg/kg, bolus
0.2 mg/kg, lockout 20 min, background infusion 0.4 mg/
kg/h) improved analgesia and reduced tramadol consump-
tion. However, investigating patients undergoing total ab-
dominal hysterectomy, Murdoch, et al.19 did not find any
benefit of adding ketamine 0.75 mg/mL to morphine 1 mg/
mL IV-PCA (10 mL/m2 body surface area of loading dose,
bolus 1 mL, lockout 5 min, background infusion 1 mL/h).
Reeves, et al.20 found no pain-reducing or morphine-spar-
ing benefits of ketamine bolus 1 mg/mL plus morphine 1
mg/mL IV-PCA (bolus, lockout, and background infusions
were determined by the anesthesiologists) in patients after
major abdominal surgery.
In our study, adding ketamine to fentanyl IV-PCA reduced
the cumulative fentanyl consumption by approximately
22%, reduced pain scores, and reduced additional analgesic
use, with parent satisfaction in pain control. Although these
reduction levels were different, the results appear to be in
agreement with prior studies.8,9,13,15-18 We conclude that there
is a benefit to adding ketamine to opioids for IV-PCA for
thoracic surgery.8,9,15 However, controversies remain regard-
ing the benefits of adding ketamine to opioids for IV-PCA
for abdominal and orthopedic surgery.10-14,16-20 These contra-
dictory results may reflect differences in the methodology of
each study, degree of postoperative pain, nature of surgical
procedure, and nature and source of postoperative pain.
There is a significant incidence of nausea/vomiting when
fentanyl IV-PCA is used postoperatively after the Nuss pro-
cedure, observed in 30-50% pediatric patients.2-4 In our study,
the incidence of nausea/vomiting was 53% in the fentanyl
group and 23% in the fentanyl plus ketamine group. Our
results agree with prior studies that adding ketamine to
morphine IV-PCA reduces the incidence of nausea/vomit-
ing.13,15-17 However, nausea/vomiting can be induced by ket-
amine itself in a dose dependent pattern. Badrinath, et al.21
investigated the dose-dependent effects of ketamine during
propofol sedation and reported that 24 μg/kg/min of ket-