Download The Effect of Intraoperative Dexmedetomidine on Postoperative

Pediatric Anesthesiology
Section Editor: Peter J. Davis
The Effect of Intraoperative Dexmedetomidine
on Postoperative Analgesia and Sedation in
Pediatric Patients Undergoing Tonsillectomy
and Adenoidectomy
Olutoyin A. Olutoye, MD,*† Chris D. Glover, MD,*† John W. Diefenderfer, BS,†
Michael McGilberry, RN,† Matthew M. Wyatt, MD,† Deidre R. Larrier, MD,*‡
Ellen M. Friedman, MD,*‡ and Mehernoor F. Watcha, MD*†
BACKGROUND: The immediate postoperative period after tonsillectomy and adenoidectomy,
one of the most common pediatric surgical procedures, is often difficult. These children
frequently have severe pain but postoperative airway edema along with increased sensitivity to
the respiratory-depressant effects of opioids may result in obstructive symptoms and hypoxemia.
Opioid consumption may be reduced by nonsteroidal antiinflammatory drugs, but these drugs
may be associated with increased bleeding after this operation. Dexmedetomidine has mild
analgesic properties, causes sedation without respiratory depression, and does not have an
effect on coagulation. We designed a prospective, double-blind, randomized controlled study to
determine the effects of intraoperative dexmedetomidine on postoperative recovery including pain,
sedation, and hemodynamics in pediatric patients undergoing tonsillectomy and adenoidectomy.
METHODS: One hundred nine patients were randomized to receive a single intraoperative dose
of dexmedetomidine 0.75 ␮g/kg, dexmedetomidine 1 ␮g/kg, morphine 50 ␮g/kg, or morphine
100 ␮g/kg over 10 minutes after endotracheal intubation.
RESULTS: There were no significant differences among the 4 groups in patient demographics,
ASA physical status, postoperative opioid requirements, sedation scores, duration of oxygen
supplementation in the postanesthetic care unit, and time to discharge readiness. The median
time to first postoperative rescue analgesic was similar in patients receiving dexmedetomidine
1 ␮g/kg and morphine 100 ␮g/kg, but significantly longer compared with patients receiving
dexmedetomidine 0.75 ␮g/kg or morphine 50 ␮g/kg (P ⬍ 0.01). In addition, the number of
patients requiring ⬎1 rescue analgesic dose was significantly higher in the dexmedetomidine
0.75 ␮g/kg group compared with the dexmedetomidine 1 ␮g/kg and morphine 100 ␮g/kg
groups, but not the morphine 50 ␮g/kg group. Patients receiving dexmedetomidine had significantly
slower heart rates in the first 30 minutes after surgery compared with those receiving morphine (P ⬍
0.05). There was no significant difference in sedation scores among the groups.
CONCLUSIONS: The total postoperative rescue opioid requirements were similar in tonsillectomy
patients receiving intraoperative dexmedetomidine or morphine. However, the use of dexmedetomidine 1 ␮g/kg and morphine 100 ␮g/kg had the advantages of an increased time to first
analgesic and a reduced need for additional rescue analgesia doses, without increasing
discharge times. (Anesth Analg 2010;111:490 –5)
D
exmedetomidine, a selective ␣-2 agonist with anxiolytic, sedative, and analgesic properties, has been
shown to decrease postoperative analgesic or opioid consumption in adults.1–5 This drug has been used in
children undergoing postoperative mechanical ventilation,
cardiac catheterization, magnetic resonance imaging (MRI),
endoscopic, and other minor procedures.6,7 However, its
From the Departments of *Pediatrics, †Anesthesia, and ‡Otolaryngology,
Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas.
Accepted for publication March 31, 2010.
Supported by intramural departmental sources.
Disclosure: The authors report no conflicts of interest.
Address correspondence and reprint requests to Olutoyin A. Olutoye, MD,
Texas Children’s Hospital, 6621 Fannin St., Suite A-300, MC 2-1495, Houston, TX 77030. Address e-mail to [email protected].
Copyright © 2010 International Anesthesia Research Society
DOI: 10.1213/ANE.0b013e3181e33429
490
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usefulness as an analgesic in the pediatric population has
not yet been well established. Tonsillectomy and adenoidectomy, one of the most common surgical procedures in
this patient population, is usually indicated for the management of recurrent pharyngotonsillitis and obstructive
sleep apnea. The immediate postoperative period after
tonsillectomy and adenoidectomy is often difficult because
these children frequently have severe pain, but edema of
the operative site may result in transient worsening of
obstructive symptoms and hypoxemia. In addition, children with obstructive sleep apnea are particularly sensitive
to the respiratory-depressant effects of perioperative opioids such as morphine.8,9 Nonsteroidal antiinflammatory
drugs reduce opioid consumption but may be associated
with increased bleeding after this operation.10 Dexmedetomidine has mild analgesic properties, causes sedation without respiratory depression, and does not have an effect on
August 2010 • Volume 111 • Number 2
coagulation. It has sympatholytic effects that can result in
decreased arterial blood pressure and heart rate, which
may be of concern in anesthetized children with a ratedependent cardiac output.7,11 This study was designed to
determine the effects of intraoperative dexmedetomidine
on postoperative recovery including pain, sedation, and
hemodynamics in pediatric patients undergoing tonsillectomy and adenoidectomy.
METHODS
This prospective, randomized, double-blind study was
conducted in 109 pediatric patients undergoing tonsillectomy and adenoidectomy, after receiving approval from
both the Baylor College of Medicine IRB and the Food and
Drug Administration (investigational new drug, IND#
79,290). In addition, we obtained written informed consent
from the legal guardian and, when appropriate, assent
from the child older than 7 years. Children between the
ages of 3 and 12 years with ASA classification of I or II were
eligible for inclusion in the study. Exclusion criteria were a
body mass index more than the 95th percentile for age, ASA
classification III or more, and the presence of confirmed severe
obstructive sleep apnea by a polysomnograph test. Patients
with a history of snoring or sleep-disordered breathing, but
without a polysomnogram test, were included.
After consent was obtained, children were randomized
to 1 of 4 groups based on a computer-generated random
number to receive a single IV dose of (a) dexmedetomidine
0.75 ␮g/kg, (b) dexmedetomidine 1 ␮g/kg, (c) morphine 50
␮g/kg, or (d) morphine 100 ␮g/kg intraoperatively. Doses
of dexmedetomidine were chosen to exceed those from a
previous pilot study in which patients who received
dexmedetomidine 0.5 ␮g/kg IV intraoperatively during
tonsillectomy and adenoidectomy did not demonstrate a
decrease in postoperative rescue analgesic requirements
compared with morphine 50 ␮g/kg.12
After a preoperative fasting period of a minimum of 6
hours, all patients received a standardized anesthetic regimen that included premedication with oral midazolam 0.5
mg/kg (maximum of 10 mg), and induction with sevoflurane and nitrous oxide in oxygen via facemask. Endotracheal intubation was facilitated with 0.5 mg/kg atracurium.
The study drug was administered over a 10-minute period
immediately after endotracheal intubation. Anesthesia was
maintained with sevoflurane and nitrous oxide in oxygen,
adjusted to maintain heart rate and arterial blood pressure
within 20% of preinduction levels. No additional opioid,
acetaminophen, or propofol was used during the procedure. Intraoperative dexamethasone 0.5 mg/kg (maximum
dose of 20 mg), IV antibiotics, and ondansetron 0.15 mg/kg
(maximum of 4 mg) were administered per routine intraoperative management of tonsillectomy and adenoidectomy patients at our institution. All patients received a
lactated Ringer solution infusion for fluid maintenance and
deficit replacement. Replacement of calculated fluid deficit
was commenced in the operating room and completed in
the postanesthetic care unit (PACU). Neuromuscular blockade was antagonized with neostigmine 0.07 mg/kg and
glycopyrrolate 0.01 mg/kg at the end of the operation and
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anesthetic gases were discontinued. The trachea was extubated when patients were awake as defined by eye opening, purposeful movement, or response to command. The
child was then transported to the PACU with supplemental
oxygen. Oxygen administration was continued after extubation until the patient was awake and could sustain room
air saturations ⬎95% for 5 minutes. Duration of oxygen
requirement was recorded as the time from tracheal extubation to cessation of oxygen supplementation in the
PACU.
Data for each individual patient were obtained by 1 of 2
observers who were blinded to patient assignment. Routine
vital signs, Ramsay sedation score,13 and Children’s Hospital of Eastern Ontario Pain Scale14 score were measured
and recorded on arrival in the PACU at 5, 10, and 15
minutes, and then every 15 minutes until the child was
discharged. Patients with a Children’s Hospital of Eastern
Ontario Pain Scale score ⬎8 received morphine 25 ␮g/kg IV
at 10-minute intervals until the score was ⬍8. Patients in the
PACU who were crying, restless, disoriented, unresponsive to
the parent’s voice, with nonpurposeful thrashing movements
requiring additional personnel to prevent bodily harm, and
inconsolable even after parental presence, rescue analgesia
and additional measures of comfort were considered to have
emergence agitation.15,16 Patients were considered ready for
discharge from the PACU when they attained an Aldrete
score17 of 9 or more and were free from pain, nausea, and
vomiting. The duration of surgery and anesthesia, time to first
postoperative rescue analgesic, amount of rescue analgesic
received, need for antiemetics, and total duration of PACU
stay were also recorded.
Statistical Analysis
The primary outcome measure was the amount of postoperative rescue morphine required for analgesia during the
patient’s stay in the PACU. Secondary outcome measures
were the time to first analgesic rescue, the number of
patients who needed more than 1 analgesic rescue dose, the
degree of sedation as determined by the Ramsay sedation
score, oxygen requirement, heart rate, respiratory rate, time
to discharge readiness, along with the incidence of emergence agitation and postoperative nausea and vomiting.
Sample size calculation was based on the following
assumptions. (1) The primary end point was the amount of
morphine required in the PACU. (2) In a previous pilot
study, there were no differences noted in postoperative
rescue morphine administered to patients receiving
dexmedetomidine 0.5␮g/kg or morphine 50 ␮g/kg.12 We
therefore assumed the rescue analgesic requirements in the
morphine 50 ␮g/kg group in the current study would be
similar to those in the dexmedetomidine 0.5 ␮g/kg group
in the pilot study (rescue analgesic requirement: 46.75 ⫾ 25
␮g/kg morphine). (3) We assumed that the rescue analgesic
requirements in the group receiving dexmedetomidine 1
␮g/kg would be 50% less than in the morphine 50 ␮g/kg
group. This was based on the adult study by Arain et al.,1
which showed a 66% reduction in postoperative opioid
consumption in patients who had received this dose of
dexmedetomidine compared with a group receiving morphine 80 ␮g/kg. We thought it would be reasonable to base
our power analysis on a more conservative estimate of a
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Dexmedetomidine in Pediatric Tonsillectomy and Adenoidectomy
Table 1. Demographic Data and Recovery Data in the Four Study Groups
No. of patients
Age (y)
Male/female
Duration of surgery (mean ⫾ SD) (min)
Duration of anesthesia (mean ⫾ SD) (min)
Rescue morphine (␮g/kg) (mean ⫾ SD)
Morphine rescue doses (n)
0 dose
1 dose
⬎1 dose
Mean duration of oxygen supplementation (min ⫾ SD)
Mean time to discharge readiness (min ⫾ SD)
Emergence agitation, n (%)
Nausea, n (%)
Vomiting, n (%)
Dexmedetomidine
(0.75 ␮g/kg)
26
6.3
8/18
22.0 ⫾ 8.4
48.0 ⫾ 19.3
45.2 ⫾ 30.8
Dexmedetomidine
(1 ␮g/kg)
27
6.6
11/16
21.3 ⫾ 9.7
44.7 ⫾ 10.8
37.0 ⫾ 25.4
Morphine
(50 ␮g/kg)
30
6.3
15/15
22.8 ⫾ 7.6
43.3 ⫾ 9.7
43.3 ⫾ 23.6
Morphine
(100 ␮g/kg)
26
6.3
10/16
25.9 ⫾ 9.5
49.5 ⫾ 13.3
36.5 ⫾ 31.0
6
2
18
17 ⫾ 11
115 ⫾ 0.04
5 (19)
2 (8)
0
3
14
10*
19 ⫾ 12
116 ⫾ 0.03
4 (15)
0
0
1
13
16
20 ⫾ 19
117 ⫾ 0.03
4 (13)
0
0
4
14
8*
18 ⫾ 14
122 ⫾ 0.06
1 (4)
3 (11.5)
2 (8)
All 4 groups were similar in patient demographics, operative timeline, and postoperative course.
* P ⬍ 0.05 versus dexmedetomidine 0.75 ␮g/kg.
50% reduction in opioid use compared with a group
receiving a smaller intraoperative dose of morphine (50
␮g/kg) than in the study by Arain et al. Based on these
assumptions, we calculated that a sample size of 26 would
have an 80% power of detecting a difference at a 0.05 level
of significance.
Data are presented as mean ⫾ SD, numbers, and percentages. The postoperative opioid requirement, time to
first analgesic rescue dose, and time to discharge readiness
were compared using parametric 1-way analysis of variance (ANOVA) or the nonparametric Kruskal-Wallis test,
after testing for normal distribution and equal variance.
The numbers of patients who required more than 1 rescue
analgesic dose in the PACU were compared by a ␹2 test.
The Ramsay sedation scores and heart rate over time were
compared among groups using the 2-way repeatedmeasures ANOVA. When indicated by a significant F
statistic (ANOVA) or H statistic (Kruskal-Wallis) ⬍0.05,
specific significant differences were isolated using the
Holm-Sidak and Dunn’s methods, respectively. P values
⬍0.05 were considered statistically significant.
RESULTS
One hundred ninety-four patients who qualified for the
study were approached and 109 consented to participate,
and 85 refused. The 109 patients were randomized after
obtaining consent, and all were included in the analysis. All
procedures were performed by 1 of 4 otolaryngologic
surgeons with an even distribution of cases among the 4.
There were no differences among the groups of patients
with regard to age, gender, duration of surgery and anesthesia, the time to tracheal extubation, duration of oxygen
supplementation in the PACU, and time to discharge
readiness (Table 1).
There were no significant differences in the mean
amount of supplemental rescue opioid required among the
4 groups (Table 1). However, the median time to first
postoperative rescue analgesic was significantly longer in
the dexmedetomidine 1 ␮g/kg and morphine 100 ␮g/kg
groups compared with the dexmedetomidine 0.75 ␮g/kg
and morphine 50 ␮g/kg groups (P ⬍ 0.01) (Fig. 1). In
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Figure 1. Kaplan-Meier curves for median time to first rescue opioid
administration. Horizontal line indicates time at which 50% of
patients in each medication group received the first postoperative
dose of morphine. Dex ⫽ dexmedetomidine.
addition, the number of patients requiring ⬎1 rescue
analgesic dose was significantly higher in the dexmedetomidine 0.75 ␮g/kg group compared with the dexmedetomidine 1 ␮g/kg (␹2 ⫽ 4.293, P ⫽ 0.03) and morphine 100
␮g/kg (␹2 ⫽ 6.231, P ⫽ 0.013) groups, but not the morphine
50 ␮g/kg group (␹2 ⫽ 0.885, P ⫽ 0.347).
There were no significant differences in the postoperative respiratory rate, oxygen saturation, or duration of
supplemental oxygen therapy among the 4 groups. Eightyfive percent of the enrolled patients had at least 2 of 3
symptoms of obstruction: gasps while sleeping, snoring,
and mouth breathing. None of these children exhibited
signs of airway obstruction, prolonged oxygen requirement, or required unanticipated hospital admission after
surgery.
There were no differences in the preoperative heart rate
among the groups, but 2-way repeated-measures ANOVA
revealed a significantly slower postoperative heart rate in
patients who received dexmedetomidine compared with
patients who received morphine (Fig. 2). These differences
were statistically significant at 5, 10, 15, and 30 minutes
after arrival in the PACU.
The Ramsay sedation score in the PACU decreased over
time in all 4 groups, but there were no significant intergroup differences in sedation in the PACU over time using
2-way repeated-measures ANOVA (Fig. 3). By 60 minutes
ANESTHESIA & ANALGESIA
Figure 2. Postoperative heart rate over time. Chart
depicting postoperative heart rate compared with
preoperative values. Patients receiving dexmedetomidine (Dex) had significantly slower heart rates
compared with those who received morphine.
Those who received morphine 50 or 100 ␮g/kg had
significantly increased heart rate in the first 15
minutes in the recovery room compared with preoperative values. 0 min ⫽ arrival in the recovery room;
preoperative (pre-op) ⫽ baseline values. #P ⫽
0.002 dexmedetomidine 0.75 ␮g/kg versus both
morphine 100 and 50 ␮g/kg. ¶P ⫽ 0.002 dexmedetomidine 1 ␮g/kg versus both morphine 100 and
50 ␮g/kg. *P ⬍ 0.001 morphine 50 and 100
␮g/kg versus preoperative heart rate. §P ⬍ 0.001
versus preoperative heart rate.
Figure 3. Ramsey sedation scores over time in
the postanesthesia care unit (PACU). Sedation
scores decreased over time in all groups. Dex ⫽
dexmedetomidine.
in the PACU, patients in all 4 groups had a mean Ramsay
score ⬍4. There were also no differences among the 4
groups in the incidence of emergence agitation.
There were no unanticipated hospital admissions for
analgesia, airway management, prolonged supplemental
oxygen requirement, or emesis management and no patient
required readmission for recurrent tonsillar bed bleeding.
Of the 109 patients, 5 had nausea and 2 of these had
associated emesis in the PACU, but no patient required
admission for this complication.
DISCUSSION
This study was designed to determine the postoperative
rescue opioid requirement among tonsillectomy and adenoidectomy patients receiving 2 different doses of dexmedetomidine (0.75 or 1 ␮g/kg) and 2 different doses of
morphine (50 or 100 ␮g/kg). Our primary result demonstrated that there were no significant differences in
postoperative morphine requirements among the 4 different treatment groups. We did demonstrate differences
in 2 secondary outcomes: time to first analgesia, and
number of children requiring ⬎1 dose of morphine in the
PACU. The time to first analgesia was longer and the
number of children who required ⬎1 dose of morphine in
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the PACU were decreased in the dexmedetomidine 1.0
␮g/kg and morphine 100 ␮g/kg groups compared with the
other groups (dexmedetomidine 0.75 ␮g/kg and morphine
50 ␮g/kg).
Dexmedetomidine is a potent ␣-2 agonist with an affinity for ␣ receptors that is 8 times greater than that of
clonidine. The primary analgesic effect of dexmedetomidine is mediated via activation of the ␣-2 receptors on the
dorsal horn of the spinal cord and also by inhibition of
substance P.18 Adult studies have shown that intraoperative use of dexmedetomidine decreases postoperative opioid consumption.1,19 However, this reduction in opioid
requirement has been recently shown in only 1 pediatric
study in which IV dexmedetomidine was used.20 Reduction in opioid requirement was also noted in 2 studies in
which dexmedetomidine was administered in children as a
caudal analgesic.21,22 The failure to show a statistically
significant difference in the primary outcome in our study
is related to the fact that the differences in opioid rescue
requirements among the high-dose and low-dose dexmedetomidine and morphine groups was 17%, suggesting that
the effect size was much lower than that assumed in the
sample size calculation. Post hoc sample size calculations
show that ⬎200 patients per group would be required to
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Dexmedetomidine in Pediatric Tonsillectomy and Adenoidectomy
show a statistically significant difference between dexmedetomidine 1 ␮g/kg and morphine 50 ␮g/kg. The difference in effect size noted in our study may be related to
differences in patient population (pediatric versus adult)
and/or surgical procedure (adenotonsillectomy versus major inpatient surgery).
Based on the small differences among the postoperative
rescue opioid requirements for dexmedetomidine 0.5
␮g/kg used in the pilot study, and dexmedetomidine 0.75
and 1 ␮g/kg used in this study, there may not be a dose
response for dexmedetomidine and postoperative analgesic
requirements. We did not obtain time-related pain scores or
data on oral opioid use after discharge. Therefore, we
cannot comment on the possibility that there was a doserelated residual analgesic effect of the intraoperative study
drug on the time-related area under the pain curve after
discharge.
Previous studies have investigated the use of alternative
non-opioid drug regimens for tonsillectomy and adenoidectomy including ␣-2 agonists.8 These drugs provide adequate analgesia without causing respiratory depression
typically associated with opioid therapy. The perioperative
use of the ␣-2 agonist clonidine in pediatric adenotonsillectomy has been associated with findings of increased sedation and conflicting results on its effect on postoperative
opioid consumption.23,24 In our study, a single intraoperative dose of dexmedetomidine did not significantly increase
sedation in the PACU, the time to tracheal extubation,
discharge readiness, duration of supplemental oxygen requirement, or unanticipated hospital admission compared
with the morphine groups. Our results suggest that benefits
to administration of larger doses of dexmedetomidine for
intraoperative analgesia in the studied patient population
are limited to the secondary outcomes of a reduced frequency of additional rescue medications and the time to
first rescue analgesia.
It is important, however, to note that we studied a
relatively healthy patient population and excluded children
with documented sleep apnea by polysomnography because we were concerned that the use of a more rigid, fixed
dose of morphine or dexmedetomidine required in the
study protocol may subject these children to unacceptably
greater risks for postoperative respiratory complications. In
our institution, the threshold for ordering a polysomnogram varies among surgeons and is usually reserved for
those with severe sleep apnea or an uncertain diagnosis of
sleep-disordered breathing. Our local institution criteria for
considering a diagnosis of sleep-disordered breathing include, but are not limited to, a history of snoring, mouth
breathing, and periods of apnea while asleep,25 and 85% of
the enrolled patients had at least 2 of these symptoms.
None of these children exhibited signs of airway obstruction, prolonged oxygen requirement, or required unanticipated hospital admission after surgery. A recent study
suggested airway obstruction was decreased when dexmedetomidine was used for sedation for MRI scans in children
with sleep apnea, compared with propofol.26 However, the
patients were not randomized in this study. It is also
unclear if data from children undergoing nonpainful procedures such as MRI can be applied to the tonsillectomy
patient population. An appropriately powered randomized
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controlled trial comparing dexmedetomidine and the current standard opioid regimen needs to be performed in
children with documented sleep apnea by polysomnography to determine whether the incidence of airway obstruction is reduced after tonsillectomy. In the absence of such a
study, we would urge caution in the use of dexmedetomidine in children with documented sleep apnea.
Other potential side effects of concern with the use of
dexmedetomidine include severe bradycardia.27–29 This
was not observed in any patient in our study, although
patients who received dexmedetomidine had a slower
heart rate over time compared with those who received
morphine. We agree that dexmedetomidine should be
used cautiously in patients with a critically ratedependent cardiac output because increased side effects
may be observed.11
As reported in 1 study, the benefit of dexmedetomidine
administration just before the end of adenotonsillectomy
procedures was a decreased incidence of emergence agitation compared with a placebo group.30 In our study, the
incidence of postoperative emergence agitation was similar
after a single dose of dexmedetomidine or morphine given
at induction.
In summary, this prospective, randomized, doubleblind study suggests that total postoperative rescue opioid
requirements were similar in tonsillectomy patients receiving intraoperative dexmedetomidine or morphine. However, the use of dexmedetomidine 1 ␮g/kg and morphine
100 ␮g/kg had the advantages of an increased time to first
analgesic and a reduced need for additional rescue analgesia doses in the PACU.
AUTHOR CONTRIBUTIONS
OAO helped with study design, conduct of study, data analysis, and manuscript preparation; CDG, DRL, and EMF helped
with conduct of study and manuscript preparation; JD and
MM helped with conduct of study; MMW helped with data
analysis; MFW helped with conduct of study, data analysis,
and manuscript preparation.
ACKNOWLEDGMENTS
The authors thank Dean Andropoulos, MD, for encouragement
and assistance with this study. The assistance of O’Brien Smith,
PhD, Tara McCartney, RPh, Carla Giannoni, MD, Marcelle Sulek,
MD, recovery room nurses, and Stephen Stayer, MD, is also
greatly appreciated.
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