[Fund project]
:High School Scientific Research Fund Project of Educational Ofiice in Liaoning Province,China
The effect of continuous infusion of remifentanil on the incidence
of emergency agitation after sevoflurane general anesthesia in
preschool-aged children
Dong Yunxia; Meng Lingxin, PhD*; Wang Yuan; Zhang Jiaojiao;Zhao Guanyi;Jiajia
Department of Anesthesia, Shengjing Hospital, China Medical University, Shenyang 110004, China
Abstract
Background:Sevoflurane has a lot of optimal character such as a lower blood/gas partition
coefficient ,less irritation to the airway,less toxicity the heart,liver and kidney,so it is well accepted
by pediatric anesthesiologists for general anesthesia in children .But sevoflurane may be
associated with a significant proportion of preschool children’ severe emergence agitation (EA)
after aneshthesia.
Objectives:The aim of the present study was to assess the effect of remifentanil(REM)
administered during the surgery on the incidence and severity of EA in preschool-aged children
undergoing sevoflurane general anesthesia.
Medthods:Sixty preschool-aged (3-7 years old) children(American Society of
Anesthesiologists[ASAI or II]) scheduled for adenotonsillectomy were enrolled in this randomized
double-blind study. These children were randomly divided into two groups:sevoflurane/REM
group and sevofluranen group. Each child was intramuscular injected atropine before entering into
the operating room. Anesthesia was induced with a bolus injection of 3µg/kg fentanyl and
2.5mg/kg propofol. Endotracheal intubation was facilitated by 0.1mg/kg vecuronium . All the
patients were ventilated with 50% nitrous oxide in oxygen to maintain an end-tidal CO2 of
35±4mmHg monitoring by end-tidal gas measurement. (volume-controlled ventilation: tidal
volume 10ml/kg,respiratory rate 15 times/min). For anesthesia maintenance, children were
randomized to sevoflurane group:inhalation of sevoflurane 1.5%-2.5% and sevoflurane/REM
group: inhalation of sevoflurane 1.5%-2.5% and at the same time infusion of 0.1µg/kg/min REM.
Two observers who were blind to the trial recorded BP, HR, SpO2,eye-open time and extubation
time during operating room. Another two nurses accessed the incidence and severity of EA by
Ramsay sedation scales and Pediatric Anesthesia Emergence Delirium scale (PAEDs) in recovery
time.
Result: We observed that the eye-open time, extubation time, intraoperative hemodynamic datas
of two groups were similar(P>0.05).In recovery time, the incidence and severity of EA in the
sevoflurane group was significantly higher than that in sevoflurane/REM group(P<0.05).
Correspondence to: Meng Lingxin, PhD, Department of Anesthesia, Shengjing Hospital, China Medical
University, Shenyang 110004, China(Email:meng_lingxin@hotmail.com)
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Conclusion: REM administered during the surgery is effective in significantly decreasing the
incidence and severity of EA in preschool-aged children undergoing sevoflurane general
anesthesia in adenotonsillectomy.
Key word: emergence agitation; remifentanil; sevoflurane; pediatric anesthesia
Introduction
Emergence agitation(EA),also referred to as emergence delirium in international literature, is a
well-documented postoperative behavior that may occur particularly in children. There is no
definitive etiology and pathogenesis for EA.Many different effect factors have been suggested,
such as age,the presence of pain ,the site of the operation ,the duration of anesthesia ,anesthetic
premedication and the anesthetics used1.
Sevoflurane has gained popularity among pediatric anesthetists because of the rapidity of
induction and emergence from anesthesia,great hemodynamic stability,less irritation to the
airway,lower solubility and less side effect ,as compared with other volatile anesthetics.
Nevertheless,through long term clinical observation, a lot of anesthesiologists have detected an
increased incidence of EA with inhaled general anesthesia using sevoflurane,when compared
with halothane2-6.Norifumi Kuratani et had wrote a meta-analysis of randomized controlled trials
which proved greater incidence of EA in children after sevoflune anesthesia as compared with
other halothane7 powerfully. However,the efficacy of switching to isoflurane maintenance is
debatable8-10. So our pediatric anesthesiologists should consider methods to reduce the risk of EA
after sevoflurane anesthesia. The strategies regarding prevention and treatment of emergence
agitation have been used to decrease its occurrence with variable efficacy 1. Remifentanil (REM)is
a new synthetic short-acting opioid considered to be an optimal one as an analgesic combined with
inhalational anesthetics in children 11,12. In this paper,the authors compared the incidence and
severity of emergence agitation in children who received remifentanil administered during the
surgery undergoing sevoflurane general anesthesia and only using sevoflurane in preschool-aged
children.
Methods
After obtaining the approval of the institutional committee of China Medical University and
informed parental consent,from December 2007 to July 2008,60 pre-school children ,ranging from
3-7years(ASA physical statusⅠandⅡ), who were undergoing adenotonsillectomy under
sevoflurane general anesthesia were studied prospectively.The exclusion criteria were that the
children with psychological or emotional disorders, abnormal cognitive
development,developmental delay and knowing the history of allergy to the drugs which we may
use during the anesthesia.Then 60 patients were randomized into two groups to receive either
sevoflurane combined with REM or sevoflurane anesthesia:sevoflurane/REM(R group:30 children)
and sevoflurane(S group:30 children ) using a concealed random number generator.
Each child was intramuscular injected 0.01mg/kg atropine 30 minutes and no sedative
medication was given before entering into the operating room.Routine monitors: noninvasive
mean arterial pressure cuff (MAP):3 minutes per time , heart rate(HR), electrocardiogram(ECG)
and pulse oximeter (SPO2)were applied and a peripheral catheter was introduced and a two lumens
catheter extension with anti-reflux system was used.One of the two lumens was dedicated to REM
infusion,and the other was used to bolus inject anesthesia drugs.The same two pediatric
anesthesiologists conducted all anesthesia procedures. Anesthesia was induced with a bolus
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injection of 3µg/kg fentanyl and 2.5mg/kg propofol. endotracheal intubation was facilitated by
0.1mg/kg vecuronium . All the patients were ventilated with 50% nitrous oxide in oxygen to
maintain an end-tidal CO2 of 35±4mmHg monitoring by end-tidal gas measurement. For
anesthesia maintenance, children were randomized to S group :inhalation of sevoflurane
1.5%-2.5% and R group: inhalation of sevoflurane 1.5%-2.5% and at the same time infusion of
0.1µg/kg/min REM.The anesthesiologists’ primary goal is to maintain adequate anesthesia and
stable hemodynamics:sevoflurane concentration was adapted to clinical signs. Neither muscle
relaxants nor other drugs were asministered to either group. Normal saline 0.9% was administered
to correct volume deficit from fasting and for maintenance. In both groups,3-5 minutes before the
completion of surgery,defined as the time when the mouth gag was removed,the inhaled anesthetic
agents were discontinued.Controlled ventilation was maintained at the same setting with a total
gas flow of 3L/min of oxygen. REM was discontinued simultaneously at the completion of
surgery in R group.The anesthesiologists waited for the return of the cough reflex to allow the
children breathe spontaneously. When the patients could be called to open eyes and demonstrated
regular respiratory pattern ,facial grimacing and purposeful movement of limbs,the trachea was
extubated.After extubation, all the children were inhaled 100% oxygen via a facemask at the same
time to observe vital signs.If there is no abnormal behavior, the children were transferred to the
postanesthesia care unit (PACU) and monitored and scored the response by two nursing staffs who
was blinded to the anesthetic used.
Observation and Monitoring: Two observers who were blinded to this trial
recorded :MAP ,HR,SPO2 at the time of entering into the operation room(T0) , after incubation
(T1), after extubation(T2), after transfer to ward(T3) ; duration of anesthesia , eye-open time (time
from discontinuation of sevoflurane to eye opening), time to extubation (time from the
discontinuation of sevoflurane to extubation). We used Ramsay sedation score to access sedation
level of children in the PACU.(See Table 1).EA was assessed on a four-point scale as follows:1,
calm; 2, not calm but could be easily calmed, moderately agitated or restless; 4, crying and
delusion,excited,or disoriented13 . Grade 1 or 2 was considered as no EA , and grade 3 or 4 was
considered as the presence of EA. The degree of sedation and agitation was evaluated and
recorded every 5 min during the first 30 min after arriving PACU and the peak-recorded value was
used for evaluation.
Table 1. Ramsay sedation score
Grade (point)
Children’s behavior
1
anxiety; restless; or both
2
quiet ,cooperation, normal orientation
3
drowsiness with reaction to commands
4
Sleeping with reaction to severe stimulation(hiting glabella or loud sound)
5
Sleeping with slow reaction to severe stimulation(hiting glabella or loud
sound)
6
Deep sleeping with no reaction to any stimulation
1 point: restlessness
2～4 point: satisfied sedation 5～6 point: excessive sedation
All the result datas are presented as means±SD and numbers. Demographic datas and vital sign
datas were analyzed by the Student’s T-test. The rate of the results between two groups was
analyzed by χ2 test . P value <0.05 was considered statistically significant in all tests.
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Result
All of sixty enrolled children completed this randomized double-blind trial. There were no
significant differences (P>0.05)in age ,sex distribution ,weight, duration of anesthesia, eye-open
time and time to extubation are similar between two groups.(Table 2).During the anesthesia ,there
were no differences in MAP ,HR ,SPO2 at four points between two groups. MAP and HR are
higher at T1 than T0,T2,T3 in both groups (Table 3).
Table 2. Patient demographics and duration of anesthesia, eye-open time, time to extubation
Age
Sex (M/F)
Weight
Duration of anesthesia(min)
S group
5.85±2.04
13/17
23.23±6.17
R group
5.92±1.84
14/16
24.07±5.58
eye-open time
time to extubation
59.00±5.97
7.92±1.79
11.38±2.49
59.20±6.32
7.67±1.67
11.45±2.42
Datas are expressed as mean±SD or numbers ,P>0.05
Table 3. MAP ,HR ,SPO2 at four points between two groups
hemodynamic sign
group
MAP
T0
S group
72.64± 4.54
R group
HR
SPO2
T1
71.23±6.89
89.03±2.73
△
△
84.45±3.32
△
T2
T3
79.53±9.56
75.53±6.50
75.47 ±2.79
S group
85.90±5.17
100.53±5.83
R group
88.34±4.37
96.94±6.58△
S group
98.43±0.98
99.02±7.24
98.07 ±1.21
R group
98.21±0.32
99.08±0.87
98.23±0.12
73.13±7.05
91.32±2.58
86.78±8.11
94.87±5.40
89.31±6.36
98.53±0.97
98.19±0.42
No differences in MAP ,HR ,SPO2 at four points between two groups. MAP and HR are higher at T1 than T0,T2,T3
△
in both groups, P<0.05
The rate of satisfied sedation in R group is 26.7% which is lower than that in S group(63.3%).
Restless rate in R group is significantly lower than that in S group, and excessive sedation rate
between the two groups are same, both 6.7%.( Table 4) .In S group there were 20 children who
had EA，meanwhile there were only 7 children with EA in R group.The incidence of EA in R
group is lower than that in S group significantly( Table 5).
Table 4. Ramsay sedation score in PACU
1: restlessness
2～4: satisfied sedation
5～6: excessive sedation
S group
20/30 (66.7%)
8/30(26.7%)
2/30(6.7%)
R group
9/30* (30%)*
19/30* (63.3%)*
2/30(6.7%)
*
P<0.05 versus S group
Table 5.
Incidence of EA in two groups
EA
No EA
S group
20/30(66.7%)
10/30(33.3%)
R group
7/30(23.3%)
23/30(76.7%)*
*
*
P<0.05 versus S group
Discussion
EA is a common adverse reaction that may occur in extubation period undergoing general
anesthesia with inhaled agents, especially in children. It is characterized by restless，confusion
mental ,hallucination，irrigation, disorientation, inconsolable crying and delusion. Restless
recovery after anesthesia has a lot of harm. When EA happens, sympathetic nervous system would
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be greatly activated which leading to increasing of body oxygen consumption ,tachycardia and
hypertension. It also could cause self-injury ,the accidental removal of monitoring instruments or
catheters, corneal abrasions, wound dehiscence, hemorrhage and asphyxia which increase the risk
of anesthesia.
The results of our prospective study show that REM asministered during the surgery is effective in
significantly decreasing the incidence and severity of EA in preschool-aged children undergoing
sevoflurane general anesthesia. There were no significant differences in hemodynamic values
between the two groups at the various intraoperative stress points. The eye opening time and
extubation time are similar for both groups. When EA occurs, we found that the heart rate
increased with no blood pressure changed.
In this study, we found that the incidence of EA under only use of sevoflurane anesthesia is
66.6% which is higher than other related studies 4,15. There may be three reasons accounting for
our results: our surgical site , the age of the children we choose in this study and preoperative
intramuscular injection of atropine .It is reported that otorhinolaryngological surgical procedures,
such as tonsillectomy,thyroidectomy and ophthalmological operations appear to exhibit an
increased incidence of agitation16. It may be related to the sensation of suffocation in
adenotonsillectomy which can contribute to EA. In S group,the age of children is 5.85±2.04,which
is smaller than some other studies. Previous studies have found that younger children are prone to
develop EA after sevoflurane anesthesia3,17. Shin Nakayama et al. observed a EA of 42% after
sevoflurane anesthesia in preschool-aged children15. In addition, preoperative intramuscular
injection of atropine and no use of premedication of sedative drugs in every child may also cause
this higher incidence of EA . Many articles pointed out that atropine also can cause postoperative
delirium. Oppositely, many researches showed that preoperative sedative drugs such as oral
clonidine and midazolam,can reduce the restlessness in children.
Combining with opioids appropriately during general anesthesia in children can make
hemodynamic stability and reduce recovery restlessness. But the brain of child is not well
developed ,so it is prone to respiratory depression in children after anesthesia . REM is a new
synthetic short-acting opioid considered to be an optimal one as an analgesic combined with
inhalational anesthetics in children with the characters of fast onset and off-set.Its metabolite has
no biological activity and its effect to the hemodynamics is moderate. Thus, the drug appears to be
one that anesthesiologists have sought for use in young children whose metabolic pathways in
kidney or liver may be immature. Many studies have shown that application of REM in pediatric
anesthesia is safe11,12 . In this trial, we observed incidence and severity of emergence agitation in
children who received remifentanil administered.There is no adverse reactions observed with
infusion of 0.1µg/kg/min REM in sixty children. Both anesthetics provided patients with
hemodynamic stability, and opioid-induced respiratory depression was not observed in the
remifentanil-anesthetized infants.The result showed that REM administered during the surgery
could significantly reduced the incidence of EA after sevoflurane anesthesia,from66.7%to
23.3%.It may due to some reasons: Infusion of REM reduces the minimum alveolar concentration
(MAC) of sevoflurane,meaning that lower concentrations of the anesthetic can be used, thereby
reducing the incidence of postoperative EA.REM also can eliminate the comfortlessness and pain
of children which may account for the EA in the recovery time.
There is no definitive reason for emergence agitation of children. Many different causes have
been suggested such as ages,postoperative pain, psychological, social and environmental factors
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related to the operation,type of surgical procedures, inhaled and intravenous anesthetics, anesthetic
premedication and adjuvant drugs 1.Sevoflurane which has many characters is well accepted by
pediatric anesthesiologists for general anesthesia in children .However, more and more pediatric
anesthesiologists find that sevoflurane can cause greater incidence of delirium during recovery
than other inhaled anesthetics . Recently, a meta-analysis done by Norifumi et al showed the
strength of the evidence of higher incidence of emergence agitation after sevoflurane anesthesia
compared with halothane,with a pooled OR of 2.21(95%CI,1.77-2.77) 7.But the reason for this
phenomenon is not fully studied. No sole factor can explain the etiology of EA after anesthesia
with sevoflurane. One of the important hypotheses offered to explain this is the low solubility of
sevoflurane in blood, when compared with halothane, promoting rapid emergence from anesthesia
in a nonfamiliar environment which contributed to EA in children with psychological
immaturity12,13. It is also reported that sevoflurane in sometimes had a particular side effect on the
central nervous system which was gained by the observation of the electroencephalography to
epileptiform seizure activity in previously nonepilepic patients during sevoflurane anesthesia
18,19.However, intrinsic mechanism of cortical epileptogenicity by sevoflurane is still unclear 20.
Our study demonstrated the use of short-acting opioids REM combined with sevoflurane seems
to be a safe and appropriate anesthetic technique to reduce incidence of EA for chidren in
adenotonsillectomy just as our hypothesis .In the future ,REM maybe the most popular and effect
opioids which have reliable therapy for emergency agitation of sevoflurane anesthesia.
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