Journal of Clinical Anesthesia 85 (2023) 111044

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Journal of Clinical Anesthesia

journal homepage: www.elsevier.com/locate/jclinane

Original Contribution

Nalbuphine reduces the incidence of emergence agitation in children

undergoing Adenotonsillectomy: A prospective, randomized, double-blind,
multicenter study
Jian He, MD, PhD a, 1, Lei Zhang, MD a, 1, Tao Tao, MD, PhD b, Xianjie Wen, MD, PhD c,
Daguang Chen, MD d, Xueqin Zheng, MD a, Changhui Luo, MD a, Hua Liang, MD, PhD a, *,
Hanbing Wang, MD, PhD a, *
a
Department of Anesthesiology, The First People’s Hospital of Foshan, Foshan City 528000, China
b
Department of Anesthesiology, Central People’s Hospital of Zhanjiang, Zhanjiang City 524045, China
c
Department of Anesthesiology, Affiliated Foshan Hospital of the Southern Medical University and The Second People’s Hospital of Foshan City, Foshan City 528000,
China
d
Department of Anesthesiology, Luoding People’s Hospital, Yunfu City 527200, China

H I G H L I G H T S

• Nalbuphine could reduce emergence agitation in children after general anesthesia.

• Nalbuphine did not increase extubation time and duration of PACU stay.
• Nalbuphine did not increase the incidence of breath depression and nausea and vomiting.

A R T I C L E I N F O A B S T R A C T

Keywords: Objective: To evaluate the effect of nalbuphine on emergence agitation (EA) in children undergoing
Nalbuphine adenotonsillectomy.
Emergence agitation Design: Multicenter, prospective, double-blind, randomized controlled trial.
General anesthesia
Setting: The First People’s Hospital of Foshan and three other participating institutions in China, from April 2020
Postoperative pain
to December 2021.
Patients: Eight hundred patients, 3–9 years of age, American Society of Anesthesiologists (ASA) classification I or
II, undergoing elective adenotonsillectomy were included.
Interventions: Nalbuphine (0.1 mg/kg) or saline was administered intravenously.
Measurements: The incidence of EA; the pediatric anesthesia emergence delirium (PAED) scale; and the faces,
legs, activity, cry, and consolability (FLACC) scales. Extubation time, duration of post-anesthesia care unit
(PACU) stay, anesthesia nurses’ and parents’ satisfaction, and other side effects.
Main results: The incidence of EA in the nalbuphine group was lower than that in the saline group 30 min
after extubation (10.28% vs. 28.39%, P = 0.000). In addition, the FLACC scores in the nalbuphine group
were lower than those in the saline group 30 min after extubation (P < 0.05). Furthermore, the proportion
of moderate-to-severe pain cases (FLACC scores >3) was significantly lower in the nalbuphine group than in
the saline group (33.58% vs. 60.05%, P = 0.000). Adjusting the imbalance of postoperative pain intensity,
the risk of EA was still lower in the nalbuphine group at 0 min (OR, 0.39; 95% CI, 0.26–0.60; P = 0.000),
(OR, odds ratio; CI, confidence interval), 10 min (OR, 0.39; 95% CI, 0.19–0.79; P = 0.01), and 20 min (OR,
0.27; 95% CI, 0.08–0.99; P = 0.046) than in the saline group. There were no significant differences in
extubation time, duration of PACU stay, nausea and vomiting, or respiratory depression between the two
groups (P > 0.05).

* Corresponding authors at: Anesthesiolgy department, The First People’s Hospital of Foshan, Foshan City 528000, China.
E-mail addresses: lhlh2003@126.com (H. Liang), wanghanbing2@126.com (H. Wang).
1
Jian He and Lei Zhang were the co-first authors.

https://doi.org/10.1016/j.jclinane.2022.111044
Received 30 September 2022; Received in revised form 16 November 2022; Accepted 19 December 2022
Available online 23 December 2022
0952-8180/© 2022 Elsevier Inc. All rights reserved.

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Conclusion: Nalbuphine reduced the incidence of EA in children after adenotonsillectomy under general anes-
thesia, which may be involved in both analgesic and non-analgesic pathways.
1. Introduction
Emergence agitation (EA) is a common and serious complication in
patients recovering from general anesthesia [1–3]. The incidence of EA
is reported to be up to 20% [4] in adult patients and up to 80% [3] in
children. EA in pediatric patients often manifests as crying, disorienta-
tion, excitement and delirium [1,2]. Although EA is self-limiting, it can
induce potential problems in children, such as self-injury, bleeding and
cracking of the wound, falling off of the indwelling catheter, and falling
off of the bed, which can cause some difficulties for medical staff and
serious anxiety for family members [5,6]. In addition, children with EA
are at a higher risk of post hospitalization behavioral changes, which
may last longer [7]. Furthermore, EA treatment increases the burden on
healthcare providers and increases the medical expenses of patients. EA
commonly occurs after the most common surgeries in children like
adenoidectomy and tonsillectomy [8]. Therefore, implementing effec-
tive measures to prevent EA in children undergoing these types of sur-
geries is crucial.
Although the underlying mechanisms of EA remain unclear, some
pharmacological interventions have been used to prevent and treat EA
[9]. Previous studies have demonstrated that propofol [10], benzodi-
azepines [11], α2 agonists [12], and opioids [6,13] can prevent EA in
children to varying degrees. However, these medications may lead to
respiratory depression, delay in anesthesia recovery and post-anesthesia
care unit stay, and other adverse reactions. Thus, the most favorable
prophylactic treatment to decrease such an incidence remains unknown,
and the ideal approaches to prevent EA merit further exploration.
Nalbuphine is a synthetic opioid receptor agonist-antagonist (agonist
К receptor, antagonistic part μ receptor) that can produce a central
analgesic effect and partial sedation. The inhibitory effect of nalbuphine
on respiration is slight and it has a capping effect [14]. Owing to these
advantages, it is widely used in pediatric surgical analgesia [15]. Dalens
et al. [16] discovered that nalbuphine could significantly reduce the
incidence of EA in children using magnetic resonance imaging (MRI)
with sevoflurane anesthesia. However, the sample size of this study was
relatively small and the factors of surgical injury were not considered.
Currently, a multicenter, large-sample clinical study of nalbuphine for
the prevention of EA has not yet been reported.
Therefore, we designed a prospective, randomized, double-blind,
multicenter study to investigate whether nalbuphine can prevent EA
after tonsillectomy and adenotonsillectomy in children under general
anesthesia. In addition, the characteristics of anesthesia recovery and
the incidence of adverse effects were also evaluated in this study.
2. Materials and methods
2.1. Study design
This multicenter, prospective, randomized clinical trial was con-
ducted in 4 separate hospitals in China. The study was approved by each
participating hospital ethics committee. Individual written informed
consent was provided by the parents or legal guardians before inclusion.
The study was registered in the China Clinical Trial Registry
(ChiCTR2000029340). This multicenter study was performed from April
21, 2020, to December 27, 2021. Data were collected from each
participating institution and analyzed at the First People’s Hospital of
Foshan.
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2.2. Patients
Children with American Society of Anesthesiologists (ASA) status
I–II, aged 3–9 years, scheduled for adenoidectomy and adenotonsillec-
tomy, were included in this study. The exclusion criteria were as follows:
allergy to nalbuphine and other medications used in this study, and any
sedative, analgesic, antiemetic, or anti-itching drugs administered 24 h
before the operation, had respiratory inhibition diseases or asthma
combined with respiratory, cardiovascular, and nervous system dis-
eases; moderate to severe liver and kidney dysfunction; emergency in-
dications; and received any other trial drug within 3 months.
2.3. Randomization and masking
The individuals were randomly assigned to two groups in a ratio of
1:1 to receive nalbuphine or saline intravenous injections according to a
randomization list generated by www.Randomization.com at each
participating site. Each assignment number was preserved in a sealed
envelope and was only revealed to a staff member who prepared the
study medications prior to drug administration. The sample size was
distributed to each institution based on the number of procedures per-
formed in the previous year. The patient in the nalbuphine group was
intravenously injected with 0.1 mg/kg nalbuphine (H20130127,
Yichang Humanwell Pharmaceutical) during general anesthesia induc-
tion, and the patient in the saline group was intravenously injected with
0.1 ml/kg saline. Nalbuphine was diluted to 1 mg/ml using isotonic
saline. The research medication was prepared by an independent staff
member who was not involved in the subsequent research. The anes-
thesiologist, outcome evaluator, guardian, and children were blinded to
the allocation of the study drugs.
2.4. Procedure
The patients were sedated by intravenously injected atropine 0.1
mg/kg and propofol (2–4 mg/kg) in the induction room and then
transferred to the operating room. All patients underwent standard
monitoring in the operating room, including electrocardiography (ECG),
noninvasive blood pressure (NIBP), pulse oximetry (SpO2), and bis-
pectral index (BIS). Anesthesia was induced using sevoflurane (vol 3%)
with 100% oxygen (6 l/min), sufentanil 0.2 μg/kg iv and cisatracurium
besilate 0.1 mg/kg iv. About 3–5 min later, tracheal intubation was
performed to provide mechanical ventilation. Dexamethasone (0.1 mg/
kg) was injected intravenously to minimize tissue edema and prevent
vomiting and nausea. During the anesthesia induction period, nalbu-
phine or saline was administered intravenously according to the
grouping requirements. Anesthesia was maintained with inhalation of
2% to 3% sevoflurane and infusion of remifentanil with 0.1–0.5 μg.kg−1.
min−1. The inhalation concentration of sevoflurane and the rate of
remifentanil infusion were adjusted to maintain a BIS value of 40–60
and a heart rate of 80–120% of the baseline values throughout the
operation. The tidal volume and respiratory rate were adjusted to
maintain the end-expiratory carbon dioxide partial pressure (PetCO2) at
35–45 mmHg. Sevoflurane and remifentanil were discontinued at the
end of the operation. All patients underwent adenoidectomy or adeno-
tonsillectomy according to medical indications. With regard to the sur-
gical method, tonsil surgeries were performed using coblation
tonsillectomy with inferior pole capsule preservation, whereas adenoid
surgeries were performed using endoscopic-assisted coblation adenoi-
dectomy. During the operation, 0.9% sodium chloride-2.5% glucose
mixed solution was administered via an intravenous drip to maintain
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normal blood volume. The body temperature of the children was
maintained using a warm blanket set at 42 ◦ C. The children were sent to
the post-anesthesia care unit (PACU) for recovery after the operation.
The wake-extubation technique was performed in the PACU. All patients
were observed for at least 1 h before transfer to the ward after ensuring a
modified Aldrete score of 9 [17].
2.5. Outcomes
The primary outcome was the incidence of EA evaluated using the
Pediatric Anesthesia Emergence Delirium (PAED) scale [18] (Table 1)
within 30 min after extubation in the PACU. PAED scales ≥12 were
defined as EA.
The secondary outcomes were as follows:
1) Incidence of EA at 0, 10, 20, and 30 min after extubation in the
PACU. A single dose of propofol (1 mg/kg) was administered intra-
venously to patients with EA (PAED scale score ≥ 12).
2) Postoperative pain was assessed using the face, legs, activity, crying,
consolability, and scale (FLACC) at 0, 10, 20, and 30 min after
extubation in the PACU. The total FLACC score ranged from 0 (no
pain) to 10 (maximum pain). When the FLACC scale of children was
>3, 0.1 μg/kg sufentanil was intravenously administered. Ten mi-
nutes later, a second dose of sufentanil was administered if the scores
remained >3 points.
3) Changes in vital signs (heart rate, blood pressure, SpO2) at 0 min, 10
min, 20 min and 30 min after extubation in the PACU.
4) Extubation time: the time from the end of the surgery to the
extubation.
5) Duration of PACU stay: The time from the end of surgery to discharge
from the PACU.
6) Nurse satisfaction and parental satisfaction were evaluated when
patients left the PACU and patients were discharged, respectively,
using a five-point scale:1, very dissatisfied; 2, dissatisfied; 3,
commonly; 4, satisfied; and 5, very satisfied.
7) Side effects: incidence of postoperative nausea, vomiting, and res-
piratory depression within 24 h after surgery.
Data were collected and registered by an independent staff member
using a case report form (CRF). This study closely followed guidelines
for good clinical practice (GCP). An investigator was specifically
assigned to collect, file, and transfer data, and another investigator
verified the accuracy and safety of the data in each center.
2.6. Statistical analyses
The primary endpoint of this study was EA incidence. The incidence
of EA after sevoflurane anesthesia has been reported to be 30% in
children after sevoflurane anesthesia [16]. At a design inspection effi-
ciency (1-β) = 0.8, inspection level α = 0.05 (bilateral), if we expected a
30% reduction in the incidence of EA with prophylactic nalbuphine
treatment (21% of the children in the nalbuphine group may have EA),
367 patients in each group were required. During the trial, an estimated
10% of patients dropped out of the study; therefore, we planned to re-
cruit 400 patients in each group.
Outcomes were analyzed according to a modified intention-to-treat
principle in the full analysis set (FAS). Children who received the allo-
cated intervention and had at least one data point after treatment were
included in the FAS. The statistical software SAS 9.4 was used for sta-
tistical analysis. The general incidence of EA was expressed as a per-
centage and analyzed using the chi-square test. Logistic regression
analysis was used to compare the incidence of EA, and the Wald χ2 test
was used to estimate the parameters in the two groups at different times
after extubation. FLACC scores were expressed as the mean ± standard
deviation and analyzed using repeated-measures analysis of variance
within the groups. An independent sample t-test was used to compare
groups at different time points. Demographic data and anesthesia
characteristics were analyzed using the chi-square test and t-test, when
appropriate. The incidence of adverse events is expressed as frequencies
and percentages (n, %). Bilateral P < 0.05 indicates that the difference
was statistically significant.
3. Results
3.1. Demographic, surgery, and anesthesia data
A total of 1024 patients from four participating centers were
screened for eligibility. A total of 224 patients were excluded since they
did not meet the inclusion criteria or refused to participate. A total of
800 patients were enrolled in this study. Three patients (one in the
nalbuphine group and two in the saline group) were excluded due to
postoperative bleeding that required secondary surgery. No primary
measurements were obtained for these patients. Therefore, 399 patients
in the nalbuphine group and 398 patients in the saline group were
included in the statistical analysis (Fig. 1). There were no significant
differences in demographics, preoperative vital signs, ASA status,
extubation time, anesthesia time, operation time, or duration of PACU
stay (P > 0.05) (Table 2).
3.2. Primary endpoint Molluslow
PAED is widely used to evaluate EA, and a cut-off score of ≥12 is
defined as EA in the PACU. The incidence of EA was significantly lower
in the nalbuphine group compared to the saline group 30 min after
extubation (10.28% vs. 28.39%, χ2 = 41.95, P < 0.0001). Single-factor
logistic regression analysis was used to compare the incidence of EA, and
the Wald χ2 test was used to estimate the parameters in the two groups at
different times after extubation. The results showed that the incidence of
EA in the nalbuphine group was significantly lower than that in the
saline group at 0, 10, and 20 min after extubation (Table 3). The Chi-
square test of multi-group frequency distribution was used to analyze
the trend of the incidence of EA at different time points after extubation
in the two groups. The trend P-values t were lower than 0.001 in both
groups, indicating a decreasing trend in the incidence of EA after extu-
bation (Table 3).

Table 1 3.3. Secondary endpoints

Pediatric anesthesia emergence delirium scale (PAED).
Yinr
Description Not at Just a Quite a Very Extremely Since postoperative pain intensity plays a vital role in the incidence
all little bit much ymronri.tt
of EA, we assessed the pain intensity in children using FLACC scores in
The child makes eye 4 3 2 1 0 the PACU. The FLACC scores in the nalbuphine group were significantly
contact with the lower than those in the saline group using repeated-measure analysis of
caregiver
variance (F = 22.43, P < 0.0001). The differences in FLACC scores at
The child shows 4 3 2 1 0
purposeful actions different time points were analyzed using the t-test. The results showed
The child is aware of his 4 3 2 1 0 that FLACC scores were lower in the nalbuphine group than in the saline

I
or her surroundings group at 0, 10, 20, and 30 min after extubation (Table 4). The overall
The child is restless 0 1 2 3 4 proportion of moderate-to-severe pain cases (FLACC scores >3) was
The child is inconsolable 0 1 2 3 4
significantly lower in the nalbuphine group than in the saline group

3 muumuuon
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J. He et al.
Assessed for eligibility (n=1024)
Enrollment
Allocated to nalbuphine group (n=400)
Received allocated intervention(n=400)
Allocation
Lost to follow-up(n=1)
Follow-up
Due to postoperative bleeding
Analyzed(n=399)
Analysis
Excluded from analysis(n=1)
Fig. 1. Consolidated standards of reporting trials flow diagram.
(33.58% vs. 60.05%, χ2 ¼ 56.06, P = 0.000). These results indicate that
nalbuphine can reduce postoperative pain intensity in children.
Considering that age, sex, and pain were risk factors for EA, we con-
ducted a subgroup analysis of the incidence of EA between the two
groups by adjusting for these factors. The results indicated that nalbu-
phine could still reduce the incidence of EA, despite adjusting for the
difference in pain intensity after extubation (Table 3).
The hemodynamic measurements, temperature, respiratory rate, and
SpO2 of the children in the PACU are summarized in Table 5. There were
at
no significant differences in hemodynamic measurements, temperature,
or respiratory rate between the two groups within 30 min after extu-
bation. The SpO2 in the nalbuphine group was slightly lower than that in
the saline group at 20 min (98.98 ± 1.16 vs 99.15 ± 1.00, P = 0.03) and
30 min (98.88 ± 1.16 vs 99.13 ± 0.99, P = 0.001) after extubation.
However, we believe that this difference was not clinically significant.
The incidence of cough was lower in the nalbuphine group compared to
I
the saline group (0.5% vs. 2.76%, P = 0.01). There were no significant
differences in the incidence of nausea and vomiting (0 vs. 0.5%) or X
respiratory depression (0 vs. 0.25%) between the two groups. One pa-
tient in the saline group had respiratory depression, and SpO2 was 95%.
This side effect may have been induced by a single dose of analgesic
injection and quickly improved by oxygen inhalation with a mask. There
were higher satisfaction scores in anesthesia nurses and children’s
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Journal of Clinical Anesthesia 85 (2023) 111044
Excluded(n=224)
! Not meeting inclusion criteria
(n=58)
! Declined to participate (147)
! others (19)
Randomized(n=800)
Allocated to saline group (n=400)
Received allocated intervention(n=400)
Lost to follow-up(n=2)
Due to postoperative bleeding
Analyzed(n=398)
Excluded from analysis(n=2)
parents in the nalbuphine group than in the saline group (Table 6).
4. Discussion
To the best of our knowledge, this is the first study to investigate the
effects of nalbuphine on EA in children undergoing adenoidectomy and
tonsillectomy. In this study, we discovered that intravenous injection of
nalbuphine (0.1 mg/kg) during the anesthesia induction period could
reduce the incidence of EA in children who underwent adenotonsillec-
tomy surgery. Moreover, nalbuphine did not increase the occurrence of
adverse events such as emergence delay, breath depression, nausea, and
vomiting.
A previous study demonstrated that PAED >12 has 100% sensitivity
and 94.5% specificity for diagnosing EA [19]. Therefore, we chose PAED
>12 as a criterion to diagnose EA within 30 min after extubation. In this
study, the incidence of EA in the children who underwent adenoidec-
tomy and tonsillectomy was 28.39% in the control group. Previous
studies have shown that the incidence of EA ranges from 20 to 77.5%
[11]. We speculate that this discrepancy is mainly due to differences in
the anesthesia methods. In our study, we combined sevoflurane with
remifentanil to maintain anesthesia, which may induce a lower inci-
dence of EA than sevoflurane alone. Additionally, propofol was used
during the induction period of anesthesia, which may also decrease the
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J. He et al. Journal of Clinical Anesthesia 85 (2023) 111044

Table 2 children than in adults. In addition, nausea and vomiting would increase
Comparison of different characteristics between two groups. the risk of gastric reflux and aspiration. In the present study, the inci-
Characteristics Nalbuphine group(n = Saline group(n = P dence of breath depression was low and there was no difference between
399) 398) value the two groups. Unlike other opioids, nalbuphine did not increase breath
Gender (M/F) 268/131 278/120 0.42 depression. Surprisingly, one child in the saline group developed res-
Age(years) 5.03 ± 1.78 5.14 ± 1.76 0.37 piratory depression after the second dose of sufentanil injection for
BMI 15.51 ± 2.06 15.68 ± 2.49 0.30 rescue analgesia. This result implies that the dosage of sufentanil used
Surgery (AD/AT) 163/236 178/220 0.27 for rescue analgesia in children should be considered with caution.
Temperature (◦ C) 36.55 ± 0.23 36.56 ± 0.20 0.54
Pulse (beats/min) 102.12 ± 14.23 102.38 ± 13.13 0.79
There was a significant difference in SpO2 at 20 and 30 min after
Heart rate (beats/min) 102.11 ± 14.21 102.35 ± 13.14 0.81 extubation between the two groups. However, the SpO2 values of all the
Respiratory rate (per patients in the two groups were within the normal range, indicating that
19.82 ± 1.20 19.67 ± 1.39 0.11
min) the difference in SpO2 was not clinically significant. These results indi-
Systolic pressure (mm
101.93 ± 10.25 99.95 ± 9.12 0.06 cate that nalbuphine did not increase respiratory depression, which is a
Hg)
Diastolic pressure (mm side effect of other opioids. Moreover, there was no significant differ-
61.75 ± 10.74 60.45 ± 9.27 0.22 ence in the incidence of postoperative nausea and vomiting between the
Hg)
SPO2 (%) 98.93 ± 4.58 99.17 ± 0.96 0.32 two groups.
ASA status (I/II) 389/10 395/3 0.05 Although postoperative pain is a key factor inducing EA, painless
Extubation time(min) 66.71 ± 31.22 66.66 ± 30.49 0.98
Anesthesia time(min) 58.84 ± 38.83 57.20 ± 37.47 0.89
procedures can also cause EA. Dalens [16] reported that EA could occur
Operation time(min) 29.37 ± 21.40 29.04 ± 20.74 0.83 in children under sevoflurane anesthesia during MRI examinations.
Length of PACU stay Moreover, some non-analgesic drugs may reduce the incidence of EA
53.18 ± 15.71 50.10 ± 16.174 0.34
(min) [26]. In our study, the incidence of EA in children with FLACC scores <3
Data are presented as mean ± standard deviation or numbers. was 17.4% and that of others was 36.9%. This result indicated that
BMI: Body mass index, AD: adenoidectomy, AT: adenotonsillectomy, ASA: patients with no severe postoperative pain also had EA. Moreover, we
American society of anesthesiologists, PACU: pos-anesthesia care unit, adjusted for the imbalance of FLACC scores in the statistical analysis; the
incidence of EA in the nalbuphine group was still lower than that in the
incidence of EA. Many risk factors can be considered during the devel- saline group. These results indicate that nalbuphine can reduce the
opment of EA, such as postoperative pain, age, different types of surgery, incidence of EA through a non-analgesic pathway. Moreover, nalbu-
inhaled anesthetics with rapid emergence, and anesthetic techniques phine has a sedative effect with minimal breath depression. Previous
such as sevoflurane [5,9]. Although sevoflurane is considered to induce studies have demonstrated that sedation can also reduce EA. Sedative
a higher incidence of EA than propofol [20,21], it is still the preferred medications can also induce breath depression and delay its emergence.
anesthetic agent for the induction and maintenance of anesthesia in Previous studies have indicated that propofol can prevent the occur-
pediatric patients due to its rapid induction and recovery characteristics rence of EA, but it increases the time to awakening and the time to
[22]. Likewise, sevoflurane was also the most commonly used anesthetic discharge from the PACU [1,27]. Midazolam is another widely used
in pediatric surgery at our institution. If the side effects of the high sedative administered at the end of surgery to prevent EA in children
incidence of EA could be improved, sevoflurane would likely be more [11]. Otherwise, it would induce respiratory depression and post-
widely available for pediatric anesthesia. operative behavioral changes such as cognitive impairment and para-
Postoperative pain is another risk factor for postoperative EA in- doxical reactions [28,29]. Recently, dexmedetomidine (DEX), a
duction. Some previous studies have shown that analgesic drugs can selective α2-adrenoceptor agonist, was used to prevent EA without
effectively reduce the incidence of EA after sevoflurane anesthesia increasing respiratory depression and postoperative nausea and vomit-
[23,24]. In the present study, FLACC scores were significantly lower in ing [30,31]. Notably, it could slow the heart rate, which is a key factor in
the nalbuphine group than those in the control group. In addition, the
incidence of moderate and severe pain (FLACC>3) in the nalbuphine Table 4
group (33.58%) was significantly lower than that in the control group Comparison of FLACC scores between two groups after extubation.
(60.05%). These results highlight that nalbuphine could decrease the Groups Time after extubation
incidence of EA by alleviating postoperative pain. Chen et al. [25] found
0 min 10 min 20 min 30 min
that nalbuphine had a better postoperative analgesic effect than fentanyl
in children who underwent adenotonsillectomy and indicated a simi- Nalbuphine group (n = 2.26 ± 1.27 ± 0.90 ± 0.45 ±
399) 1.96 1.68 1.54 1.02
larly strong analgesic effect. Moreover, previous studies have shown that
3.79 ± 2.08 ± 1.25 ± 0.87 ±
opioids, such as sufentanil, alfentanil, and fentanyl, can prevent EA Saline group (n = 398)
2.86 2.61 2.03 1.75
[6,9,13,23], but these medications have some disadvantages, such as t value −8.80 −5.25 −2.75 −4.20
breath depression and nausea or vomiting. Low oxygen storage and high P value <0.0001 <0.0001 0.006 <0.0001
oxygen consumption make breath depression more dangerous in FLACC: face, legs, activity, cry, consolability.

Table 3
Comparison of incidence of emergence agitation between two groups at different time points after extubation.
Nalbuphine group, n(%) Saline group, n(%) OR (95% CI) P value Adjust pain intensity

OR (95% CI) P value

0 min after extubation 40 (10.03) 109 (27.39) 0.30 (0.20–0.44) <0.0001 0.39(0.26–0.60) 0.000
10 min after extubation 11 (2.76) 36 (9.05) 0.29 (0.14–0.57) 0.0004 0.39(0.19–0.79) 0.010
20 min after extubation 3 (0.75) 13 (3.27) 0.22 (0.06–0.79) 0.02 0.27(0.08–0.99) 0.046
30 min after extubation 1 (0.25) 7 (1.76) 0.14 (0.02–1.15) 0.07 0.19(0.02–1.59) 0.120
χ2 73.42 178.20
P value <0.001 <0.001
Ptrend <0.001 <0.001

OR: Odd Ratio, CI: Confidence interval.

IA 8 8 D )A A E E D A F3 H F . EC F D A 0 ,E H D A1 D (
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J. He et al. Journal of Clinical Anesthesia 85 (2023) 111044

Table 5
Comparison of vital signs between two groups at different time points after extubation.
0 min after extubation P 10 min after extubation P 20 min after extubation P 30 min after extubation P
value value value value
Nalbuphine Saline Nalbuphine Saline Nalbuphine Saline Nalbuphine Saline
group group group group group group group group

Temperature 36.50 ± 36.51 ± 36.52 ± 36.52 ±

36.49 ± 0.19 0.45 36.51 ± 0.19 0.86 36.52 ± 0.19 0.79 36.52 ± 0.19 0.99
(◦ C) 0.19 0.20 0.21 0.22
Pulse (beats/ 126.59 ± 2 124.47± 123.07± 121.65± 119.18± 118.58± 117.08 ± 116.56
0.16 0.30 0.63 0.68
min) 1.56 20.88 19.75 18.49 17.17 17.99 17.02 ± 17.80
Heart rate 126.54± 124.36 123.11 ± 121.65 119.18 ± 118.54 117.07± 116.55
0.14 0.28 0.61 0.67
(beats/min) 21.60 ± 20.81 19.75 ± 18.49 17.17 ± 18.03 17.02 ± 17.79
Respiratory rate 21.33 ± 21.27 ± 21.20 ± 21.14 ±
21.11 ± 1.90 0.14 21.04 ± 1.94 0.10 20.92 ± 1.87 0.047 20.90 ± 1.89 0.08
(per min) 2.40 2.05 2.04 2.03
Systolic
100.91± 101.29± 98.87± 99.25 ± 97.35 ± 97.04±
pressure 0.86 0.85 96.89 ± 9.86 0.82 95.22 ± 9.32 0.37
10.10 10.08 10.77 9.24 9.51 10.44
(mmHg)
Diastolic
55.54± 58.94 ± 54.28± 56.38 ± 51.59± 53.67 ± 50.39± 53.23 ±
pressure 0.11 0.34 0.33 0.17
11.18 9.31 11.62 9.47 11.35 9.23 10.52 9.28
(mmHg)
99.3 ± 99.22 ± 99.15 ± 99.13 ±
SPO2 (%) 99.27 ± 1.09
1.07
0.71 99.13 ± 1.06
1.85
0.86 98.98 ± 1.16
O1.00
0.03 98.88 ± 1.16
0.99
0.001

Data are presented as mean ± standard deviation.

lack of follow-up after discharge was another limitation and late-onset

Table 6
nausea or vomiting would not be observed [35]. However, it seems
Satisfaction of anesthesia nurses and children’s parents.
that nausea or vomiting does not increase the risk of regurgitation and
Nalbuphine group(n = Saline group(n = P value pulmonary aspiration in sufficiently awake patients. Third, sevoflurane
399) 398)
and remifentanil were used to maintain anesthesia. This anesthesia
Satisfaction of anesthesia nurses, n (%) technique may not be the conventional technique used by many anes-
Very
1(0.25) 3(0.75) thesiologists. It is unclear whether nalbuphine can decrease the inci-
dissatisfied
Dissatisfied 20(5.01) 44(11.06)
dence of EA following other anesthetic methods in children, and further
Commonly 8(2.01) 34(8.54)
<0.0001 studies should be conducted. Finally, we did not compare the effects of
Satisfied 87(21.80) 89(22.36) nalbuphine and dexmedetomidine on EA prevention, which has recently
Very satisfied 283(70.93) 228(57.29) been widely used to prevent EA. Further studies are required to deter-
mine the ideal medications for the prevention and treatment of EA.
Satisfaction of children parents, n (%) In conclusion, nalbuphine can reduce the incidence of EA in children
Very after adenotonsillectomy, which may occur through both analgesic and
0 0
dissatisfied
Dissatisfied 6(1.50) 18(4.52)
non-analgesic pathways. Furthermore, nalbuphine did not increase the
Commonly 17(4.26) 86(21.61) incidence of respiratory depression or other adverse effects. Thus our
study will help in the better management of children who undergo
<0.0001
Satisfied 71(17.79) 101(25.38)
Very satisfied 305(76.44) 193(48.49) adenotonsillectomy.

Availability of data and material

maintaining cardiac output in children [32,33]. A previous study
showed that nalbuphine produced more sedation and less agitation
The data supporting the findings of this study are available from the
during the early postoperative period in children who underwent ton-
corresponding author upon request.
sillectomy [34]. Notably, in that study, there was an increased incidence
of breath depression in patients with a 0.25 mg/kg nalbuphine injection
Disclosures
[34]. Dalens et al. [16] found that the use of 0.1 mg /kg nalbuphine can
significantly reduce the incidence of agitation without increasing side
This research received no grants from public, commercial, or not-for-
effects in children under sevoflurane anesthesia. Nalbuphine takes effect
profit funding agencies.
immediately after intravenous injection, reaching its maximum in 30
min. The mean duration of adenotonsillectomy was about 30 min. To
CRediT authorship contribution statement
preventing emergence delay, nalbuphine was administered during
anesthesia induction. In our study, injection of nalbuphine (0.1 mg/kg)
Jian He: Investigation, Writing – original draft. Lei Zhang: Data
during the induction period of anesthesia did not increase breath
curation, Writing – original draft, Visualization. Tao Tao: Conceptual-
depression and delayed the emergence of the patient. Therefore, the
ization, Investigation. Xianjie Wen: Conceptualization, Supervision.
dosage and timing of nalbuphine administration should also be
Daguang Chen: Conceptualization, Investigation. Xueqin Zheng:
considered. In our study, considering the sedative effect and the long
Investigation. Changhui Luo: Investigation. Hua Liang: Conceptuali-
action time of nalbuphine, it is possible to prolong the duration of PACU
zation, Investigation. Hanbing Wang: Conceptualization, Project
stay; therefore, it was selected for administration during the anesthesia
administration, Formal analysis.
induction period.
This study had some limitations. Firstly, since most of the children
Declaration of Competing Interest
were discharged on the day of surgery, we did not investigate the liver
and kidney function of the patients after surgery, which affected the
None.
evaluation of the safety of nalbuphine. However, nalbuphine has been
used clinically for >30 years, and there are few reports about liver,
kidney, and other organ injuries induced by nalbuphine. Secondly, the

IA 8 8 D )A A E E D A F3 H F . EC F D A 0 ,E H D A1 D (
D C DE A E A 2 F D E EIF F C D EE A C D FK , E H D /A ) D FE D E DH 8
J. He et al.
Acknowledgments
The authors thank Wenbin Peng (MD) for his invaluable assistance
with the statistics.
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A 0 ,E H D A1 D (
, E H D /A ) D FE D E DH 8