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INTRODUCTION
Tonsillectomy is one of the most common surgical procedures performed on pediatric patients [1]. Given the high incidence of perioperative respiratory complications [2], optimizing the reversal of neuromuscular blockade is crucial for improving patient outcomes.
Younger age, obesity, and recent upper respiratory tract infections are risk factors for respiratory complications in children undergoing tonsillectomy. These factors can increase the risk of respiratory complications in up to 50% of high-risk patients [3]. Additionally, residual neuromuscular blockade (train-of-four [TOF] ratio < 0.9) after administering neuromuscular blocking agents can impair the functions of all respiratory muscles, resulting in airway obstruction and increased perioperative respiratory complications [4].
Neostigmine is commonly used to reverse neuromuscular blockade; however, improper use after complete reversal can paradoxically suppress upper airway muscle function. In contrast, sugammadex is a selective neuromuscular blocking reversal agent with an encapsulating mechanism of action that does not affect respiratory muscle function and reverses neuromuscular blockade more rapidly and effectively than neostigmine [5-7]. Sugammadex also reduces the incidence of postoperative pulmonary complications in high-risk patients [8-10]. Despite these advantages, sugammadex is not without risks. Reports of laryngospasm [11,12] and anaphylaxis [13] exist, highlighting the need for careful usage, even though it has recently been approved for use in children over 2 years old.
Few studies have investigated emergence-related respiratory adverse events in pediatric patients. Furthermore, the potential association between sugammadex and emergence delirium—beyond its known respiratory effects—has also drawn growing attention, as previous studies have reported inconsistent findings in adult and pediatric populations [14,15].
We hypothesized that reversing neuromuscular blockade in children undergoing tonsillectomy with sugammadex would lead to a higher rate of complete recovery of upper airway muscle function compared to using conventional neostigmine, thereby reducing the incidence of immediate perioperative respiratory complications. Therefore, this study compared the occurrence of respiratory adverse events—including oxygen desaturation, laryngospasm, bronchospasm, airway obstruction, severe coughing, postoperative stridor—and recovery time between sugammadex and neostigmine. We also compared the incidence of emergence delirium between sugammadex and neostigmine when used for reversing neuromuscular blockade in children undergoing tonsillectomy.
MATERIALS AND METHODS
Trial design
We performed a prospective randomized controlled trial with an allocation ratio of 1:1. The study was approved by the Institutional Review Board of the Seoul National University Hospital (No. 2203-061-1305). The trial was approved by our Institutional Review Board and registered at https://clinicaltrials.gov/ prior to patient enrollment (No. NCT05354466, date of registration: April 26, 2022). Patients whose guardians provided written informed consent after being informed of the study protocol were enrolled in the trial. The patients were registered between June 27, 2022, and September 2, 2024. This trial adhered to the Declaration of Helsinki and the ethical principles for medical research involving human subjects.
Participants
Eligible participants were pediatric patients aged 2–6 years who underwent tonsillectomy at a tertiary hospital in Seoul, Korea. Patients with a history of recent upper respiratory infection within the past 2 weeks, history of respiratory disease, known allergy to sugammadex or neostigmine, reduced renal or liver function, or arrhythmias were excluded.
Randomization and blinding
The participants were randomly assigned to either the neostigmine or sugammadex group at a 1:1 allocation ratio. A randomization table was generated using a reproducible randomization table generation site (https://sealedenvelope.com/), and envelopes marked with screening numbers were created and managed by a researcher. The names of each group were placed in envelopes marked with a screening number. When a participant was enrolled, the envelope marked with their screening number was opened to reveal the assigned group. Multiple personnel, including an independent nurse, verified the group assignment to ensure allocation concealment and reduce potential bias. A nurse who was not a member of the researcher team prepared the neostigmine or sugammadex according to a predefined protocol. The participant, anesthesiologist, and researcher who analyzed the data were blinded to the assigned groups.
Anesthesia protocol
After obtaining written informed consent, one of the patients’ guardians completed the Korean Obstructive Sleep Apnea-18 (KOSA-18) questionnaire to define the severity of the preoperative obstructive sleep apnea [16]. The symptoms of obstructive sleep apnea were graded as mild (< 60), moderate (60–80), or severe (> 80) according to the KOSA-18 score.
In our center’s routine practice, an intravenous line is placed before commencing anesthesia. Upon arrival in the operating theatre, routine hemodynamic monitoring, including electrocardiography, pulse oximetry (SpO2), non-invasive blood pressure, Patient State IndexTM (PSI, Masimo), and TwitchView electromyography (Blink Device Company) was initiated. Anesthesia was induced with 2 mg/kg propofol and 4–6 vol% sevoflurane and maintained with sevoflurane adjusted to a PSI target of 25–50. After confirming loss of consciousness with a PSI of less than 50, 0.6 mg/kg of rocuronium and 0.2 μg/kg of sufentanil were administered to facilitate endotracheal intubation and control pain, respectively. Intraoperative ventilation was provided using volume-controlled ventilation with a tidal volume of 8 ml/kg, a positive end-expiratory pressure of 5 cmH₂O, and a respiratory rate adjusted to maintain an end-tidal CO₂ between 35 and 40 mmHg throughout anesthesia. At the end of the surgery, 0.3 mg/kg (maximum 10 mg) dexamethasone and 0.1 mg/kg (maximum 4 mg) of ondansetron were administered to prevent pain, nausea, and vomiting.
Neuromuscular blockade reversal
After surgery, the TOF response and PSI were assessed and recorded prior to the administration of neuromuscular blockade reversal agents. According to established guidelines for neuromuscular block management, neostigmine should be administered when the TOF count has recovered to 1–3. For sugammadex, 4 mg/kg is recommended in cases of deep block, defined as a post-tetanic count of 1–2 or TOF count of 0, while 2 mg/kg is recommended when the second twitch reappears in response to TOF stimulation, indicating moderate block in children [4,17].
Reversal agents were administered based on the TOF count measured at the end of surgery. If the TOF count was 0, 4 mg/kg of sugammadex was administered regardless of group allocation, reflecting the practical limitations of busy clinical settings where waiting for spontaneous recovery was not always feasible. If the TOF count was greater than 0, patients in the neostigmine group received 0.05 mg/kg of neostigmine and 0.01 mg/kg of glycopyrrolate. In the sugammadex group, 4 mg/kg was administered when the TOF count was 1, and 2 mg/kg when the TOF count was between 2 and 4. All study drugs were prepared in advance, with their contents concealed and appropriately labeled.
Outcomes
The primary outcome was the occurrence of emergence-related respiratory adverse events, defined as the occurrence of any of the following respiratory events during emergence and the post-anesthesia care unit (PACU) stay: (1) oxygen desaturation < 95%, this limit was selected in line with the institutional guidelines based on the PACU discharge criteria; (2) airway obstruction, the presence of airway obstruction in combination with snoring noise and/or respiratory efforts; (3) laryngospasm, complete airway obstruction with associated muscle rigidity of the abdominal and chest wall; (4) bronchospasm, increased respiratory effort, particularly during expiration and wheeze on auscultation; (5) severe coughing, a series of pronounced, persistent severe coughs lasting more than 10 s; and (6) postoperative stridor, high-pitch sound during breathing in the postoperative period [2,18].
The secondary outcomes were the incidences of each respiratory adverse event, the lowest SpO2, incidence of bradycardia (20% lower compared with drug administration), nausea and vomiting, allergic reaction to the study drug, the recovery profile, the time to a TOF ratio of 90 (time from administration of the reversal agent to recovery of the T4/T1 ratio > 0.9 at TOF), time to extubation (time from end of surgery to extubation), PACU length of stay, and the incidence of emergence delirium.
We performed awake extubation after confirming a TOF ratio ≥ 0.9, spontaneous breathing with a tidal volume > 5 ml•kg⁻¹, and the presence of the following clinical signs: eye opening, facial grimace, purposeful movement, and conjugate gaze [19]. For consistency in assessment, an experienced anesthesiologist conducted the awakening and recorded the time to extubation.
Emergence delirium was scored 15 min after PACU arrival using the Pediatric Anesthesia Emergence Delirium (PAED) scale. The PAED scale consists of five criteria scored on a 5-point scale, with a maximum score of 20. For diagnosing emergence delirium, a cut-off value of ≥ 10 has 64% sensitivity and 86% specificity, and a cut-off value of > 12 has 100% sensitivity and 94.5% specificity [20]. Accordingly, we defined emergence delirium as PAED scores > 12.
Sample size
In a previous study, the overall incidence of respiratory adverse events was approximately 40% in patients who underwent tonsillectomy [2]. Previous reports on perioperative respiratory adverse events associated with sugammadex are lacking. Therefore, we assumed that sugammadex would reduce the incidence of respiratory adverse events to 20% based on evidence that residual paralysis occurs in up to 50% of pediatric patients and that sugammadex provides rapid and complete reversal of neuromuscular blockade [21]. With an alpha error of 0.05 and a beta error of 0.8, 79 participants were needed per group. Considering a 10% dropout rate, 176 participants were required for the study (https://powerandsamplesize.com/calculators/).
Statistical methods
An intention-to-treat (ITT) approach was used for the primary analysis. Patients were analyzed according to their randomized group allocation, regardless of the actual drug administered. The incidence of respiratory adverse events was assessed using the chi-square or Fisher’s exact test. Continuous variables were analyzed using the Student’s t-test or the Mann–Whitney U test.
A per-protocol analysis was additionally performed to assess the effect of the actual reversal agent administered. In this analysis, patients were grouped according to the agent they received, regardless of their initial randomization. This was particularly relevant for cases in which sugammadex was administered despite neostigmine group allocation due to a TOF count of 0 at the end of surgery. All statistical analyses were performed using MedCalc® version 23.0.2 (MedCalc Software Ltd.).
RESULTS
Patient demographics
We assessed 198 patients undergoing tonsillectomy for eligibility and excluded those with recent upper respiratory infection symptoms (n = 18) or who declined to participate (n = 6). Therefore, 174 patients were randomized into neostigmine (n = 87) or sugammadex (n = 87) groups. After allocation, one patient in each group denied recent upper respiratory symptoms but exhibited purulent sputum after intubation; therefore, both were excluded. In the final analysis, 86 and 86 patients were included in the neostigmine and sugammadex groups, respectively (Fig. 1).
Table 1 presents the patients’ baseline characteristics. The KOSA-18 results, representing the severity of airway obstruction symptoms from tonsil and adenoid hypertrophy, were similar between groups in both score (P = 0.098, mean difference and 95% confidence interval [CI]: –3.90, –8.52 to 0.73) and grade (P = 0.318).
ITT analysis
Table 2 presents the outcome variables. Regarding the primary outcome, the occurrence of emergence-related respiratory adverse events did not differ between the groups (sugammadex: 25/86 patients, 29.0%; neostigmine: 26/86 patients, 30.2%; P = 0.858). The incidence of each respiratory event was also similar between groups. The median lowest SpO2 during emergence and the PACU stay was 99% in both groups (P = 0.639). Bradycardia occurred in only one patient in the sugammadex group but recovered shortly after emergence (P = 0.317). No cardiac arrest or anaphylaxis was observed. One patient in the neostigmine group experienced an allergic reaction (redness and hives) after drug administration. The incidence of nausea and vomiting did not differ between the groups.
For the recovery profile, the TOF count at the end of surgery did not differ between the groups (P = 0.300). The median (interquartile range) values of PSI at the end of surgery were 41 (32, 55) in the neostigmine group and 37 (27, 45) in the sugammadex group (P = 0.004). Time to TOF recovery to 90% was significantly shorter in the sugammadex group (1 [1, 2] min) compared to the neostigmine group (4 [1, 6] min; P < 0.001). However, the time to extubation (neostigmine: 8 [6, 10] min; sugammadex: 8 [5, 11] min; P = 0.679) and PACU length of stay (neostigmine: 51 [39, 61] min; sugammadex: 50 [34, 63] min; P = 0.463) were similar between the groups.
Emergence delirium occurred in 27.9% of patients overall (48/172), with a significantly higher incidence observed in the sugammadex group than in the neostigmine group (34.9% vs. 20.9%; relative risk, 1.214; 95% CI, 1.005–1.467; P = 0.044).
Per-protocol analysis
Seven patients had a TOF count of 0 at the end of surgery, resulting in sugammadex administration (4 mg/kg) to facilitate neuromuscular recovery. Upon analysis, we found that two patients in the neostigmine group had received sugammadex instead of neostigmine for this reason. Therefore, to account for deviations from the allocated intervention, we performed a per-protocol analysis, which yielded results consistent with the ITT analysis.
Neuromuscular blockade reversal was significantly faster in the sugammadex group (n = 88) than in the neostigmine group (n = 84). However, the overall incidence of respiratory adverse events remained similar between the groups (sugammadex: 29.5% [26/88] vs. neostigmine: 29.7% [25/84]; P = 0.975), as did the time to extubation (sugammadex: 8.1 ± 3.8 min vs. neostigmine: 8.4 ± 4.0 min; P = 0.639). Notably, the incidence of emergence delirium was significantly higher in the sugammadex group (35.2% [31/88]) compared with the neostigmine group (20.2% [17/84]; P = 0.03; relative risk, 1.74).
DISCUSSION
This prospective randomized study compared the incidence of respiratory adverse events in pediatric patients undergoing tonsillectomy who received sugammadex or neostigmine for neuromuscular blockade reversal, finding no significant differences between the two. Although neuromuscular blockade reversal occurred more rapidly in the sugammadex group than in the neostigmine group, the time to extubation did not differ significantly. Furthermore, the incidence of emergence delirium was higher in the sugammadex group than in the neostigmine group.
The incidence of adverse respiratory events in children undergoing tonsillectomy ranges from 30% to 50%, which is consistent with our findings and highlights the high-risk nature of this population [2,3,18]. Yet, we found no difference in emergence-related respiratory complications between the sugammadex and neostigmine groups in this study, perhaps for one of three reasons.
First, sufentanil was used in both groups to ensure consistent analgesia and stable anesthetic conditions during surgery. Previous studies have shown that sufentanil provides better postoperative sleep quality, lower pain scores, and more stable intraoperative hemodynamics compared to fentanyl in pediatric patients undergoing tonsillectomy and adenoidectomy [22]. Although the clinical effect of a single bolus is relatively short, the elimination half-life of sufentanil (approximately 164 min) may exceed the surgical duration, potentially affecting emergence profiles, such as the time to extubation, regardless of the neuromuscular blockade reversal agent [23].
Second, at the end of surgery, approximately 70% of patients in both groups exhibited shallow or minimal neuromuscular blockade. This comparable depth of blockade at the time of reversal may have contributed to similar recovery patterns, including extubation time.
Finally, the limited observation period in our study—from the administration of the reversal agent to discharge from the PACU—combined with the inclusion of relatively low-risk patients, may have further reduced the likelihood of respiratory complications and minimized between-group differences. These factors should be considered when interpreting the study outcomes.
The incidence of emergence delirium observed in this study (approximately 27% and 35% in the ITT and per-protocol analyses, respectively) is relatively high but falls within the broad range previously reported (2–80%). This variability is likely attributable to differences in patient characteristics, anesthetic techniques, and diagnostic criteria. In our cohort, several established risk factors—such as the use of volatile anesthetics, tonsillectomy as a high-stimulation surgery, and patient age between 3 and 9 years—may have contributed to the elevated incidence [24]. Nonetheless, the incidence of emergence delirium was higher in the sugammadex group than in the neostigmine group in this study. To date, the association between sugammadex and delirium has yielded conflicting results. Rapid reversal leading to an abrupt return of consciousness or imbalance in cortical modulation may underlie an increased delirium risk. Rössler et al. [15] reported a significant association between sugammadex and an increased incidence of early postoperative delirium in adults, with an estimated odds ratio of 1.71. However, the overall odds did not differ between the sugammadex and neostigmine groups. Conversely, Korkmaz et al. [25] reported that the incidence of agitation was lower when sugammadex was used as a reversal agent versus neostigmine. In pediatric patients undergoing strabismus surgery, the incidence of emergence delirium was similar between the sugammadex and neostigmine groups [14]. Recently, several studies have highlighted the potential neuroprotective effects of sugammadex, attributing them to its rapid reversal of neuromuscular blockade, as well as its direct effects on inflammation and glial cells [26-28]. These conflicting findings highlight the need for further investigation into the potential neurological effects of sugammadex. Additional studies are warranted to better understand the mechanisms underlying emergence delirium and to determine whether sugammadex plays a direct role in its development.
In our study, hypersensitivity reactions or anaphylaxis did not occur in the sugammadex group. However, previous studies have reported incidence rates of 0.3% for hypersensitivity reactions and 0.02–0.04% for anaphylaxis [17,29], although data specifically representing pediatric patients remain limited. Bradycardia, a known adverse effect of sugammadex, has been reported in 8% of children [30], but it is generally self-limiting and does not require intervention.
Our study has some limitations. First, although the study protocol was designed to align with real-world clinical practice, the administration of 4 mg/kg sugammadex in some patients with a TOF count of 0—regardless of group allocation—may have diluted the differences between the groups and reduced the statistical power to detect significant effects. This protocol decision was made to address logistical constraints in a busy operating room environment, where waiting for TOF recovery prior to reversal was not always feasible. Second, while we conducted both ITT and per-protocol analyses, the result similarity between the two approaches may reflect the limited variability introduced by the protocol itself. These factors should be considered when interpreting the study findings. Third, this was a single-center study with a relatively small sample size, which may limit the generalizability of our findings. Larger multicenter trials are needed to validate these results in broader pediatric populations. Fourth, the use of sufentanil for analgesia in both groups may have influenced the outcomes, such as the time to extubation and emergence delirium, potentially confounding the effects attributed to the neuromuscular reversal agent. Finally, we did not evaluate long-term outcomes related to respiratory complications or emergence delirium, which could have provided further insight into the safety profile of sugammadex in children.
In conclusion, administering sugammadex instead of neostigmine to reverse neuromuscular blockade may not reduce emergence-related respiratory adverse events in children undergoing tonsillectomy. Although sugammadex enables faster neuromuscular blockade reversal, it does not significantly shorten the time to extubation and may increase the risk of emergence delirium. Further studies are needed to optimize anesthetic and analgesic strategies in this patient population.
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