Comparison of sugammadex and pyridostigmine bromide for reversal of rocuronium-induced neuromuscular blockade in short-term pediatric surgery: A prospective randomized study.

BACKGROUND: Sugammadex reverses rocuronium-induced neuromuscular blockade quickly and effectively. This study compared efficacy of sugammadex and pyridostigmine for reversal of rocuronium-induced light block or minimal block in children scheduled for elective entropion surgery.
METHODS: A prospective randomized study was conducted on 60 pediatric patients aged 1 to 11 years and scheduled for entropion surgery under sevoflurane anesthesia. Neuromuscular blockade was achieved by administration of 0.6 mg/kg rocuronium and assessed using train-of-four (TOF) ulnar nerve stimulation. Patients were randomly assigned to 2 groups receiving sugammadex 2 mg/kg or pyridostigmine 0.2 mg/kg plus glycopyrrolate 0.01 mg/kg. Primary outcomes were time from reversal agents administration to TOF ratio 0.9 and time from reversal agent administration to TOF ratio 1.0. Time from TOF ratio 0.9 to extubation, time from TOF ratio 1.0 to extubation, and postoperative adverse events were also recorded.
RESULTS: There were no substantial differences in demographic variables. Time from reversal agents administration to TOF ratio 0.9 and time from reversal agents to TOF ratio 1.0 were significantly faster in sugammadex group: 1.30 ± 0.84 versus 3.53 ± 2.73 minutes (P < .001) and 2.75 ± 1.00 versus 5.73 ± 2.83 minutes (P < .001). Extubation time was shorter in sugammadex group. Incidence of skin rash, nausea, vomiting, and postoperative residual neuromuscular blockade (airway obstruction) was not statistically different between groups. Incidence of patients agitation in recovery room was lower in sugammadex group.
CONCLUSION: Sugammadex provided more rapid reversal of rocuronium-induced neuromuscular blockade in pediatric patients undergoing surgery lasting 30 to 60 minutes than did pyridostigmine plus glycopyrrolate, with no differences in incidence of adverse events between groups.

RCT Entities:   Population Interventions Outcomes

Introduction

Neuromuscular blocking agents are frequently used during anesthesia to facilitate tracheal intubation, artificial ventilation, and surgical procedures. Acetylcholinesterase inhibitors (eg, neostigmine or pyridostigmine) are often administered as reversal agents to accelerate recovery from neuromuscular blockade and to prevent postoperative residual neuromuscular blockade.[

Postoperative residual neuromuscular blockade has been associated with impairment of the respiratory response to hypoxemia,[ dysfunction of the pharynx and upper esophagus resulting in possible increased risk of aspiration,[ and increased risk of postoperative pulmonary complications.[ Postoperative residual neuromuscular blockade can also occur with use of acetylcholinesterase inhibitors.[ In addition, acetylcholinesterase inhibitors are associated with undesirable muscarinic side effects such as bradycardia, hypotension, hypersalivation, and bronchoconstriction.[ These side effects can be avoided with use of anticholinergic drugs, although anticholinergic drugs can cause blurring of vision, mouth dryness, tachycardia, and sedation.[

Sugammadex is an alternative to cholinesterase inhibitors for use in reversing neuromuscular blockade. Postoperative residual neuromuscular blockade and muscarinic adverse effects are not observed when sugammadex is used to reverse rocuronium-induced neuromuscular blockade.[ However, pharmacokinetic and pharmacodynamic properties of neuromuscular blockade in children differ from those in adults because of the larger volume of distribution and the presence of immature neuromuscular receptors.[ Therefore, studies on the reversal of neuromuscular block in pediatric patients should be conducted separately from those on adults. A study comparing sugammadex with neostigmine was recently published, but comparisons of sugammadex with pyridostigmine in pediatric anesthesia are rare.[ Previous studies have compared the effects of reversal agents administered at moderate blocks (neuromuscular block of train-of-four [TOF] count 1–3).[ The neuromuscular blockade is in a minimal block (TOF ratio 0.1–0.4) to light block (0.4 < TOF ratio < 0.9) state at the end of a short 30- to 60-minute surgical procedure.[

This study aimed to compare the efficacy of sugammadex and pyridostigmine in reversing light block or minimal block of pediatric patients scheduled for elective entropion surgery.

Materials and methods

This prospective, randomized study was performed after obtaining approval from the ethics committee of Daegu Fatima Hospital (Daegu, Korea) and obtaining written consent from the person legally responsible for each child. Sixty healthy American Society of Anesthesiologists physical status classification I/II pediatric patients aged 1 to 11 years and scheduled for entropion surgery were enrolled in this study. Exclusion criteria were developmental delays, intellectual disability, anxiety disorder, chronic illness (renal disease, liver disease, neuromuscular disease, etc), previous anesthetic experience, known malignant hyperthermia in the family history, and upper respiratory infection symptom.

Randomization was performed using a random number table generated by Microsoft Excel (Microsoft Corp., Redmond, WA). Patients were classified into 2 groups of 30 patients each on the basis of the reversal agent used: sugammadex (group S) or pyridostigmine plus glycopyrrolate (group P).

A researcher blinded to the 2 types of reversal agents in syringes made of the same amount (3 mL) injected the reversal agents. An anesthesiologist responsible for TOF monitoring and data collection was blinded to the administration of the neuromuscular blockade reversal agents.

Both groups were administered atropine as premedication 30 minutes before surgery. Basic monitoring was carried out as follows: electrocardiogram, noninvasive blood pressure, pulse oximetry, capnography, and midesophageal temperature. Basic monitoring and neuromuscular monitoring were applied after injection of ketamine to avoid agitation and pain in pediatric patients.

Neuromuscular block was monitored with the TOF Watch SX (Organon, Dublin, Ireland) using the acceleromyographic response of the adductor pollicis muscle to repetitive TOF stimulation of the ulnar nerve, using surface electrodes. The peripheral heat sensor was placed on the ventral side of the hand. The acceleromyographic transducer was positioned on the palmar side of the top of the thumb. The monitored arm was immobilized on the operating table. Stabilization was achieved within 5 s at 50-Hz tetanic stimulation; 1 minute after tetanic stimulation, the fingers – excluding the thumb – were fixated and completely immobilized, and repetitive TOF stimulation was performed for at least 3 min. Calibration was then achieved by pressing the CAL button. After calibration, supramaximal stimulation was applied (current < 60 mA) with square wave pulses of 0.2-ms duration that were delivered at 2 Hz at intervals of 15 s; the TOF monitor was removed after confirmation of TOF ratio = 1.0.

After application of neuromuscular monitoring, rocuronium 0.6 mg/kg was administered. Fentanyl 1 μg/kg was used for endotracheal intubation in both groups, and dexamethasone 0.2 mg/kg was administered to prevent postoperative sore throat and spasm. Intubation was performed by 1 anesthesiologist after confirmation of TOF count 0.

Anesthesia was maintained with fraction of inspired oxygen 0.5 and 2% to 3% sevoflurane. If the surgery was expected to last longer than 30 minutes, another bolus dose of rocuronium 0.2 mg/kg was administered after the first 40 minutes. The total dose of rocuronium and the time of the last dose of rocuronium were recorded.

At the end of surgery, sugammadex 2 mg/kg or the combination of pyridostigmine 0.2 mg/kg with glycopyrrolate 0.01 mg/kg was injected after confirming TOF ratio ≥ 0.1 (minimal to light block) and sevoflurane was discontinued. If neuromuscular blockade degree at the end of surgery was TOF count 0 to 3 (intense-to-moderate block), sevoflurane was continued with 0.4 minimum alveolar concentration until reappearance of T4. If the TOF ratio did not reach 0.9 after 10 minutes of reversal agent administration, or if postoperative neuromuscular blockade symptoms were present, the rescue dose that is equal to the initial was planned to be administered. Time of administration of sugammadex or pyridostigmine-glycopyrrolate after last rocuronium administration and TOF ratio at that time were recorded. Tracheal extubation was performed when TOF ratio > 1.0 and spontaneous ventilation (tidal volume > 5 mL/kg) was maintained with appropriate oxygenation and ventilation as measured by breathing capnography, hemodynamic stability, and recovery of response to verbal commands. Extubation time was recorded. After extubation, each patient was transferred to the postanesthesia care unit (PACU). Propacetamol 30 mg/kg mixed with 50 mL normal saline was administered for 20 minutes for postoperative pain control. If the visual analogue scale score was ≥6 or if screaming and crying were present or physical restraint was required, fentanyl 1 μg/kg was administered.

Primary outcomes were time from injection of reversal agents to TOF ratio 0.9 and time from reversal agent administration to TOF ratio 1.0. Secondary outcomes were time from TOF ratio 0.9 to extubation, time from TOF ratio 1.0 to extubation, additional reversal agents, and adverse events. Adverse events included bradycardia (>20% decrease from baseline heart rate), tachycardia (increased >20% from baseline heart rate), hypotension (mean blood pressure < 50 mm Hg), nausea, vomiting, upper airway obstruction, such as laryngospasm and bronchospasm, diplopia, fever, skin rash, dry mouth, and postoperative residual neuromuscular blockade in the PACU. Postoperative neuromuscular blockade adverse events included upper airway obstruction requiring intervention, hypoxemia (<94% oxygen saturation), reintubation, and length of stay in the PACU. Patient agitation is assessed using a four-point agitation scale (FPAS)(Table 1) at 5 minutes of arrival in the recovery room and pediatric agitation emergence delirium (PAED) scales (Table 2) at 20, 40, and 60 minutes of arrival in the recovery room. The occurrence of emergence agitation was defined as when FPAS was above 3 or PAED scale was above 10. Each time agitation is assessed, the patient's pain is checked using the Wong–Baker FACES pain rating scale.

Table 1

Four point agitation scale.

Table 2

Pediatric anesthesia emergence delirium scale.

Statistical analysis

Power and sample calculators (http://powerandsamlpesize.com/Calculators/) were used for sample size calculation. In a study by Kara et al,[ recovery time (time to TOF ratio 0.9) was 0.46 ± 0.70 minutes for the experimental group versus 1.97 ± 2.14 minutes for the control group. The suggested minimum sample size was 20 per experimental group and 20 per control group at power = 0.9 and α = 0.05. Considering dropouts and failures, 32 subjects were recruited for each group; 4 patients (2 patients in each group) were excluded after refusal by patients’ guardians.

Student t tests were used to compare variables that were normally distributed, and Mann–Whitney U tests were used to compare variables that were not normally distributed. Fisher exact chi-squared tests were used to examine the development of adverse events in both groups. All statistical analyses were performed with IBM SPSS 21 (version 21.0, IBM Corp., New York, NY). Statistical significance was set at P < .05.

Results

Sixty-four subjects were recruited for this study from September 1, 2017 to June 30, 2018; 4 patients were excluded after refusal by patients’ guardians. Patients were classified into 2 groups of 30 patients each on the basis of the reversal agent used: sugammadex (group S) or pyridostigmine plus glycopyrrolate (group P). There were no substantial differences in demographic variables between groups (Table 3). The palm temperatures before injection of reversal agents were not statistically different between groups (group S: 35.7°C; [35.4–35.9°C], group P: 35.7°C; [35.1–35.9°C], P = .826) (Table 4). TOF ratios before administration of reversal agents were not statistically different between groups (group S: 23.83 ± 23.91; group P: 32.50 ± 22.48, P = .152) (Table 5). The mean time from administration of reversal agent to TOF ratio 0.9 was about 2.5 times shorter for group S (P < .001) than it was for group P. The mean time from administration of reversal agent to TOF ratio 1.0 was also about 2 times shorter for group S than for group P (P < .001). The mean time from reversal agent administration to extubation was about 2 minutes shorter for group S (P = .022) (Table 5). Mean anesthesia time was 4.68 minutes shorter for group S than for group P, but this difference was not statistically significant.

Table 3

Demographic data, by group.

Table 4

Intraoperative parameters.

Table 5

TOF ratio and evaluation of time variations, by group.

There was no significant difference in postoperative residual neuromuscular blockade. Upper airway obstructions after extubation such as bronchospasm and laryngospasm occurred in 3 patients in group S and in 7 patients in group P. The conditions of 3 patients in group P did not resolve with positive mask ventilation and improved only after lidocaine 1 mg/kg administration. However, there was no significant difference in incidence of upper airway obstruction. There was no additional reversal agent and no reintubation in both groups (Table 6). Two cases of nausea were reported in group P, but none were reported in group S; vomiting occurred in 1 patient from each group. Three patients in group P complained of dry mouth, but there were no such reports in group S (Table 6). FPAS and PAED scale at 20  minutes were statistically lower in group S, and there was no difference between the 2 groups at PAED scale at 40 minutes and 60 minutes. Incidence of emergence agitation was statistically lower in group S (Table 7). The face pain rating scale did not differ between the 2 groups at all times in the recovery room.

Table 6

Incidence of adverse events, by group.

Table 7

Emergence agitation.

Discussion

Pediatric patients have larger volumes of distribution than do adult patients because of their large volume of extracellular fluid relative to total water in the body and relative immaturity of the neuromuscular junction. Therefore, a higher dose of neuromuscular blocking agents is needed to achieve the same degree of neuromuscular blockade in a child than is required for an adult.[ In addition, the diaphragm and intercostal muscles do not achieve adult configurations of type 1 muscle fibers until a child is approximately 2 years old that are more susceptible to neuromuscular blockade than are other muscles.[ Therefore, use of neuromuscular blockade in children increases the risk of postoperative residual neuromuscular blockade.

Postoperative residual neuromuscular blockade is a clinically important complication and has been associated with hypoxic ventilatory response.[ Eikermann et al[ reported impairment of inspiratory air flow, upper airway obstruction, and a marked decrease in upper airway volumes and upper airway dilator muscle function. Herbstreit et al[ reported increased upper airway closing pressure and collapsibility. Consequently, residual neuromuscular blockade increases risk of postoperative pulmonary complications.[

For decades, cholinesterase inhibitors (neostigmine, pyridostigmine, and edrophonium) were used as reversal agents despite their undesirable muscarinic effects. In a recent study, a new reversal agent, sugammadex, was reported to cause no muscarinic effects and to have a faster recovery time than neostigmine.[ The pyridostigmine used in our study is 1/5 as potent as neostigmine, and the onset of action for pyridostigmine is 16 minutes, which is longer than the 7–11 minutes for neostigmine.[

We expected that the difference in time from reversal agent administration to TOF ratio 0.9 between the sugammadex group and pyridostigmine group would be greater than that seen in previous studies comparing neostigmine and sugammadex (in which the recovery time was up to 5 times faster for sugammadex[) and that the frequency of postoperative residual neuromuscular blockade would be higher[ because of the lower potency and later onset of pyridostigmine. Unexpectedly, our results showed that the time from reversal agent administration to TOF ratio 0.9 and the time from reversal agent administration to TOF ratio 1.0 were only 2 times faster for sugammadex than for pyridostigmine and that neither group exhibited postoperative residual neuromuscular blockade. In previous studies, additional neuromuscular blockers were administered to maintain TOF count < 2, and a reversal agent was administered when the second twitch (T2) of TOF was observed at the end of the procedure.[ In our study, additional rocuronium was not administered unless surgery was expected to continue for >30 minutes; in that case, additional rocuronium was administered after the first 40 minutes. As a result, most patients (with the exception of 3 patients: 2 patients at T2 and 1 patient at T0) had already reached a light block or minimal block state when the reversal agents were administered. This is the reason there was less difference in the time from reversal agent administration to TOF ratio 0.9 between the 2 groups than was observed in the previous study. As in other studies,[ use of sugammadex in minimal-to-light block state induced effective reversal and reduced time to TOF ratio 0.9.

Kara et al[ and Khuenl-Brady et al[ reported that the time from reversal agent to extubation was 2 times shorter for the sugammadex group. In our study, time from reversal agent to extubation was 2 minutes shorter in sugammadex group (6.23 ± 3.48 minutes) compared with pyridostigmine group (8.58 ± 3.89, P = .022). Although the time to extubation was shorter in sugammadex group as in the previous studies, the difference was smaller compared to the previous studies. This is considered a result of the shallow neuromuscular blockade state compared to previous study. In addition, the synergic effect of fentanyl used at induction and sevoflurane resulted in prolongation of extubation time compared to previous study.[ And the difference of extubation criteria may affect extubation time. The midesophageal temperature measured at the end of surgery was normal in both groups, so it did not affect time from TOF 0.9 to extubation and time from TOF 1.0 to extubation.

There was a difficulty in measuring the adverse events because the subjects were pediatric patients who were not as clear as adults in reporting symptoms. Even when patients felt dizzy, nauseous, or pain, they could not properly express their symptoms, and they exhibited nonspecific symptoms such as restlessness, grimacing, struggling, and crying. Therefore, postoperative agitation was also evaluated. Postoperative agitation may be the consequence of other etiologies, including hypoxemia, pain, bladder distension, and nausea.[ However, the causes of postoperative agitation following general anesthesia are not known exactly, and the risk factors such as preschool age, otolaryngologic procedure, and the use of sevoflurane are suggested.[ In this study, all patients in both groups were anesthetized with sevoflurane and there was no difference in nausea, vomiting, and pain in the recovery room. This might be due to less sense of suffocation because TOF 0.9, TOF 1.0, and extubation time were shorter in the sugammadex group.

There were some limitations of this study. First, it was a single-institutional study. Second, there was a difficulty in finding statistical differences between the 2 groups in terms of adverse effects because the number of patients participating in the study was small. Third, dexamethasone administration at induction may affect the frequency of nausea, vomiting, and upper airway obstruction. Fourth, sevoflurane concentration data were not collected. Sevoflurane may enhance the effect of rocuronium and affect the reversal of rocuronium-induced neuromuscular blockade.[

Reversal of rocuronium-induced neuromuscular blockade was more rapid with sugammadex than was reversal with pyridostigmine plus glycopyrrolate in pediatric patients undergoing short surgery (30–60 minutes). Overall differences in extubation time and anesthesia time were statistically insignificant. There were no statistical differences in frequency of adverse events between reversal with sugammadex and reversal with pyridostigmine plus glycopyrrolate.

Author contributions

Conceptualization: Jihyun An.

Data curation: Eunju Kim, Hyunkyum Kim.

Methodology: Ji-hyang Lee.

Resources: Kyeongyoon Woo, Donghwan Lee.

Supervision: Jihyun An.