Sugammadex: Applications in Pediatric Critical Care

Abstract

Sugammadex is a novel pharmacologic agent, which reverses neuromuscular blockade with a mechanism that differs from acetylcholinesterase inhibitors such as neostigmine. There is a growing body of literature demonstrating its efficacy in pediatric patients of all ages. Prospective trials have demonstrated a more rapid and more complete reversal of rocuronium-induced neuromuscular blockade than the acetylcholinesterase inhibitor, neostigmine. Unlike the acetylcholinesterase inhibitors, sugammadex effectively reverses intense or complete neuromuscular blockade. It may also be effective in situations where reversal of neuromuscular blockade is problematic including patients with neuromyopathic conditions or when acetylcholinesterase inhibitors are contraindicated. This article reviews the physiology of neuromuscular transmission as well as the published literature, regarding the use of sugammadex in pediatric population including the pediatric intensive care unit population. Clinical applications are reviewed, adverse effects are discussed, and dosing algorithms are presented.

Introduction

Neuromuscular blocking agents (NMBAs) remain a frequent and integral component of intraoperative anesthetic care to facilitate endotracheal intubation, ensure immobility, and provide relaxation of the skeletal musculature for specific surgical procedures. In addition to their perioperative applications, neuromuscular blockade may also be required in specific clinical scenarios in the pediatric intensive care unit (PICU) setting such as emergent or elective endotracheal intubation, as an adjunct in the control of intracranial pressure, to prevent shivering when hypothermia is instituted following cardiac arrest, and during the early care of patients with adult respiratory distress syndrome. ^{1 2 3 4 5 6}

In specific clinical scenarios, reversal of neuromuscular blockade may be indicated or necessary. This is performed most commonly at the completion of surgical procedures in the operating room (OR) when residual neuromuscular blockade is reversed to allow for the return of skeletal muscle function, resumption of effective spontaneous ventilation, and tracheal extubation. In the PICU setting, when there is no longer a need for neuromuscular blockade, the agent is generally discontinued followed by spontaneous recovery as ongoing tracheal intubation and mechanical ventilation will likely be provided for some period of time following the discontinuation of the NMBA. However, there may be other clinical circumstances which mandate the reversal of neuromuscular blockade such as the “cannot intubate, cannot ventilate (CICV)” scenario or when a neurological examination is required in patients with altered mental status. Previously, the only medications to accomplish this task were those that inhibited acetylcholinesterase (neostigmine and edrophonium). Through inhibition of acetylcholinesterase, these agents increase the concentration of acetylcholine at the neuromuscular junction thereby competitively reversing residual neuromuscular blockade (see later). ^{7 8}

Sugammadex: Basic Principles

Sugammadex (Bridion; Merck & Co, Whitehouse Station, New Jersey, United States) is a novel pharmacologic agent for reversal of neuromuscular blockade in that its mechanism of action does not depend on inhibition of acetylcholinesterase. ^{9 10} Approval for clinical use in adults was granted in December 2015 by the U.S. Food and Drug Administration (FDA). Sugammadex is a modified cyclic oligosaccharide (cyclodextrin), with a unique three-dimensional chemical structure. The cyclodextrin chemical structure is similar to other novel molecules including cucurbiturils, calixarenes, and pillararenes, which are being developed for drug delivery and other therapeutic or diagnostic purposes. A hydrophobic core is surrounded by peripheral hydrophilic chains, which chemically hold the structure open. The hydrophobic sequesters aminosteroidal NMBAs in a 1:1 ratio resulting in a complex of sugammadex and NMBA. The binding is nonreversible thereby preventing the release of the NMBA back into the circulation. The complex with the NMBA is water soluble and excreted in the urine.

Sugammadex can reverse neuromuscular blockade with either rocuronium or vecuronium, although the affinity for rocuronium is greater. By surrounding and encapsulating the steroidal NMBAs, rocuronium or vecuronium, it provides rapid and complete reversal and recovery of neuromuscular function even in the setting of profound or complete neuromuscular blockade. ^{11 12 13} Sugammadex forms a one-to-one complex with rocuronium or vecuronium, encapsulates the molecule, and reduces its effective concentration at the neuromuscular junction. ^{14 15} This article reviews the literature regarding the use of sugammadex in the pediatric population with a special emphasis on its potential applications in the PICU setting. Dosing algorithms are presented and its adverse effect profile is discussed.

Pharmacology of the Neuromuscular Junction

Normal neuromuscular transmission starts with depolarization of the nerve terminal (neurolemma). The depolarization of the neurolemma opens calcium channels (P channel). The translocation of calcium through the channels of the presynaptic membrane results in the movement of synaptic vesicles toward and fusion with the end plate. This is followed by the release of acetylcholine into the synaptic cleft. Acetylcholine diffuses across the synaptic cleft and binds to acetylcholine receptors on the postsynaptic membrane (sarcolemma). The subsequent depolarization of the sarcolemma leads to the release of calcium from the sarcoplasmic reticulum, its binding to troponin, and muscle contraction.

NMBAs act as competitive antagonists for acetylcholine at the acetylcholine receptor. For anticholinesterase inhibitors to be effective in reversing competitive blockade of neuromuscular transmission, the concentration of the NMBA in the synaptic cleft must be low. As such, reversal of neuromuscular blockade with acetylcholinesterase inhibitors is not clinically possible immediately after the administration of a full (“intubating”) dose of a nondepolarizing NMBA. In fact, reversal is not possible for some period of time after the NMBA has been administered based on the amount of drug given and the specific NMBA. ⁸ This translates into the clinical fact that reversal of neuromuscular blockade by acetylcholinesterase inhibitors is feasible only when significant neuromuscular function is present.

Physical monitoring of neuromuscular blockade can be accomplished using train-of-four (TOF) monitoring. TOF monitoring involves placement of monitoring electrodes over a peripheral nerve such as the facial, ulnar, or common peroneal nerves. When stimulated, this will result in movement in the muscles of the hand, face, or leg. ^{16 17} The peripheral nerve stimulator delivers two stimuli per second for 2 seconds, hence termed train-of-four. Depending on the number of acetylcholine receptors that are blocked by the nondepolarizing NMBA, there will be anywhere from zero to four responses or twitches. For reversal of neuromuscular blockade to be feasible, several or all four of the responses to TOF stimulation must be present. In clinical practice, the TOF monitoring is combined with clinical assessment at the end of the case to ensure that the patient is strong enough for tracheal extubation. Techniques for clinical assessment for effective reversal of neuromuscular blockade include measurement of negative inspiratory force or maximum inspiratory pressure, hand grip, or head lift. ¹⁸

One of the challenges with conventional reversal agents (inhibitors of acetylcholinesterase) is that even with significant residual neuromuscular function and appropriate dosing, residual blockade may still be present and compromise postoperative respiratory function by impairing both diaphragmatic/intercostal function and upper airway patency. ^{19 20 21} The presence of such residual neuromuscular has been shown to result in an increased incidence of critical respiratory events including pneumonia in the adult population. ¹⁹ Although the incidence of residual neuromuscular blockade was previously thought to be lower in children, recent studies have suggested a high incidence regardless of the patient's age with the potential for its presence to impact postoperative respiratory function. ^{21 22 23}

Sugammadex: Initial Experience

One of the primary differences and clinical advantages of the pharmacodynamics of sugammadex compared with acetylcholinesterase inhibitors is that its novel mechanism of action allows the possibility of reversing complete and profound neuromuscular blockade. ^{24 25} In a prospective trial, adult patients anesthetized with propofol and an opioid were randomized to receive either rocuronium (1.2 mg/kg) or succinylcholine (1 mg/kg). ²⁴ Sugammadex (16 mg/kg) was administered 3 minutes after rocuronium. Recovery of neuromuscular function was evaluated by measuring the time to the return of T1 to 10 and 90% of its baseline height and the return of the TOF ratio (T4/T1) to 0.9. With sugammadex, the mean times to recovery of T1 to 10 and 90% were significantly shorter (4.4 and 6.2 minutes, respectively) than spontaneous recovery following succinylcholine (7.1 and 10.9 minutes). When timed from sugammadex administration, the mean time to recovery of T1 to 10 and 90%, and TOF ratio to 0.9 was 1.2, 2.9, and 2.2 minutes, respectively.

Sugammadex has not received FDA approval for use in children; however, there is expanding clinical experience regarding its administration to pediatric-aged patients of all ages including neonates. Its use will likely continue to increase given its advantages over conventional agents for reversal of neuromuscular blockade (acetylcholinesterase inhibitors) including limited residual blockade, rapid onset, reversal of blockade in difficult clinical scenarios including patients with neuromuscular disorders (see later), and the reversal of profound blockade, its use can be expected to increase.

Sugammadex: Pediatric Applications

Prospective Perioperative Clinical Trials in Children

One of the first prospective clinical trials to include children was a multicenter, randomized, study which administered one of four doses of sugammadex (0.5, 1, 2, or 4 mg/kg) or placebo. ²⁶ The plan was an enrollment of six patients for each sugammadex dose in the following age groups: infants (28 days–23 months), children (2–11 years), adolescents (12–17 years), and adults (18–65 years). Due to expiration of study drug and early study termination, the final study cohort included 84 healthy adults and children. Following a single intraoperative dose of rocuronium (0.6 mg/kg), sugammadex was administered within 2 minutes of reappearance of T2 of the TOF. The median time from the administration of sugammadex to return of the TOF ratio to 0.9 was 0.6 ( n  = 1), 1.2 ( n  = 4), 1.1 ( n  = 6), and 1.2 ( n  = 5) minutes, respectively, in infants, children, adolescents, and adults. A longer time to full recovery of the TOF ratio to ≥ 0.9 was noted in two of the pediatric patients including 4.4 minutes in a child receiving 4 mg/kg of sugammadex and 5.2 minutes in an adolescent receiving 2 mg/kg of sugammadex. No significant adverse effects were noted. The authors concluded that sugammadex is a new reversal agent that rapidly, effectively, and safely reverses rocuronium-induced neuromuscular blockade in children, adolescents, and adults. Given the small enrollment, they cautioned that additional studies, particularly in infants were needed to fully determine the efficacy and safety of sugammadex, particularly with profound levels of neuromuscular blockade.

Several other prospective studies have compared reversal of neuromuscular blockade using sugammadex with the acetylcholinesterase inhibitor, neostigmine ( Table 1 ). ^{27 28 29 30 31} These five prospective trials involving a total of 287 pediatric patients have demonstrated various clinical advantages of sugammadex over neostigmine including a more rapid return of the TOF ratio to ≥ 90% and a shorter time to tracheal extubation with sugammadex than with neostigmine. Although the TOF ratio time varies based on the degree of neuromuscular blockade, one of the studies reported that the time required for the TOF ratio to return to 0.9 was 1.4 ± 1.2 minutes with sugammadex versus 25.16 ± 6.49 minutes with neostimgine. ²⁷

Table 1. Pediatric trials comparing sugammadex and neostigmine.

Author/reference	Study cohort and design	Outcomes
Ghoneim and El Beltagy 27	Prospective randomized trial in a cohort of 40 pediatric patients. Reversal with sugammadex (4 mg/kg) or neostigmine (0.04 mg/kg) and atropine (0.02 mg/kg) at T2 of the TOF	Time to achieve a TOF ratio ≥ 0.9 was shorter with sugammadex than neostigmine (1.4 ± 1.2 vs. 25.16 ± 6.49 min). Mean arterial pressure and heart rate were significantly higher in the neostigmine group at 2, 5, and 10 min after reversal of neuromuscular blockade
Ozgün et al 28	Prospective, randomized, blinded trial in a cohort of 60 healthy pediatric patients (2–12 y of age). NMB with rocuronium (0.6 mg/kg). Reversal at T2 of the TOF with sugammadex (2 mg/kg) or neostigmine (0.06 mg/kg) and atropine (0.2 mg/kg)	Patients receiving sugammadex exhibited more rapid and complete reversal of NMB. Recovery of TOF ratio ≥ 0.9 and tracheal extubation times were shorter with sugammadex
Kara et al 29	Prospective, randomized trial in 80 pediatric patients (2–12 y of age). NMB with rocuronium (0.6 mg/kg). Reversal with sugammadex (2 mg/kg) or neostigmine (0.03 mg/kg)	Although the TOF ratio at the time of reversal was higher in patients receiving neostigmine, tracheal extubation time and time to TOF ratio ≥ 0.9 were longer with neostigmine than with sugammadex. The TOF ratio at the time of tracheal extubation was lower with neostigmine
El Sayed and Hassan 30	Prospective, randomized trial in 70 pediatric patients. NMB with rocuronium. Reversal with sugammadex (2 mg/kg) or neostigmine (0.05 mg/kg and atropine 0.01 mg/kg)	Time to tracheal extubation and time to reach TOF ratio ≥ 0.9 were less with sugammadex. TOF after reversal was less with neostigmine
Güzelce et al 31	Prospective, randomized trial in 37 pediatric patients. Reversal with sugammadex (2 mg/kg) or neostigmine (0.05 mg/kg)	Time to recovery to the TOF ratio ≥ 0.9 and tracheal extubation time (mean of 4.30 vs. 6.06 min) were less with sugammadex

Abbreviations: NMB, neuromuscular blockade; TOF, train-of-four; T2, second twitch; TOF ratio, T4/T1.

Open Label Pediatric Trials

Other large, open label series, and retrospective reviews have reported the successful use of sugammadex to reverse perioperative neuromuscular blockade in various clinical scenarios in the pediatric-aged patient. ^{32 33 34 35} The first of these, published in the Russian literature, outlined the use of sugammadex in a cohort of 42 pediatric patients (2–17 years of age) undergoing surgery for oncologic conditions. ³² Retrospective experience has also demonstrated the efficacy of sugammadex as a component of a “fast track” anesthesia protocol to reverse neuromuscular blockade in a cohort of 14 pediatric patients following surgery for congenital heart disease using cardiopulmonary bypass. ³³ Residual neuromuscular blockade was reversed despite the impact of mild hypothermia (35–36°C) and allowed for early tracheal extubation in the OR.

Two large retrospective cohorts provide additional clinical information. Gaver et al retrospectively reviewed their experience with sugammadex and provided outcome data using a case-matched study design with patients who had received neostigmine. ³⁴ The study cohort included 1,946 patients who received sugammadex. In patients receiving sugammadex, there was a decreased incidence of bradycardia in the overall cohort and in the subgroups of older children and adolescents. As a measure of speed of recovery and tracheal extubation time, the authors measured the time from administration of the reversal agent to time out of the OR. This was significantly shorter in sugammadex-treated patients in the overall cohort (mean difference of 2.8 minutes). However, another group of investigators reported no difference in time from administration of reversal agent to time out of the OR (19.4 minutes for sugammadex vs. 19.6 minutes for neostigmine). ³⁵

Specific Clinical Scenarios

Neuromyopathic Conditions

Anecdotal experience has demonstrated the use of sugammadex to reverse neuromuscular blockade in patients with neuromyopathic conditions and weakness that may predispose to adverse effects related to the residual effects of NMBAs. ^{36 37 38 39 40 41} Even with intermediate acting NMBAs such as atracurium and vecuronium, prolonged neuromuscular blockade may occur with a single dose and reversal with acetylcholinesterase inhibitors may be ineffective. These anecdotal reports have included patients with various neuromyopathic conditions including muscular dystrophies (Duchenne, Becker, and Ullrich), myotonic dystrophy, spinal muscular atrophy, and myasthenia gravis. Furthermore, sugammadex has been shown to be safe and effective in patient populations with contraindications to reversal of neuromuscular blockade with acetylcholinesterase inhibitors such as myotonic dystrophy and Angelman's syndrome. ^{42 43 44}

Heart Transplant Recipients

With the administration of acetylcholinesterase inhibitors such as neostigmine, the increased concentration of acetylcholine at sites away from the neuromuscular junction may result in adverse physiologic effects including bradycardia. In routine clinical practice, these issues are prevented or at least mitigated by the concomitant administration of an anticholinergic agent such as atropine. However, these concerns may be magnified in a denervated heart following cardiac transplant as profound bradycardia or asystole may occur following the administration of neostigmine. In this clinical scenario, neostigmine is postulated to cause bradycardia as a result of either variable parasympathetic reinnervation or direct stimulation of nicotinic cholinergic receptors on the postganglionic parasympathetic neurons. This results in the release of acetylcholine with activation of inhibitory cardiac receptors. ⁴⁵ The cardiac allograft may also develop denervation hypersensitivity to the cholinergic effects of neostigmine that involves both the postganglionic neurons and the muscarinic myocardial receptors to the cholinergic effects of neostigmine. These factors combined with any associated intrinsic allograft sinoatrial node dysfunction may lead to profound bradycardia or sinus arrest when acetylcholinesterase inhibitors are administered to heart transplant recipients. ^{46 47} The potential for such problems has been illustrated by anecdotal reports of profound bradycardia or asystole when acetylcholinesterase inhibitors are administered to this patient population. ^{48 49 50} Given these concerns, avoidance of acetylcholinesterase inhibitors is generally recommended when caring for patients who have received a cardiac transplant.

Pharmacologic and theoretical data suggest the potential utility and safety of sugammadex to reverse neuromuscular blockade in this patient population. This has been supported by anecdotal clinical experience. ^{51 52 53} Although sugammadex generally has a limited adverse effect profile on hemodynamic function, during preclinical trials, marked bradycardia with the occasional progression to cardiac arrest has been observed within minutes after its administration (see later for a full discussion of bradycardia as a possible adverse effect of sugammadex). Furthermore, an anecdotal report outlines the temporal association of the abrupt onset of bradycardia immediately following the administration of intravenous sugammadex to reverse neuromuscular blockade at the completion of a cardiac catheterization procedure in 10-year-old heart transplant recipient. ⁵⁴ The patient had also received dexmedetomidine so its role in the bradycardia could not be ruled out.

Renal Transplant Recipients and Renal Failure Patients

Following administration, both sugammadex and sugammadex–NMBA complex are cleared unchanged via glomerular filtration without tubular secretion, absorption, or metabolism. ^{55 56} Given this elimination pathway, concern has been expressed regarding the potential for alterations in renal function to affect its pharmacokinetics or efficacy. Additionally, neither sugammadex nor the sugammadex–rocuronium complex are removed by standard forms of dialysis. ⁵⁷ The FDA package insert for sugammadex states that it is not recommended for use in patients with end‐stage renal disease as there is a theoretical concern that the prolonged plasma half-life of the sugammadex–rocuronium complex would result in a clinical scenario in which the two molecules would dissociate with a recurrence of neuromuscular blockade. Despite these concerns, sugammadex has been used both in the setting of renal insufficiency/failure and in patients undergoing renal transplantation. ^{58 59 60 61 62} Carlos et al reported reversal of profound neuromuscular blockade following renal transplantation in two pediatric patients (a 7-year-old girl and a 14-year-old girl). ⁵⁸ Despite significant residual neuromuscular blockade at the completion of the surgical procedure, sugammadex was effective and allowed for tracheal extubation.

Two pharmacokinetic studies in patients with end‐stage renal disease failed to demonstrate recurrence of neuromuscular blockade, while a third demonstrated no recurrence of neuromuscular blockade or clinical evidence of residual weakness. ^{59 60 61} Recently, the need for postoperative reintubation was evaluated in cohort of 158 adult surgical patients with end‐stage renal disease who preoperatively required renal replacement therapy and received sugammadex to reverse neuromuscular blockade. ⁶² Of the cohort, 48 patients (30%) underwent renal transplantation and 110 (70%) underwent nonrenal transplantation procedures. Of the 136 patients who had their trachea extubated at the completion of the surgical procedure, 3 required reintubation including 2 for pulmonary edema and 1 due to sepsis. No recurrence of neuromuscular blockade was observed. Additionally, when inadequate reversal of neuromuscular blockade was noted with neostigmine in 24 patients, reversal and tracheal extubation were accomplished with sugammadex. Despite these data, there remains some concern regarding the fate of the sugammadex–rocuronium complex in patients with end‐stage renal disease since the complex is dependent on renal elimination and is not removed by standard forms of dialysis. Free rocuronium is slowly cleared by hepatic metabolism and biliary excretion. Although there may be a theoretical concern for dissociation of the sugammadex–rocuronium complex, the potential for such issues is minimal as the association constant of sugammadex and rocuronium is high. ⁶³

Neonates

Clinical data regarding the use of sugammadex in the neonatal population remains somewhat limited. The neonatal population remains a group of significant interest given the sensitivity of the neonatal neuromuscular junction to the effects of NMBAs and the potential for altered pharmacokinetics of NMBAs due to maturational changes in renal, hepatic, and enzymatic function. These factors lead to the potential for difficulties with reversal of residual neuromuscular blockade in neonates.

The previously referenced article of Gaver et al included only 18 neonates in the retrospective cohort of 968 pediatric patients who had received sugammadex. ³⁴ Despite the limited number of neonates, the difference in the end-interval time (administration of reversal agent to OR exit time) between patients receiving sugammadex and those receiving neostigmine was greatest in the neonatal group as patients receiving sugammadex left the OR on an average of 11.94 minutes faster. No adverse effects and no difficulties with reversal of neuromuscular blockade were noted in neonates.

Two case reports and one open label trial, published only in abstract form, outline additional anecdotal experience with the use of sugammadex in the neonatal population. ^{64 65 66} The two case reports describe the use of sugammadex in a total of three neonates following abdominal surgery. ^{64 65} Neuromuscular blockade with rocuronium was rapidly reversed with sugammadex (2–4 mg/kg) after excision of an ovarian cyst, pyloromyotomy, and antireflux surgery. No adverse effects were noted. In addition to these case reports, Alonso et al presented, in abstract form, data regarding the reversal of neuromuscular blockade with sugammadex in 23 neonates. ⁶⁶ The study cohort included 8 patients who were 1 day old and 15 patients who were 1 to 7 days old. Despite profound residual neuromuscular blockade at the completion of surgery in all patients, reversal with sugammadex (4 mg/kg) was rapid with the TOF ratio returning to 0.9 in a median time of 1.3 minutes (range: 0.6–3.0 minutes) in the 1 day old group and a median time of 1.2 minutes (range: 0.4–2.2 minutes) in the 1 to 7 days old group.

The “Cannot Intubate, Cannot Ventilate” Scenario

In rare clinical circumstances, a NMBA that is administered to facilitate endotracheal intubation is followed by the “CICV” scenario. ⁶⁷ Although a full description of identification and management of the difficult airway is beyond the scope of this review article, sugammadex may theoretically play a role if a NMBA has been administered. ⁶⁸ The feasibility of rapid reversal of complete neuromuscular blockade immediately after the administration of an intubating dose of rocuronium was demonstrated by one of the early prospective trials in adult patients. ²⁴ This trial demonstrated the reversal of neuromuscular blockade with rocuronium (1.2 mg/kg) with sugammadex in a dose of 16 mg/kg with an average time to recovery of the TOF ratio to 0.9 of 2.2 minutes. The evidence from this clinical trial in adults is supported by anecdotal experience of reversal of neuromuscular blockade with sugammadex following failed rapid sequence intubation and a CICV scenario in an adult patient. ²⁵

Similar anecdotal experience was reported by Wołoszczuk-Gębicka et al in a 10-month-old, 5.9 kg infant who presented to the OR for upper airway evaluation due to stridor. ⁶⁸ Anesthesia was induced with propofol (3 mg/kg) and fentanyl (2 µg/kg) followed by vecuronium (0.1 mg/kg), which was administered after effective bag-valve-mask ventilation had been demonstrated. Attempts at direct laryngoscopy failed and bag-valve-mask ventilation became problematic due to insufflation of the stomach. As there was decrease in the oxygen saturation to 75%, the decision was made to abandon the procedure and sugammadex (8 mg/kg) was administered. Effective spontaneous ventilation returned within 25 seconds followed by return of a normal oxygen saturation in 90 seconds.

Additional anecdotal experience was reported by Wakimoto et al in a l.77-kg, 34 weeks' gestation neonate with duodenal atresia and tracheoesophageal fistula (TEF), who presented to the OR for gastrostomy tube placement and ligation of the TEF. ⁶⁹ Following the induction of anesthesia and endotracheal intubation, effective ventilation was feasible with positive pressure ventilation. However, after the administration of rocuronium (1 mg/kg), ventilation became problematic, insufflation of air into the stomach was noted, and the oxygen saturation decreased to 72%. Sugammadex (8 mg/kg) was administered followed in 1 to 2 minutes by the return of spontaneous ventilation and a return of the oxygen saturation to the normal range. Anesthesia was maintained with sevoflurane with spontaneous and/or assisted ventilation, while the gastrostomy tube was placed and the TEF was ligated.

Although anecdotal success with the use of sugammadex to reverse neuromuscular blockade when difficulties with ventilation are noted and its use in the CICV scenario has been suggested, this has not been met with universal support. Simulation models have been developed to evaluate the duration of anesthesia, apnea, and respiratory depression following anesthetic induction with commonly used medications. ⁷⁰ This modeling has been used to predict rates of oxygen desaturation and explore the potential efficacy of reversal of neuromuscular blockade with sugammadex and the return of spontaneous ventilation in a CICV situation. In these simulations, the duration of neuromuscular blockade and ineffective ventilation was determined to be longer with succinylcholine (1 mg/kg) than with rocuronium (1.2 mg/kg) followed 3 minutes later by sugammadex (16 mg/kg). The time to return of effective spontaneous ventilation was estimated to be 10.0 versus 4.5 minutes. Based on the expected variability in the responses to medications, the duration of intolerable depression of ventilation even with sugammadex reversal may be as long as 15 minutes in 5% of individuals. The authors concluded that clinical management of the CICV should focus primarily on restoration of airway patency, oxygenation, and ventilation by following the difficult airway algorithm of the American Society of Anesthesiologist's practice guidelines. ⁷¹ Similar sentiment was offered by Black et al in their guidelines for the management of the unanticipated difficult airway from the Association of Paediatric Anaesthetists of Great Britain and Ireland. ⁷² They concluded that sugammadex should not be administered if the child is rapidly deteriorating as they opined that a surgical airway was the priority. The concern was expressed that the administration of sugammadex may delay institution of rescue techniques and restoration of oxygenation. Additionally, the administration of sugammadex does not guarantee a return to spontaneous ventilation, particularly when an anatomical cause of upper airway obstruction exists.

Miscellaneous Applications

Anecdotal reports have outlined additional unique applications of sugammadex. Langley et al administered sugammadex to reverse residual neuromuscular and what they postulated be adverse central nervous system (CNS) effects of rocuronium in a 2-day-old neonate following TEF repair. ⁷³ Postoperatively, in addition to residual weakness and hypotonia, the infant was noted to have bilaterally dilated pupils, thought to be the result of the CNS effects of rocuronium which had penetrated the immature blood–brain barrier. Following the administration of sugammadex, there was prompt improvement in muscular strength and resolution of the mydriasis. Others have reported the administration of sugammadex to treat anaphylaxis or bronchospasm following rocuronium. ^{74 75}

Adverse Effect Profile

The reported adverse effect profile with sugammadex has generally been mild including nonspecific and self-limited issues such as nausea, vomiting, pain, hypotension, and headache. A mild prolongation of the prothrombin and partial thromboplastin times was reported in patients receiving large doses (16 mg/kg). ⁷⁶ However, no clinically significant bleeding was noted and this effect was determined to be the result of a laboratory artifact.

Significant adverse effects reported during preclinical trials included bradycardia and anaphylaxis. As noted in the package insert, marked bradycardia with the occasional progression to cardiac arrest has been observed within minutes after administration. No mechanism has been proposed for this response. Rare anecdotal reports have supported the temporal association of bradycardia or cardiac conduction disturbances following sugammadex administration. ^{54 77 78 79 80} However, the incidence of bradycardia is lower with sugammadex than with neostigmine with adult studies reporting an incidence of 2% with limited data regarding the hemodynamic impact of heart rate (HR) changes or the need to treat bradycardia due to clinical compromise. ^{80 81 82} In a prospective study in 221 pediatric-aged patients, bradycardia, defined as HR less than the fifth percentile for age, was noted in 18 patients (8%), occurring at a median of 2 minutes after the administration of sugammadex. ⁸³ Bradycardia was more common in patients with comorbid cardiac conditions (7 of 18 or 38%). None of the 18 patients required treatment with vasoactive medications, anticholinergic agents, or fluid. No associated hypotension was noted. Given these issues, continuous cardiac monitoring is suggested with ready availability of medications to treat bradycardia if needed.

Data from the preclinical trials estimated the incidence of allergic phenomena to be ∼0.3% in healthy volunteers, requiring treatment with only an H ₁ -antagonist such as diphenhydramine. Anecdotal reports have reported clinical symptoms spanning the entire spectrum including a mild skin rash, urticaria, bronchospasm to anaphylactic shock requiring resuscitation. ^{84 85 86 87} In a comprehensive review of the published literature, which included patients of all ages, Tsur and Kalansky identified 15 cases of hypersensitivity reactions following the administration of sugammadex. ⁸⁸ All of the reactions occurred within 5 minutes of administration. Eleven of 15 met the World Anaphylaxis Organization criteria for anaphylaxis. The authors cautioned that awareness should be raised for drug-induced hypersensitivity reactions during the critical 5-minute period immediately following sugammadex administration.

A single-center, retrospective review identified 6 cases of possible anaphylaxis to sugammadex over a 3-year period including 15,479 patients. ⁸⁹ During the study period, the overall incidence of intraoperative hypersensitivity reactions was 0.22% and the incidence of anaphylaxis was 0.059%. The incidence of anaphylaxis associated with sugammadex was 0.039%, which led the authors to conclude that the incidence of sugammadex-associated anaphylaxis could be as high as that of any other medication administered intraoperatively including the NMBAs, succinylcholine or rocuronium. However, other investigators have suggested a lower incidence and perhaps one no greater than placebo or neostigmine. ^{90 91} Future trials are indicated to more clearly define the incidence of allergic reactions including true anaphylaxis with sugammadex. Regardless of its incidence, as with any medication administered perioperatively or to critically ill patients, ongoing patient monitoring is mandatory to allow for prompt recognition and treat of these issues. This is especially important as clinical reviews have suggested that there may be concerns with the intraoperative treatment of true anaphylactic reactions including delayed administration of epinephrine. ^{92 93}

In general, one of the major advantages of sugammadex over neostigmine and other acetylcholinesterase inhibitors is that reversal of neuromuscular blockade is more complete with no residual weakness. With the use of any agent to reverse neuromuscular blockade, a phenomenon known as “recurarization” may be of concern. Recurarization refers to the clinical scenario where reversal of neuromuscular blockade appears adequate and the patient initially appears strong, but then later during the immediate postoperative period develops weakness. Albeit rare, anecdotal reports have demonstrated the potential for this phenomenon even with sugammadex. ^{94 95 96 97}

One final issue that should be addressed with sugammadex is the concern that it may interfere with hormonal contraceptive agents. In vitro binding studies have demonstrated the binding of progesterone thereby decreasing the free plasma concentration. The administration of sugammadex has been suggested to be equivalent to missing a dose of oral contraceptive agents. The package insert suggests that if an oral contraceptive is taken on the same day that sugammadex is administered, the patient must use an additional, nonhormonal contraceptive method of contraception for the next 7 days. ^{98 99} Given these concerns, we have modified our electronic medical record to automatically print an information sheet regarding these concerns. This information is given to all female patients of child-bearing age.

Conclusion

Sugammadex is a novel pharmacologic agent that was approved for clinical use in adults by the U.S. FDA in 2015. It has a novel mechanism of action, which does not rely on inhibition of acetylcholinesterase to reverse neuromuscular blockade induced by the steroidal NMBAs. There is a growing body of literature demonstrating its efficacy in pediatric patients of all ages. Prospective trials in both adult and pediatric patients have demonstrated a more rapid and more complete reversal of rocuronium-induced neuromuscular blockade than the acetylcholinesterase inhibitor, neostigmine. Unlike the acetylcholinesterase inhibitors, sugammadex effectively reverses intense or complete neuromuscular blockade. It may also be effective in situations where reversal of neuromuscular blockade is problematic including patients with neuromyopathic conditions or when acetylcholinesterase inhibitors are contraindicated. Although reversal of neuromuscular is feasible even immediately following a dose of rocuronium, when faced with the CICV scenario, treatment should follow standard recommended algorithms. Although the administration of sugammadex may be considered, it should not detract from following these algorithms.

Dosing is generally based on the TOF response with a dose of 2 mg/kg when there are ≥ 2 twitches of the TOF and 4 mg/kg if there are only one to two posttetanic twitches. A larger dose may be required for complete or more intense blockaded. The preliminary clinical experience in the neonatal population has demonstrated a preference to use the 4 mg/kg dose in this age group. The maximum dose of 16 mg/kg is recommended for reversal immediately following an intubating dose of rocuronium (1.2 mg/kg). While costs vary significantly from region to region, the acquisition costs at our institution when using sugammadex are relatively equivalent to reversal of neuromuscular blockade with a combination of neostigmine and glycopyrrolate.

Should reinstitution of neuromuscular blockade be required following reversal with sugammadex, there are several potential options including the administration of a nonsteroidal NMBA (cis-atracurium) or succinylcholine. ^{100 101} Depending on the dose of sugammadex and the duration of time after its administration, it may be feasible to use a larger dose of rocuronium. One case report outlines the effective re-establishment of neuromuscular blockade with rocuronium (2 mg/kg), administered 30 minutes after sugammadex, although a longer time to onset of maximal blockade (6 minutes) was noted. ¹⁰²