1574 SECTION XIV Pediatric Critical Care Anesthesia Principles in the Pediatric Intensive Care Unit endotracheal intubation when there are concerns regarding the use of succinylcholine (see earlier di[.]
1574 S E C T I O N X I V Pediatric Critical Care: Anesthesia Principles in the Pediatric Intensive Care Unit endotracheal intubation when there are concerns regarding the use of succinylcholine (see earlier discussion) Various investigators have evaluated potential techniques to increase the onset time of rocuronium without the need to increase the dose These studies also demonstrated that the agent or agents chosen for sedation and anesthesia during endotracheal intubation may affect not only the onset time but also the conditions for endotracheal intubation Although there was no difference noted in the time to 50% blockade (42 14 vs 45 10 s) or onset time when comparing rocuronium 0.6 mg/kg administered with either ketamine 1.5 mg/kg or thiopental mg/kg, endotracheal intubation at 50% blockade was easily performed in all patients in the ketamine group while it was difficult in 75% of patients who received thiopental.64 A significant decrease in the onset time of rocuronium (0.6 mg/kg) was also demonstrated in patients who received ephedrine (70 µg/kg) 30 seconds before the start of rapid-sequence endotracheal intubation compared with patients receiving placebo (72 19 vs 98 31 s).65 As ephedrine increases cardiac output through the release of endogenous catecholamines, drug delivery to the skeletal muscle is increased, accelerating the onset time As with other nondepolarizing NMBAs, the principle of priming has been used to accelerate the onset time of rocuronium.66 Priming involves the administration of a small percentage (10%) of the dose followed in to minutes by the remainder of the dose In a prospective trial, 84 children undergoing endotracheal intubation were randomized into one of four groups: (1) salinerocuronium 0.45 mg/kg, (2) rocuronium 0.045 mg/kg– rocuronium 0.405 mg/kg, (2) saline, (3) rocuronium 0.6 mg/kg, or (4) rocuronium 0.06–rocuronium 0.054 mg/kg.66 The median onset times and 95% confidence intervals (CIs) in the groups were 122.5 (95% CI, 8–186), 92.5 (95% CI, 68–116), 85 (95% CI, 60–142), and 55 (95% CI, 48–72) seconds, respectively, demonstrating a clinical advantage of priming regardless of whether the total dose was 0.45 or 0.6 mg/kg As noted previously, there may be issues with priming, including the potential to induce upper airway or respiratory muscle weakness with the potential for aspiration, airway obstruction, or hypoventilation, especially in critically ill patients even with the small priming dose Additionally, the majority of studies that have used priming have waited at least 60 seconds from the administration of the priming dose until the administration of the remainder of the dose, prolonging the process of medication administration for endotracheal intubation Given its rapid onset and lack of adverse effects—most notably, rhabdomyolysis and hyperkalemia with underlying neuromuscular disorders—the use of rocuronium via the IM route instead of succinylcholine in the treatment of emergencies, such as laryngospasm during anesthetic induction when IV access is lacking, would be clinically applicable However, when evaluating onset and recovery times following IM rocuronium, adequate or good to excellent intubating conditions took an average of 2.5 minutes in infants following a dose of mg/kg and minutes in children following a dose of 1.8 mg/kg.67 The clinical duration was 57 13 minutes in infants and 70 23 minutes in children The authors also demonstrated a more rapid and predictable onset with IM administration into the deltoid as compared with the quadriceps muscle, an effect similar to that noted with succinylcholine (see earlier discussion) Given these onset times, the authors concluded that IM rocuronium was not an alternative to IM succinylcholine for the emergent treatment of laryngospasm An additional issue with rocuronium in clinical practice includes pain on injection through a peripheral IV cannula.68 When rocuronium is administered immediately after the induction agent for endotracheal intubation, limb withdrawal and grimacing may be seen The incidence of pain has been reported to be as high as 50% to 80%, with a higher incidence in females than males As with propofol, various techniques have been suggested to prevent or lessen this problem, including diluting the rocuronium solution to 0.5 mg/mL instead of the commercially available 10 mg/mL or the pre-administration or co-administration of various pharmacologic agents, including lidocaine, ketamine, dexmedetomidine, thiopental, magnesium, alfentanil, and ondansetron.68,69 All of these have met with varying degrees of success When rocuronium is co-administered with thiopental into the same IV site, a precipitate may form and occlude the IV cannula or tubing This problem can be prevented by thoroughly flushing the IV site between the thiopental and rocuronium As with the other aminosteroid NMBAs, chronic anticonvulsant therapy causes resistance to the neuromuscular blocking effects of rocuronium.70 This effect is mediated by not only stimulation of the hepatic microsomal enzymes responsible for metabolism of these medications but also the upregulation of acetylcholine receptors given their low-grade antagonism of these receptors at the neuromuscular junction Although used most commonly by bolus injection for rapidsequence endotracheal intubation, there are reports of the use of rocuronium infusions in the PICU setting.71 In a cohort of 20 PICU patients, rocuronium was administered by continuous infusion to maintain to twitches of the TOF The duration of the rocuronium infusion varied from 26 to 172 hours with a total of 1492 hours of administration Following the initial bolus dose of 0.6 mg/kg, there was a mild increase in heart rate and blood pressure The infusion requirements on day varied from 0.3 to 0.8 mg/kg per hour (0.76 0.3 mg/kg per h) When evaluating all patient days, the infusion requirements varied from 0.3 to 2.2 mg/kg per hour (0.95 0.4 mg/kg per h) The infusion requirements were 0.5 to 0.8 mg/kg per hour in 45 of the 64 patient days (70%) and 0.3 to 1.0 mg/kg per hour in 58 of the 64 patient days (90%) As with other agents, there was an increase in infusion requirements over time In 14 patients who received rocuronium for days or more, infusion requirements increased from 0.65 mg/kg per hour on day to 0.84 mg/kg per hour on day In five patients who received rocuronium for days, the infusion requirements increased from 0.67 mg/kg per hour on day to 1.2 mg/kg per hour on day When the infusion was discontinued, spontaneous return of neuromuscular function occurred in 24 to 44 minutes (31 12 min) No adverse effects related to the use of rocuronium were noted Rapacuronium Although it was withdrawn from the market, a brief review of rapacuronium is helpful to outline the history of NMBAs and provide insight into their potential effects on sites other than the neuromuscular junction of skeletal muscle In an effort to meet the need for a nondepolarizing NMBA whose onset and offset parallel that of succinylcholine, rapacuronium was introduced into clinical practice in the United States in 1998 The initial clinical experience demonstrated a rapid onset, paralleling that of succinylcholine or larger doses of rocuronium, with a recovery time of less than 10 minutes, offering a specific clinical advantage over rocuronium Hemodynamic effects included vagolysis with a mild tachycardia Metabolism was hepatic with the presence of CHAPTER 131 Neuromuscular Blocking Agents active metabolites that were dependent on renal excretion, although there was no clinically significant alteration in the duration of action with renal failure or insufficiency With increased clinical use came the recognition that profound and even potentially fatal bronchospasms were associated with its administration.72 Although these problems were initially postulated to result from an inadequate depth of sedation/anesthesia during airway instrumentation, subsequent studies suggested a direct effect on the cholinergic receptors of the airway In a retrospective review of their clinical database, Rajchert et al reported that bronchospasm occurred in 12 of 287 (4.2%) of patients receiving rapacuronium.72 Five of the episodes with rapacuronium resulted in an inability to provide effective gas exchange with no exhaled end-tidal carbon dioxide following endotracheal intubation The authors noted that the risk of bronchospasm was 10.1 times greater with rapacuronium compared with other NMBAs Additional clinical data demonstrating the potential for alterations in respiratory compliance and resistance were reported in a prospective trial in 20 adults randomized to receive either cis-atracurium or rapacuronium.73 Rapacuronium was administered during general anesthesia with propofol and remifentanil in a cohort of intubated adult patients No change in compliance or resistance of the respiratory system was noted following the administration of cis-atracurium Following the administration of rapacuronium, compliance decreased and resistance increased, with clinically significant increases in peak inflating pressure As rapacuronium was administered separate from the intubation event, the changes were postulated to be directly related to the medication itself Subsequent work has further defined the potential mechanisms, including alterations in cholinergic function with antagonism of the M2 muscarinic receptor, augmentation of acetylcholine effects at the M3 muscarinic receptor, and potentiation of vagal nerve and acetylcholine-induced bronchoconstriction.74,75 The M2 muscarinic mechanism may be of particular interest, as various NMBAs have been shown to have differing degrees of activity at this receptor Similar, albeit lesser, effects have been reported with other aminosteroid NMBAs, including pipecuronium and rocuronium.76,77 During normal function at the neuromuscular junction of smooth muscle, including the airway, some of the acetylcholine that is released diffuses back to the prejunctional (M2) receptor and shuts off ongoing acetylcholine release Thus, the M2 receptor is a negative feedback receptor that regulates acetylcholine release With blockade of the M2 receptor, there may be exaggerated release of acetylcholine and, hence, exaggerated muscle contraction or bronchospasm As a result of these concerns, rapacuronium was removed from the clinical market in 2001 Mivacurium Mivacurium is a benzylisoquinolinium NMBA, which is the shortest acting of the nondepolarizing NMBAs, undergoing non– organ-dependent elimination (see later discussion) Mivacurium is available in a premixed solution in a concentration of mg/mL in 5- or 10-mL vials Following a dose of 0.2 mg/kg, onset times vary from to minutes, with a duration of action of approximately 10 minutes In a cohort of 62 children anesthetized with nitrous oxide and fentanyl, mivacurium infusion rates to maintain neuromuscular blockade were 375 19 µg/m2 per minute with a spontaneous recovery time (T4/T1 0.75) of 9.8 0.4 minutes.78 There is no accumulation during prolonged infusions Mivacurium is metabolized by nonspecific plasma cholinesterases Prolonged blockade can occur in similar clinical situations as 1575 described with succinylcholine (see earlier discussion), including congenital and acquired deficiencies of the enzyme system, butyrylcholinesterase.79,80 The metabolites of mivacurium, which are renally excreted, have little to no effect on the neuromuscular junction As with other benzylisoquinoliniums, mivacurium can produce histamine release In children, the histamine release may be associated with flushing and erythema of the skin; however, the hemodynamic effects are generally of limited clinical significance.81 The potential application for mivacurium in clinical practice has been when neuromuscular blockade is required for brief procedures (,10 minutes) in either the operating room or PICU Mivacurium can be a useful agent to provide a brief duration of neuromuscular blockade for direct laryngoscopy in the PICU to follow the progression of airway problems and then allow for the prompt spontaneous return of neuromuscular function In the intraoperative setting, the rapid and spontaneous recovery of neuromuscular function eliminates the need for the use of reversal agents, such as neostigmine (see later discussion), which may increase the incidence of postoperative nausea and vomiting Another potential use for mivacurium has been in combination with other nondepolarizing NMBAs to provide a rapid onset of neuromuscular blockade and yet avoid the prolonged duration seen when large doses of vecuronium (0.3 mg/kg) or rocuronium (1.0–1.2 mg/kg) are administered.82,83 The onset time to 90% neuromuscular blockade was 39.0 2.3 seconds with mg/kg succinylcholine and 48.0 3.5 seconds with vecuronium 0.16 mg/ kg and mivacurium 0.20 mg/kg.82 Conditions for endotracheal intubation were graded as excellent in 10 of 10 patients in both groups Despite the rapid onset, recovery times were prolonged with the combination of vecuronium and mivacurium Similar results were reported with a combination of mivacurium 0.2 mg/kg and rocuronium 0.6 mg/kg.83 Although the onset times paralleled that of succinylcholine, the recovery times (49.0 9.6 minutes) were prolonged Mivacurium may also be potentially advantageous in patients with underlying neuromuscular disorders (e.g., muscular dystrophy) In such patients, prolonged neuromuscular blockade may occur even following a single dose of intermediate-acting agents such as vecuronium, atracurium, or cis-atracurium Therefore, the use of an agent with the shortest clinical duration may be beneficial.84–86 When compared with healthy control subjects, patients with Duchenne muscular dystrophy demonstrated only a modest prolongation of the clinical effect of mivacurium.84 The median times for recovery of the first twitch of the TOF to 10%, 25%, and 90% of baseline in controls and patients with muscular dystrophy were 8.4 versus 12.0 minutes, 10.5 and 14.1 minutes, and 15.9 and 26.9 minutes, respectively Atracurium Atracurium is a nondepolarizing NMBA of the benzylisoquinolinium class, which was released for clinical use in the 1980s Following a dose of 0.6 mg/kg, acceptable conditions for endotracheal intubation are achieved in to minutes with complete twitch suppression for 15 to 20 minutes followed by another 10 to 15 minutes with a variable degree of blockade (twitch height 5%–25%) Spontaneous recovery (T4/T1 0.7) generally occurs in 40 to 60 minutes As with all the NMBAs, the use of a smaller dose (0.3–0.4 mg/kg) is feasible but will prolong the time to the onset of acceptable conditions for endotracheal intubation as well as shortening the recovery time Atracurium’s recovery profile makes it an intermediate-acting agent Atracurium can lead to 1576 S E C T I O N X I V Pediatric Critical Care: Anesthesia Principles in the Pediatric Intensive Care Unit histamine release, limiting dose escalations to speed the onset of neuromuscular blockade Although facial cutaneous flushing and erythema may occur as with mivacurium, effects on heart rate and blood pressure are generally minimal following doses up to 0.6 mg/kg.87 With larger doses, hypotension may occur In the pediatric patient, histamine release is less frequent and less profound than in adults Even when histamine release occurred, no hemodynamic changes were noted.88 Following its introduction into clinical practice, ongoing safety surveillance demonstrated no difference in the adverse effect profile of atracurium related to histamine release when compared with other NMBAs.89 Extremely rare anecdotal case reports exist regarding anaphylactoid reactions with severe bronchospasm temporally related to its administration; however, a true causal relationship cannot be proven, as the patients also received thiopental during anesthetic induction.90 Atracurium undergoes spontaneous degradation via a process known as Hofmann elimination and ester hydrolysis Therefore, its duration of action is unchanged in the presence of renal or hepatic insufficiency or failure Because of these properties, it rapidly gained favor for providing neuromuscular blockade in ICU patients, generally by continuous infusion (see later discussion) Although the metabolites of atracurium not possess significant neuromuscular blocking properties, one of the metabolic by-products of Hofmann degradation, laudanosine, has been shown to be epileptogenic in animals The actual concentrations required to cause seizures in humans is unknown, and no formal study has ever documented clinical effects from a high laudanosine level Laudanosine is renally excreted; its accumulation in patients with renal insufficiency is at least a theoretic concern although no clinically significant adverse effects have been demonstrated Infusion requirements to maintain clinical neuromuscular blockade, defined as a single twitch height of 1% to 10% of baseline, averaged µg/kg per minute during a nitrous oxide-opioid– based anesthetic.91 Recovery remains predictable and stable regardless of the duration of the infusion Within 30 minutes of discontinuation of the infusion, twitch height had spontaneously recovered to T4/T1 of 0.7 or greater.92 Reversal of neuromuscular blockade with neostigmine (see later discussion) is generally feasible within 10 to 15 minutes of discontinuing an infusion or following the administration of a single dose of 0.6 mg/kg When compared with a longer-acting agent, such as pancuronium, spontaneous recovery following a continuous infusion occurred at an average time of 15 minutes (range, 6–34 minutes) with atracurium compared with 25 minutes (range, 10.5–37 minutes) with pancuronium.93 Given its intermediate duration of action and stable recovery profile, atracurium has been used safely and effectively in patients with neuromuscular disorders, including myasthenia gravis, myotonic dystrophy, and muscular dystrophy.94,95 However, prolonged neuromuscular blockade with a recovery time of to hours has also been reported following a single dose of 0.6 mg/kg Given its predictable recovery characteristics in most patient populations, its limited hemodynamic effects, and its lack of dependence on end-organ function for elimination, atracurium remains a popular agent for neuromuscular blockade in the PICU setting In a cohort of 20 infants and children requiring neuromuscular blockade for 10 to 163 hours during mechanical ventilation, the mean effective dose of atracurium was 1.4 mg/kg per hour (range, 0.44–2.4 mg/kg per h).96 When no TOF could be elicited, the time required for the first twitch to become evident with discontinuation of the infusion was only 13.8 minutes (range, 1–38 min) The authors reported that there was no correlation between the recovery time and dose being administered However, they did note a faster recovery time when the infusion had been administered for more than 48 hours Given its non– organ-dependent elimination, atracurium has also been used in pediatric patients following orthotopic liver transplantation.97 Recovery time (T4/T1 0.7) when the infusion was discontinued averaged 23.6 minutes (range, 12–27 min) and was not prolonged compared with the general pediatric population As with rocuronium, administration with thiopental and other barbiturates may result in precipitation and occlusion of the IV cannula, necessitating flushing the line with normal saline between these two agents Hofmann elimination is a temperaturedependent process; therefore, elimination will be prolonged during induced or inadvertent hypothermia.98 During induced hypothermia (32°C) in a cohort of children, atracurium infusion requirements were 784 µg/kg per hour or 56% of that in normothermic children (1411 µg/kg per h) Recovery times were also prolonged to two to three times those in normothermic patients A similar effect has been reported with cis-atracurium during hypothermia (see later discussion) Cis-atracurium Cis-atracurium is one of the stereoisomers contained in solutions of atracurium It is six to eight times as potent as atracurium but devoid of clinically significant histamine release and hemodynamic effects.99 Cis-atracurium is available as a 2-mg/mL solution Like atracurium, cis-atracurium is an intermediate-acting neuromuscular blocking agent with a duration of action of 20 to 30 minutes following a bolus dose of 0.2 mg/kg Acceptable conditions for endotracheal intubation are provided in approximately minutes In a cohort of 80 adult patients, cis-atracurium in doses of 0.1, 0.15, and 0.2 mg/kg provided acceptable conditions for endotracheal intubation in 4.6, 3.4, and 2.8 minutes with a clinically effective duration of 45, 55, and 61 minutes.100 In a cohort of 27 infants (1–23 months of age) and 24 children (2.0–12.5 years of age), the onset time to achieve maximal blockade following a dose of 0.15 mg/kg was more rapid in infants (2.0 0.8 vs 3.0 1.2 min; P 0011).99 The clinical duration (recovery to 25% of baseline) was longer in infants (43.3 6.2 vs 36.0 5.4 min; P , 0001) Once neuromuscular function started to recover, the rate of recovery was similar between the two groups However, de Ruiter and Crawford101 reported no difference in the ED50, ED95, or infusion rate required to maintain 90% to 99% block when comparing 32 infants (0.3–1.0 year of age) and 32 children (3.1–9.6 years of age) The ED50 in the two groups was 29 versus 29 µg/kg, the ED95 was 43 versus 47 µg/kg, and the infusion rate required to maintain 90% to 99% blockade in the two groups was 1.9 versus 2.0 0.5 µg/kg per minute A prospective study evaluated cis-atracurium dosing requirements in 15 PICU patients ranging in age from 10 months to 11 years and in weight from to 28 kg.102 The cis-atracurium infusion was adjusted to maintain one twitch of the TOF Infusion requirements varied from 2.1 to 3.8 µg/kg per minute (average of 3.1 0.6 µg/kg per min) on day 1, from 2.9 to 8.1 µg/kg per minute (average of 4.5 1.6 µg/kg per min, P , 01 compared with day 1) on day 3, and from 1.4 to 22.7 µg/kg per minute during all patient days The highest infusion requirements were noted following the administration of the drug for prolonged periods of time (150 and 224 h) When the infusion was discontinued, spontaneous return of neuromuscular function was CHAPTER 131 Neuromuscular Blocking Agents noted in 14 to 33 minutes Effective neuromuscular blockade was provided, and no adverse effects related to cis-atracurium were noted In particular, no hemodynamic changes were noted with bolus dosing Odetola et al.103 evaluated the dosing requirements of cis-atracurium in a cohort of 11 PICU patients ranging in age from to years The duration of the infusions varied from 14 to 122 hours (64.5 36 h) The infusion requirements to maintain 90% to 95% neuromuscular blockade were 5.36 3.0 µg/kg per minute Laudanosine concentrations during the infusion were 163.3 116 ng/mL As in the previous study, there was an increase in dose requirements over time, and no hemodynamic effects were noted with cis-atracurium Reich et al.104 compared vecuronium and cis-atracurium, administered by continuous infusion, to provide neuromuscular blockade following surgery for congenital heart disease in a cohort of 19 patients younger than years of age The NMBA was administered to maintain one twitch of the TOF with median infusion times of 64.5 hours for cis-atracurium and 46 hours for vecuronium Median recovery time, defined as a normal TOF without fade, was shorter with cis-atracurium than with vecuronium (30 vs 180 min, P , 05) Recovery time was more than hours in of patients who received vecuronium Two of these patients had high vecuronium plasma concentrations while the other had an elevated 3-OH vecuronium level There was no difference in time to tracheal extubation, ICU stay, or hospital stay As with other NMBAs, resistance to the effects of cis-atracurium may be seen in patients treated with anticonvulsant agents.105 This effect is unrelated to metabolism and results from changes at the neuromuscular junction in patients receiving anticonvulsant agents Time to recovery of T to 25% of baseline was 69 13 minutes in patients not receiving anticonvulsant medications, 64 19 minutes in those receiving acute therapy with anticonvulsants, and 59 19 minutes in those receiving chronic anticonvulsant therapy As with atracurium, altered clearance and decreased infusion requirements are noted during decreases in body temperature.106 During induced hypothermia (34°C) to control increased ICP, cis-atracurium infusion requirements decreased to 1.7 µg/kg per minute and increased to 3.4 µg/kg per minute with return to normothermia Cis-atracurium’s predictable pharmacokinetics even in the presence of end-organ dysfunction make it a favorite choice for neuromuscular blockade in the adult patient As its chemical structure does not contain a steroid backbone, like rocuronium or vecuronium, it is postulated that it may have less potential to result in myopathic conditions resulting in prolonged weakness following its administration in the ICU setting.107 Although the practice is not paralleled in the PICU arena, it remains the primary medication used in the adult setting It is the recommended drug for neuromuscular blockade according to the adult guidelines from the Society for Critical Care Medicine.108 Reversal of Neuromuscular Blockade Although neuromuscular blockade is necessary for many surgical procedures or used for various indications in the PICU setting, even a small residual amount of blockade may compromise ventilation or upper airway patency in the critically ill patient or during the immediate postoperative period In the operating room setting, residual neuromuscular blockade is frequently reversed at the completion of the procedure to ensure adequate strength to maintain airway patency and ventilatory function following extubation of the trachea.109 In the PICU setting, when there is no 1577 longer a need for neuromuscular blockade, the agent is discontinued and spontaneous recovery is allowed The latter is appropriate, as ongoing tracheal intubation and mechanical ventilation will likely be provided for some period following the discontinuation of the NMBA Acetylcholinesterase Inhibitors Reversal of neuromuscular blockade with medications that inhibit acetylcholinesterase is possible only with nondepolarizing NMBAs Inhibition of acetylcholinesterase results in an increased concentration of acetylcholine at the neuromuscular junction to compete with the NMBA at the nicotinic receptor However, reversal of neuromuscular blockade is not feasible immediately after the administration of an NMBA; some degree of residual neuromuscular function is necessary In general clinical practice, this means that there should be one to two twitches of the TOF or that the T1 has recovered to 25% of its baseline height Depending on the dose administered, some time, generally 15 to 30 minutes with intermediate-acting agents, is necessary (see later discussion of reversal of neuromuscular blockade with sugammadex) The commonly used acetylcholinesterase inhibitors—or reversal agents—include neostigmine, pyridostigmine, and edrophonium Despite a similar mechanism of action, the clinical effects (onset, duration, and so on) of these agents differ Neostigmine and pyridostigmine are hydrolyzed by acetylcholinesterase During this process, the enzyme is carbamylated and inactivated Edrophonium does not break down the enzyme acetylcholinesterase Rather, it competitively and reversibly inhibits its function The difference in the molecular mechanism of these agents has little impact on clinical use or practice With these three agents, the peak plasma concentration is achieved at to 10 minutes following bolus administration followed by an elimination half-life of 60 to 120 minutes Clearance is markedly reduced in the setting of renal failure or insufficiency There is a marked difference in the onset times of the three reversal agents The onset of peak effect is to minutes with edrophonium, to 11 minutes with neostigmine, and 16 minutes with pyridostigmine.110,111 An additional difference is the efficacy of these agents when reversing intense blockade (90%) in that neostigmine is more effective Adverse effects related to the use of reversal agents generally relate to their inhibition of acetylcholinesterase at sites away from the neuromuscular junction These agents should always be preceded by an anticholinergic agent, such as atropine or glycopyrrolate, since the inhibition of acetylcholinesterase occurs at not only nicotinic receptors (neuromuscular junction) but also muscarinic receptors Therefore, unless preceded by an anticholinergic (antimuscarinic) agent, bradycardia and asystole can occur The time course of the bradycardic effects varies on the basis of the onset time of the agents (see earlier discussion) As such, if edrophonium is used, glycopyrrolate should be administered first and followed in to minutes by edrophonium given that the onset time of glycopyrrolate is longer than that of edrophonium The onset time of glycopyrrolate correlates well with that of neostigmine and pyridostigmine; therefore, these agents may be administered at the same time Given that the onset of atropine is rapid, it may be administered with any of the three reversal agents Other adverse effects related to the reversal agents include augmentation of cholinergic function in the gastrointestinal tract (salivation, diarrhea, nausea, and vomiting) and the respiratory tract (bronchospasm) Although the anticholinergic agents may block salivation and alterations in airway tone, their efficacy in blocking the increased gastrointestinal motility is somewhat limited 1578 S E C T I O N X I V Pediatric Critical Care: Anesthesia Principles in the Pediatric Intensive Care Unit Sugammadex Sugammadex (Bridion) is a novel pharmacologic agent that received approval for clinical use in adults from the US Food and Drug Administration (FDA) in December 2015.112 Sugammadex is a cyclodextrin; instead of inhibiting the enzyme acetylcholinesterase, it forms a tight 1:1 complex with it and encapsulates the steroidal neuromuscular blocking agents It represents a novel pharmacologic agent, being the first noncompetitive antagonist for the reversal of neuromuscular blockade Sugammadex rapidly and completely reverses the effects of rocuronium and vecuronium.113,114 There is a limited dissociation rate so that the reversal is maintained Unlike the use of acetylcholinesterase inhibitors, reversal using sugammadex is feasible even with intense blockade, providing the potential for the rapid reversal of NMBAs even immediately after their administration The potential for reversing profound neuromuscular blockade was demonstrated in a prospective trial in adult patients who were randomized to receive either rocuronium or succinylcholine for endotracheal intubation.115 Sugammadex (16 mg/kg) was administered minutes after rocuronium Mean times to recovery of T1 to 10% and 90% of baseline were significantly faster in the rocuroniumsugammadex group than the succinylcholine group The time from sugammadex administration to recovery of T1 to 90% and TOF ratio to 0.9 was 2.9 and 2.2 minutes Although sugammadex has not received FDA approval for use in pediatric patients, there is an increasing body of literature demonstrating its use in this population Three of the initial trials in the pediatric patient compared reversal of neuromuscular blockade using sugammadex (2–4 mg/kg) with the acetylcholinesterase inhibitor neostigmine.116–118 These three prospective trials involving a total of 180 pediatric patients demonstrated a significantly more rapid return of the TOF to 90% or greater and a more rapid time to tracheal extubation with sugammadex than with neostigmine No significant adverse effects were noted in these trials Dosing of sugammadex is based on the TOF response with recommendations for a dose of mg/kg when there are two or more twitches of the TOF and mg/kg if there are one or two posttetanic twitches The preliminary clinical experience in the neonatal population has shown a tendency to use the 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) when faced with a cannot intubate/ cannot ventilate scenario Although this dose is recommended, there are limited clinical data to demonstrate its lifesaving efficacy if faced with this scenario Black et al., in their published guidelines for the management of the unanticipated difficult airway in pediatric practice, concluded that sugammadex should not be administered if the child is rapidly deteriorating with decreasing oxygen saturation and hemodynamic compromise.119 The authors expressed concerned that in such a circumstance, a surgical airway is the priority and the administration of sugammadex may delay rescue techniques and restoration of oxygenation The reversal of neuromuscular blockade may take time as well as not guaranteeing a return to spontaneous ventilation, particularly when an anatomic cause of upper airway obstruction exists Therefore, although the administration of sugammadex can be considered, it should not detract from following the difficult airway algorithm The reported adverse effect profile with sugammadex has contained generally minor and self-limited issues, including nausea, vomiting, pain, hypotension, and headache A mild prolongation of the prothrombin time (PT) and partial thromboplastin time (PTT), lasting for 60 minutes, has been reported in patients receiving large doses of sugammadex (16 mg/kg).120 No clinically significant bleeding complications were noted This effect results from a laboratory artifact and not a true in vivo effect Severe adverse effects during preclinical trial 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 postulated for this response Administration of an anticholinergic agent (atropine) or a catecholamine (epinephrine), depending on the progression of the heart rate, is recommended if clinically significant bradycardia is observed In preclinical trials, allergic phenomena occurred in 0.3% of healthy volunteers, requiring treatment with only an H1-antagonist such as diphenhydramine However, in a comprehensive literature review in patients of all ages, 15 cases of hypersensitivity reactions following sugammadex administration were noted.121 All of these reactions occurred within minutes of administration The majority of the patients (11 of 15) were found to meet the World Anaphylaxis Organization criteria for anaphylaxis The authors suggested that awareness must be raised for the possibility of drug-induced hypersensitivity reactions during the critical 5-minute period immediately following sugammadex administration With these concerns in mind, sugammadex is a novel pharmacologic agent, which effectively reverses neuromuscular blockade with a mechanism that differs from the commonly used acetylcholinesterase inhibitors The pediatric data have been primarily focused on its use for reversal of rocuronium-induced neuromuscular blockade, but anecdotal experience has been reported regarding its use to reverse neuromuscular blockade from vecuronium Prospective trials in children have demonstrated a more rapid and more effective reversal of rocuronium-induced neuromuscular blockade than neostigmine Reversal of neuromuscular blockade with sugammadex offers the advantage of a decreased incidence of residual neuromuscular blockade and may be advantageous in clinical situations in which reversal of neuromuscular blockade is problematic, including patients with intense residual blockade, in the presence of hypothermia, and in those with myopathic conditions and increased sensitivity to NMBAs Sugammadex may be clinically advantageous in certain conditions in which acetylcholinesterase inhibitors are relatively contraindicated, including myotonic dystrophy and in cardiac transplantation patients Should reinstitution of neuromuscular blockade be required following reversal with sugammadex, there are several potential options, including reestablishment of neuromuscular blockade with succinylcholine, cis-atracurium, or even rocuronium using a larger dose (2 mg/kg) Monitoring Neuromuscular Blockade In the operating room, NMBAs may be used as a single dose at the start of the case to facilitate endotracheal intubation or by repeated doses or a continuous infusion to provide ongoing neuromuscular blockade Some means of monitoring neuromuscular blockade is necessary since administration of excessive doses may mandate the use of postoperative mechanical ventilation until neuromuscular blockade has worn off or can be reversed Additionally, given concerns regarding prolonged paralysis, monitoring neuromuscular function may also be considered in the PICU setting Monitoring may include some combination of visual, tactile, or electronic means of measuring the residual neuromuscular function following electrical stimulation The technique, most ... intubate/ cannot ventilate scenario Although this dose is recommended, there are limited clinical data to demonstrate its lifesaving efficacy if faced with this scenario Black et al., in their published... occasional progression to cardiac arrest has been observed within minutes after administration No mechanism has been postulated for this response Administration of an anticholinergic agent (atropine)... anesthetic.91 Recovery remains predictable and stable regardless of the duration of the infusion Within 30 minutes of discontinuation of the infusion, twitch height had spontaneously recovered to