Pancuronium

Pancuronium is an aminosteroid compound, generally available in a solution containing 1 mg/mL or 2 mg/mL of pancuronium depending on the manufacturer. A dose of 0.1 to 0.15 mg/kg provides adequate conditions for endotracheal intubation in 90 to 120 seconds. Although the higher end of the dosing range may speed the onset time for acceptable conditions for endotracheal intubation, the clinical duration is prolonged from 40 to 60 minutes to 70 to 80 minutes. Given its duration of action, pancuronium is considered a long-acting NMBA ( Box 131.5 ). The ED ₉₅ (effective dose in 95% of the population) in children is 52 µg/kg during halothane anesthesia and 81 to 93 μg/kg during an opioid-based anesthetic. The latter is more applicable to the PICU setting. The ED ₉₅ in children is slightly higher than that of adolescents. Following a dose of 70 µg/kg, the onset of neuromuscular blockade occurs more quickly in children than in adults, with 90% twitch ablation occurring at an average of 2.4 minutes in children and 4.3 minutes in adults. The time to return of the twitch height to 10% of baseline was 25 minutes in children and 46 minutes in adults while spontaneous recovery of full neuromuscular function will take significantly longer (up to 80–90 minutes).

Vagal blockade and release of norepinephrine from adrenergic nerve endings result in an increase in heart rate and blood pressure. Intraoperatively, this effect was formerly used to balance the negative chronotropic effects of the volatile anesthetic agent halothane. This physiologic effect may also result in a mild proarrhythmogenic effect for atrial tachyarrhythmias in patients with comorbid diseases or when administered with other agents that increase heart rate. Elimination is primarily renal (80%), resulting in a significantly prolonged effect with renal insufficiency or failure. Hepatic metabolism is primarily via hydroxylation with production of an active 3-OH metabolite, which retains approximately 50% of the neuromuscular blocking effects of the parent compound. The 3-OH metabolite is also dependent on renal excretion, further prolonging the effect in the setting of renal insufficiency or failure.

With its longer half-life, pancuronium is generally used by intermittent dosing to provide ongoing neuromuscular blockade in the PICU setting. Prior to the introduction of the recent generation of NMBAs (cis-atracurium, vecuronium, and rocuronium), pancuronium was the most commonly used agent in the PICU. A prospective study evaluated dosing requirements in the PICU population with pancuronium administered by a continuous infusion. Dosing for the study was an initial bolus dose of 0.1 mg/kg followed by an infusion starting at 0.05 mg/kg per hour. The infusion was titrated up and down to maintain 1 to 2 twitches of the TOF (see later discussion). Pancuronium infusion requirements varied from 0.3 to 0.22 mg/kg per hour with an average infusion rate of 0.07 ± 0.03 mg/kg per hour for the 1798 hours of the infusion. Approximately 70% of the time, the infusion requirements varied from 0.05 to 0.08 mg/kg per hour. Increased infusion requirements were noted in patients receiving anticonvulsant agents (0.14 ± 0.06 vs. 0.056 ± 0.03 mg/kg per h) and in patients who received pancuronium for more than 5 days (day 1 requirements of 0.059 mg/kg per h vs. 0.083 mg/kg per h on day 5). On discontinuation of the infusion, time to spontaneous recovery of neuromuscular function (return of the TOF to baseline and sustained tetanus to 50 Hz) varied from 35 to 75 minutes. The authors concluded that pancuronium could be effectively administered by continuous infusion to provide neuromuscular blockade in the PICU setting, being a cost-effective alternative to other agents in many clinical scenarios.

Despite its efficacy in many clinical situations, the use of pancuronium has decreased markedly over the past 20 years since the introduction of intermediate-acting agents with limited concerns of prolonged blocking following intraoperative use. With the availability of generic forms of the newer NMBAs, the cost advantages of pancuronium have decreased, limiting its use. Most recently, pancuronium has been removed from many hospital formularies, and its production may soon be discontinued.

Vecuronium

Like pancuronium, vecuronium is an aminosteroid compound. It was released for clinical use in the 1980s. Despite minor differences in its pharmacologic structure from pancuronium, its plasma clearance is 2 to 3 times as rapid. Vecuronium is available as a lyophilized powder that, in common clinical practice, is diluted to a concentration of 1 mg/mL. Its initial introduction and acceptance into anesthesia practice were facilitated by its lack of clinically significant hemodynamic effects, as it does not cause tachycardia or hypotension. In the usual clinically used doses of 0.10 to 0.15 mg/kg, acceptable conditions for endotracheal intubation are present in 80 to 90 seconds with a clinical duration of action of 30 to 40 minutes, making it an intermediate-acting agent. To speed the onset and allow for endotracheal intubation in 60 to 75 seconds, the dose can be increased to 0.3 mg/kg. However, higher doses will also provide a more prolonged duration of neuromuscular blockade of 60 to 90 minutes. Even with higher doses, vecuronium is devoid of cardiovascular effects. Metabolism is primarily hepatic (70%–80%); however, hepatic metabolism results in the production of pharmacologically active metabolites that are water soluble and therefore dependent on renal excretion. These metabolites possess roughly half of the neuromuscular blocking effects of the parent compound. This, combined with the 20% to 30% renal excretion of the parent compound, results in a prolonged clinical duration in patients with renal insufficiency. Given its 70% to 80% dependency on hepatic metabolism, the duration of action is also prolonged in patients with hepatic insufficiency. Given the immaturity of hepatic microsomal enzymes, metabolism is prolonged and its duration of action extended in neonates and young infants. ^, Vecuronium in doses of 0.10 mg/kg and 0.15 mg/kg maintained neuromuscular blockade at 90% or more of baseline for 59 and 110 minutes in neonates and infants, 18 and 38 minutes in children, and 37 and 68 minutes in adolescents.

Resistance to its effects develops with the chronic administration of the anticonvulsant phenytoin. This effect relates not only to increased hepatic metabolism but also a mild upregulation of acetylcholine receptors. That latter effect is a direct effect on the neuromuscular junction related to a mild neuromuscular blocking effect of phenytoin. Similar interactions have been reported with other anticonvulsant agents and NMBAs of the aminosteroid class. Given its lack of hemodynamic effects and current availability in generic form, thereby providing a cost-effective agent for neuromuscular blockade, vecuronium remains a commonly used agent by bolus dosing and continuous infusion for neuromuscular blockade in the PICU setting.

Rocuronium

Rocuronium is an aminosteroid NMBA that was released for clinical use in the early to mid-1990s. It is commercially available in a solution containing 10 mg/mL in either 5- or 10-mL vials. Following the dose for routine nonemergent endotracheal intubation of 0.6 mg/kg, the duration of action is 20 to 40 minutes, making it an intermediate-acting agent. However, larger doses (1.0–1.2 mg/kg) are frequently used during rapid-sequence or urgent/emergent endotracheal intubation to speed the onset time to parallel that of succinylcholine (see later discussion). As with other agents, the duration of action increases when larger doses are administered, so that 60 to 90 minutes of neuromuscular blockade generally occurs following a dose of 1.0 mg/kg. Given its dependence on hepatic metabolism, a prolonged effect can be expected in neonates and infants. A mild vagolytic effect, less in intensity than that seen with pancuronium, may increase heart rate and mean arterial pressure following bolus dosing.

Rocuronium undergoes primarily hepatic elimination (90%) with limited metabolism (1%) to active metabolites and only 10% renal excretion. ^, Although hepatic and renal disease may prolong the effect of rocuronium, this is to a much lesser extent than with pancuronium or vecuronium. When comparing adults with and without renal failure, Robertson et al. reported that there was prolongation of the clinical duration (time to recovery of the first twitch of the TOF to 25% of baseline) from 32 to 49 minutes following a dose of 0.6 mg/kg in patients with renal failure. The same investigators reported no difference in the pharmacodynamics in adults with and without renal failure with the use of a smaller dose (0.3 mg/kg). With the smaller dose of 0.3 mg/kg, the onset time was 4 minutes and neuromuscular blockade was reversible at 20 minutes. When comparing adults with renal failure and those with normal renal function, Cooper et al. reported that following rocuronium (0.6 mg/kg), onset time (65 ± 16 vs. 61 ± 25 s), clinical duration (55.0 ± 26.9 vs. 42.0 ± 9.3 min), and spontaneous recovery (time for return of the final twitch of the TOF to 70% of baseline) were all prolonged (99 ± 41 vs. 73 ± 24 min). Following an initial dose of 0.3 mg/kg, pediatric patients with renal failure had a longer onset time (19 ± 71 vs. 87 ± 43 s); however, there was no difference in the clinical duration. More specific pharmacokinetic data and an explanation for the prolonged elimination half-life of rocuronium in renal failure patients are provided by Szenohradszky et al. in their evaluation of rocuronium in a cohort of 10 adult patients undergoing renal transplantation. Following a dose of 0.6 mg/kg, although the total plasma clearance and volume of the central compartment did not differ between renal failure and control patients, the volume of distribution at steady state was larger in patients with renal failure. This resulted in a longer elimination half-life with renal failure (97.2 ± 17.3 vs. 70.9 ± 4.7 min). A summary of these studies demonstrates a slightly prolonged onset time with rocuronium and a prolonged elimination half-life (and therefore a prolonged clinical effect) in the presence of renal failure. These findings may result from alterations in the volume of distribution rather than primary alterations in clearance due to renal elimination. The prolonged duration of action may be clinically significant with doses 0.6 mg/kg or greater and can be minimized with doses of 0.3 mg/kg. However, with the smaller doses, onset times for successful endotracheal intubation will be prolonged to 2 to 3 minutes.

Given its dependence on hepatic metabolism, alterations in clearance are likely in not only patients with primary hepatic diseases but also neonates and infants owing to the immaturity of the hepatic microsomal enzymes. When comparing infants (0.1–0.8 years old) and children (2.3–8 years old), plasma clearance is decreased (4.2 ± 0.7 vs. 6.7 ± 1.1 mL/kg per min), the volume of distribution is increased (231 ± 32 vs. 165 ± 44 mL/kg), and the mean residence time is increased (56 ± 10 vs. 26 ± 9 min). Also of note, the plasma concentration required to exert a 50% neuromuscular blocking effect is decreased in neonates and infants compared with older children (1.2 ± 0.4 vs. 1.7 ± 0.4 mg/mL). The latter effect, which indicates that the neuromuscular junction of neonates and infants is more sensitive to the effects of NMBAs, is not specific for rocuronium and is seen with all NMBAs. Similar results were reported by Rapp et al., as they reported progressive increases in the clinical duration with a decrease from 5 to 12 months to 2 to 4 months to 0 to 1 month of age. The effect was further magnified when increasing the dose from 0.45 to 0.60 mg/kg. The authors also reported excellent or good conditions for endotracheal intubation in all infants with doses of 0.45 mg/kg and ablation of the twitch response at 15 to 30 seconds in neonates, demonstrating a rapid onset even with the use of lower doses (0.45 mg/kg). As with other medications that undergo primary hepatic metabolism, the clinical effects of rocuronium are prolonged in neonates and infants. Metabolism and clinical effects approach those of the adult population by 6 to 12 months of age. In the neonate or younger infant, acceptable conditions for endotracheal intubation can be achieved at 45 to 60 seconds with doses of 0.30 to 0.45 mg/kg.

The acceptance of rocuronium into the clinical arena was been expedited by its reported clinical advantage of a more rapid onset over other nondepolarizing NMBAs, thereby making it an acceptable alternative to succinylcholine for rapid-sequence intubation. Clinical studies have demonstrated acceptable conditions for endotracheal intubation in the majority of older children and adolescents within 60 seconds following a dose of 1.0 mg/kg. Of the currently available nondepolarizing NMBAs, only rocuronium has an onset of action comparable with that of succinylcholine. The remainder of the NMBAs require 90 to 120 seconds to provide conditions acceptable for endotracheal intubation even when larger doses are used. In both the pediatric and adult populations, various studies have demonstrated that rocuronium in a dose of 1.0 to 1.2 mg/kg provides acceptable conditions for endotracheal intubation within 60 seconds in the majority of patients. Mazurek et al. prospectively compared the onset times of rocuronium (1.2 mg/kg) and succinylcholine (1.5 mg/kg) in a cohort of 26 children. Anesthesia was induced with thiopental (5 mg/kg). Endotracheal intubation attempts were initiated 30 seconds after the administration of the agent. Time to endotracheal intubation was comparable between the two groups (41.8 ± 2.9 s, range: 36–45 s with succinylcholine and 40.2 ± 4.0 s, range: 33–48 s with rocuronium). However, the conditions for endotracheal intubation were slightly less favorable with rocuronium, as 7 were excellent, 5 good, and 1 fair versus 10 excellent, 2 good, and 1 fair with succinylcholine. Scheiber et al. compared conditions for endotracheal intubation provided by three of the commonly used NMBAs (rocuronium 0.6 mg/kg, vecuronium 0.1 mg/kg, and atracurium 0.5 mg/kg). Endotracheal intubation was attempted every 30 seconds. Conditions for all of the endotracheal intubations were graded as excellent or good 60 seconds after rocuronium, 120 seconds after vecuronium, and 180 seconds after atracurium. Although a larger dose of rocuronium speeds the onset time to acceptable conditions for endotracheal intubation, there is also a prolonged duration of action (60–80 min) unlike that of succinylcholine (5–10 min). The longer duration of action may be problematic should difficulties arise with the performance of endotracheal intubation, resulting in a cannot intubate/cannot ventilate scenario. Additionally, in patients with traumatic brain injury or other conditions resulting in alteration of mental status, the neurologic examination will be lost for 60 to 80 minutes following rocuronium in doses of 1 mg/kg. Despite these issues, because of its rapid onset, rocuronium remains the drug of choice for rapid-sequence or urgent/emergent 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 4 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. 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). 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. Priming involves the administration of a small percentage (10%) of the dose followed in 2 to 3 minutes by the remainder of the dose. In a prospective trial, 84 children undergoing endotracheal intubation were randomized into one of four groups: (1) saline-rocuronium 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. The median onset times and 95% confidence intervals (CIs) in the 4 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 1 mg/kg and 3 minutes in children following a dose of 1.8 mg/kg. 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. 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. ^, 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. 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 rapid-sequence endotracheal intubation, there are reports of the use of rocuronium infusions in the PICU setting. In a cohort of 20 PICU patients, rocuronium was administered by continuous infusion to maintain 1 to 2 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 1 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 3 days or more, infusion requirements increased from 0.65 mg/kg per hour on day 1 to 0.84 mg/kg per hour on day 3. In five patients who received rocuronium for 5 days, the infusion requirements increased from 0.67 mg/kg per hour on day 1 to 1.2 mg/kg per hour on day 5. 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 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. 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. 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. 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 M ₂ muscarinic receptor, augmentation of acetylcholine effects at the M ₃ muscarinic receptor, and potentiation of vagal nerve and acetylcholine-induced bronchoconstriction. ^, The M ₂ 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. ^,

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 (M ₂ ) receptor and shuts off ongoing acetylcholine release. Thus, the M ₂ receptor is a negative feedback receptor that regulates acetylcholine release. With blockade of the M ₂ 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 2 mg/mL in 5- or 10-mL vials. Following a dose of 0.2 mg/kg, onset times vary from 2 to 3 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/m per minute with a spontaneous recovery time (T ₄ /T ₁ ≥0.75) of 9.8 ± 0.4 minutes. There is no accumulation during prolonged infusions.

Mivacurium is metabolized by nonspecific plasma cholinesterases. Prolonged blockade can occur in similar clinical situations as described with succinylcholine (see earlier discussion), including congenital and acquired deficiencies of the enzyme system, butyrylcholinesterase. ^, 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.

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. ^, The onset time to 90% neuromuscular blockade was 39.0 ± 2.3 seconds with 1 mg/kg succinylcholine and 48.0 ± 3.5 seconds with vecuronium 0.16 mg/kg and mivacurium 0.20 mg/kg. 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. 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. When compared with healthy control subjects, patients with Duchenne muscular dystrophy demonstrated only a modest prolongation of the clinical effect of mivacurium. 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 2 to 3 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 (T ₄ /T ₁ ≥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 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. 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. 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. 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.

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 do 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 9 µg/kg per minute during a nitrous oxide-opioid–based anesthetic. 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 T ₄ /T ₁ of 0.7 or greater. 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. 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. ^, However, prolonged neuromuscular blockade with a recovery time of 3 to 4 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). 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. Recovery time (T ₄ /T ₁ ≥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 temperature-dependent process; therefore, elimination will be prolonged during induced or inadvertent hypothermia. 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. 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 2 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. 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). 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 Crawford reported no difference in the ED ₅₀ , ED ₉₅ , 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 ED ₅₀ in the two groups was 29 ± 3 versus 29 ± 2 µg/kg, the ED ₉₅ was 43 ± 9 versus 47 ± 7 µg/kg, and the infusion rate required to maintain 90% to 99% blockade in the two groups was 1.9 ± 4 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 4 to 28 kg. 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 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. evaluated the dosing requirements of cis-atracurium in a cohort of 11 PICU patients ranging in age from 0 to 2 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. 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 2 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 4 hours in 3 of 9 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. This effect is unrelated to metabolism and results from changes at the neuromuscular junction in patients receiving anticonvulsant agents. Time to recovery of T ₁ 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. 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. 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.

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 T ₁ 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 5 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 1 to 2 minutes with edrophonium, 7 to 11 minutes with neostigmine, and 16 minutes with pyridostigmine. ^, 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 1 to 2 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.

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. 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. ^, 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. Sugammadex (16 mg/kg) was administered 3 minutes after rocuronium. Mean times to recovery of T1 to 10% and 90% of baseline were significantly faster in the rocuronium-sugammadex 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. 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 2 mg/kg when there are two or more twitches of the TOF and 4 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 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) 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. 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). 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 H ₁ -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. All of these reactions occurred within 5 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).