1569CHAPTER 131 Neuromuscular Blocking Agents end plate occurs with contraction of the muscle fascicles or fas ciculations These fasciculations are responsible for the myalgias that may occur followin[.]
CHAPTER 131 Neuromuscular Blocking Agents • BOX 131.2 Adverse Effects of Succinylcholine Prolonged blockade with acquired or inherited pseudocholinesterase deficiency Cardiac arrhythmias • Bradycardia • Tachycardia • Asystole • Atrial and ventricular ectopy Hypertension Increased intraocular pressure Increased intragastric pressure Increased intracranial pressure Myalgias and myoglobinuria Malignant hyperthermia Hyperkalemia (see Box 131.3) signs include persistence neuromuscular blockade with a failure of the return of the train-of-four (TOF) with peripheral nerve stimulation (see later discussion) Although such problems are rare, documentation of a normal TOF is suggested before the administration of succinylcholine as well as after its administration prior to the administration of a nondepolarizing agent If problems are suggested by failure of the return of the TOF and ongoing neuromuscular blockade, treatment includes continuation of mechanical ventilation until the patient’s muscle strength returns and the provision of amnesia with an anesthetic agent (benzodiazepine, propofol, volatile anesthetic agent) Although the enzyme plasma cholinesterase is contained in fresh-frozen plasma (FFP), owing to the infectious disease concerns with the use of blood products, reversal with the administration of FFP cannot be recommended.11–13 Purified human plasma cholinesterase has also been used; however, such a practice is expensive and is not available in most centers.14 Despite its clinical efficacy, there are potentially severe or even lethal adverse effects associated with the administration of succinylcholine (Box 131.2) Direct effects on cardiac rhythm have been reported, including bradycardia, tachycardia, and atrial or ventricular ectopy.15 Succinylcholine has a chemical structure resembling that of acetylcholine and may result in bradycardia from activation of cardiac muscarinic receptors.16 Bradycardia may be more common in several specific clinical scenarios: (1) infants and young children, (2) in the presence of hypoxemia, (3) with intravenous (IV) as compared with intramuscular (IM) administration, (4) when succinylcholine is administered concurrently with other medications that have negative chronotropic effects (propofol, fentanyl), (5) in the presence of hypothermia, (6) in patients with ICP, or (7) with repeated dosing The need for repeated dosing is uncommon but may occur if endotracheal intubation is problematic and prolonged when the first dose is wearing off Although the universal administration of anticholinergic agents such as atropine is not routinely advocated, succinylcholine should be preceded by atropine in these scenarios.17 Arrhythmias— although fairly common, occurring in up to 50% of patients following the administration of succinylcholine—are generally short lived and of limited clinical significance The use of an anticholinergic agent will decrease, but not eliminate, the incidence of arrhythmias As with the potential for bradycardia, arrhythmias tend to be more common with repeated doses of succinylcholine As succinylcholine activates the acetylcholine receptor before producing neuromuscular blockade, depolarization of the muscle 1569 end plate occurs with contraction of the muscle fascicles or fasciculations These fasciculations are responsible for the myalgias that may occur following succinylcholine.18 Although not a primary concern when succinylcholine is used in the emergency setting for rapid sequence intubation, succinylcholine may not be the optimal NMBA for facilitating endotracheal intubation in more elective situations, such as outpatient surgery, as the muscle pain that results from the fasciculations may cause significant pain and interfere with activities of daily living.19 One advantage of fasciculations is that their cessation signals that neuromuscular blockade is complete and one can proceed with direct laryngoscopy and endotracheal intubation The severity of the fasciculations can be prevented by the administration of a small dose of a nondepolarizing NMBA, generally one-tenth of the dose normally used for endotracheal intubation, such as curare (0.03–0.05 mg/kg), rocuronium (0.05 mg/kg), or pancuronium (0.01 mg/kg) before succinylcholine.20 This is referred to as a defasciculating dose The technique is commonly used in the operating room as a means of preventing or attenuating the postoperative myalgias when succinylcholine is administered to adults Defasciculation is not commonly used in the pediatric population for several reasons: (1) children younger than years of age not fasciculate; (2) the defasciculating dose delays the onset of neuromuscular blockade and increases the dose of succinylcholine needed; (3) in patients with severe respiratory or hemodynamic compromise, the defasciculating dose can cause a significant degree of neuromuscular blockade, leading to respiratory insufficiency or laryngeal incompetency with the risk of aspiration; and (4) to achieve the maximal effect of the defasciculating dose, it should be administered up to to minutes prior to succinylcholine, making the technique less optimal when emergent securing of the airway is necessary If a defasciculating dose is used in patients who are awake and coherent, they should be warned that they may feel the effects of the medication, with the development of diplopia related to the effects of the drug on the extraocular muscles Additionally, some patients may feel the effects on the muscles of ventilation, resulting in complaints of shortness of breath or dyspnea In addition to myalgias, the fasciculations caused by succinylcholine may result in a transient increase in plasma creatinine phosphokinase (CPK) and myoglobin levels Myoglobinemia has been reported in up to 40% of patients receiving concomitant administration of general anesthesia with halothane.21 Plasma myoglobin levels high enough to result in myoglobinuria occur in up to 8% of patients The increase in plasma CPK and myoglobin levels does not generally occur with IM administration and may be attenuated by the administration of a defasciculating dose (see earlier discussion) These effects should be differentiated from the potentially lethal complications of rhabdomyolysis, which may occur in patients with specific disorders of the neuromuscular junction and malignant hyperthermia (see later discussion) These latter disorders absolutely contraindicate the use of succinylcholine Fasciculations may also increase intragastric pressure (IGP) and intraocular pressure (IOP) The transient and minimal rise in IGP is generally of limited clinical significance and does not increase the risk of vomiting or passive regurgitation during endotracheal intubation In the emergency setting, when succinylcholine is chosen for endotracheal intubation, rapid-sequence intubation will be used with the application of cricoid pressure to protect against acid aspiration.22 The contraction of extraocular muscles leads to an increase of IOP following the administration 1570 S E C T I O N X I V Pediatric Critical Care: Anesthesia Principles in the Pediatric Intensive Care Unit of succinylcholine The increase is transient, with a return of the IOP to baseline within to minutes The administration of succinylcholine to patients with an open-globe injury is generally contraindicated due to the theoretic risk of causing extrusion of the intraocular contents.23 In settings with an open globe in which the use of succinylcholine is considered warranted on the basis of the patient’s status, various medications—including dexmedetomidine—may blunt the increase in IOP.24,25 The effects of succinylcholine on ICP and its use in patients with altered intracranial compliance remain controversial.26 Succinylcholine may result in a mild to modest ICP increase through various postulated mechanisms, including muscle fasciculations and increased venous tone, as well as a direct cholinergic mechanism due to activation of muscle spindles in the peripheral skeletal musculature.27 The effects on ICP are generally mild and transient; however, its use in patients with altered intracranial compliance remains controversial Succinylcholine’s effects on muscle spindles have also been postulated to cause central nervous system (CNS) activation and dreaming during general anesthesia.28 The dreaming has not been associated with awareness or recall Given its rapid onset (30–45 s), succinylcholine allows for rapid endotracheal intubation and control of arterial oxygenation and ventilation As the latter are primary determinants of ICP, any direct effect on ICP due to succinylcholine can be rapidly controlled and reversed The authors of a review article evaluating the evidencebased medicine regarding succinylcholine and ICP concluded: “There is insufficient evidence that administration of suxamethonium causes an increase in intracranial pressure when administered to patients with traumatic brain injury Further adequately powered studies are required to assess such a relationship Until such evidence exists, the superior intubation conditions created by suxamethonium in comparison with rocuronium mean that suxamethonium should remain the first-choice agent for neuromuscular blockade as part of a rapid sequence induction in head-injured patients unless absolute contraindications to suxamethonium use exist.”29 Succinylcholine can also cause a transient increase in the tone of the masseter muscles The incidence of this problem was significantly higher in the perioperative setting when the volatile anesthetic agent, halothane, was still in common use and coadministered with succinylcholine A defasciculating dose of a nondepolarizing NMBA may abolish or blunt this phenomenon This effect may be seen in all the peripheral skeletal musculature but is accentuated in the masseter muscles, resulting in what is clinically known as masseter spasm Although the effect is generally mild and can be overcome by manual opening of the mouth, in rare circumstances, the masseter spasm may be severe, preventing mouth opening and precluding standard oral endotracheal intubation.30 Patients who manifest masseter spasm to this degree may be at risk for malignant hyperthermia (MH), a rare inherited disorder of muscle metabolism (see later discussion) The data regarding the relationship between masseter spasm and MH are conflicting In a prospective evaluation with monitoring of masseter muscle tone, patients who developed significant increases in masseter muscle tone did not proceed to develop MH.31 However, retrospective series have suggested that the development of masseter spasm may be a prelude to MH, clouding the issue as to how to deal with such patients.32 In the emergency situation, should patients develop masseter spasm following the administration of succinylcholine, they must be monitored for signs of MH, including hypercarbia, hyperthermia, tachycardia, and rhabdomyolysis with myoglobinuria Treatment with dantrolene is suggested should there be a concern regarding the development of MH (see later discussion) The major concerns with succinylcholine are its potential to trigger MH and the occurrence of clinically significant and potentially lethal hyperkalemia if administered to patients with various comorbid disease processes.33,34 MH is an inherited disorder (autosomal dominant) of muscle metabolism with abnormalities of the ryanodine receptor (the calcium release channel of the SR of skeletal muscle).35,36 The point mutation of the ryanodine receptor leads to ongoing release of calcium and therefore sustained muscle contraction following exposure to succinylcholine or a potent inhalational anesthetic agent During MH, ongoing muscle contraction and metabolism lead to hyperthermia, acidosis, tachycardia, hypercarbia, and rhabdomyolysis with secondary hyperkalemia Treatment includes discontinuation of the triggering agent; treatment of hyperthermia and the biochemical derangements, including acidosis and hyperkalemia; and administration of dantrolene, which blocks ongoing calcium release from the sarcoplasmic reticulum Therefore, in clinical scenarios in which succinylcholine may be administered, ready access to dantrolene is recommended Lethal hyperkalemia following succinylcholine may occur in patients with certain underlying disorders or comorbid diseases (Box 131.3).33 Although many of these disorders are clinically apparent, such as the muscular dystrophies, the occurrence of cardiac arrest following succinylcholine administration during elective surgery in apparently healthy children led to a restructuring of the package insert and recommendations for the use of succinylcholine Children with muscular dystrophy may not manifest symptoms until they are to years of age If succinylcholine is administered during routine anesthetic care or other clinical scenarios, lethal hyperkalemia can occur in apparently healthy children who have not manifested signs of their comorbid disease process Because of such problems, the current recommendations are that succinylcholine be used only for emergency airway management when rapid-sequence endotracheal intubation is necessary, when there is a concern about the ability to provide endotracheal intubation (potentially or documented difficult airway), or when IM administration is necessary because IV access cannot be secured These guidelines, which are included in the package insert, include the use of succinylcholine for rapid-sequence intubation, making it an acceptable choice in many PICU scenarios • BOX 131.3 Conditions Associated With Hyperkalemia After Succinylcholine Administration Preexisting hyperkalemia Muscular dystrophy Burns after 48 h involving 10%–15% body surface area Profound metabolic acidosis Paraplegia or quadriplegia Denervation injury Metastatic rhabdomyosarcoma Parkinson disease Disuse atrophy or prolonged bedrest Polyneuropathy Degenerative central nervous system disorders Purpura fulminans Tetanus Guillain-Barré syndrome Myotonia dystrophy Prolonged administration of nondepolarizing neuromuscular blocking agent CHAPTER 131 Neuromuscular Blocking Agents Also of concern in the pediatric population are patients with relatively rare genetic, chromosomal, or metabolic defects in whom the effects of succinylcholine have not been fully evaluated or studied Given the rarity of such syndromes, there is limited evidence-based medicine on which to provide recommendations regarding the safety of succinylcholine use In such settings, the risk-benefit ratio should be examined In many of these patients, the use of a rapidly acting, nondepolarizing NMBA such as rocuronium may be the better option The safety of succinylcholine use with minimal increases in serum potassium concentrations has been demonstrated in children with cerebral palsy as well as those with meningomyelocele.37–39 Regardless of the clinical scenario, if adverse effects occur following the administration of succinylcholine, hyperkalemia should be suspected and the resuscitation tailored accordingly In emergency situations when IV access cannot be readily obtained, succinylcholine can be administered intramuscularly in a dose of to mg/kg IM administration will result in neuromuscular blockade sufficient to allow for endotracheal intubation in to minutes and will rapidly (,30 s) treat laryngospasm occurring during anesthetic induction when IV access is not available, allowing for effective bag-valve-mask ventilation Use of the IM route for the administration of succinylcholine is most commonly chosen intraoperatively during the inhalation induction of anesthetic when IV access is not present.40 In this scenario, succinylcholine should be administered into the deltoid muscle, as the onset times in that location are more rapid than with administration into the quadriceps Alternatively, administration into the tongue or the submental space has been suggested, as blood flow to this area is generally well maintained even when peripheral vasoconstriction has occurred.41 Unlike IV administration, there is limited incidence of bradycardia with IM administration.42 The IM route is not recommended in patients with conditions that decrease cardiac output or blood flow to the muscles, such as shock or bradycardia, as the onset of action will be significantly delayed Given these concerns, IM administration is not recommended in critically ill children Rather, intraosseous administration (1–2 mg/kg) is suggested when IV access is not available.43,44 Currently, the package insert and good clinical practice allow for administration of succinylcholine when there may be a potentially difficult airway, in the emergency situation when rapid securing of the airway is necessary (full stomach when a rapidsequence intubation is performed), and when there is no IV access (IM administration), provided that there is no contraindication to its use (see Box 131.3).33 When dealing with the potentially difficult airway or unrecognized difficult airway, the major advantage of succinylcholine is that there should be return of normal neuromuscular function within 10 minutes as opposed to 60 minutes following a mg/kg intubating dose of rocuronium (see later discussion) For IV administration, dosing recommendations for succinylcholine vary from to mg/kg.45 Larger doses not improve the conditions for endotracheal intubation; however, the duration of neuromuscular blockade will be prolonged Neuromuscular Blocking Agents: Nondepolarizing Agents Nondepolarizing NMBAs function as competitive antagonists at the neuromuscular junction, antagonizing the effects of acetylcholine at the acetylcholine receptor Unlike succinylcholine, these agents not activate the acetylcholine receptor and therefore not result in fasciculations and their associated problems 1571 • BOX 131.4 Chemical Classification of Nondepolarizing Neuromuscular Blocking Agents Aminosteroid Compounds Pancuronium Rocuronium Vecuronium Pipecuronium Rapacuronium (no longer available) Benzylisoquinolinium Compounds Mivacurium Atracurium Cis-atracurium Doxacurium (see earlier discussion) Nondepolarizing NMBAs are used most commonly intraoperatively to facilitate endotracheal intubation and to provide ongoing neuromuscular blockade for specific surgical procedures, such as exploratory laparotomy When used to provide ongoing neuromuscular blockade in the operating room or ICU, these agents can be administered by intermittent bolus dosing or continuous infusions There are two basic chemical structures of the nondepolarizing NMBAs available for clinical use: aminosteroid and benzylisoquinolinium compounds (Box 131.4) The difference in their chemical structure has limited clinical significance Of more importance are differences in onset, duration of action, cardiovascular effects, metabolism, metabolic products, and cost These principles are reviewed in the remainder of this chapter The first generation of nondepolarizing NMBAs (curare, gallamine, metocurine), which were introduced into clinical practice in the 1940s, are no longer used in today’s clinical practice The past 20 years have seen a rapid growth in the development and introduction of nondepolarizing NMBAs for clinical use As these agents have more favorable profiles (onset times, recovery times, metabolic fate), they have displaced the original group introduced in the 1940s Pancuronium Pancuronium is an aminosteroid compound, generally available in a solution containing mg/mL or 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 ED95 (effective dose in 95% of the population) in children is 52 µg/kg during halothane anesthesia and 81 to 93 mg/kg during an opioid-based anesthetic.46 The latter is more applicable to the PICU setting.37 The ED95 in children is slightly higher than that of adolescents.47 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.48 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) 1572 S E C T I O N X I V Pediatric Critical Care: Anesthesia Principles in the Pediatric Intensive Care Unit • BOX 131.5 Duration of Action of Neuromuscular Blocking Agents Short Acting (10 Min) Succinylcholine Mivacurium Rapacuronium Intermediate Acting (20–40 Min) Atracurium Vecuronium Cis-atracurium Rocuronium Long Acting (60–90 Min) Pancuronium Pipecuronium Doxacurium 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.49 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 to 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 days (day 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 to times as rapid Vecuronium is available as a lyophilized powder that, in common clinical practice, is diluted to a concentration of 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.50 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.51,52 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.51 Resistance to its effects develops with the chronic administration of the anticonvulsant phenytoin.53 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 CHAPTER 131 Neuromuscular Blocking Agents 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.54,55 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.54 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).55 With the smaller dose of 0.3 mg/kg, the onset time was minutes and neuromuscular blockade was reversible at 20 minutes When comparing adults with renal failure and those with normal renal function, Cooper et al.56 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.57 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.58 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 to 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 min).59 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) 1573 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.,60 as they reported progressive increases in the clinical duration with a decrease from to 12 months to to months to to 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 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.61–63 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.62 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 were excellent, good, and fair versus 10 excellent, good, and fair with succinylcholine Scheiber et al.63 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 mg/kg Despite these issues, because of its rapid onset, rocuronium remains the drug of choice for rapid-sequence or urgent/emergent ... with succinylcholine A defasciculating dose of a nondepolarizing NMBA may abolish or blunt this phenomenon This effect may be seen in all the peripheral skeletal musculature but is accentuated in... 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... Care Unit of succinylcholine The increase is transient, with a return of the IOP to baseline within to minutes The administration of succinylcholine to patients with an open-globe injury is generally