Neuromuscular blocking agents









  • Through the blockade of skeletal muscle function, neuromuscular blocking agents (NMBAs) cause cessation of respiratory function, mandating airway control and the institution of mechanical ventilation. NMBAs should not be administered if there is any question as to the normalcy of the airway and the ability to successfully accomplish bag-valve-mask ventilation.



  • The term NMBA rather than muscle relaxant may be preferable, as the latter may imply some type of sedative or relaxant property that these agents do not possess. Use of the term NMBAs identifies in their name their mechanism of action, further emphasizing that they are devoid of sedative or analgesic properties.



  • NMBAs can broadly be divided into two separate classes on the basis of their mechanism of action. Depolarizing agents such as succinylcholine mimic the action of acetylcholine at the neuromuscular junction and activate or depolarize the muscle, whereas nondepolarizing agents such as vecuronium act as a competitive antagonist to the effects of acetylcholine at the neuromuscular junction, thereby blocking its effects.



In the pediatric ICU (PICU) setting, there are clinical circumstances in which prevention of movement is necessary, mandating the use of neuromuscular blocking agents (NMBAs; Box 131.1 ). Although these agents can be used as a single dose to facilitate brief procedures such as endotracheal intubation, prolonged administration may be necessary in specific clinical scenarios. With an improved understanding of the techniques for providing sedation and analgesia in the PICU setting and data demonstrating not only their adverse effect profile but also their lack of efficacy in specific clinical scenarios, there has been a decrease in the prolonged administration of NMBAs. However, these agents are still used in various clinical scenarios, most commonly as an adjunct in the control of intracranial pressure (ICP), to prevent shivering during hypothermia following cardiac arrest, and during the early care of patients with acute respiratory distress syndrome.



• BOX 131.1

Potential Applications of Neuromuscular Blockade in the Pediatric Intensive Care Unit





  • Facilitation of procedures or diagnostic studies




    • Endotracheal intubation



    • Invasive procedures (central line placement)



    • Radiologic imaging (magnetic resonance imaging or computed tomography scanning)




  • Immobilization during interhospital or intrahospital transportation



  • Intensive care indications




    • Facilitating mechanical ventilation (early phases of acute respiratory distress syndrome)



    • Controlling increased intracranial pressure



    • Eliminating shivering (during therapeutic hypothermia)



    • Decreasing peripheral oxygen utilization



    • Controlling severe agitation unresponsive to adequate sedation



    • Maintaining immobilization after surgical procedures



    • Controlling pulmonary vasospasm in patients with pulmonary hypertension



    • Management of patients with tetanus





Given their adverse effect profile, including the potential for increased nosocomial infections, longer duration of mechanical ventilation, atelectasis with ventilation-perfusion mismatching, and pressure injuries, NMBAs should be used only when absolutely indicated. Daily review of their continued need is suggested. Their administration should be guided by healthcare personnel with training in NMBAs’ pharmacologic adverse effect profile. Use of the term muscle relaxant should be avoided, as this seems to imply some implicit sedative or relaxing property, which these agents do not possess. Because these agents provide no amnestic, analgesic, or sedative properties, coadministration of an amnestic agent (benzodiazepine, ketamine, or propofol) is necessary whenever they are used. The term NMBA is preferred because it identifies the mechanism of action of these agents as a competitive antagonist for acetylcholine at the neuromuscular junction.


Following the administration of an NMBA and the blockade of skeletal muscle function, including the diaphragm, cessation of ventilation with apnea necessitates airway control with endotracheal intubation and the institution of mechanical ventilation. The inability to manage the airway, including the provision of bag-valve-mask ventilation and endotracheal intubation, will result in the potential for hypoxemia and death. As such, before these agents are used for endotracheal intubation, the normalcy of the airway and ability to provide bag-valve-mask ventilation and endotracheal intubation should be assessed. , If problems managing the airway or accomplishing endotracheal intubation are anticipated, NMBAs should not be administered. Furthermore, when using these medications, one should be familiar with the “cannot intubate/cannot ventilate” algorithm and have ready access to the needed equipment for rescue in this scenario.


Neuromuscular junction


Normal neuromuscular transmission results from the release of acetylcholine from the presynaptic nerve terminal, its movement across the synaptic cleft, and binding to the postsynaptic nicotinic receptor on the sarcolemma of the skeletal muscle. Acetylcholine is synthesized in the cytoplasm of the neuron from acetyl coenzyme A and choline and stored in synaptic vesicles in the axonal terminals of the presynaptic membrane. Depolarization of the presynaptic axonal membrane opens calcium channels (P channel). The movement of calcium through the channels in the presynaptic membrane results in the movement of synaptic vesicles to and fusion with the membrane. This is followed by the release of acetylcholine into the synaptic cleft. After its release from the synaptic vesicles, acetylcholine diffuses across the synaptic cleft and binds to acetylcholine receptors on the postsynaptic membrane (sarcolemma). This results in depolarization of the sarcolemma, the release of calcium from the sarcoplasmic reticulum, and muscle contraction.


The P channel can be blocked by cations such as magnesium and lithium but generally not to a clinically significant degree by calcium channel antagonists. Given their ability to block the inward movement of calcium and thereby disrupt the release of acetylcholine into the synaptic cleft, magnesium or lithium will potentiate the effect of nondepolarizing NMBAs. The excessive administration of either cation can have significant effects on normal neuromuscular function and cause muscle weakness.


The acetylcholine receptor (nicotinic receptor on the sarcolemma) is a pentameric protein composed of five subunits. There are five possible subunits (α, β, γ, δ, and ε), each of which is encoded by a different gene. The normal acetylcholine receptor found in adults includes two α subunits combined with one each of the β, δ, and ε subunits. Binding of an acetylcholine molecule to each of the two α subunits is necessary for depolarization of the sarcolemma. During various stages of development or in pathologic disease states, the composition of the acetylcholine receptor may change. Immature and denervated acetylcholine receptors have a γ subunit instead of the e, while a demyelinated neuromuscular junction contains acetylcholine receptors composed of a pentamer of α subunits. The importance of these variants is that their response (opening of the ion channel) may be dramatically different from the normal adult variant of the acetylcholine receptor. These differences can have devastating consequences following the administration of the depolarizing NMBA succinylcholine. The channel may remain open for a prolonged period, resulting in the release of intracellular potassium and systemic hyperkalemia. The acetylcholine receptor occupies the entire membrane from the outside of the muscle through the cell membrane to the inside, regulating the transmembrane movement of ions. The receptor acts to convert the chemical stimulus (acetylcholine) into an electrical impulse that results in the depolarization of the sarcolemma. The depolarization of the sarcolemma results in the release of calcium from the sarcoplasmic reticulum (SR) and muscle contraction.


Stimulation of the acetylcholine receptor opens ion channels, allowing the movement of small, positively charged cations such as sodium, potassium, and calcium. The sodium influx depolarizes the muscle membrane, leading to the release of calcium from the SR and muscle contraction. Cessation of muscle contraction is mediated by the metabolism of acetylcholine by the enzyme acetylcholinesterase, which is present in the synaptic cleft. Once acetylcholine is metabolized, the sarcolemma can repolarize, resetting the muscle for the next round of depolarization. Failure to metabolize acetylcholine that is bound to the receptor results in prolonged depolarization, inability to repolarize the sarcolemma, and cessation of further contraction.


Neuromuscular blocking agents: Depolarizing agents


The two general classes of NMBAs (depolarizing and nondepolarizing agents) differ in their basic mechanism of action. Depolarizing agents such as succinylcholine (suxamethonium in Europe and the United Kingdom) mimic the effects of acetylcholine, binding to the acetylcholine receptor at the neuromuscular junction and activating it. As succinylcholine is resistant to degradation by acetylcholinesterase, there is sustained occupation of the receptor and failure of repolarization, which results in neuromuscular blockade. This action of succinylcholine accounts for the clinical effects observed, including the initial muscle fasciculations followed by flaccid paralysis lasting 5 to 10 minutes, the time necessary for the degradation of succinylcholine by pseudocholinesterase and subsequent repolarization of the sarcolemma. The onset of action of succinylcholine is more rapid than any of the nondepolarizing agents with neuromuscular blockade, occurring in 30 to 45 seconds, allowing for rapid control of the airway with endotracheal intubation. Additionally, studies comparing succinylcholine to nondepolarizing NMBAs suggest that it produces better conditions for endotracheal intubation.


After occupancy of the acetylcholine receptor, succinylcholine undergoes rapid redistribution and metabolism by the plasma enzyme pseudocholinesterase (butyrylcholinesterase), which limits its clinical duration to 5 to 10 minutes. In rare clinical circumstances, the congenital or acquired deficiency of pseudocholinesterase can prolong the duration of action of succinylcholine. Clinical conditions may result in defects in the total amount or concentration of the enzyme (quantitative defect) or efficacy of the enzyme (qualitative defect). Decreased enzyme levels (quantitative defects) are usually acquired while qualitative issues are inherited.


The inherited form of pseudocholinesterase deficiency, resulting in a qualitative defect in the enzyme, is an autosomal-recessive trait with an incidence of 1:2500 to 1:3500 of the general population. Only homozygotes have a clinically significant prolongation of the effect of succinylcholine, with neuromuscular blockade lasting up to 4 to 8 hours following a single dose of succinylcholine (1–2 mg/kg). Conditions that lead to a quantitative decrease in pseudocholinesterase levels include severe hepatic disease, thyroid dysfunction (myxedema), pregnancy, protein-calorie malnutrition, and certain malignancies. Drugs and medications can also affect pseudocholinesterase levels, including chemotherapeutic agents such as cyclophosphamide and echothiophate ophthalmic drops. Deficiency can also result from the recent use of plasmapheresis, as the enzyme is removed with the plasma. With either qualitative or quantitative defects of pseudocholinesterase, clinical 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. Purified human plasma cholinesterase has also been used; however, such a practice is expensive and is not available in most centers.


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. Succinylcholine has a chemical structure resembling that of acetylcholine and may result in bradycardia from activation of cardiac muscarinic receptors. 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. 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.



• 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 )




As succinylcholine activates the acetylcholine receptor before producing neuromuscular blockade, depolarization of the muscle end plate occurs with contraction of the muscle fascicles or fasciculations. These fasciculations are responsible for the myalgias that may occur following succinylcholine. 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. 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. 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 6 years of age do 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 2 to 3 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. 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. The contraction of extraocular muscles leads to an increase of IOP following the administration of succinylcholine. The increase is transient, with a return of the IOP to baseline within 5 to 8 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. 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. ,


The effects of succinylcholine on ICP and its use in patients with altered intracranial compliance remain controversial. 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. 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. 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 evidence-based 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.”


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. 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. 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. 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. , 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). , 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 ). 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 4 to 6 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




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. 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 4 to 5 mg/kg. IM administration will result in neuromuscular blockade sufficient to allow for endotracheal intubation in 2 to 3 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. 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. Unlike IV administration, there is limited incidence of bradycardia with IM administration. 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. ,


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 rapid-sequence 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 ). 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 1 mg/kg intubating dose of rocuronium (see later discussion). For IV administration, dosing recommendations for succinylcholine vary from 1 to 2 mg/kg. Larger doses do 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 do not activate the acetylcholine receptor and therefore do not result in fasciculations and their associated problems (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.



• 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




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 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).



• 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. 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.


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. In the PICU setting, when there is no 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 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).


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 commonly used by anesthesiologists in the operating room to monitor the degree of neuromuscular blockade, is peripheral nerve stimulation or TOF monitoring. TOF monitoring involves placement of standard electrocardiographic electrodes over a peripheral nerve. The nerves most commonly used are the facial, ulnar, or common peroneal, which result in corresponding movement in the muscles of the hand, face, or leg. In some circumstances, direct stimulation of the muscle may occur, giving the false impression that an appropriate amount of neuromuscular blockade has not been achieved. To avoid such problems, it may be appropriate to place the TOF monitor and assess the twitch response before the administration of the initial dose of the NMBA. The electrodes of the TOF monitor are connected to a handheld peripheral nerve stimulator, which delivers two stimuli per second at 50 mA for 2 seconds. A total of four stimuli are administered over 2 seconds—hence, the term train-of-four. As this is painful, it should only be performed in patients who are anesthetized or sedated. Depending on the number of acetylcholine receptors that are occupied by the nondepolarizing NMBA, there will be anywhere from zero to four responses or twitches. Despite the availability of other more sophisticated machines to monitor the degree of neuromuscular blockade in the operating room and ICU setting, these monitors are generally used only for clinical research purposes. In clinical practice in either the operating room or PICU, TOF monitoring remains the technique that provides the most useful information with limited requirements for training and equipment.


In clinical practice, the TOF monitoring is combined with clinical assessment at the end of the case to ensure that the patient is strong enough for tracheal extubation. Following reversal of neuromuscular blockade, clinical assessment of strength is combined with neuromuscular monitoring. These latter measures become necessary as residual weakness may be present despite apparent reversal using TOF monitoring. Techniques of clinical assessment to evaluate the presence of residual neuromuscular blockade include measurement of negative inspiratory force (NIF) or maximum inspiratory pressure (MIP), hand grip, or head lift. Although head lift and hand grip require the ability to follow a simple command, the measurement of NIF does not. The technique involves measuring the inspiratory force that the patient can generate against an occluded airway. The test can be completed with a simple manometer attached to the 15-mm adaptor of the endotracheal tube. Initial studies suggested that an NIF of at least −20 cm H 2 O indicated sufficient muscle strength to maintain an adequate minute ventilation. Subsequently, a value of −25 to −30 cm H 2 O became the generally accepted value for use in clinical practice. However, subsequent work suggested that although strength was adequate to maintain minute ventilation, it may not be adequate to maintain upper airway patency. Therefore, the use of voluntary responses (head lift for 5 s or hand grip) was suggested as an adjunct to ensure adequate reversal of neuromuscular blockade. In infants, reflex leg lift (both legs lifted off the operating room table) was shown to correlate with a mean NIF or MIP of −51 cm H 2 O. Thus, the authors concluded that this was a sign of adequate reversal of neuromuscular blockade in infants. Given the variability of these responses and their correlation with reversal of neuromuscular blockade, the best clinical approach may be the use of several clinical maneuvers if TOF monitoring is not available. The literature suggests that the ability to maintain a sustained head lift for 5 seconds is the most sensitive clinical tool.


In the ICU setting, given the degree of neuromuscular blockade that is induced, voluntary measures of muscle strength are not adequate. Therefore, titration of NMBAs should be guided by TOF monitoring. The technique may allow the use of the lowest possible dose of agents and theoretically avoid complications such as prolonged blockade (see later discussion). In a prospective randomized trial in 77 adults, TOF monitoring (maintaining one twitch of the TOF) was compared with clinical parameters (patient breathing over the preset ventilator rate) as a means of titrating NMBAs. TOF monitoring resulted in a lower total dose and lower average infusion rate of vecuronium, as well as a more rapid recovery once the infusion was discontinued. A subsequent study in adults revealed a decreased incidence of persistent neuromuscular weakness when using TOF monitoring.


Although data are lacking to clearly demonstrate the superiority of TOF monitoring in the PICU setting, its use is suggested as a means of titrating the administration of NMBA agents. Of note are the significant interpatient variability that has been reported in the PICU setting and therefore the inability to ensure an appropriate dose without some monitoring modality. The choice of the number of twitches to maintain has not been prospectively studied. The majority of the clinical evidence suggests that maintaining one twitch of the TOF ensures an adequate degree of neuromuscular blockade while potentially limiting the incidence of persistent neuromuscular weakness. However, the least amount of blockade that can be clinically tolerated is suggested. In some patients, maintaining two twitches may be acceptable, especially with the use of an appropriate degree of sedation and analgesia. When TOF monitoring is not in use or is not feasible, drug holidays are commonly employed in which the NMBA agent is temporarily discontinued until some clinical sign of neuromuscular function, such as motor movement, is noted. At that time, if needed, the infusion is restarted or an additional bolus is administered.


No study has evaluated the best nerve (facial, ulnar, common peroneal) to monitor. In clinical practice, any accessible nerve can be used. However, several patient and technical factors may affect the response. As such, whenever feasible, placement of the monitor before the institution of neuromuscular blockade is suggested to ensure that a TOF can be obtained before the administration of the NMBA. If no response is obtained, the technique should be evaluated by first evaluating the monitor (faculty monitor, electrodes, or batteries). Is the electrode too far from the nerve (improper placement, edema, obesity)? If these technical problems are ruled out, the infusion can be decreased by 10% to 15%, and the TOF measured again in 2 hours. When two or more twitches are noted, if the patient is stable and a more profound degree of blockade is not required, ongoing observation is suggested. If a deeper level of blockade is required, a bolus equivalent to the hourly infusion rate should be administered and the infusion increased by 10% to 15%.


Adverse effects of neuromuscular blockade


As with any medication used in the PICU patient with comorbid diseases, adverse effects may occur with NMBAs. Perhaps the most devastating of these adverse effects is the inability to provide adequate ventilation following the administration of a medication that induces apnea. Therefore, these medications should never be used if there is any suspicion that the airway cannot be controlled. In rare circumstances, endotracheal intubation using direct laryngoscopy may be impossible. In even rarer circumstances, adequate bag-mask ventilation cannot be provided. In such scenarios, death or permanent CNS morbidity will result with the administration of NMBAs. Measures to avoid such problems include an assessment of the airway before the administration of these agents and knowledge of the cannot intubate/cannot ventilate algorithm as outlined by the American Society of Anesthesiologists.


Various physical characteristics may suggest that direct laryngoscopy and endotracheal intubation will be difficult, including micrognathia, a short neck, limited neck mobility (flexion/extension), limited mouth opening, a large tongue, and a small mouth. An additional tool is the Mallampati grade, which describes the ability to visualize the tip of the uvula and the tonsillar pillars. , If there is a suspicion that endotracheal intubation using direct laryngoscopy will not be possible and there is time, other techniques to control the airway are suggested. Some of the more commonly used approaches to the difficult airway in infants and children are described elsewhere. The techniques needed for the cannot intubate/cannot ventilate scenario should be understood and available in any situation in which NMBAs are being administered. This should consist of alternative options for endotracheal intubation, including repositioning the patient or using a different type of laryngoscope—for example, indirect laryngoscopy, such as the Glidescope. , Physicians using NMBAs should also have a working knowledge of the laryngeal mask airway, as it can be used to rescue patients when laryngoscopy, endotracheal intubation, and bag-valve-mask ventilation fail.


Other adverse effects from NMBAs relate to the elimination of protective physiologic functions. Eye care with the use of artificial tears or a moisturizing eye ointment at fixed intervals during the administration of NMBAs is necessary to avoid drying and damage to the cornea. Repositioning of the patient at frequent intervals is necessary to avoid pressure sores. For prolonged immobility, the use of special mattresses may be considered as an adjunct to frequent patient moving. Passive range of motion may also be implicated with splinting to prevent forearm and ankle contractures while sequential compression devices may be indicated to prevent deep vein thrombosis. Ineffective coughing and clearance of secretions mandates the implementation of suctioning protocols to limit the risk of nosocomial pneumonias. Alterations in normal physiologic respiratory parameters include a decrease in functional residual capacity, increase in dead space, and ventilation-perfusion ratios that may result in ventilatory issues, for example, hypoxemia or hypercarbia and the need to adjust ventilatory parameters.


Although these agents prevent movement, they provide no degree of sedation or analgesia. As such, monitoring sedation using clinical scoring systems is generally not feasible. Therefore, some other measure of the depth of sedation may be required. In the majority of clinical situations, physiologic parameters such as heart rate and blood pressure are used as a means of titrating sedative and analgesic agents. However, issues arise in critically ill patients in whom alterations in heart or blood pressure may not occur in response to stress or pain. In this patient population, exogenous vasopressors may be in use and thereby eliminate the reliability of physiologic parameters. In the operating room setting, the availability of depth of anesthesia monitors is recommended, and it is suggested that their use be considered in patients at high risk for awareness. Despite the rare occurrence of such events, means for their prevention of awareness during the use of neuromuscular blocking agents in the PICU appear indicated given the consequences of such problems.


In the operating room setting, various depth of sedation or anesthesia monitors are currently available. To date, there are no data in the PICU to demonstrate their efficacy in preventing recall during the use of neuromuscular blocking agents. The bispectral (BIS) index is a processed electroencephalographic parameter expressed as a numeric value ranging from 0 (isoelectric electroencephalogram) to 100 (awake, eyes open, no sedative agent). In the pediatric population, its intraoperative use has been suggested to decrease the incidence of awareness. In the PICU population, the BIS value has been shown to generally correlate with the depth of sedation assessed using various clinical scoring systems. , In one such study, BIS monitoring was used to evaluate the depth of sedation in a cohort of 12 PICU patients receiving NMBAs. BIS monitoring was used for a total of 476 hours and revealed that the desired depth of sedation (BIS number 50–70) was achieved 57% of the time. The BIS number demonstrated a deeper than desired depth of sedation (BIS number ≤49) 35% of the time and an inadequate depth of sedation in patients receiving neuromuscular blockade (BIS number ≥71) 8% of the time. At the time that additional sedation was administered by the bedside nurse who was not allowed to view the monitor, the BIS number was 71 or greater 64% of the time, 50 to 70 during 31% of the time, and 49 or less 5% of the time. Although no long-term follow-up or assessment of awareness was pursued, the authors concluded that physiologic parameters are not a viable means of assessing the depth of sedation during the use of NMBAs.


The adverse effect that has received the most attention in the adult population with the administration of NMBAs is residual neuromuscular paralysis. In clinical practice, it appears that there are two distinct entities that may account for prolonged neuromuscular paralysis: (1) prolonged recovery from neuromuscular blockade related to excessive dosing or delayed clearance of the parent compound or metabolites due to renal or hepatic issues and (2) what is now termed the acute quadriplegic myopathy syndrome (AQMS). Potential concern regarding such problems was first reported in 1992 with the use of vecuronium in patients with renal insufficiency. Complications related to excessive dosing or inadequate clearance of an active metabolite generally resolve spontaneously over time with clearance of the parent compound or its metabolites. In clinical practice, prolonged recovery is defined as a recovery time of more than 100% of the predicted parameter. In distinction, AQMS presents with acute paresis, myonecrosis with increased plasma markers demonstrating muscle breakdown, such as CPK, and abnormal electromyography (EMG) with the demonstration of reduced compound motor action potential amplitude, decreased motor nerve conduction, and evidence of acute denervation. Clinical findings include flaccid paralysis, relative preservation of extraocular movements, decreased deep tendon reflexes, respiratory insufficiency, intact sensory function, and normal findings in the cerebrospinal fluid. Recovery may require weeks to months, with the need for prolonged rehabilitation care, and tracheostomy with chronic ventilatory support, all of which may significantly affect the cost of ICU care. Although initially reported only with aminosteroid compounds, it has been subsequently also reported with the benzylisoquinolinium derivatives. ,


Given that CPK values are elevated in up to 50% of patients with AQMS, periodic screening of patients receiving ongoing neuromuscular blockade may be indicated. As problems have been noted more commonly following the prolonged, continuous infusion of NMBAs, it has also been suggested that drug holidays or periodic interruption of the infusion be considered. However, there are no data to demonstrate that this practice will alter the incidence of AQMS, and even the periodic withdrawal of neuromuscular blockade must be considered on a risk-benefit ratio. Termination of the use of NMBAs is suggested whenever it is clinically feasible given their adverse effect profile. Other factors and comorbid processes that may contribute to the development of AQMS include nutritional deficiencies; coadministration of other medications (cyclosporine, corticosteroids, aminoglycosides); hyperglycemia; hepatic or renal insufficiency; and electrolyte disturbances. The association is most profound with the coadministration of NMBAs and corticosteroids, suggesting a heightened awareness in such patients. In addition to AQMS, other conditions to consider in the differential diagnosis of patients with prolonged weakness following the use of NMBAs include neuromuscular conditions (myasthenia gravis, Eaton-Lambert syndrome, Guillain-Barré syndrome); acquired or primary myopathic conditions (mitochondrial myopathy, steroid myopathy); central nervous system injury; spinal cord injury; critical illness polyneuropathy; disuse atrophy; and electrolyte or metabolic disturbances. Critical illness polyneuropathy may be confused with AQMS. It is a combined motor and sensory neuropathy that results from ischemia of the microvasculature of the nerves, which is seen most commonly in patients with multisystem organ failure. EMG demonstrates a pattern different from that seen in AQMS.


Summary: Neuromuscular blocking agents in the PICU


In addition to their use in the operating room, specific situations that mandate the use of NMBAs in the PICU may arise. Although these agents are generally administered as intermittent bolus doses in the operating room, a more stable baseline level of neuromuscular blockade may be desired in the PICU; therefore, a continuous infusion may be used. When choosing an agent for use in the PICU population, the major issues are cardiovascular effects, metabolism, and cost. Because many of the patients in the PICU have some degree of hemodynamic instability, agents that cause excessive histamine release should be avoided. Additionally, the presence of hepatic or renal insufficiency may affect metabolism or elimination or the parent compound as well as its metabolites. In the absence of end-organ dysfunction, pancuronium offers an inexpensive means of achieving neuromuscular blockade. Its vagolytic effect will result in tachycardia with an increase in heart rate of 10 to 20 beats per minute above baseline. Given its duration of action, intermittent dosing is feasible. With its availability in generic form, vecuronium provides another cost-effective option in the PICU setting while eliminating the tachycardia that is seen with pancuronium. Although vecuronium and pancuronium are generally effective and inexpensive in patients without end-organ dysfunction, significant alterations in infusion requirements occur in patients with renal insufficiency/failure (pancuronium and vecuronium) or hepatic insufficiency/failure (vecuronium). Atracurium or cis-atracurium may be a more appropriate choice in patients with hepatic or renal failure because these conditions do not alter dosing requirements of either agent.


In the PICU setting, like the operating room, adjustment of the dose based on monitoring with a peripheral nerve stimulator is recommended. Regardless of the agent used, significant interpatient variability with up to 10-fold variations in infusion requirements may be noted. This results from not only interpatient variability but also multiple associated conditions that may increase or decrease the sensitivity to NMBAs ( Boxes 131.6 and 131.7 ). On the basis of this knowledge, the recommended doses ( Table 131.1 ) for the various NMBAs are starting guidelines. The infusion should be increased or decreased as needed to maintain one twitch of the TOF or provide the required depth of neuromuscular blockade. An additional problem that occurs in the ICU patient who receives NMBAs for a prolonged period is the development of tachyphylaxis or an increased dose requirement over time. The primary cause is an upregulation of acetylcholine receptors in patients who are chronically exposed to NMBAs. Dodson et al. demonstrated an increased density of acetylcholine receptors in muscle from patients who had received prolonged infusions of NMBAs. Prolonged neuromuscular blockade, like partial or complete deafferentation, leads to proliferation of acetylcholine receptors at the neuromuscular junction. This requires that the dose of the NMBA be increased over time to maintain the same amount of neuromuscular blockade.


May 20, 2021 | Posted by in RHEUMATOLOGY | Comments Off on Neuromuscular blocking agents
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