Neuromuscular Blocking Agents

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Summary

Neuromuscular blocking agents (NMBAs) are used to facilitate endotracheal intubation and provide skeletal muscle relaxation during surgery or mechanical ventilation.

NMBAs do not provide sedation, analgesia, or amnesia; administer only after unconsciousness has been induced and maintain adequate amnesia and analgesia throughout paralysis.

NMBA selection depends on clinical application and patient factors; consider the onset and duration of action, adverse effects, and metabolism/excretion of each agent.

Pharmacology Neuromuscular blocking agents (NMBAs) cause skeletal muscle relaxation by blocking acetylcholine, and therefore, the transmission of nerve impulses at the neuromuscular junction. Depolarizing NMBAs bind to and activate cholinergic receptor sites, making the muscle fiber refractory to the action of acetylcholine. Nondepolarizing NMBAs competitively antagonize cholinergic receptors. Nondepolarizing NMBAs are divided into 2 broad structural classes: aminosteroidal and benzylisoquinolinium agents. Differences in chemical structure reflect little but variance in drug elimination pathways.[52452][52486] [65358][65369][65389]

Neuromuscular Blocking Agent General Pharmacology[65358][65369]

Metabolism/ Drug Mechanism Class Elimination

plasma esterase/ Atracurium Nondepolarizing Benzylisoquinolinium Hofmann elimination

plasma esterase/ Cisatracurium Nondepolarizing Benzylisoquinolinium Hofmann elimination*

Mivacurium Nondepolarizing Benzylisoquinolinium plasma cholinesterase

Pancuronium Nondepolarizing Aminosteroidal renal > hepatic

Rocuronium Nondepolarizing Aminosteroidal renal < hepatic Succinylcholine Depolarizing Acetylcholine-like plasma cholinesterase

Vecuronium Nondepolarizing Aminosteroidal renal <= hepatic

*Less than 20% of elimination occurs via renal and hepatic pathways combined

Onset and Duration of Action of Neuromuscular Blocking Agents[52452][52486][65358][65369][65389]

Drug Onset (minutes) Duration (minutes)

Succinylcholine 0.5 to 1.5 5 to 10 Short-acting Mivacurium 2 to 3 10 to 20

Atracurium 3 to 5 20 to 35

Cisatracurium 2 to 5 20 to 60 Intermediate-acting Rocuronium 1 to 2 20 to 35

Vecuronium 3 to 5 20 to 45

Long-acting Pancuronium 2 to 5 60 to 100

Pharmacodynamics of Neuromuscular Blocking Agents[42613][52452][65345] [65358][65369]

Histamine Ganglionic/Vagal Drug Muscarinic Receptor Effect Prolonged Blockade Release Blockade

Atracurium low to minimal none minimal to none rare

Cisatracurium minimal to none none none rare

Mivacurium low to minimal none none rare

Pancuronium minimal to none moderate blockade yes yes

Rocuronium minimal to none minimal blockade at high doses no

Succinylcholine minimal stimulation none with reduced plasma cholinesterase activity

Vecuronium none none at high doses yes

Therapeutic Use Therapeutic Use Table

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Atracurium Cisatracurium Mivacurium Pancuronium Rocuronium Succinylcholine Vecuronium Indications Besylate Besylate Chloride Bromide Bromide Chloride Bromide

Renal Impairment Yes Yes Yes Yes Dosing Adjustment

Hepatic Impairment Yes Yes Yes Dosing Adjustment endotracheal Yes Yes Yes Yes Yes Yes Yes intubation neuromuscular blockade during Yes Yes Yes Yes Yes Yes mechanical ventilation neuromuscular blockade Yes Yes Yes Yes Yes Yes Yes during surgery rapid- sequence Yes † Yes Yes Yes † intubation

Yes – Labeled Yes † – Off-label, Recommended NR – Off-label, Not Recommended

Neuromuscular blocking agent (NMBA) selection depends on clinical application and patient factors; consider the onset and duration of action, adverse effects, and metabolism/elimination of each agent.

Succinylcholine is the NMBA of choice for rapid-sequence intubation (RSI) due to its rapid onset and short duration; it can also be given intramuscularly in patients without venous access. Several adverse effects (i.e., hyperkalemia, malignant hyperthermia, increased intraocular and intracranial pressures) limit its use.[44868][52452][65345]

Aminosteroidal NMBAs depend on organ function for metabolism and excretion; they tend not to cause histamine release, making them preferred NMBAs in patients with asthma.

Rocuronium and vecuronium are considered preferred NMBAs in patients with cardiac conditions or hemodynamic instability due to their cardiovascular stability. Rocuronium is an attractive alternative for RSI due to its relatively short onset.[44868][52441][52452][65345]

Pancuronium may cause significant tachycardia and hypertension. Due to its long duration, intermittent doses can be considered as an alternative to continuous infusions of shorter-acting NMBAs in patients requiring sustained paralysis.[52443]

Benzylisoquinolinium NMBAs undergo organ-independent degradation; they lack vagolytic activity but are more likely to cause histamine release.[52452]

Atracurium and cisatracurium are attractive for continuous infusion use in critically ill patients, as their metabolism is largely unrelated to hepatic or renal function.[65358]

A short course (48 hours or less) of NMBA by continuous infusion is recommended for patients with

early acute respiratory distress syndrome (ARDS) with a PaO2/FiO2 less than 150 mmHg.[61770] [62859]

Comparative Efficacy

Succinylcholine is considered the neuromuscular blocking agent (NMBA) of choice for rapid- sequence intubation (RSI) due to its rapid onset and shorter duration; however, adverse effects limit its use. Rocuronium is an attractive alternative.[44868][52452][65345]

Both agents offer similar safety and efficacy for RSI when used in various patient populations. [65441][65442][65443] When dosed at 0.9 to 1.2 mg/kg, rocuronium's onset of action is similar to succinylcholine with a longer duration.[65442]

Neuromuscular Blocking Agent Comparative Efficacy Trials for Rapid-Sequence Intubation (RSI)

Citation Design/Regimen Results Conclusion

Marsch SC, et Randomized, controlled, single-blind trial comparing Incidence of Incidence and severity of oxygen al. Crit Care succinylcholine 1 mg/kg IV (n = 208) vs. rocuronium oxygen desaturations, quality of intubation 2011;15:R199. 0.6 mg/kg IV (n = 208) for rapid-sequence intubation desaturation, conditions, and incidence of failed intubation [65441] in critically ill adults. Patients were premedicated with defined as a attempts did not differ between fentanyl 1 mcg/kg IV, and etomidate 0.2 mg/kg IV or decrease in succinylcholine and rocuronium in critically ill propofol 1 mg/kg IV were used for induction. oxygen adults. The mean intubation sequence was saturation of 14 seconds shorter after succinylcholine 5% or more: compared to rocuronium. Hemodynamic effects of intubation were similar in both Succinylcholine: groups. 37%

Rocuronium: 34%

(p = 0.67)

Incidence of severe oxygen desaturation, resulting in a saturation value of 80% or less:

Succinylcholine: 10% Rocuronium: 10%

(p = 1)

Duration of intubation sequence:

Succinylcholine:

81 +/- 38 seconds

Rocuronium:

95 +/- 48 seconds

(p = 0.002)

Incidence of failed first intubation attempt:

Succinylcholine: 16%

Rocuronium: 18%

(p = 0.4)

Intubation conditions (maximal score = 9):

Succinylcholine:

8.3 +/- 0.8

Rocuronium:

8.2 +/- 0.9

(p = 0.7)

Magorian T, et Randomized, controlled trial comparing rocuronium Mean onset of Onset of action for rocuronium 0.9 and 1.2 al. 0.6, 0.9, or 1.2 mg/kg IV, vecuronium 0.1 mg/kg IV, or action: mg/kg was similar to succinylcholine. Anesthesiology succinylcholine 1 mg/kg IV (total n = 50) for rapid- Rocuronium's duration of action was 1993;79:913- sequence induction of anesthesia in adult patients Rocuronium 0.6 prolonged compared to succinylcholine at mg/kg: 918. [65442] who were ASA physical status 1 thru 3. Patients were these doses; duration of action with premedicated with midazolam 0.02 to 0.05 mg/kg IV, rocuronium 1.2 mg/kg was significantly and incremental doses of thiopental 1 to 2 mg/kg IV 89 seconds longer compared to all other agents/doses. were given before neuromuscular blockade. Rocuronium 0.9 Recovery index was significantly shorter for mg/kg: succinylcholine but similar for all other agents/doses. 75 seconds

Rocuronium 1.2 mg/kg:

55 seconds

Vecuronium 0.1 mg/kg: 144 seconds

Succinylcholine 1 mg/kg: 50 seconds

Mean duration of action:

Rocuronium 0.6 mg/kg: 37 minutes

Rocuronium 0.9 mg/kg: 53 minutes

Rocuronium 1.2 mg/kg: 73 minutes

Vecuronium 0.1 mg/kg: 41 minutes

Succinylcholine 1 mg/kg: 9 minutes

Mean recovery index:

Rocuronium 0.6 mg/kg: 14 minutes

Rocuronium 0.9 mg/kg: 22 minutes

Rocuronium 1.2 mg/kg: 24 minutes

Vecuronium 0.1 mg/kg: 20 minutes

Succinylcholine 1 mg/kg: 2 minutes April MD, et al. International, multicenter, observational series Incidence of First-pass intubation success, glottic view, Ann Emerg comparing succinylcholine (n = 2,275; mean dose: first-pass and incidence of adverse effects did not Med 1.8 mg/kg IV) and rocuronium (n = 1,800; mean intubation differ between succinylcholine and 2018;72:645- dose: 1.2 mg/kg IV) for rapid-sequence intubation in success: rocuronium during emergency department 653. [65443] the emergency department in patients older than 14 intubation. years. Sedation agents included etomidate, Succinylcholine ketamine, and propofol. 87% Rocuronium 87.5%

(risk difference 0.5%; 95% CI -1.6% to 2.6%)

Cormack- Lehane grade 1 or 2 view:

Succinylcholine: 88.5%

Rocuronium: 89%

Incidence of adverse events:

Succinylcholine: 14.7%

Rocuronium: 14.8%

Adverse Reactions / Side Effects Top 20 Adverse Reactions / Side Effects Table

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Adverse Atracurium Cisatracurium Mivacurium Pancuronium Rocuronium Succinylcholine Vecuronium Reaction / Besylate Besylate Chloride Bromide Bromide Chloride Bromide Side Effect

acute quadriplegic Reported Reported Reported Reported Reported Reported Reported myopathy syndrome

bronchospasm Reported 0.2 - 1.5% <1% Reported <1% Reported Reported

erythema 0.5 - 0.6% Reported <1% Reported Reported Reported Reported

flushing 1 - 29.2% 0.2% 16 - 25% Reported Reported Reported Reported

hypotension 0.6% 0.2% 0.3 - 4% Reported 0.1 - 2% Reported Reported

pruritus Reported Reported Reported Reported <1% Reported Reported

rash Reported 0.1% <1% Reported <1% Reported Reported Adverse Atracurium Cisatracurium Mivacurium Pancuronium Rocuronium Succinylcholine Vecuronium Reaction / Besylate Besylate Chloride Bromide Bromide Chloride Bromide Side Effect sinus Reported Reported <1% Reported <1.4% Reported Reported tachycardia urticaria Reported Reported <1% Reported Reported Reported Reported wheezing 0.2 - 0.3% Reported <1% Reported <1% Reported Reported bradycardia Reported 0.4% <1% Reported hypertension Reported 0.1 - 2% Reported injection site Reported <1% <1% reaction dizziness <1% edema <1% hiccups <1% muscle <1% cramps nausea <1% phlebitis <1% vomiting <1%

Anaphylactoid reactions Although rare, severe anaphylactic or anaphylactoid reactions to neuromuscular blocking agents (NMBAs) have been reported; some cases have been fatal. Immediate availability of appropriate emergency treatment for anaphylaxis is advised because of the potential life-threatening severity of a reaction.[42039] [48672] NMBAs are the most common cause of IgE-mediated anaphylaxis in anesthesia, with succinylcholine and rocuronium being the most frequent culprits.[65358] Cross-reactivity between NMBAs, both depolarizing and nondepolarizing, has been reported.[42039] [48672]

Histamine-related reactions Neuromuscular blocking agents (NMBAs) with histamine-releasing properties (e.g., atracurium, mivacurium, succinylcholine) are more likely to cause bronchospasm, flushing, hypotension, and/or tachycardia. Histamine release may be related to dose or administration rate.[42613] [52452] [65358] [65389]

Cardiovascular reactions Pancuronium, atracurium, and succinylcholine have the greatest potential among neuromuscular blocking agents (NMBA) to cause adverse cardiovascular effects. Pancuronium causes tachycardia and increased blood pressure as a result of vagal blockade and norepinephrine release from adrenergic nerve endings. Atracurium causes significant histamine release which may result in hypotension and tachycardia. Succinylcholine can cause vagal-mediated bradycardia, hypotension, and cardiac arrhythmias; tachycardia and hypertension may occur due to sympathetic stimulation.[52452] [54407] Pretreatment with atropine may prevent bradycardia associated with anticholinesterases.[42039] [65330] [65345]

Seizures Seizures have been reported in intensive care unit patients after long-term infusion of atracurium to support mechanical ventilation. These patients usually had predisposing causes, such as head trauma, cerebral edema, hypoxic encephalopathy, viral encephalitis, or uremia. Laudanosine, a major biologically active metabolite of atracurium and cisatracurium without neuromuscular blocking activity, produces cerebral excitatory effects (i.e., generalized muscle twitching and seizures) at higher doses when administered to several species of animals; however, the relationship between CNS excitation and laudanosine concentrations in humans has not been established.[42614] [48671]

Tachyphylaxis Patients who receive neuromuscular blocking agents for a prolonged period may develop tachyphylaxis. Prolonged blockade leads to proliferation of acetylcholine receptors at the neuromuscular junction resulting in increased drug requirements. Switch patients who develop tachyphylaxis to 1 agent and still require paralysis to another agent. Continuous monitoring of neuromuscular transmission with a peripheral nerve stimulator is strongly recommended during continuous infusion or repeated dosing. [52441][52503]

Acute quadriplegic myopathy syndrome Acute quadriplegic myopathy syndrome (AQMS) has been associated with prolonged neuromuscular blocking agent (NMBA) exposure and presents as acute paresis, myonecrosis with increased creatine phosphokinase (CPK), and abnormal electromyography (EMG). Flaccid paralysis, decreased deep tendon reflexes, and respiratory insufficiency are present after drug discontinuation. Prolonged rehabilitation as well as chronic ventilatory support are often needed in patients with AQMS. Recovery may take weeks to months. To reduce the risk of prolonged recovery and AQMS, periodic screening of CPK during ongoing neuromuscular blockage may be helpful. Though periodic interruption of therapy is often not feasible and there is no direct evidence showing that it reduces the incidence of AQMS, daily 'drug holidays' may be considered for patients who will tolerate an interruption in therapy.[52503] [52486]

Immobility complications Prolonged paralysis is associated with pooling and stasis of blood in the veins, which increases the risk of thrombosis. Skin breakdown, slowed gastrointestinal motility, peripheral muscle weakness, muscle atrophy are other complications of immobility.[65358] Prophylactic interventions, including frequent repositioning, physical therapy, and sequential compression devices are warranted in intensive care patients receiving prolonged neuromuscular blockade.[52482] [52503]

Corneal ulcers Paralysis results in impaired eyelid closure and loss of corneal reflex, placing the cornea at risk for drying, scarring, ulceration, and infection.[65358] Prophylactic eye care is essential; use artificial tears or ophthalmic ointment at regular intervals in critically ill patients receiving prolonged neuromuscular blockade.[52482][52503] Malignant hyperthermia Malignant hyperthermia, an inherited disorder of muscle metabolism, often presents as prolonged masseter spasm (jaw rigidity), which may progress to generalized rigidity, rhabdomyolysis, increased oxygen demand, lactic acidosis, increased heart rate, profound fever, disseminated intravascular coagulation (DIC), and cardiac arrhythmia. Malignant hyperthermia can be precipitated by succinylcholine; consider patients receiving nondepolarizing neuromuscular blocking agents (NMBAs) also to be at risk. If malignant hyperthermia is suspected, discontinue anesthesia immediately, implement supportive care, and administer dantrolene.[52486][54418][54419]

Hyperkalemia Succinylcholine-induced depolarization may cause sufficient potassium efflux to produce hyperkalemia. [65369] In predisposed patients, a sudden, large increase in serum potassium may cause cardiac dysrhythmias and cardiac arrest.[52452] There have been rare reports of acute rhabdomyolysis with hyperkalemia followed by ventricular dysrhythmias, cardiac arrest, and death after the administration of succinylcholine to apparently healthy pediatric patients who were subsequently found to have undiagnosed skeletal muscle myopathy, most frequently Duchenne's muscular dystrophy. This syndrome often presents as peaked T-waves and sudden cardiac arrest within minutes after the administration of succinylcholine in healthy appearing pediatric patients (usually, but not exclusively, males, and most frequently 8 years or younger). There have also been reports in adolescents. Therefore, when a healthy appearing infant or child develops cardiac arrest soon after administration of succinylcholine, not felt to be due to inadequate ventilation, oxygenation, or anesthetic overdose, institute immediate treatment for hyperkalemia, including intravenous calcium, bicarbonate, glucose with insulin, and hyperventilation. Due to the abrupt onset of this syndrome, routine resuscitative measures are likely to be unsuccessful. However, extraordinary and prolonged resuscitative efforts have resulted in successful resuscitation in some reported cases.[42039]

Increased intracranial pressure Succinylcholine may cause transient increased intracranial pressure immediately after administration and during the fasciculation phase. Slight increases in pressure may persist after the onset of paralysis. Induction of adequate anesthesia before succinylcholine administration may minimize the drug's effect on intracranial pressure.[42039] [52486]

Drug Interactions

Antibiotics Systemic administration of certain antibiotics, such as aminoglycosides, clindamycin, vancomycin, tetracyclines, bacitracin, polymyxins, colistin, and sodium colistimethate, may enhance or prolong the neuromuscular blocking action of neuromuscular blocking agents (NMBAs). If these or other newly introduced antibiotics are used in conjunction with NMBAs, consider unexpected prolongation of neuromuscular block a possibility. The use of peripheral nerve stimulator is strongly recommended to evaluate the level of neuromuscular blockade, to assess the need for additional doses of the NMBA, and to determine whether adjustments need to be made to the dose with subsequent administration. [42031] [42614] [48672]

Anticonvulsants Concomitant use of a nondepolarizing neuromuscular blocking agent (NMBA) in patients receiving anticonvulsants, such as carbamazepine or phenytoin, may increase resistance to the neuromuscular blockade action of nondepolarizing NMBAs, resulting in shorter durations of neuromuscular blockade and higher infusion rate requirements. The use of peripheral nerve stimulator is strongly recommended to evaluate the level of neuromuscular blockade, to assess the need for additional doses of NMBA, and to determine whether adjustments need to be made to the dose with subsequent administration. While the mechanism for development of resistance is not known, receptor up-regulation may be a contributing factor.[42031] [42614]

Corticosteroids An acute myopathy has been observed with the use of high doses of corticosteroids in patients receiving concomitant long-term therapy with neuromuscular blockers. Limit the period of use of neuromuscular blockers and corticosteroids and only use when the specific advantages of the drugs outweigh the risks for acute myopathy. Clinical improvement or recovery after stopping therapy may require weeks to years.[41961] [42031] [54278] [61750]

Inhalational anesthetics Use of volatile inhalational anesthetics with neuromuscular blocking agents (NMBAs) will enhance neuromuscular blockade. Potentiation is most prominent with use of enflurane and isoflurane. Reduction of the initial dose or infusion rate of the NMBA may need to be considered.[41961] [42031] [42613] [42614] [48671] [48672]

Local anesthetics Local anesthetics have been shown to increase the duration of neuromuscular block and decrease infusion requirements of neuromuscular blocking agents (NMBAs). The use of peripheral nerve stimulator is strongly recommended to evaluate the level of neuromuscular blockade, to assess the need for additional doses of NMBA, and to determine whether adjustments need to be made to the dose with subsequent administration.[42031][42039][42614]

Magnesium salts Magnesium may enhance or prolong the neuromuscular blocking action of neuromuscular blocking agents. The use of peripheral nerve stimulator is strongly recommended to evaluate the level of neuromuscular blockade, to assess the need for additional doses of NMBA, and to determine whether adjustments need to be made to the dose with subsequent administration.[42031][42039][42614][48672]

Drugs that reduce plasma cholinesterase activity Consider the possibility of prolonged neuromuscular block after administration of mivacurium or succinylcholine in patients with reduced plasma cholinesterase activity. Plasma cholinesterase activity may be diminished by chronic administration of oral contraceptives, corticosteroid therapy, certain monoamine oxidase inhibitors, or by drugs that irreversibly inhibit plasma cholinesterase, such as organophosphate insecticides and certain antineoplastic drugs.[42039] [42613]

Safety Issues Safety Issues Table

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Atracurium Cisatracurium Mivacurium Pancuronium Rocuronium Succinylcholine Vecuronium Safety Issue Besylate Besylate Chloride Bromide Bromide Chloride Bromide

REMS

MedGuide

benzyl alcohol X hypersensitivity

bromide X X X hypersensitivity

burns X

children BBW

hyperkalemia BBW

infants BBW

malignant X hyperthermia

myopathy X

neonates X BBW

neuromuscular blocking agent X hypersensitivity

premature X neonates

requires an experienced BBW BBW clinician

rhabdomyolysis BBW

trauma X

X – Contraindicated X-BBW – Contraindicated and Black Box Warning BBW – Black Box Warning, Not Contraindicated Yes – REMS or MedGuide is available

Requires specialized care setting Neuromuscular blocking agent administration requires an experienced clinician who is familiar with its actions and the possible complications that may occur after its use as well as requires a specialized care setting where facilities for intubation, artificial respiration, oxygen therapy, and reversal agents are immediately available.[42031] [42614] [48672]

Awareness Neuromuscular blocking agents (NMBAs) do not provide sedation or analgesia and, in general, should be administered only after unconsciousness has been induced. Maintain adequate amnesia and analgesia throughout paralysis to avoid patient distress. Use of a peripheral nerve stimulator will permit the most advantageous use of NMBAs, minimize the possibility of overdosage or underdosage, and assist in the evaluation of recovery. Monitor visual and tactile stimulation on muscle movement as well as heart rate, blood pressure, and mechanical ventilator status during administration.[52441]

Burns Succinylcholine is contraindicated in patients after the acute phase of major burn injury due to the risk of hyperkalemia. In addition, patients with burns have a decreased sensitivity to nondepolarizing agents' ability to produce neuromuscular blockade. Resistance to blockade usually develops in patients with burns more than 10% total body surface area approximately 1 week after thermal injury. Increased doses may be required in burn patients; alteration in drug effect may be seen for up to 1 year.[52478] [52482]

Electrolyte and acid-base imbalance Electrolyte imbalance can alter a patient's sensitivity to neuromuscular blocking agents (NMBAs). Hypercalcemia can decrease sensitivity to NMBAs, while most other electrolyte disturbances increase sensitivity (e.g., hypokalemia, hypocalcemia, hypermagnesemia). Use NMBAs cautiously in patients with conditions that may lead to electrolyte imbalances, such as adrenal insufficiency. Severe acid/base imbalance may alter a patient's sensitivity to NMBAs: metabolic alkalosis, metabolic acidosis, and respiratory acidosis may enhance neuromuscular blockade and/or prolong recovery time, while respiratory alkalosis reduces the potency of the drug.[42031] [48672] [52846] Use succinylcholine with caution in patients with electrolyte abnormalities because of the potential for developing severe hyperkalemia.[42039] [52486] Do not use succinylcholine in any patient with a serum potassium of more than 5.5 mEq/L.[54427]

Neuromuscular disease Use neuromuscular blocking agents with caution in patients with neuromuscular disease (e.g., myasthenia gravis, myasthenic syndrome [Eaton Lambert syndrome]); prolonged or exaggerated neuromuscular blockade may occur after neuromuscular blocking agent use.[48672] [52486] [53645] Because myasthenia gravis involves destruction of acetylcholine receptors instead of receptor upregulation, as seen in other neuromuscular diseases, these patients tend to be less sensitive to the effects of succinylcholine compared to nondepolarizing agents (e.g., rocuronium, vecuronium).[53645] [54397] Additionally, patients with weak muscle tone are at an increased risk for airway and ventilation complications. Monitor patients carefully until recovery is fully complete.[48672]

Obesity Obese patients are at an increased risk for airway and ventilation complications. [48672] Use ideal body weight or adjusted body weight for dosing in obese and morbidly obese adult patients (body mass index

30 kg/m2 or more).[62859] Guidelines for sustained neuromuscular blockade in critically ill children recommend calculating the dose according to IBW.[52443]

Pseudocholinesterase deficiency Consider the possibility of prolonged neuromuscular block after administration of mivacurium or succinylcholine in patients with reduced plasma cholinesterase activity (pseudocholinesterase deficiency). Plasma cholinesterase activity may be diminished in the presence of genetic abnormalities of plasma cholinesterase (e.g., patients heterozygous or homozygous for atypical plasma cholinesterase gene), liver or kidney disease, malignant tumors, infection, burns, anemia, decompensated heart disease, peptic ulcer disease, or myxedema. Plasma cholinesterase activity may also be diminished by chronic administration of oral contraceptives, corticosteroid therapy, or certain monoamine oxidase inhibitors and by cholinesterase inhibitor toxicity due to irreversible inhibitors of plasma cholinesterase (e.g., organophosphate insecticides, echothiophate, and certain antineoplastic drugs). Use mivacurium with caution, if at all, in patients known or suspected of being homozygous for the atypical plasma cholinesterase gene; initial doses more than 0.03 mg/kg are not recommended in homozygous patients. Mivacurium infusions are not recommended in homozygous patients. Mivacurium has been used safely in patients heterozygous for the atypical plasma cholinesterase gene and in genotypically normal patients with reduced plasma cholinesterase activity. After an initial dose of mivacurium 0.15 mg/kg, the clinically effective duration of block in heterozygous patients may be approximately 10 minutes longer than in patients with normal genotype and normal plasma cholinesterase activity. Lower infusion rates of mivacurium are recommended in these patients.[42039] [42613]

Pediatric patients Based on physiologic differences, neonates and infants tend to be more sensitive to paralysis with neuromuscular blocking agents, while children tend to require larger doses than those of infants or adults.[52501] [52452] Acute rhabdomyolysis, hyperkalemia, cardiac dysrhythmia, and fatal cardiac arrest has been associated with succinylcholine use in pediatric patients with undiagnosed myopathies. Because it is difficult to assess which patients are at risk, limit the use of succinylcholine in pediatric patients for emergency intubation or when immediate securing of the airway is necessary (e.g., laryngospasm, difficult airway, full stomach) or for intramuscular use when a suitable vein is inaccessible.[42039]

Hepatic impairment Hepatic impairment may enhance or prolong neuromuscular blockade associated with aminosteroidal neuromuscular blocking agents due to prolonged half-life and reduced clearance.[42031] [48672] [65345] Although organ-independent elimination is the primary pathway for cisatracurium elimination, the liver plays a minor role in metabolite elimination. Metabolite (e.g., laudanosine) half-life is prolonged and concentrations may be higher after long-term cisatracurium administration in patients with hepatic dysfunction.[42614]

Renal impairment Substantial variability can be seen in the duration of neuromuscular blockade associated with aminosteroidal neuromuscular blocking agents in patients with renal impairment.[42031] [48672] [65345] Although organ-independent elimination is the primary pathway for cisatracurium elimination, the kidneys play a minor role in metabolite elimination. Metabolite (e.g., laudanosine) half-life is prolonged and concentrations may be higher after long-term cisatracurium administration in patients with renal dysfunction.[42614]