Neuromuscular Blocking Agents

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]

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]

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 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]

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 (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]

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]

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, 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]

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]

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]

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]

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]

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]

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 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 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]

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]

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]

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]

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 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]

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]

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]

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]

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 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]

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]