Neuromuscular Blockers

Pharmacology
1. Neuromuscular blocking agents produce skeletal muscle paralysis by inhibiting the action of acetylcholine at the neuromuscular junction (NMJ). Depolarizing agents (succinylcholine; Table III-12) depolarize the motor end plate and block recovery; transient muscle fasciculations occur with the initial depolarization. Nondepolarizing agents (rocuronium and others; see Table III-12) competitively block the action of acetylcholine at the motor end plate, preventing depolarization. Therefore, with nondepolarizing agents, no initial muscle fasciculations occur.
2. The neuromuscular blockers produce complete muscle paralysis with no depression of CNS function. Thus, patients who are conscious will remain awake but be unable to move, and patients with status epilepticus may continue to have seizure activity despite paralysis. Furthermore, the neuromuscular blockers do not relieve pain or anxiety and have no sedative or amnestic effects.
3. Succinylcholine produces the most rapid onset of neuromuscular blockade. After intravenous administration, total paralysis ensues within 30-60 seconds and lasts 10-20 minutes. It is hydrolyzed rapidly by pseudocholinesterase, an enzyme present in the vascular compartment but not at the NMJ.
4. Rocuronium, a nondepolarizing agent, also has a rapid onset of effect. However, the duration of the blockade (20-90 minutes) is considerably longer than that of succinylcholine. Sugammadex, a specific and rapid reversal agent for rocuronium and vecuronium, has recently received FDA approval for use in adult patients undergoing surgery.
5. Cisatracurium and atracurium may be preferred in the setting of hepatic and/or renal disease because they are both eliminated primarily by Hoffman degradation.
Indications
1. Neuromuscular blockers are used to induce rapid paralysis to improve the view of the larynx and other relevant anatomy during endotracheal intubation. They are also employed when excessive muscular movement may produce or aggravate mechanical injury, rhabdomyolysis, or hyperthermia (eg, status epilepticus, serotonin syndrome, strychnine poisoning, tetanus).
Contraindications
1. Lack of preparedness or inability to intubate the trachea and ventilate the patient after total paralysis ensues. Proper equipment and trained personnel must be assembled before the drug is given.
2. Known or family history of malignant hyperthermia is an absolute contraindication to the use of succinylcholine.
3. Known hypersensitivity or anaphylactic reaction to the agent or its preservative.
4. Known history of or high risk for succinylcholine-induced hyperkalemia (see Item IV. B below).
Adverse effects
1. Complete paralysis results in respiratory depression and apnea. The intubating healthcare provider must be prepared to provide adequate and sustained ventilation and oxygenation in paralyzed patients.
2. Succinylcholine: Black Box Warning (hyperkalemia). Succinylcholine often causes a transient rise in serum potassium of approximately 0.5 mEq/L. This relatively modest increase is distinct from the pathologic levels as high as 5-10 mEq/L that can occur in clinical situations featuring postjunctional acetylcholine receptor upregulation or rhabdomyolysis.
  1. Receptor upregulation can become clinically relevant about 3-5 days after denervation (eg, spinal cord injury or stroke), burns, radiation and crush injuries, and infection by Clostridium botulinum and C. tetani. Receptor upregulation can also occur in the setting of prolonged neuromuscular blockade, especially when it is coupled with another trigger, such as lengthy immobilization or burn injury.
  2. Patients with a disease characterized by chronic denervation, such as an inherited myopathy (eg, Duchenne or Becker muscular dystrophy), Guillain-Barre syndrome, multiple sclerosis, or amyotrophic lateral sclerosis, are at risk for pathologic hyperkalemia if exposed to succinylcholine. Succinylcholine carries a black box warning issued by the FDA for pediatric use, reflecting the small but nontrivial danger of its use in the setting of undiagnosed inherited skeletal myopathy in children (primarily boys 8 years of age or younger).
  3. It is unclear whether preexisting mild hyperkalemia (eg, from acute renal failure or diabetic ketoacidosis) represents a significant clinical risk with the use of succinylcholine.
3. Succinylcholine: other adverse effects.
  1. Sinus bradycardia and AV block. Infants can experience significant bradycardia with the first dose of succinylcholine, but in older children or adults, bradycardia is more often seen with repeated doses. In either case, this effect can be mitigated with atropine pretreatment (0.02 mg/kg IV).
  2. In high doses, succinylcholine can cause catecholamine release, resulting in hypertension and tachycardia.
  3. Muscle fasciculations may cause increased intracranial, intraocular, and intragastric pressure. A defasciculating dose of a nondepolaring neuromuscular blocking agent can be administered before the succinylcholine.
  4. Mild rhabdomyolysis may occur owing to muscular activity associated with fasciculations, especially in children.
  5. Patients with certain genetic abnormalities that affect the cellular physiology of calcium in skeletal muscle are susceptible to malignant hyperthermia after exposure to succinylcholine. Malignant hyperthermia is a life-threatening condition that requires immediate treatment with the antidote dantrolene. Tachycardia is usually the first sign; other features can include trismus, autonomic instability, muscular rigidity, hypo- or hypercalcemia, rhabdomyolysis, hyperkalemia, altered mental status, and a severe lactic acidosis. Hyperthermia is a late finding and an ominous sign.
  6. Trismus or masseter spasm. Succinylcholine increases the muscular tone of the masseter muscle, especially in children undergoing concurrent anesthesia with halothane anesthetics. Usually, this effect is transient. Very rarely, trismus—in which the teeth are clamped shut, preventing visualization of the laryngeal structures—may develop. In this situation, administration of a nondepolarizing agent may facilitate intubation, but the intubator should be prepared to establish an alternative airway.
4. Many benzylisoquinolines (eg, cisatracurium, mivacurium, atracurium, and especially tubocurarine) can cause histamine release, resulting in hypotension and bronchospasm. These effects can be mitigated by slow infusion. Tubocurarine is unique in that it also blocks nicotinic acetylcholine receptors at the sympathetic ganglia, preventing the reflex tachycardia that usually accompanies vasodilation.
5. Aminosteroids. Bronchospasm occurs at a rate of 5-10% with rapacuronium (which was withdrawn from the United States market by the manufacturer for this reason). The vagal blockade associated with rapacuronium and pancuronium can cause tachycardia, hypertension, and increased myocardial oxygen consumption. In contrast, rocuronium and vecuronium are associated with minimal cardiovascular side effects. Patients with renal or hepatic insufficiency may experience prolonged neuromuscular blockade with vecuronium, which is partially metabolized by the liver to an active metabolite that is dependent on renal elimination.
6. Neuromuscular blockade can be potentiated by acidosis, hypokalemia, hypocalcemia, and hypermagnesemia. Prior administration of certain agents (eg, aminoglycosides, propranolol, calcium channel blockers) may increase the potency of neuromuscular blocking agents. Theophylline, glucocorticoids, and carbamazepine can antagonize nondepolarizing neuromuscular blockade.
7. Prolonged effects may occur after succinylcholine or mivacurium use in patients who have genetic variants of plasma pseudocholinesterase or liver disease, or who have recently used cocaine (which is metabolized by plasma pseudocholinesterases). A defective pseudocholinesterase gene may lead to markedly prolonged paralysis after administration of succinylcholine (3-8 hours).
8. Prolonged effects may also occur in patients with neuromuscular disease (eg, myasthenia gravis, Eaton-Lambert syndrome). Patients with myasthenia gravis are unpredictably sensitive to nondepolarizing agents and resistant to usual doses of succinylcholine.
9. Prolonged use of neuromuscular blockade has been associated with critical illness myopathy, also known as acute quadriplegic myopathy syndrome.
10. “Gasping baby” syndrome is caused by benzyl alcohol (a common preservative) in newborn infants, all of whom lack the capacity to fully metabolize the preservative. This entity is dose-dependent and is not a hypersensitivity reaction. Preservative-free preparations are available for pediatric use.
11. Use in pregnancy. FDA Category C (indeterminate). This does not preclude their acute, short-term use in a seriously ill patient (Introduction).
Drug or laboratory interactions
1. Actions of the nondepolarizing agents are potentiated by volatile anesthetics and inhibited or reversed by anticholinesterase agents (eg, neostigmine, physostigmine, and carbamate and organophosphate insecticides). Sugammadex is a recently approved rapid reversal agent for rocuronium and vecuronium.
2. Organophosphate or carbamate insecticide intoxication may potentiate or prolong the effect of succinylcholine.
3. Numerous drugs may potentiate neuromuscular blockade. These include calcium antagonists, dantrolene, aminoglycoside antibiotics, propranolol, membrane-stabilizing drugs (eg, quinidine), magnesium, lithium, and thiazide diuretics.
4. Anticonvulsants (carbamazepine and phenytoin) and theophylline may delay the onset and shorten the duration of action of some nondepolarizing agents. Carbamazepine has additive effects, and reduction of the neuromuscular blocker dose may be required.
5. Dysrhythmias are possible with myocardial sensitizers (eg, halothane) and sympathetic stimulating agents (eg, pancuronium).
Dosage and method of administration (see Table III-12).

TABLE III-12. SELECTED NEUROMUSCULAR BLOCKERS

Drug	Onset (minutes)	Duration (minutes)^a	Dose^b (All Intravenous)
Depolarizing
Succinylcholine^c,d	0.5-1	2-3	0.6 mg/kg TBW (children: 1 mg/kg) over 10-20 seconds; repeat as needed.
Nondepolarizing
Atracurium	3-5	20-45	0.4-0.5 mg/kg TBW (children <2 years: 0.3-0.4 mg/kg).
Cisatracurium	1.5-2	55-61	0.15-0.2 mg/kg TBW (children 2-12 years: 0.1 mg/kg), then 1-3 mcg/kg/min to maintain blockade.
Pancuronium	2-3	35-45	0.06-0.1 mg/kg IBW; then 0.01-0.02 mg/kg every 20-40 minutes as needed to maintain blockade.
Rocuronium	0.5-3	22-94	0.6-1 mg/kg IBW; then 0.01 mg/kg/min to maintain blockade.
Vecuronium	1-2	25-40	For children older than 1 year and adults: 0.08-0.1-mg/kg IBW bolus, then 0.01-0.02 mg/kg every 10-20 minutes to maintain blockade.

^aFor most agents, onset and duration are dose- and age-dependent. With succinylcholine, effects may be prolonged in patients who have a genetic plasma cholinesterase deficiency or organophosphate intoxication.

^bIBW = ideal body weight; TBW = total body weight

^cTo prevent fasciculations, administer a small dose of a nondepolarizing agent (eg, pancuronium, 0.01 mg/kg) 2-3 minutes before succinylcholine.

^dPretreat children with atropine at 0.005-0.01 mg/kg to prevent bradycardia or atrioventricular block.

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Introduction