Clinical Responses and Monitoring of Phase I and Phase II Neuromuscular Blockade by Succinylcholine Infusion

Response

Phase I

Phase II

End-plate membrane potential Onset

Dose-dependence

Recovery

Train of four and tetanic stimulation Acetylcholinesterase inhibition Muscle response

Depolarized to -55 mV

Immediate Lower

Rapid No fade Augments

Repolarization toward -80 mV Slow transition Usually higher or follows prolonged infusion More prolonged Fade*

Reverses or antagonizes

Fasciculations ^ flaccid paralysis Flaccid paralysis

*Post-tetanic potentiation follows fade.

blocking agents (e.g., bronchospasm, hypotension, excessive bronchial and salivary secretion) appear to be caused by the release of histamine. Succinylcholine, mivacurium, doxacurium, and atracurium also cause histamine release, but to a lesser extent unless administered rapidly. The ammonio steroids, pancuronium, vecuronium, pipecuronium, and rocuronium, have even less tendency to release histamine after intradermal or systemic injection. Histamine release typically is a direct action of the muscle relaxant on the mast cell rather than IgE-mediated anaphylaxis.

ACTIONS OF NEUROMUSCULAR BLOCKING AGENTS WITH LIFE-THREATENING IMPLICATIONS Depolarizing agents can release K+ rapidly from intracellular sites; this may be a causative factor in production of the prolonged apnea in patients who receive these drugs while in electrolyte imbalance.

Succinylcholine-induced hyperkalemia is a life-threatening complication of that drug (e.g., in patients with congestive heart failure who are receiving digoxin or diuretics). Likewise, caution should be used or depolarizing blocking agents should be avoided in patients with extensive soft tissue trauma or burns. A higher dose of a competitive blocking agent often is indicated in these patients. In addition, succinylcholine administration is contraindicated or should be given with great caution in patients with nontraumatic rhabdomyolysis, ocular lacerations, spinal cord injuries with paraplegia or quadriplegia, or muscular dystrophies. Succinylcholine no longer is indicated for children <8 years of age unless emergency intubation or securing an airway is necessary. Hyper-kalemia, rhabdomyolysis, and cardiac arrest have been reported; a subclinical dystrophy frequently is associated with these adverse responses. Neonates also may have an enhanced sensitivity to competitive neuromuscular blocking agents.

DRUG INTERACTIONS From a clinical viewpoint, important pharmacological interactions of these drugs occur with certain general anesthetics, certain antibiotics, Ca2+ channel blockers, and anti-ChE compounds. Since the anti-ChE agents neostigmine, pyridostigmine, and edrophonium preserve endogenous ACh and also act directly on the neuromuscular junction, they can be used in the treatment of overdosage with competitive blocking agents. Similarly, on completion of the surgical procedure, many anesthesiologists employ neostigmine or edrophonium to reverse and decrease the duration of competitive neuromuscular blockade. Succinylcholine should never be administered after reversal of competitive blockade with neostigmine; in this circumstance, a prolonged and intense blockade often results (see Table 9-2). A muscarinic antagonist (atropine or glycopyrrolate) is used concomitantly to prevent stimulation of muscarinic receptors and thereby to avoid slowing of the heart rate. Many inhalational anesthetics (e.g., halothane, isoflurane, enflu-rane) "stabilize" the postjunctional membrane and act synergistically with the competitive blocking agents; this requires a reduction in the dose of the nicotinic receptor blocking drugs.

Aminoglycoside antibiotics produce neuromuscular blockade by inhibiting ACh release from the preganglionic terminal (through competition with Ca2+) and to a lesser extent by noncompetitively blocking the receptor. Tetracyclines also can produce neuromuscular blockade, possibly by chelation of Ca2+. Additional antibiotics that have neuromuscular blocking action, through both presynaptic and postsynaptic actions, include polymyxin B, colistin, clindamycin, and lincomycin. Ca2+ channel blockers enhance neuromuscular blockade produced by both competitive and depolarizing antagonists. When neuromuscular blocking agents are administered to patients receiving these agents, dose adjustments should be considered; if recovery of spontaneous respiration is delayed, Ca2+ salts may facilitate recovery.

Miscellaneous drugs that may have significant interactions with either competitive or depolarizing neuromuscular blocking agents include trimethaphan (no longer marketed in the U.S.), opioid analgesics, procaine, lidocaine, quinidine, phenelzine, phenytoin, propranolol, magnesium salts, corticosteroids, digitalis glycosides, chloroquine, catecholamines, and diuretics.

TOXICOLOGY The important untoward responses of the neuromuscular blocking agents include prolonged apnea, cardiovascular collapse, those resulting from histamine release, and, rarely, anaphylaxis. Related factors may include alterations in body temperature; electrolyte imbalance, particularly of K+ (discussed earlier); low plasma butyrylcholinesterase levels, resulting in a reduction in the rate of destruction of succinylcholine; the presence of latent myasthenia gravis or of malignant disease such as small cell carcinoma of the lung (Eaton-Lambert myasthenic syndrome); reduced blood flow to skeletal muscles, causing delayed removal of the blocking drugs; and decreased elimination of the muscle relaxants secondary to reduced renal function. Great care should be taken when administering these agents to dehydrated or severely ill patients.

MALIGNANT HYPERTHERMIA Malignant hyperthermia is a potentially life-threatening event triggered by certain anesthetics and neuromuscular blocking agents. Clinical features include contracture, rigidity, and heat production from skeletal muscle resulting in severe hyperthermia, accelerated muscle metabolism, metabolic acidosis, and tachycardia. Uncontrolled release of Ca2+ from the sarcoplasmic reticulum of skeletal muscle is the initiating event. Although the halogenated hydrocarbon anesthetics (e.g., halothane, isoflurane, and sevoflurane) and succinylcholine alone reportedly precipitate the response, most incidents arise from the combination of depolarizing blocking agent and anesthetic.

Susceptibility to malignant hyperthermia, an autosomal dominant trait, is associated with certain congenital myopathies such as central core disease. In the majority of cases, however, no clinical signs are visible in the absence of anesthetic intervention.

Susceptibility relates to a mutation in RyR-1, the gene encoding the skeletal muscle ryanodine receptor (RYR-1); other loci have been identified on the L-type Ca2+ channel and on associated proteins.

Treatment entails intravenous administration of dantrolene (dantrium), which blocks Ca2+ release and its sequelae in skeletal muscle. Rapid cooling, inhalation of 100% oxygen, and control of acidosis should be considered adjunct therapy in malignant hyperthermia.

Central core disease has five allelic variants of RyR-1; patients with central core disease are highly susceptible to malignant hyperthermia with the combination of an anesthetic and a depolarizing neuromuscular blocker. Patients with other muscle syndromes or dystonias also have an increased frequency of contracture and hyperthermia in the anesthesia setting.

RESPIRATORY PARALYSIS Treatment of respiratory paralysis arising from an adverse reaction or overdose of a neuromuscular blocking agent includes positive-pressure artificial respiration with oxygen and maintenance of a patent airway until recovery of normal respiration is ensured. With the competitive blocking agents, this may be hastened by the administration of neostigmine methylsulfate (0.5-2 mg intravenously) or edrophonium (10 mg intravenously, repeated as required).

INTERVENTIONAL STRATEGIES FOR OTHER TOXIC EFFECTS Neostigmine effectively antagonizes only the skeletal muscular blocking action of the competitive blocking agents and may aggravate side effects (e.g., hypotension) or induce bronchospasm. In such circumstances, sympathomimetic amines may be given to support the blood pressure. Atropine or gly-copyrrolate is administered to counteract muscarinic stimulation. Antihistamines will counteract the responses that follow the release of histamine, particularly when administered before the neuro-muscular blocking agent.

ABSORPTION, FATE, AND EXCRETION Quaternary ammonium neuromuscular blocking agents are poorly and irregularly absorbed from the gastrointestinal (GI) tract. Absorption is adequate from intramuscular sites. Rapid onset is achieved with intravenous administration. The more potent agents must be given in lower concentrations, and diffusional requirements slow their rate of onset.

With long-acting competitive blocking agents (e.g., D-tubocurarine, pancuronium), blockade may diminish after 30 minutes owing to redistribution of the drug, yet residual blockade and plasma levels of the drug persist. Subsequent doses show diminished redistribution. Long-acting agents may accumulate with multiple doses.

The ammonio steroids contain ester groups that are hydrolyzed in the liver. Typically, the metabolites have about half the activity of the parent compound and contribute to the total relaxation profile. Ammonio steroids of intermediate duration of action (e.g., vecuronium, rocuronium; see Table 9-1) are cleared more rapidly by the liver than is pancuronium. The more rapid decay of neu-romuscular blockade with compounds of intermediate duration argues for sequential dosing of these agents rather than administering a single dose of a long duration neuromuscular blocking agent.

Atracurium is converted to less active metabolites by plasma esterases and spontaneous degradation. Because of these alternative routes of metabolism, atracurium does not exhibit an increased t1/2 in patients with impaired renal function and therefore is the agent of choice in this setting. Mivacurium shows an even greater susceptibility to butyrylcholinesterases, and thus has the shortest duration among nondepolarizing blockers. The extremely brief duration of action of succinyl-choline also is due largely to its rapid hydrolysis by the butyrylcholinesterase of liver and plasma. Among the occasional patients who exhibit prolonged apnea following the administration of suc-cinylcholine or mivacurium, most (but not all) have atypical or deficient plasma cholinesterase, hepatic or renal disease, or a nutritional disturbance.

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