AN
Anesthesiology

Neuromuscular blockade and reversal

April 07, 2012.
Allen Keebler, DO,

Educational Objectives

The goal of this program is to improve reversal of neuromuscular blockade. After hearing and assimilating this program, the clinician will be better able to:

1. Define the phases of depolarization associated with succinylcholine.

2. Explain the differences between depolarizing and nondepolarizing neuromuscular blockade.

Summary

Neuromuscular junction: synapse between presynaptic neuron and postsynaptic muscle membrane; 50 to 70 nanometers wide; contains high concentration of acetylcholinesterase

Types of acetylcholine (ACh) receptors: prejunctional, postjunctional, and extrajunctional (rare; proliferate after burns and in certain neuromuscular disorders)

Action potential: calcium enters as impulse travels along axon; calcium leads to release of ACh, which binds to nicotinic receptors on motor endplate; results in influx of sodium, which depolarizes motor endplate; if depolarization sufficiently large, muscle contraction occurs

Postjunctional nicotinic receptor: has 5 subunits; ACh binds to 2 α subunits; results in opening of sodium channels for ≈1 msec

Extrajunctional receptors: no effect on nondepolarizing agents, except to divert drugs away from intended site of action; depolarizing agents open channels in extrajunctional as well as junctional receptors, leading to exit of potassium from muscle cells, which may cause hyperkalemia and cardiac arrest

Succinylcholine: 2 ACh molecules linked by methyl group; metabolized by pseudocholinesterase; action prolonged when enzyme concentration decreased, as in pregnancy, liver disease, or with certain drugs; atypical forms may be present

Phase I depolarization: initial brief depolarization of postjunctional membrane; fasciculations seen; further depolarization inhibited, but cell cannot repolarize

Phase II: occurs with increasing dose and exposure to depolarizing drugs; associated with distortion of postjunctional membrane and nondepolarizing blockade; succinylcholine binds more avidly than ACh to α subunits; cell cannot repolarize until succinylcholine diffuses away from receptor

Side effects: stimulates cholinergic autonomic receptors; may cause dysrhythmias, cardiac arrest (largely from hyperkalemia), increased intragastric pressure, muscle spasm or pain, prolonged paralysis (in patients with pseudocholinesterase deficiency), malignant hyperthermia, and increased intraocular and intracranial pressure

Drug interactions: nondepolarizing muscle relaxants (NDMRs) antagonize ACh; larger dose of agonist (succinylcholine) needed to achieve good blockade; true of all NDMRs except pancuronium (potent inhibitor of pseudocholinesterase; potentiates action of succinylcholine); action of succinylcholine irreversible because most reversal agents also inhibit pseudocholinesterase, and inhibition of acetylcholinesterase along with depolarizing block results in further depolarization of membrane

Nondepolarizing muscle relaxants: antagonists that compete with ACh for postsynaptic receptors; interfere with entry of calcium at presynaptic receptors, which inhibits release of ACh

Steroidal compounds: long-acting — pancuronium; pipecuronium; intermediate-acting — rocuronium; vecuronium; short-acting — rapacuronium

Benzylisoquinolines: long-acting — D-tubocurarine, metocurine; doxacurium; intermediate-acting — atracurium; cisatracurium; short-acting — mivacurium

Autonomic effects: autonomic ganglia blockade, sometimes leading to hypotension and tachycardia (D-tubocurarine amd metocurine); blockade of cardiac muscarinic receptors, leading to tachycardia and hypertension (pancuronium and gallamine); histamine release (D-tubocurarine, metocurine, atracurium, and mivacurium); mivacurium metabolized by pseudocholinesterase (action can be reversed if more ACh present to compete for receptors); 20% of atracurium and cisatracurium metabolized through Hofmann elimination (nonenzymatic breakdown at physiologic temperature and pH); remaining 80% broken down through ester hydrolysis

Potentiators of nondepolarizing muscle blockade: acidosis; local anesthetics (lidocaine and bupivacaine); hypothermia; hypokalemia; some antibiotics; calcium channel blockers (verapamil); magnesium; trimetaphan (antihypertensive)

ED95: dose of relaxant required to reduce single twitch height by 95%; 2 to 3 times ED95 dose needed for complete paralysis and optimal intubating conditions

Reversal agents: neostigmine and pyridostigmine — have delayed onset of action; glycopyrrolate anticholinergic of choice to minimize muscarinic side effects; edrophonium — inhibits acetylcholinesterase but not pseudocholinesterase; ideal reversal agent for mivacurium; has fast onset of action (use with atropine); physostigmine — rarely used; crosses blood-brain barrier

Sugammadex: large sugar molecule that encapsulates steroidal NDMR (prevents drug from occupying ACh receptors); reverses action of rocuronium more than vecuronium, and vecuronium more than pancuronium; approval delayed due to association with bronchospasm in pediatric patients

Tests of neuromuscular monitoring

Twitch: single pulse delivered every 1 to 10 sec

Train of four (TOF): 4 successive stimuli in 2 sec; TOF ratio — ratio of fourth to first stimulus responses

Tetanus: at 50 or 100 Hz, continuous stimulus and sustained contraction for 5 sec with no fade; indicates adequate neuromuscular recovery

Double burst stimulation: 3 short bursts at 50 Hz, followed 750 msec later by 2 or 3 more bursts; less painful than tetanus in awake patients; more sensitive than TOF ratio for evaluating fade

Fade: gradual diminution of evoked response during repeated nerve stimulation; seen only with NDMRs; NDMRs block normal positive feedback loop (ie, ACh released and binds to presynaptic ACh receptors, which increases release of ACh) by blocking presynaptic receptors

Posttetanic potentiation: calcium accumulates in nerve ending during tetanic stimulation; stimulation after tetanus results in excessive release of ACh and larger-than-normal final twitch

Differences between depolarizing and nondepolarizing phase I blockade: depolarizing — no fade with TOF or tetanic stimulation; no posttetantic potentiation; TOF ratio >0.7; nondepolarizing — fade with TOF and tetanic stimulation; posttetanic potentiation occurs; TOF ratio <0.7

Site of neuromuscular monitoring: diaphragm requires 1.5 to 2 times as much muscle relaxant as peripheral muscles for identical degree of blockade; onset and offset of paralysis shorter for central than peripheral muscles; monitoring orbicularis oculi more closely resembles pattern of central muscles and laryngeal adductors, but monitoring adductor pollicis ensures no residual paralysis in diaphragm and laryngeal muscles

Reasons for reversing residual muscle relaxants: may hasten patient’s readiness to leave postanesthesia care unit; TOF ratio >0.9 associated with greater margin of safety; residual blockade may predispose to pulmonary complications

Reliable signs of adequate neuromuscular recovery: under anesthesia — sustained tetanus >0.5 sec; TOF ratio >0.9; awake patient — sustained head lift or leg lift >5 sec (gold standard); negative inspiratory force

Readings

Disclosures

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, Dr. Keebler and the planning committee reported nothing to disclose.

Acknowledgements

Dr. Keebler was recorded at Comprehensive Anesthesiology Review, held March 28 to April 2, 2011, in Cleveland, OH, and sponsored by the Cleveland Clinic. For CME information from the Cleveland Clinic, go to http://www.ccfcme.org, or check the Audio-Digest Foundation website, http://www.audio-digest.org, under Upcoming Meetings. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

AN540702

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.

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