Use of Neuromuscular Blocking Agents

Chapter 6


Use of Neuromuscular Blocking Agents



Neuromuscular blocking drugs (NMBDs) have been used in clinical practice since 1935 when d-tubocurarine was first isolated. NMBDs are most commonly employed in the operating theater to immobilize patients and enhance surgical exposure. Pharmacologic paralysis is now considered an important adjunct to the management of the critically ill patient in a variety of disease states in the intensive care unit (ICU). The intensivist who uses NMBDs should understand the indications and contraindications for their use, the pharmacodynamics and pharmacokinetics of the available agents, their possible interactions with other drugs, and complications associated with their use in the ICU.


It is imperative for ICU care providers to remember that NMBDs have no intrinsic sedating or analgesic activity and that paralyzed patients must always be given sedatives such as opioids or benzodiazepines prior to the initiation of neuromuscular blockade. Similarly, in patients who are receiving continuous pharmacologic paralysis, there should be frequent assessment and acknowledgment by all care providers regarding the adequacy of underlying sedation. How this is measured in the paralyzed patient is controversial (adjusted dose, frequent cessation of neuromuscular blockade, cerebral monitors, etc.). Some have advocated for continuous bispectral index monitoring despite the lack of studies in the ICU that have shown superiority of this method over any other. Finally, although pharmacologic paralysis is rarely desired, its use is sometimes necessary. When prolonged paralysis is warranted, the minimum total dose (dose administered × length of time) should be the goal. Many intensive care units that use therapeutic paralysis monitor the depth of neuromuscular inhibition with a peripheral nerve stimulator. When used, the dose of muscle relaxant should be titrated to maintain one to two twitches out of a “train-of-four.”



Physiology of Neuromuscular Excitation


Neural excitation commences within the nerve body. The neural impulse is then propagated along the axon of a motor neuron, as a result of ion-regulated membrane voltage differentials. As the signal reaches the nerve terminal, it is converted and transmitted by means of a chemical messenger across a synapse to a motor unit. The neuromuscular synapse consists of the nerve terminal, the synaptic cleft (20 to 50 μm wide), and the motor end plate on the muscle. The neural signal stimulates the release of chemical messengers that then cross the synapse and bind to receptors on the motor unit. Upon binding to its postsynaptic receptor, ion flux is stimulated, a membrane voltage differential ensues, and electrical transmission resumes in the motor unit.


Acetylcholine (ACh) is the primary chemical messenger responsible for mediating neuromuscular transmission. ACh serves as the messenger not only for neural communication at the neuromuscular junction but also for many central nervous system pathways, autonomic ganglia, and postganglionic parasympathetic nerve endings. When a nerve impulse arrives at the nerve terminal of the neuromuscular junction, intracytoplasmic vesicles containing ACh fuse with the nerve cell membrane, and the contents are released into the synapse. The ACh binds to the nicotinic ACh receptor (AChR) on the muscle cell, causing a conformational change and increasing the cellular permeability to sodium. When a sufficient number of sodium channels open, the transmembrane potential exceeds −50 mV and, as a result, the membrane depolarizes, creating an action potential that propagates to the entire motor unit and results in muscular contraction. The process of contraction requires calcium and is inhibited by magnesium.


The termination of physiologic depolarization follows diffusion of free ACh from the synaptic cleft, unbinding of ACh from the postganglionic receptor, and degradation of the ACh molecule by the membrane-bound enzyme acetylcholinesterase. Acetylcholine is hydrolyzed to acetate and choline, which are reabsorbed into the nerve terminal, reconstituted to ACh by the enzyme choline acyltransferase, and repackaged into intracytoplasmic vesicles.



Mechanism of Neuromuscular Blocking Drugs


There are two general categories of NMBDs with effects at the neuromuscular junction: depolarizing and nondepolarizing neuromuscular blocking agents.



Depolarizing Neuromuscular Blocking Drugs (D-NMBDs)


Depolarizing neuromuscular blocking agents (of which succinylcholine is the sole agent currently available for clinical use) act as ACh receptor agonists. The initial effect of D-NMBD binding is depolarization followed by muscle contraction. The blockade that follows contraction is caused by the relatively slow hydrolysis of the drug relative to that of ACh. Persistence of the D-NMBD at the receptor site renders adjacent sodium channels inactive. Repolarization is therefore delayed, and successive nerve impulses find the muscle refractory to depolarization.


Succinylcholine is used to achieve rapid (<60 seconds) paralysis and is frequently used for patients who are at risk for regurgitation of gastric contents during emergent intubation. Recovery from the paralytic effects of succinylcholine is also rapid because of rapid degradation of the drug by butyrylcholinesterase. This “rapid on, rapid off” effect is particularly beneficial for spontaneously breathing patients in whom positive pressure ventilation might be detrimental or in cases where securing the airway via endotracheal intubation may be difficult and rapid resumption of spontaneous ventilation is desired. Succinylcholine in rare instances can be delivered by a continuous infusion but is usually not used for prolonged paralysis in critically ill patients.


Of note, succinylcholine has potentially dangerous cardiac side effects that may preclude its use in some critically ill patients. Arrhythmias caused by autonomic stimulation (via nicotinic receptors on both sympathetic and parasympathetic ganglia) include sinus tachycardia, sinus bradycardia, junctional rhythms, and sinus arrest. Marked hyperkalemia following succinylcholine administration can lead to ventricular fibrillation or asystole. In most individuals, an increase in serum potassium level of 0.5 mEq/L is expected. This rise in serum potassium results from the depolarization of ACh receptors (primarily extrajunctional) and subsequent potassium release from muscle cells. Patients who have sustained denervation injuries or disorders (e.g., spinal cord transection, amyotrophic lateral sclerosis [ALS]) may have a much larger increase in serum potassium concentration, to the point of hyperkalemic cardiac arrest, if given succinylcholine. Patients with recent burns and muscular dystrophies are also at risk of life-threatening hyperkalemia after succinylcholine. Although renal failure per se is not a contraindication to succinylcholine use, its use is contraindicated in patients with hyperkalemia resulting from renal failure or other etiologies (e.g., digoxin toxicity [see Chapters 39 and 81]). Labeling by the Food and Drug Administration (FDA) also indicates cautious use in patients with renal failure because of prolongation of the blockade.

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Jul 7, 2016 | Posted by in CRITICAL CARE | Comments Off on Use of Neuromuscular Blocking Agents

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