Use of Paralytic Agents in The Intensive Care Unit

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Chapter 71 Use of Paralytic Agents in The Intensive Care Unit

David W. Miller, MD , Jean-François Pittet, MD

1 What are neuromuscular blocking agents (NMBs)?

NMBs (also called muscle relaxants or paralytics) are agents that act primarily on acetylcholine (ACh) receptors located on the postsynaptic motor end plate of the neuromuscular junction to cause skeletal muscle paralysis. They do not have any effect on cardiac or smooth muscle. Muscle relaxants do not have any sedating properties; therefore appropriate sedatives and analgesics are needed to avoid awareness (being alert without the ability to move).

2 How are NMBs classified?

NMBs are broadly separated into depolarizing and nondepolarizing agents. The only clinically significant depolarizing agent is succinylcholine (SCh). Nondepolarizing agents are divided into the benzylisoquinoliniums, which include agents such as cisatracurium, and the aminosteroids, of which vecuronium and rocuronium are examples.

3 Why are NMBs used in the intensive care unit (ICU)?

The most common reason for using muscle relaxants in the ICU is for facilitation of endotracheal intubation and mechanical ventilation. Examples include securing the airway for hypoxemic respiratory failure, severe patient-ventilator dyssynchrony, and increasing effectiveness of inverse ratio ventilation. Management of increased intracerebral pressure (ICP) is another indication. There are case reports of using muscle relaxants for control of muscle spasms whether from tetanus, drug overdoses, or seizures. Many protocols for controlled hypothermia after cardiac arrest advocate the use of muscle relaxants to prevent shivering. Continuous electroencephalogram monitoring should be used if muscle relaxants are used in conjunction with a hypothermia protocol or to prevent lactic acidosis in seizures. Muscle relaxants are advocated for decreasing oxygen consumption, although no study has definitively shown that they reduce oxygen consumption. NMBs will improve pulmonary compliance, however. Muscle relaxants may also be used to facilitate the transport of critically ill patients, aid in radiologic imaging, or improve conditions for bedside surgical procedures, such as bronchoscopies and tracheostomies, in the ICU. Sedation alone should always be used if feasible.

4 How does the neuromuscular junction work?

The neuromuscular junction contains the prejunctional motor nerve ending and the postsynaptic membrane on the skeletal muscle cell. Action potentials cause the release of ACh from synaptic vesicles stored in the motor nerve ending. ACh diffuses across the synaptic cleft to the postsynaptic membrane (approximately 20 nm). When two ACh molecules bind to one nicotinic cholinergic receptor within this motor end plate, depolarization occurs with the subsequent influx of calcium from the sarcoplasmic reticulum of the skeletal muscle cell. This results in contraction of the cell. ACh is rapidly hydrolyzed by acetylcholinesterase at the motor end plate, which terminates depolarization. ACh also diffuses away from the synaptic cleft or undergoes reuptake into the motor nerve ending.

5 Explain the mechanism of action of SCh

SCh is the only clinically significant depolarizing muscle relaxant in use. Its chemical structure is similar to that of ACh, and it acts as an agonist at nicotinic cholinergic receptors on the postsynaptic membrane of the neuromuscular junction. While succinylcholine is bound to the receptor further transmission is blocked. Calcium is not being shuttled back into the sarcoplasmic reticulum of the skeletal muscle cell while SCh remains bound to the receptor, which results clinically in muscle relaxation. SCh is hydrolyzed by plasma cholinesterase, which is not located at the neuromuscular junction; therefore the rate of blockade is dependent on the rate at which SCh diffuses away from the neuromuscular junction. The depolarization caused by SCh is prolonged compared with that caused by ACh, and relaxation persists as long as SCh is present.

6 What type of patients should not receive SCh?

Because of its ability to raise serum potassium concentration even in healthy patients, succinylcholine should be avoided in patients with hyperkalemia. The hyperkalemic response is pronounced in patients with extrajunctional ACh receptors. These extrajunctional receptors are more common in patients with burns or severe crush injuries and in neuromuscular disease (i.e., Duchenne muscular dystrophy, Guillain-Barré syndrome, and previous stroke). SCh should also not be used in patients with sepsis, in patients with significant immobility (> 3-5 days), or in pediatric patients (concern for undiagnosed neuromuscular disease). If a patient has a personal or known family history of pseudocholinesterase deficiency, the duration of action of SCh may be prolonged unpredictably. It may also cause sinus bradycardia via its stimulation of cardiac muscarinic receptors; therefore SCh should be used with caution in patients with bradycardia. SCh is a known trigger of malignant hyperthermia; therefore it should be avoided if personal or family history suggests a possibility of malignant hyperthermia. Evidence supports that SCh will elevate intraocular pressure (IOP) and ICP. The use of SCh to avoid aspiration in a rapid-sequence intubation should consequently be weighed against any possible harm from raising IOP or ICP in patients with open globe injuries or severe brain pathologic conditions. The rise in ICP can be avoided by pretreatment with a small dose of a nondepolarizing agent. SCh can also increase gastric pressure, but this response is inconsistent and of concern only if there is an impaired lower esophageal sphincter (i.e., hiatal hernia, esophagectomies).

7 When should SCh be used in the ICU?

Rapid-sequence intubations to avoid aspiration in patients without contraindications to its use would be the main reason. Circumstances also exist in which the brief duration of action of SCh may be desired, such as after a patient’s motor or neurologic examination after emergent intubation. In one meta-analysis, SCh was shown to give better intubating conditions than with a nondepolarizing agent.

8 What are the enzymes that metabolize SCh and ACh?

Butyrylcholinesterase (pseudocholinesterase or plasma cholinesterase), located in the plasma and liver, metabolizes SCh into succinylmonocholine, an active metabolite, and choline. It also metabolizes mivacurium, ester-type local anesthetics, and trimethaphan. Acetylcholinesterase (true cholinesterase) is present at the neuromuscular junction and metabolizes ACh. Unspecific esterases are located in plasma and certain tissue that degrade atracurium and remifentanil.

9 What is a phase II blockade?

After prolonged administration of SCh, fade will appear on train-of-four (TOF) and tetanic stimulation. This block can be reversed by anticholinesterases. The onset of this block coincides with tachyphylaxis to SCh.

10 What is the mechanism of action for nondepolarizing muscle relaxants?

Nondepolarizing NMBs are competitive antagonists of nicotinic cholinergic receptors. A single molecule is able to bind to the receptor in its resting closed state to cause blockade. This compares with SCh, which enacts its effects through a prolonged depolarization of the motor end plate, which results in no further action potentials being propagated.

11 How do nondepolarizing agents differ in their dosing and duration of action?

A summary of the pharmacology of the commonly used NMBs is given in Table 71-1.

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