Use of Paralytic Agents in The Intensive Care Unit

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.

12 How do the aminosteroid and benzylisoquinolinium differ in side effects?

Aminosteroids such as rocuronium and pancuronium can to some degree block cardiac muscarinic receptors resulting in tachycardia. The benzylisoquinoliniums cause some degree of histamine release, especially older drugs such as mivacurium, which may result in hypotension and bronchoconstriction. Atracurium has only slight histamine release, and cisatracurium has none. The aminosteroid rocuronium has been associated with cases of anaphylaxis.

13 What is Hofmann elimination?

This is the method by which atracurium and cisatracurium are primarily metabolized. It is an organ-independent process that makes these drugs useful in patients with liver and renal failure. The process is decreased by hypothermia and acidosis, which should prompt closer monitoring and dose adjustments.

14 What nondepolarizing agent is the best alternative to SCh when it is contraindicated?

Rocuronium has the shortest onset of action with an intubating dose of 0.6 to 1.0 mg/kg resulting in adequate relaxation within 2 minutes. The drug should be used for rapid-sequence intubations if SCh cannot be used.

15 What are some unique features of pancuronium?

Pancuronium has a vagolytic effect that can cause a modest increase in heart rate, cardiac output, and blood pressure. Because it is metabolized by the liver and eliminated in the bile and urine, doses should be modified in hepatic and renal failure.

16 Explain how the depth of neuromuscular blockade is monitored in the ICU. What equipment is used?

A peripheral nerve stimulator is used to monitor the degree of neuromuscular blockade. Generally contraction of the adductor pollicis muscle in response to ulnar nerve stimulation is measured. The peroneal nerve or facial nerve may be substituted.

Electrode pads or needles are placed on or in the skin over the nerve of interest and a supramaximal, monophasic current with a square wave is passed through the electrodes with the motor response being monitored by feeling or watching the muscle contract. The TOF and double-burst stimulation (DBS) are the most commonly used methods of delivering current. The TOF current is four stimuli being applied over a 2-second period. The result can be reported as the number of twitches felt out of four. A TOF ratio can be calculated as well by dividing the amplitude of the fourth twitch by the amplitude of the first twitch. DBS is performed by the stimulator giving two 50-Hz tetanic bursts 750 milliseconds apart. Each burst lasts 0.2 second and contains three impulses. DBS may improve tactile detection of residual blockade. More accurate measurements of TOF ratios may be obtained by using mechanomyography, electromyography, or acceleromyography, which quantitates the degree of movement or contraction. Of note, only nondepolarizing muscle relaxants will demonstrate fade. The TOF ratio with SCh is always 1.0; only amplitude of the twitches changes, unless a phase II blockade has occurred.

17 How does TOF count correlate with degree of neuromuscular blockade?

During a partial nondepolarizing blockade, when one twitch is detectable, the degree of neuromuscular blockade is 90% to 95%. The second twitch is detected when 80% to 90% blockade is present. The third represents 70% to 80% blockade. When the fourth twitch becomes detectable, there is still 65% to 75% of blockade remaining. In the operating room, most surgical procedures only need one to two twitches. Note that if no twitches are present, it is difficult to assess degree of blockade.

18 What depth of paralysis is necessary in most circumstances in the ICU?

It is first always encouraged to use sedation if possible instead of neuromuscular blockade. If neuromuscular blockade is needed as an infusion the lowest dose possible to obtain the clinical response should be used. If this is unclear, then it is recommended to keep the TOF count to one to two twitches. Frequent (daily) drug holidays are also useful to make sure that no accumulation of active metabolites occurs and that no other neurologic process (i.e., cerebrovascular accident or neuropathy) has occurred.

19 Name the potential adverse outcomes from the use of nondepolarizing muscle relaxants in the ICU

The main risks include awareness from inadequate sedation, generalized deconditioning and muscle atrophy, skin breakdown, corneal abrasions, ICU-acquired weakness, peripheral nerve injury from improper positioning, myositis ossificans (ossification of connective tissue), central nervous system toxicity, and the inability to clear secretions from cough suppression.

20 What is ICU-acquired weakness, and what are its risk factors?

ICU-acquired weakness is the main clinical sign of critical illness neuromyopathy (CINM), which results in either structural or functional changes in skeletal muscle. This disease prolongs ventilator time, makes ventilator weaning more difficult, and increases ICU length of stay.

Five main risk factors are multiple organ failure, muscle immobilization, hyperglycemia, use of corticosteroids, and neuromuscular blockade. A decrease in muscle action potential with spontaneous electrical activity during electrophysiologic testing diagnoses the disease. NMBs either have a direct toxic effect or increase the toxic effect of corticosteroids on muscles.

21 What are some ways ICU-acquired weakness can be treated?

Multiple studies now show that early mobilization of patients with acute respiratory failure when coupled with an aggressive sedation weaning protocol and daily physical and occupational therapy will shorten total ventilator time and ICU days. Reports also exist that daily electrical muscle stimulation will shorten ventilator time and prevent onset of CINM.

22 How do muscle relaxants interact with other commonly used drugs in the ICU?

A variety of drugs either augments or inhibits the actions of nondepolarizing muscle relaxants. A summary is given in Table 71-2.

^{Table 71-2} Drug-drug interaction of neuromuscular blocking agents

23 Describe how serum electrolyte, acid–base status, and temperature alter the action of neuromuscular blockade

The duration of action of nondepolarizing muscle relaxants is prolonged by hypothermia, especially if core temperatures drop below 36° C. This is due to altered renal and hepatic clearance and by altered enzyme function. Hypermagnesemia potentiates neuromuscular blockade by nondepolarizing muscle relaxants. This is probably due to inhibition of calcium channels at the presynaptic membrane, which trigger the release of ACh. Magnesium also makes the postjunctional membrane less excitable. Hypercalcemia, on the other hand, shortens the time course for neuromuscular blockade recovery. Both metabolic and respiratory acidosis augments nondepolarizing muscle relaxant blockade, but only respiratory acidosis limits adequate reversal with neostigmine. Hypophosphatemia and hypokalemia also potentiate the effects of muscle relaxants. Patients with elevated liver function tests or creatinine may have accumulation of NMBs and their metabolites.

24 What are the active metabolites of muscle relaxants, and what effects do they cause?

3-Deacetylvecuronium is a potent (approximately 80%) metabolite of vecuronium and has a longer duration of action with slower plasma clearance. Vecuronium should not be used in patients with hepatic and renal dysfunction, especially as a continuous infusion, because a prolonged blockade may occur. Laudanosine is an active metabolite of atracurium. It is dependent on the liver and kidney for elimination. It theoretically has central nervous system stimulatory (seizures) and cardiovascular (hypotension) effects, but these require high levels to be of concern. Cisatracurium is a more potent isomer of atracurium; therefore approximately five times less laudanosine is produced, which is not thought to be clinically significant.

25 What steps can be taken to prevent long-term muscle relaxant use?

Every effort should be given to avoid muscle relaxants and to use infrequent boluses compared with long-term infusions if possible. If infusions are needed, close monitoring both clinically and with a peripheral nerve stimulator should be undertaken. The depth of paralysis should be adjusted until one or two twitches are obtained. Deepening of sedation can usually prevent the need for neuromuscular blockade.

26 How can the effects of nondepolarizing muscle relaxants be reversed?

The easiest and most effective way for the effect of muscle relaxants to terminate is to wait for the drug to be metabolized and eliminated from the body. The effects of nondepolarizing muscle relaxants may be actively reversed in two ways, however. The first involves increasing the amount of ACh in the neuromuscular junction to overcome the muscle relaxant competing for the receptor. Drugs called cholinesterase inhibitors (anticholinesterases) inhibit the enzyme that hydrolyzes ACh, thus effectively overwhelming the muscle relaxant so that it cannot work. A list of these agents is in Table 71-3. Of note, physostigmine is another cholinesterase inhibitor that crosses the blood–brain barrier and is not used for the reversal of neuromuscular blockade. Pyridostigmine is primarily used for the treatment of myasthenia gravis and not for reversal of neuromuscular blockade. The second way muscle relaxants may be actively reversed involves the use of a novel drug that binds aminosteroid muscle relaxants. See question 28.

27 What are the side effects of anticholinesterases, and how are they attenuated?

The most significant side effects are due to these drugs increasing ACh at muscarinic cholinergic receptors (parasympathetic stimulation) in addition to the neuromuscular junction. This may result in bradycardia or asystole, increased motility of the gastrointestinal tract, pulmonary bronchospasm, increased bladder tone, and pupillary constriction (miosis). Anticholinergics with similar onset of action are given to avoid these side effects.

28 What is sugammadex?

Sugammadex is a cyclodextrin compound and is the first selective muscle relaxant–binding agent. Its three-dimensional structure forms a hydrophobic central cavity that can accommodate steroidal NMBs. These agents bind in a 1:1 fashion (rocuronium>vecuronium>>pancuronium). This drug causes a rapid drop in the serum muscle relaxant concentration with the resulting gradient leading to more agent leaving the neuromuscular junction. This terminates the action of the muscle relaxant and eliminates the need for anticholinesterases. It is currently available in Europe but not the United States.

29 Are any good effects associated with neuromuscular blockade use in the ICU?

Neuromuscular blockade with cisatracurium when compared with placebo has been shown to improve mortality in early acute respiratory distress syndrome (ARDS). Some evidence also supports a decrease in the proinflammatory state in ARDS when cisatracurium is used.