Muscle Relaxants (Neuromuscular Junction Blockers) Case File

Muscle Relaxants (Neuromuscular Junction Blockers) Case File

Lydia Conlay, MD, PhD, MBA, Julia Pollock, MD, Mary Ann Vann, MD, Sheela Pai, MD, Eugene C. Toy, MD

Case 4

A 47-year-old patient is undergoing the clipping of an intracranial aneurysm of the anterior communicating artery. The surgery is being performed under a microscope, so even the smallest movement by the patient could have devastating consequences.

➤ How can the patient be protected and the surgery allowed to proceed?

ANSWER TO CASE 4:

Muscle Relaxants (Neuromuscular Junction Blockers)

Summary: A 47-year-old patient is undergoing intracranial surgery, performed under a microscope, requiring the patient to be completely still.

➤ Best method to protect the patient: Neuromuscular blockade leading to muscle paralysis

ANALYSIS

Objectives

1. Introduce the student to the uses for neuromuscular blockers (relaxants) during general anesthesia.

2. Acquaint the student with the various classes of muscle relaxants.

3. Review some of the most common side effects associated with the use of a neuromuscular blocker.

Considerations

During intracranial aneurysm surgery, the patient is positioned with the head stabilized by pins. Moreover, the surgery is exquisitely delicate and typically performed under a microscope. Because of the necessity of keeping the patient still, she will receive vecuronium, a nondepolarizing neuromuscular blocker. This surgery usually takes many hours. However, at the end of the procedure, the patient’s paralysis will be reversed, she will be allowed to awaken, and will be extubated to allow her participation in a neurological examination.

APPROACH TO

Muscle Relaxants

CLINICAL APPROACH

Clinical Pharmacology of the Neuromuscular Blockers

Neuromuscular blockers (NMB) or muscle relaxants are intravenous drugs that are used for muscle relaxation and paralysis by interrupting the transmission of action potentials at the neuromuscular junction. They act predominantly by binding post-junctional nicotinic receptors on skeletal muscle, thereby blocking the nerve depolarization caused by acetylcholine. There are three main indications for neuromuscular blockade:

• To facilitate tracheal intubation

• To optimize surgical conditions, for example, during intra-abdominal, intrathoracic, and intracranial procedures

• To optimize ventilation in a patient who requires controlled mechanical ventilation

Muscle relaxants (or NMBs) block the transmission of action potentials at the neuromuscular junction. NMBs only produce paralysis; they have no intrinsic anesthetic or sedative effects. Paralysis with insufficient anesthesia or sedation is an unpleasant and frightening event. In rare cases, surgery has continued in paralyzed patients who are insufficiently anesthetized, leading to “awareness under anesthesia.”

Two Classes of Muscle Relaxants

NMBs are divided into two classes: depolarizing, and nondepolarizing. The only depolarizing NMB is succinylcholine. Succinylcholine acts at the nicotinic receptor to produce an initial depolarization manifested by transient skeletal muscle fasciculations, later followed by repolarization and paralysis (Figure 4–1).

Since succinylcholine is a depolarizing muscle relaxant, it causes the release of potassium in a manner similar to that observed when a neuron actually fires.

Figure 4–1. Actions of the depolarizing (noncompetitive) neuromuscular junction blocker succinylcholine on the skeletal muscle nicotinic receptor.Succinylcholine acts on skeletal muscle nicotinic receptors to produce initial depolarization followed by repolarization.

Thus, succinylcholine normally increases plasma K+ level from 0.5 to 1.0 mEq. Thus in a patient with pre-existent hyperkalemia, the use of succinylcholine may place the patient at risk for cardiac arrhythmias. The succinylcholineinduced release of potassium is exaggerated in patients with lower motor neuron disease, third-degree burns, long-term immobility, Duchene muscular dystrophy, and rarely, intra-abdominal sepsis. In these clinical settings, its use can cause a hyperkalemic arrest. Succinylcholine has also been associated with painful myalgias in the postoperative period, and it is a potent trigger for malignant hyperthermia.

Succinylcholine is metabolized by plasma pseudocholinesterase. Genetics predispose some families to have either defective, or a deficient amount of pseudocholinesterase isoenzymes in plasma. In these individuals, the duration of action of succinylcholine may be prolonged, and can range from a couple of hours to many hours, depending on the enzymatic alterations. To ensure that pseudocholinesterase deficiency is diagnosed if present, patients are allowed to recover function following succinylcholine administration, before a nondepolarizing muscle relaxant is administered.

Succinylcholine has a rapid onset, and short duration making it an ideal agent for intubation. Because of its short duration of action, its use for the maintenance of relaxation would require administration by infusion, a practice rarely used today.

Nondepolarizing muscle relaxants represent the second class of NMBs, which compete with acetylcholine for the nicotinic receptor resulting in a competitive inhibition of blockade (Figure 4–2). While they act primarily at postsynaptic receptors, some, such as pancuronium, act at pre-junctional

Figure 4–2. Actions of the competitive (nondepolarizing) neuromuscular junction blocker vecuronium on the skeletal muscle nicotinic receptor. Vecuronium competes with acetylcholine at these receptors.

receptors as well. The four nondepolarizing blockers in use today are distinguished by their duration of action and methods of excretion.

Three of the four competitive (nondepolarizing) agents have an intermediate duration of action (rocuronium, vecuronium, and cisatracurium). Rocuronium is distinguished from the other intermediate agents by its rapid onset of action which is similar to, but not quite as fast, as succinylcholine. One agent (pancuronium) is long-acting.

Rocuronium and vecuronium are largely metabolized (about 80%) and excreted by the hepatobiliary system. Thus, their duration of action may be prolonged in patients with severe liver disease. The main hepatic metabolite of vecuronium, 3-desacetyl-vecuronium, is an active metabolite excreted by the kidney. Thus, the duration of vecuronium’s action is also prolonged in patients with end-stage renal failure. Pancuronium’s clearance is about 80% renal, so its elimination may be delayed in patients with severe renal disease. Cisatracurium is independently cleared by Hoffman elimination (degradation in plasma at physiologic pH and temperature), so it is an ideal drug in patients with hepatic or renal failure.

Please refer to Table 4–1 for the clinical properties of the neuromuscular blockers.

Table 4–1 CLINICAL PROPERTIES OF NEUROMUSCULAR BLOCKERS
NEUROMUSCULAR BLOCKER	METABOLISM	EXCRETION	ONSET	DURATION
Succinylcholine	Plasma pseudocholinesterase	Insignificant	Rapid	Ultra-short
Cisatracurium	Hoffman elimination	Insignificant	Moderately rapid	Intermediate
Rocuronium	Insignificant	Biliary	Rapid	Intermediate
Vecuronium	Hepatic	Biliary	Moderately rapid	Intermediate
Pancuronium	Liver	Renal	Moderately rapid	Long

Maintenance of Blockade: How Much is Enough?

The degree of neuromuscular blockade has been shown to correlate in a nearlinear fashion with the height of the twitch derived from stimulation of the adductor pollicus longus muscle (which governs opposition of the thumb) at 2 Hz. This finding formed the basis for the Train-of-Four monitoring of muscle relaxation measured with a peripheral nerve stimulator. The Train of Four measures the response to four twitches administered over 2 seconds. If the anesthetist can feel the presence of four twitches, then the patient is 75% paralyzed or less. If he/she feels three twitches, then the patient can be up to 85% paralyzed. Two twitches indicate that the patient is 95% paralyzed, one twitch, 99%, and no twitches indicate that the patient is totally paralyzed, or more (meaning that there is an excess in muscle relaxant).

It is important to understand the implications of the two extremes of monitoring with the Train of Four. The first 75% or so of receptors paralyzed are not monitored. Thus, a patient can be paralyzed by 75% and still have all four twitches, similar to someone who is not paralyzed at all. At the other extreme, the absence of twitches gives no information as to the likely duration of the existing blockade. Thus, to measure the degree of relaxation between these two extremes, either one, two, or three twitches must be present. As the patient shows some evidence of recovery of neuromuscular function (three out of four twitches), the anesthetist can cautiously give more muscle relaxant intravenously. Generally the presence of one to three twitches is adequate for surgical relaxation.

Reversal of the Neuromuscular Blockade and Emergence

Nondepolarizing neuromuscular blockers are competitive antagonist acetylcholine at the neuromuscular junction. They are reversed by increasing the amount of acetylcholine relative to the NMB, using a peripheral anticholinesterase inhibitor, typically neostigmine, to reclaim the receptor from the blocker (Figure 4–3). Reversal of the neuromuscular blockade is possible if there is some evidence of spontaneous recovery at the neuromuscular junction, as detected by at least one out of four twitches.

However, neostigmine has some troublesome cholinergic side effects such as bradycardia, bronchospasm, and an increase in gut motility that reflect the stimulation of muscarinic receptors by increasing acetylcholine concentrations throughout the body (Figure 4–3). To reduce these untoward effects, glycopyrrolate, an anticholinergic agent, is administered concomitantly with the neostigmine.

It is important to note that clinical signs are the best indicators of an adequate reversal of neuromuscular blockade. The patient’s ability to lift the head for 5 seconds, to protrude his or her tongue, and maintain an inspiratory pressure ≥ −21 cm H2O are reliable signs of adequate reversal. The inability to sustain a prolonged muscle movement (such as extending the arm), and the 

Figure 4–3. Actions of neostigmine and glycopyrrolate on nicotinic and muscarinic receptors. Competitive (nondepolarizing) neuromuscular junction blockers are reversed with neostigmine, which acts on the cholinesterase (ChE) enzyme to increase acetylcholine (ACH) throughout the body. An increase in acetylcholine is desired at the nicotinic receptors on skeletal muscle, but not at the cardiac muscarinic receptors. Accordingly, the antimuscarinic glycopyrrolate is coadministered with neostigmine to block ACH from stimulating the muscarinic receptors, but not blocking ACH from stimulating the skeletal muscle nicotinic receptors.

sensation that one is unable to breathe or handle secretions are signs of an inadequate reversal. Tidal volume respiratory mechanics and the Train-of- Four responses are not reliable indicators for adequate reversal.

Comprehension Questions

4.1. A 28-year-old man presents for shoulder surgery. The patient had a documented episode of malignant hyperthermia in a previous surgery under general anesthesia. Which of the following neuromuscular blockers is contraindicated in this patient?

    A. Vecuronium

    B. Rocuronium

    C. Pancuronium

    D. Succinylcholine

    E. Cisatracurium

4.2. An 18-year-old man presents to the operating room for an emergency exploratory laparotomy for a gun-shot wound to the abdomen. The patient has been intubated in the emergency room and arrives to the operating room intubated. Initial vital signs: BP 68/22, heart rate (HR) 142. His abdomen is distended, tense, and rigid. Which of the following is the most appropriate NMB for maintenance of paralysis in this patient?

    A. Vecuronium

    B. Pancuronium

    C. Cisatracurium

    D. Succinylcholine

    E. Rocuronium

4.3. A 36-year-old woman with a history of hiatal hernia and acid reflux is undergoing a laparoscopic cholecystectomy under general anesthesia. Induction of general anesthesia and intubation were achieved using propofol and succinylcholine. The patient did not recover from the neuromuscular blockade before the end of surgery; she had 0/4 twitches on the Train-of-four twitch response. She was transported to the recovery room intubated, mechanically ventilated, and sedated. Which of the following is the most likely cause of this patient’s prolonged paralysis?

    A. A prolonged effect of the intravenous anesthetic propofol

    B. Atypical pseudocholinesterase enzyme

    C. Pseudocholinesterase deficiency

    D. Liver disease

    E. Renal disease

ANSWERS

4.1. D. Malignant hyperthermia is a life-threatening hypermetabolic disorder that is triggered by succinylcholine and the volatile inhaled anesthetics (isoflurane, desflurane, and sevoflurane). All triggering agents are contraindicated in patients with a history of malignant hyperthermia.

4.2. B. Although any of these agents except succinylcholine can be used to maintain muscle relaxation in this clinical scenario, pancuronium might be the most appropriate. Pancuronium has a vagolytic effect leading to tachycardia, which is vital for this patient. With significant intra-abdominal blood loss and severe hypotension, the patient’s cardiac output is dependent on the heart rate which should be maintained at high rates. For the same reason pancuronium may not be the most appropriate NMB in patients with severe angina where the tachycardia can produce myocardial ischemia due to increased myocardial work and decreased coronary blood flow.

4.3. B. Succinylcholine is metabolized in the plasma by pseudocholinesterase. Its effect does not usually last more than 10 minutes. In the rare condition of an atypical pseudocholinesterase enzyme, its paralytic effects may be prolonged for hours.

Clinical Pearls

➤ Neuromuscular blockers facilitate tracheal intubation and also provide muscle relaxation for certain types of surgery and for intubated ICU patients being mechanically ventilated.

➤ Vecuronium and rocuronium should be used with caution in patients with severe liver disease, as their clearance is 80% hepatobiliary.

➤ Pancuronium should be used with caution in the patient with severe renal disease, since its clearance is 80% renal.

➤ Succinylcholine may be used in the patient with renal disease, so long as the serum K+ level is <5.5 mEq/L and there is no other contraindication to its use.

➤ Patients may experience recall if muscle relaxants are employed without concomitant anesthetic or sedative agents.

References

Naguib M, Lien CA. Pharmacology of muscle relaxants and their antagonists. In: Miller RD, ed. Miller’s Anesthesia. 6th ed. Philadelphia, PA: Churchill Livingstone; 2005: 481-572. 

Pino RM, Ali HH. Monitoring and managing neuromuscular blockade. In: Longnecker DE, ed. Anesthesiology. New York, NY: McGraw-Hill Companies; 2008: 619-638.

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