13: Muscle Relaxants and Monitoring of Relaxant Activity

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CHAPTER 13 Muscle Relaxants and Monitoring of Relaxant Activity

James Duke, MD, MBA

1 Describe the anatomy of the neuromuscular junction

A motor nerve branches near its terminus to contact many muscle cells, losing myelin to branch further and come into closer contact with the junctional area of the muscle surface. Within the most distal aspect of the motor neuron, vesicles containing the neurotransmitter acetylcholine (ACh) can be found. The terminal neuron and muscle surface are loosely approximated with protein filaments, and this intervening space is known as the junctional cleft. Also contained within the cleft is extracellular fluid and acetylcholinesterase, the enzyme responsible for metabolizing ACh. The postjunctional motor membrane is highly specialized and invaginated, and the shoulders of these folds are rich in ACh receptors (Figure 13-1).

Figure 13-1 The neuromuscular junction.

(From Kandel ER, Schwartz JH, Jessel TM, editors: Principles of neural science, ed 3, New York, 1991, Elsevier, p 136.)

2 What is the structure of the acetylcholine receptor?

The ACh receptor is contained within the motor cell membrane and consists of five glycoprotein subunits: two alpha and one each of β, δ, and ε. These are arranged in a cylindric fashion; the center of the cylinder is an ion channel. ACh binds to the α-subunits.

3 With regard to neuromuscular transmission, list all locations for acetylcholine receptors

ACh receptors are found in several areas:

About 5 million ACh receptors per neuromuscular junction (NMJ) are located on the postjunctional motor membrane.

Prejunctional receptors are present and influence the release of ACh. The prejunctional and postjunctional receptors have different affinities for ACh.

Extrajunctional receptors are located throughout the skeletal muscle in relatively low numbers owing to suppression of their synthesis by normal neural activity. In cases of traumatized skeletal muscle or denervation injuries, these receptors proliferate.

4 Review the steps involved in normal neuromuscular transmission

A nerve action potential is transmitted, and the nerve terminal is depolarized.

ACh is released from storage vesicles at the nerve terminal. Enough ACh is released to bind 500,000 receptors.

ACh molecules bind to the α-subunits of the ACh receptor on the postjunctional membrane, generating a conformational change and opening receptor channels. Receptors do not open unless both α-receptors are occupied by ACh (a basis for the competitive antagonism of nondepolarizing relaxants).

Sodium and calcium flow through the open receptor channel generating an end-plate potential.

When between 5% and 20% of the receptor channels are open and a threshold potential is reached, a muscle action potential (MAP) is generated.

Propagation of the MAP along the muscle membrane leads to muscle contraction.

The rapid hydrolysis of ACh by acetylcholinesterase (true cholinesterase) within the synaptic cleft and return of normal ionic gradients return the NMJ to a nondepolarized, resting state, and the ACh receptors are closed.

5 What are the benefits and risks of using muscle relaxants?

By interfering with normal neuromuscular transmission, these drugs paralyze skeletal muscle and can be used to facilitate endotracheal intubation, assist with mechanical ventilation, and optimize surgical conditions. Occasionally they may be used to reduce the metabolic demands of breathing and facilitate the treatment of raised intracranial pressure (ICP). Because they paralyze all respiratory muscles, they are dangerous drugs to use in the unintubated patient unless the caregiver is trained in airway management.

6 How are muscle relaxants classified?

Depolarizing relaxants: Succinylcholine (SCH) is two molecules of ACh bound together, an agonist at the NMJ, and the only depolarizing relaxant available clinically. As such, SCH binds to the α-subunits of the ACh receptor. After binding, SCH can open the ion channel and depolarize the end plate. Although SCH, like ACh, binds only briefly to the receptor, it is not hydrolyzed in the synaptic cleft by acetylcholinesterase. In fact, SCH molecules may unbind and rebind receptors repeatedly. SCH must diffuse away and be broken down in the plasma by enzymes called plasma- or pseudocholinesterase, and time for clearance from the body is an accurate measure of its duration of effect.

Nondepolarizing relaxants: These drugs are competitive antagonists to ACh at the postsynaptic membrane. They need only bind to one of the two α-subunits to prevent opening of the ionic pore.

7 What are the indications for using succinylcholine?

SCH provides the most rapid onset and termination of effect of any neuromuscular blocker (NMB) currently available. Its onset is 60 to 90 seconds, and the duration of effect is only 5 to 10 minutes. When the patient has a full stomach and is at risk for pulmonary aspiration of gastric contents, rapid paralysis and airway control are priorities, and SCH is often the drug indicated. (Rocuronium when given in large doses also has a SCH-like onset of action, although a prolonged duration of effect would contraindicate its use in patients likely to be difficult to ventilate or intubate.) Patients at risk for full stomachs include those with diabetes mellitus, hiatal hernia, obesity, pregnancy, severe pain, bowel obstructions, and trauma.

8 If succinylcholine works so rapidly and predictably, why not use it all the time?

SCH has numerous side effects:

SCH stimulates both nicotinic and muscarinic cholinergic receptors. Stimulation of muscarinic receptors within the sinus node results in numerous bradyarrhythmias, including sinus bradycardia, junctional rhythms, ventricular escape and asystole.

SCH is a trigger for malignant hyperthermia.

Prolonged exposure of the receptors to SCH results in persistent open receptor channel and ionic fluxes through the ion pore, known as phase II or desensitization blockade. Normal depolarization/repolarization is not possible until SCH is metabolized.

In patients ambulatory soon after surgery, random generalized muscle contractions (fasciculations) have been associated with painful myalgias. Whether pretreating with a subparalyzing dose of a nondepolarizing relaxant before SCH is effective in reducing myalgias continues to be a matter of debate.

SCH increases ICP. The etiology is not completely understood, but it is known that a subparalyzing dose of a nondepolarizing relaxant before SCH administration reduces the increase in ICP; thus perhaps fasciculations are the cause of the increase in ICP.

In the presence of immature extrajunctional receptors, administration of SCH may result in severe hyperkalemia and malignant ventricular arrhythmias. Extrajunctional receptors are normally suppressed by activity. Any condition that decreases motor-nerve activity results in a proliferation of these receptors. Examples include spinal cord and other denervation injuries, upper and lower motor neuron disease, closed head injuries, burns, neuromuscular diseases, and even prolonged immobility.

SCH increases intraocular pressure (IOP). There is a theoretic risk for the use of SCH in patients with open eye injury (i.e., extrusion of extraocular contents). However, the increases in IOP are modest, and from a clinical perspective extrusion of ocular contents has not been observed. Certainly if a nondepolarizing agent is administered instead of SCH and the patient is intubated before optimal intubating conditions, coughing on the endotracheal tube (called “bucking”) increases IOP significantly and puts the patient at risk for extruding ocular contents.

9 How do mature and immature acetylcholine receptors differ?

Mature ACh receptors are also known as innervated or ε-containing receptors (because of the ε-subunit within the ACh receptor. They are tightly clustered at the NMJ and are responsible for normal neuromuscular activation. Immature receptors, also known as fetal, extrajunctional, or γ-receptors, differ from the mature receptors in that they are present during fetal development and suppressed by normal activity, are dispersed across the muscular membrane rather than localized at the NMJ, and have a γ-, not an ε-subunit as part of the receptor. The half-life of mature receptors is about 2 weeks, whereas the half-life of immature receptors is less than 24 hours. The immature receptors depolarize more easily in the presence of ACh or SCH and thus are more prone to release potassium. Also, once depolarized, immature receptors tend to stay open longer. Immature receptors are up-regulated in the presence of denervation injuries, burns, and the like. This also exaggerates the potential for hyperkalemia when SCH is administered.

10 Differentiate between qualitative and quantitative deficiencies in pseudocholinesterase

Pseudocholinesterase is produced in the liver and circulates in the plasma. Quantitative deficiencies of pseudocholinesterase are observed in liver disease, pregnancy, malignancies, malnutrition, collagen vascular disease, and hypothyroidism; they slightly prolong the duration of blockade with SCH. However, from a practical standpoint the increase in duration of SCH is probably not clinically important.

There may also be qualitative deficiencies in pseudocholinesterase (i.e., the activity of the enzyme is impaired). These are genetic diseases and as such can be present in heterozygotic or homozygotic forms. The most common form is called dibucaine-resistant cholinesterase deficiency and refers to the laboratory test that characterizes it. When added to the serum under study, dibucaine inhibits normal plasma cholinesterase by 80%, whereas the atypical plasma cholinesterase is inhibited by only 20%. Therefore a patient with normal pseudocholinesterase is assigned a dibucaine number of 80. If a patient has a dibucaine number of 40 to 60, that patient is heterozygous for this atypical pseudocholinesterase and will have a moderately prolonged and usually clinically insignificant block with SCH. If a patient has a dibucaine number of 20, he or she is homozygous for atypical plasma cholinesterase and will have an extremely prolonged block with SCH.

11 Review the properties of nondepolarizing muscle relaxants

Nondepolarizing relaxants are competitive antagonists at the NMJ and are classified by their duration of action (short-, intermediate-, and long-acting). The doses, onset, and duration of effect are described in Table 13-1.

TABLE 13-1 Properties of Nondepolarizing Muscle Relaxants

12 Review the metabolism of nondepolarizing neuromuscular blockers

Aminosteroid relaxants (e.g., pancuronium, vecuronium, pipecuronium, and rocuronium) are diacetylated in the liver, and their action may be prolonged in the presence of hepatic dysfunction. Vecuronium and rocuronium also have significant biliary excretion, and their action may be prolonged with extrahepatic biliary obstruction.

Relaxants with significant renal excretion include tubocurarine, metocurine, doxacurium, pancuronium, and pipecuronium.

Atracurium is unique in that it undergoes spontaneous breakdown at physiologic temperatures and pH (Hoffmann elimination) as well as ester hydrolysis, and thus it is ideal for use in patients with compromised hepatic or renal function.

Mivacurium, like SCH, is metabolized by pseudocholinesterase.

13 Describe common side effects of nondepolarizing neuromuscular blockers

Histamine release is most significant with d-tubocurarine but is also noted with mivacurium, atracurium, and doxacurium. The amount of histamine released is frequently dose related. Cisatracurium does not seem to cause significant histamine release. Tachycardia is usually a side effect of pancuronium because of ganglionic stimulation and vagolysis.

14 Review medications that potentiate the actions of muscle relaxants

Volatile anesthetics potentiate relaxants for a number of reasons, including central nervous system depression, increasing blood flow (and relaxant molecules) to muscle, and desensitization of the postjunctional membrane.

Local anesthetics affect the prejunctional, postjunctional, and motor membranes, depressing normal functions at all these sites.

Calcium channel and β-adrenergic blockers impair ion transport, but the clinical significance at the NMJ is probably not important.

Antibiotics, and most notably aminoglycosides, appear to have negative prejunctional and postjunctional effects. Penicillin and cephalosporins do not affect relaxant activity.

Magnesium inhibits the release and the depolarizing effect of ACh and decreases muscle fiber excitability. Lithium also potentiates neuromuscular blockade.

Long-term use of steroids results in a myopathy and also has some affect on the NMJ, particularly when muscle relaxants have been used for a prolonged period.

Dantrolene depresses skeletal muscle directly and impairs excitation-contraction.

15 What clinical conditions potentiate the actions of neuromuscular blockers?

Respiratory acidosis, metabolic alkalosis, hypothermia, hypokalemia, hypercalcemia, and hypermagnesemia potentiate blockade. Hepatic or renal dysfunction also increases the duration of action of relaxants.

16 Discuss important characteristics of a nerve stimulator

A nerve stimulator should be capable of delivering single-twitch stimulation at 0.1 Hz (1 stimulus every 10 seconds), train of four (TOF) at 2 Hz (2 per second), and tetanic stimulation at 50 Hz (50 per second). The black electrode of the stimulator is negatively charged, and the red electrode is positively charged. The black electrode depolarizes the membrane, and the red electrode hyperpolarizes the membrane. Although stimulation is possible however the electrodes are placed, maximal twitch height occurs when the negative electrode is placed in closest proximity to the nerve.

17 List the different patterns of stimulation

Single stimulus

TOF stimulation

Tetanic stimulation

Posttetanic facilitation and posttetanic count

Double-burst (DB) stimulation

18 Which is the simplest mode of stimulation?

Single stimulus is the simplest mode of stimulation. It consists of the delivery of single impulses separated by at least 10 seconds but is of limited clinical use.

19 Which mode is most commonly used to assess degree of blockade? How is it done?

TOF stimulation is the most common modality used to assess degree of blockade. Four stimuli are delivered at a frequency of 2 Hz (2 per second), and the ratio of the amplitude of the fourth to the first response in a train (T4:T1) ratio estimates the degree of block. The four twitches of the TOF disappear in reverse order as the degree of blockade deepens. The fourth twitch of the TOF disappears when 75% to 80% of the receptors are occupied, the third twitch disappears at 85% occupancy, the second twitch disappears at 85% to 90% occupancy, and the first twitch disappears at 90% to 95% occupancy. However, there is accumulating evidence that visual or tactile evaluation of the TOF response is inadequate for evaluating neuromuscular function because it has been demonstrated repeatedly that, even with experienced practitioners, subjective TOF estimations correlate poorly with true TOF fade. Recently there has been a call for more objective measures of return of motor function such as accelomyography, strain-gauge monitoring, and electromyography.

KEY POINTS: Muscle Relaxants

1. Metabolism of relaxants is more important than pharmacologic reversal for termination of relaxant effect.

2. Train-of-four assessment is highly subjective and has been repeatedly demonstrated to underestimate residual neuromuscular blockade.

3. It may be a best practice to administer reversal agents to all patients receiving nondepolarizing relaxants.

4. Leave clinically weak patients intubated and support respirations until the patient can demonstrate return of strength.

20 What is tetanic stimulation?

Tetanic stimulation consists of repetitive, high-frequency stimulation at frequencies of 50 Hz or greater. Loss of contraction during tetanic stimulation, known as tetanic fade, is a sensitive indicator of residual neuromuscular blockade. Tetanus stimulates the release of ACh from the prejunctional membrane, decreasing the validity of further nerve stimulation for upward of 30 minutes, leading to overestimating the return of neuromuscular function. A tetanic stimulus is painful.

21 Explain posttetanic facilitation and posttetanic count

This mode of stimulation is useful during periods of intense neuromuscular blockade (when there is no response to TOF stimulation) and extends our range of monitoring. It provides an indication as to when recovery of a single twitch is anticipated and thus when reversal of neuromuscular blockade is possible. An application of a 50-Hz stimulus for 5 seconds is followed in 3 seconds by repetitive single twitches at 1 Hz. The number of twitches observed is inversely related to the degree of blockade.

22 What is double-burst stimulation?

DB stimulation appears to be more sensitive than TOF stimulation for detecting small degrees of residual neuromuscular blockade. DB involves the application of an initial burst of three 0.2-ms impulses at 50 Hz followed by an identical stimulation in 750 ms. The magnitude of the responses to double burst is approximately three times greater than that of TOF stimulation, thus making it easier to assess degree of fade present.

23 What is acceleromyography?

There is concern that the visual and tactile qualities of conventional TOF stimulation and assessments of strength such as 5-second head lift are not sufficiently quantitative to detect all instances of residual neuromuscular blockade. The operating concept is, as force is proportional to acceleration, acceleration is measured during TOF stimulation. Acceleromyography is thought to provide comparatively more quantitative information about TOF stimulation, and there is growing evidence that acceleromyography should be routinely used to reduce the incidence of residual weakness.

24 Which nerves can be chosen for stimulation?

Any easily accessible nerve may be used, but the most common nerve stimulated is the ulnar nerve. Contraction of the adductor pollicis muscle of the thumb is observed. The ophthalmic branch of the facial nerve may also be stimulated, monitoring the contraction of the orbicularis oculi muscle. Stimulating the peroneal nerve near the fibular head results in dorsiflexion of the ankle. Stimulating the posterior tibial nerve and ankle results in plantar flexion of the big toe.

25 What are the characteristic responses to the various patterns of stimulation produced by nondepolarizing agents?

Repetitive stimulation (TOF or tetanus) is associated with fade in the muscle response.

Following a tetanic stimulus, response to subsequent stimulations is increased (posttetanic facilitation). This may be caused by increased ACh release or increased sensitivity at the end plate (Figure 13-2).

Figure 13-2 Response to nondepolarizing muscle relaxant blockade.

(From Bevan DR, Bevan JC, Donati F: Muscle relaxants in clinical anesthesia, Chicago, 1988, Year Book, pp 49–70.)

26 Summarize the characteristic responses to the various patterns of stimulation produced by depolarizing relaxants (succinylcholine)

The single-twitch, TOF, and tetanus amplitudes are uniformly decreased at any level of blockade. There is lack of fade in response to TOF and tetanus and lack of posttetanic facilitation. A desensitization or phase II blockade may develop with prolonged exposure to SCH. Phase II blockade has the same twitch characteristics as nondepolarizing blockade (Figure 13-3).

Figure 13-3 Response to depolarizing muscle relaxant blockade.

(From Bevan DR, Bevan JC, Donati F: Muscle relaxants in clinical anesthesia, Chicago, 1988, Year Book, pp 49–70.)

27 For surgical purposes, based on nerve stimulation, what is adequate muscular relaxation?

Adequate relaxation is generally present when one to two twitches of the TOF response are present, correlating with 80% depression of single-twitch height. However, volatile anesthetics, other medications, and the patient’s underlying health also affect strength, and under these conditions lighter levels of blockade may be satisfactory.

28 How might relaxant activity be terminated?

There may be competitive agonism at the NMJ, as when acetylcholinesterase inhibitors are administered to prevent metabolism of ACh, increasing the concentration of ACh at the NMJ. Alternatively the relaxant might migrate away from its site of action, suggesting that there is a concentration gradient favoring this. Commonly such a concentration gradient is created through metabolism of the relaxant. However, selective binding of relaxant molecules is a pharmacologic alternative that is emerging in clinical practice. The first of this class of drugs likely to become commonly available is sugammadex.

29 Review the properties of sugammadex

Sugammadex is a modified cyclodextrin that forms extremely tight water-soluble complexes with relaxants having steroidal nuclei (rocuronium > vecuronium >> pancuronium). The cyclodextrin molecule is rather doughnut shaped; the relaxant is bound within the doughnut hole, roughly speaking; and the dissociation rate is very low. Binding of the relaxant molecule to sugammadex creates a concentration gradient away from the NMJ. Its efficacy does not depend on renal excretion of the cyclodextrin-relaxant complex. Sugammadex appears to be relatively free of side effects. Sugammadex has no effect on acetylcholinesterase or any other cholinergic receptors.

30 How might sugammadex alter anesthetic practice?

The role of SCH for rapidly securing the airway has been discussed, as have the numerous side effects of SCH. Pharmacologic innovation in development of muscle relaxants per se has not resulted in a nondepolarizing relaxant with quick-onset, short duration of action and freedom from worrisome side effects. However, sugammadex may provide a useful alternative if it allows the caregiver to administer rocuronium in rapid paralysis doses (≈1.2 mg/kg) and have an avenue for pharamacologic antagonism soon after dosing of the relaxant through tight binding of circulating relaxant molecules. In fact, the use of sugammadex after rocuronium dosing may provide faster onset-offset profile than SCH given at 1 mg/kg and eliminate the need to ever administer anticholinesterase medications. Finally, it should be mentioned that elimination of residual neuromuscular blockade in the postoperative period would be of definite clinical benefit.

31 Discuss the appropriate time to reverse neuromuscular blockade based on nerve stimulation

The best method of terminating the relaxant effect is to dose sparingly and allow the relaxant to be metabolized. Recall that only one of the α-subunits of the postjunctional receptor need be occupied by a relaxant molecule to inhibit function, whereas two molecules of ACh are necessary to stimulate the receptor; thus, even though the nondepolarizing relaxants are competitive antagonists, the receptor dynamics favor the relaxants. With these caveats, neuromuscular blockade can be reversed when there is at least one twitch with TOF stimulation. However, this still reflects a very deep level of blockade, and the clinician should monitor the patient closely for clinical signs of inadequate return of strength. The greater the TOF when reversed, the better. It is also important to remember that recent tetanic stimuli will result in overestimating the TOF.

32 Review the acetylcholinesterase inhibitors commonly used to antagonize nondepolarizing blockade

Acetylcholinesterase inhibitors prevent the breakdown of acetylcholinesterase, increasing the amount of ACh available at the NMJ. Neostigmine, 25 to 70 mcg/kg, and edrophonium, 0.5 to 1 mg/kg, are commonly used for this purpose perioperatively. Edrophonium also stimulates the prejunctional membrane, increasing release of ACh. These medications contain positively charged quaternary ammonium groups, are water soluble, and are renally excreted.

33 Review important side effects of acetylcholinesterase administration

Increasing the available ACh at the NMJ (a nicotinic receptor) also stimulates muscarinic cholinergic receptors. Of particular concern is the effect on cardiac conduction. Unopposed muscarinic effects impair sinus-node conduction, resulting in sinus bradycardia, junctional rhythms, and in the extreme asystole. To prevent this, anticholinergics are administered in concert with the acetylcholinesterase. Glycopyrrolate, 7 to 15 mcg/kg, is coadministered with neostigmine and atropine, 7 to 10 mcg/kg, with edrophonium so the onset of anticholinergic activity is appropriately timed with the onset of acetylcholinesterase inhibition.

34 Should all patients who receive nondepolarizing relaxants be reversed?

There is mounting evidence that residual neuromuscular blockade and clinical weakness occur with disturbing frequency, even when the patient has received only one dose of an intermediate-duration nondepolarizing relaxant. These residual effects have been noted even 2 hours after a single dose. Part of the problem appears to be subjective misinterpretations of full return of TOF as discussed earlier. It appears that routine reversal of all patients might be a prudent practice. How sugammadex changes anesthetic practice remains to be determined.

35 Review the clinical signs associated with return of adequate strength

See Table 13-2.

TABLE 13-2 Tests of Return of Neuromuscular Function

Test	Results	Percentage of Receptors Occupied
Tidal volume	>5 ml/kg	80
Single twitch	Return to baseline	75–80
Train of four	No fade	70–75
Sustained tetanus (50 Hz, 5 seconds)	No fade	70
Vital capacity	>20 ml/kg	70
Double-burst stimulation	No fade	60–70
Sustained tetanus (100 Hz, 5 seconds)	No fade	50
Inspiratory force	>−40 cm H₂O	50
Head lift	Sustained 5 seconds	50
Hand grip	Return to baseline	50
Sustained bite	Sustained clenching of a tongue depressor	50