Handbook of Clinical Anesthesia
Neuromuscular Blocking Agents
The introduction of muscle relaxants (neuromuscular blocking drugs [NMBDs]) into clinical practice more than 60 years ago was an important milestone in the history of anesthesia (Donati F, Bevan DR: Neuromuscular blocking agents. In Clinical Anesthesia. Edited by Barash PG, Cullen BF, Stoelting RK, Cahalan MK, Stock MC. Philadelphia: Lippincott Williams & Wilkins, 2009, pp 498–530). In addition to providing immobility and better surgical conditions, NMBDs improve intubating conditions. As important as it is to provide adequate anesthesia while a patient is totally or partially paralyzed, it is also essential to make sure that the effects of NMBDs have worn off or are reversed before the patient regains consciousness. With the introduction of shorter acting NMBDs, it was thought that reversal of blockade could be omitted. However, residual paralysis is still a problem, and the threshold for complete neuromuscular recovery is now considered to be a train-of-four (TOF) of 0.9 rather than 0.7.
- Physiology and Pharmacology
- Structure.The cell bodies of motor neurons supplying skeletal muscle lie in the spinal cord. Information is carried by an elongated axon that ends in a specialized structure, the neuromuscular junction (NMJ), that is designed for the production and release of acetylcholine (Ach) (Fig. 20-1). The endplate is a specialized portion of the membrane of the muscle fiber where nicotinic Ach receptors are concentrated.
- Nerve Stimulation.Under resting conditions, the electrical potential of the inside of a nerve cell is negative with respect to the outside (typically -90 mV).
- Release of Achinto the synaptic cleft occurs when an action potential arrives at the nerve terminal.
Figure 20-1. Diagram of the neuromuscular junction.
- Postsynaptic Events
- Activation of the postsynaptic nicotinic receptor requires simultaneous occupation of the receptor's two α subunits by ACh. Skeletal muscle contraction occurs when ACh-induced changes in the muscle cell's transmembrane permeability result in inward movement of sodium sufficient to decrease intracellular negativity (depolarization) and cause an action potential.
- Propagation of the action potential initiates release of calcium from the sarcoplasmic reticulum, where activation of myosin adenosine triphosphate leads to excitation–contraction coupling of the myofilaments.
- ACh is hydrolyzed (within milliseconds to prevent prolonged depolarization) by acetylcholinesterase (true cholinesterase) to choline, which is reused for synthesis of new ACh, and acetate.
- Presynaptic Events
- The release of ACh normally decreases during high-frequency stimulation under physiologic conditions because the pool of readily releasable ACh becomes depleted faster than it can be replenished. In the presence of muscle relaxants, this decreased release of ACh produces a progressive decrease in skeletal muscle response (fade) with each stimulus.
- Fade is an important property of nondepolarizing neuromuscular blockade and is useful for monitoring purposes.
Table 20-1 Definition of Neuromuscular Blocking Drugs According to the Onset and Duration of Block at the Adductor Pollicis
- Neuromuscular Blocking Agents (Table 20-1)
- Pharmacologic Characteristics of Neuromuscular Blocking Agents.The effect of NMBDs is measured as the depression of adductor muscle contraction (twitch) after electrical stimulation of the ulnar nerve.
- Potencyis determined by constructing the dose–response curves, which describe the relationship between twitch depression and dose.
- The ED95is a clinically relevant value that corresponds to 95% block of single twitch (half of patients will reach 95% block, and half will be reach a lower percentage).
- Onset timeor time to maximum blockade can be shortened if the dose is increased (2 ÷ ED95).
- Duration of actionis the time from injection of the NMBD to return of 25% twitch height (comparisons are usually made at 2 ÷ ED95). Categories of NMBDs may be based on their durations of action.
- Recovery indexis the time interval between 25% and 75% twitch height (this reflects speed of recovery after
return of twitch is manifest). The adductor pollicis is the most commonly monitored muscle for determining the onset and duration of action of NMBDs.
III. Depolarizing Blocking Drugs: Succinylcholine
Succinylcholine (SCh) remains a useful muscle relaxant because of its ultra rapid-onset and short-duration neuromuscular blocking properties, which cannot be duplicated by any of the available nondepolarizing muscle relaxants.
- Neuromuscular Effects.SCh binds to postsynaptic nicotinic receptors, where it exhibits ACh-like activity. SCh also binds to extrajunctional receptors and presynaptic receptors.
- The net effect of SCh-induced depolarization is uncoordinated skeletal muscle activity that manifests clinically as fasciculations.
- SCh predictably increases masseter muscle tone (this may be responsible for poor intubating conditions), and masseter muscle spasm may be associated with malignant hyperthermia. It is likely that increased masseter muscle tone is mediated by ACh receptors because it is blocked by nondepolarizing drugs.
- Nonparalyzing doses of nondepolarizing drugs (pretreatment) block visible evidence of SCh-induced depolarization, suggesting that presynaptic receptors are principally involved in the production of fasciculations.
- The blocking effect of SCh at the NMJ is probably attributable to desensitization (i.e., prolonged exposure to an agonist leads to a state characterized by a lack of responsiveness of the receptors).
- Characteristics of Depolarizing Blockade
- SCh initially produces features characterized as phase I block (Table 20-2).
- Phase II block develops after prolonged exposure to SCh or high doses of SCh and has characteristics of a nondepolarizing neuromuscular blockade (Table 20-3). The onset of phase II block coincides with the appearance of tachyphylaxis to the effects of SCh.
- Pharmacology of Succinylcholine
- SCh is rapidly hydrolyzed (the elimination half-time is estimated to be 2–4 minutes) by plasma cholinesterase (pseudocholinesterase) to choline and succinylmonocholine (which has about 1/20 the neuromuscular blocking properties of the parent drug).
Table 20-2 Characteristics of Nondepolarizing Neuromuscular Blockade
- The ED95of SCh in the presence of opioid–nitrous oxide anesthesia is 0.30 to 0.35 mg/kg.
- The onset of neuromuscular blocking effect is usually within 1 minute after high doses of SCh (1–2 mg/kg intravenously [IV]), and the time until full recovery of the electromyographic response is 10 to 12 minutes after a dose of 1 mg/kg IV.
- A small proportion of patients (1:1500 to 1:3000) have a genetically determined (atypical plasma cholinesterase) inability to metabolize SCh (1–1.5 mg/kg IV lasts for 3–6 hours).
- Side Effects(Table 20-4)
- Clinical Uses
- The principal indication for SCh is to facilitate tracheal intubation (1 mg/kg IV is the usual dose, which is increased to 1.5–2.0 mg/kg IV if pretreatment is used).
Table 20-3 Characteristics of Phase I Depolarizing Blockade
Table 20-4 Side Effects of Succinylcholine
- The use of SCh in children is limited largely because of concerns about triggering hyperkalemia in young boys with unrecognized muscular dystrophy and the occasional triggering of malignant hyperthermia in children.
- Nondepolarizing Drugs
Nondepolarizing NMDBs bind to postsynaptic receptors (they must bind to one of the α subunits) in a competitive fashion to produce neuromuscular blockade.
- Characteristics of Nondepolarizing Blockade(Table 20-3)
- Pharmacokinetics(Table 20-5)
- The pharmacokinetic variables derived from measurements of plasma concentrations of nondepolarizing muscle relaxants depend on the dose administered, the sampling schedule used, and the accuracy of the assay.
Table 20-5 Typical Pharmacokinetic Data for Nondepolarizing Muscle Relaxants
- All nondepolarizing muscle relaxants have a volume of distribution that is approximately equal to extracellular fluid volume.
- Onset and Duration of Action(Table 20-6)
- Although peak plasma concentrations of nondepolarizing muscle relaxants occur within 1 to 2 minutes of injection, the onset of maximum blockade is reached only after 2 to 7 minutes, reflecting the time required for drug transfer between plasma and NMJ.
Table 20-6 Comparative Pharmacology of Nondepolarizing Muscle Relaxants
Table 20-7 Autonomic and Histamine-Releasing Effects of Muscle Relaxants
- The duration of action of nondepolarizing drugs is determined by the time required for drug concentration at site of action to decrease below a certain level, usually corresponding to 25% first-twitch blockade
- Individual Nondepolarizing Relaxants(Tables 20-5, 20-6, 20-7 and 20-8)
Table 20-8 Mechanisms for Clearance of Nondepolarizing Muscle Relaxants
- Atracuriumis an intermediate-acting benzylisoquinolinium-type nondepolarizing NMDB.
- Metabolismis by ester hydrolysis (which accounts for an estimated two thirds of the drug's metabolism) and Hofmann elimination (nonenzymatic degradation at body temperature and pH). A metabolite of atracurium, laudanosine is a cerebral stimulant, but it is unlikely that this is clinically significant with the usual clinical doses of atracurium administered.
- Hypotension and tachycardiamay accompany high doses of atracurium (>2 ÷ ED95), reflecting dose-related histamine release (attenuated by injection of the muscle relaxant over 1–3 minutes).
- Dose requirementsare similar in all age groups, presumably reflecting the absence of atracurium's dependence on renal or hepatic clearance mechanisms. The dose of atracurium, as for all nondepolarizing drugs, should be decreased on a milligram per kilogram basis to reflect lean body mass.
- Cisatracuriumis an intermediate-acting benzylisoquinolinium-type NMDB.
- As one of the 10 isomers of atracurium, this drug resembles atracurium in onset, duration of action, rate of recovery, and clearance mechanisms (Hofmann elimination rendering both drugs independent of hepatic and renal function). Cisatracurium does not undergo significant hydrolysis by nonspecific plasma esterases.
- The metabolites of cisatracurium include laudanosine (peak plasma concentrations are about fivefold less than present with atracurium) and monoquaternary acrylate. These metabolites are not active at the NMJ.
- In contrast to atracurium, cisatracurium is more potent (ED95, 0.05 mg/kg), is devoid of histamine-releasing properties even at high doses (8 ÷ ED95), and lacks cardiovascular effects.
- Neuromuscular block is easily maintained at a stable level by continuous infusion of cisatracurium at a constant rate and does not diminish over time. The rate of recovery is independent of the dose of cisatracurium or the duration of administration, presumably reflecting independence
of its clearance mechanisms from hepatic and renal function.
- Recovery from drug-induced neuromuscular blockade can be facilitated by administration of an anticholinesterase drug.
- Doxacuriumis a long-acting nondepolarizing NMBD that is devoid of histamine-releasing and cardiovascular side effects.
- Gantacuriumis a nondepolarizing NMBD whose main degradation pathway involves cysteine in the plasma and is independent of plasma cholinesterase. The ED95 is approximately 0.19 mg/kg. Cardiovascular effects at doses exceeding 3 ÷ ED95 are most likely related to histamine release. At doses required for tracheal intubation (0.4 to 0.6 mg/kg), onset at the adductor pollicis is 1.5 minutes, and duration to 25% first-twitch recovery is 8 to 10 minutes.
- Pancuroniumis a long-acting nondepolarizing NMBD with a steroid structure but lacking any endocrine effects.
- The drug is metabolized to a 3-OH compound that has one half the neuromuscular blocking activity of the parent compound.
- Pancuronium is associated with modest (usually <15%) increases in heart rate, blood pressure, and cardiac output.
- Pancuronium does not release histamine.
- The use of pancuronium to provide muscle relaxation may offer some advantage over the use of cardiovascularly neutral muscle relaxants in patients anesthetized with high doses of opioids.
- Compared with newer and more expensive short- and intermediate-acting nondepolarizing NMDBs, pancuronium's continued popularity is because of its cost. Generic pancuronium is the least expensive muscle relaxant to provide neuromuscular blockade for long surgeries (>2 hours), but its routine use in these situations may result in an increased incidence of postoperative skeletal muscle weakness.
- Pancuronium neuromuscular blockade is more difficult to reverse than blockade of the intermediate-acting nondepolarizing NMDBs.
- Rocuroniumis an aminosteroid NMBD that has a more rapid onset (intubating conditions 60 seconds after administration of 1 mg/kg IV resemble conditions after administration of SCh 1 mg/kg IV) but similar duration of action and pharmacokinetic characteristics as vecuronium.
- As for other short- and intermediate-acting NMBDs, the onset of action of rocuronium is more rapid at the diaphragm and laryngeal muscle than at the adductor pollicis, and about twice as much drug is required to produce the same degree of paralysis.
- Hemodynamic changes or release of histamine does not occur after administration of even high doses (4 ÷ ED95) of rocuronium.
- Vecuroniumis an intermediate-acting aminosteroid NMBD that is devoid of histamine-releasing and cardiovascular side effects.
- Vecuronium is a monoquaternary ammonium compound produced by demethylation of the pancuronium molecule. This demethylation decreases the ACh-like characteristics of the molecule and increases its lipophilicity, which encourages hepatic uptake.
- Vecuronium undergoes spontaneous deacetylation. The most potent of the resulting metabolites, 3-OH vecuronium, has about 60% of the activity of vecuronium, is excreted by the kidneys, and may contribute to prolonged paralysis. (It is incriminated in prolonged weakness after chronic use to maintain patients on mechanical ventilation.)
- Vecuronium is less potent and has a shorter duration of action in men than women, probably as a result of a decrease in the volume of distribution, which results in increased plasma concentrations in women.
- Accidental mixing of vecuronium and thiopental in the IV tubing may form a precipitate of barbituric acid and obstruct the IV cannula.
- The cardiovascular neutrality and intermediated duration of action make vecuronium a suitable drug for use in patients with ischemic heart disease and those undergoing short ambulatory surgery.
Table 20-9 Drug Interactions Involving Muscle Relaxants
- Drug Interactions
- Altered Responses to Neuromuscular Blocking Agents
VII. Monitoring Neuromuscular Blockade
Table 20-10 Altered Responses to Neuromuscular Blocking Agents
Table 20-11 Assessment of the Adequacy of Antagonism of Neuromuscular Blockade
- Why Monitor?The margin of safety is narrow because blockade occurs over a narrow range of receptor occupancy. Furthermore, there is considerable interindividual variability in response to the same dose of NMDB. To test the function of the NMJ, a peripheral nerve (ulnar nerve or the facial nerve) is electrically stimulated with a peripheral nerve stimulator, and the response of the skeletal muscle is assessed.
- Stimulator Characteristics.The response of the nerve to electrical stimulation depends on three factors: the current applied, the duration of the current, and the position of the electrodes.
- Monitoring Modalities(Table 20-11)
- Recording the Response
- Visual and tactile evaluationis the easiest and least expensive way to assess the response to electrical stimulation applied to a peripheral nerve. The disadvantage of this technique is the subjective nature of its interpretation.
- Measurement of forceusing a force transducer provides accurate assessment of the response elicited by electrical stimulation of a peripheral nerve.
- Electromyographymeasures the electrical rather than mechanical response of the skeletal muscle.
- Choice of Muscle
- The adductor pollicissupplied by the ulnar nerve is the most common skeletal muscle monitored clinically. This muscle is relatively sensitive to nondepolarizing muscle relaxants, and during recovery, it is blocked more than some respiratory muscles such as the diaphragm and laryngeal adductors.
- There seem to be important differences in the responses of muscles innervated by the facial nerve (stimulated 2–3 cm posterior to the lateral border of the orbit) around the eye.
- The response of the orbicularis oculi over the eyelid is similar to that of the adductor pollicis.
- The response the eyebrow (corrugator supercilii) parallels the response of the laryngeal adductors (onset is more rapid and recovery is sooner than at the adductor pollicis). This response is useful for predicting intubating conditions.
- Clinical Application
- Monitoring Onset.After induction of anesthesia, the intensity of neuromuscular blockade must be assessed to determine the time for tracheal intubation (maximum relaxation of laryngeal and respiratory muscles). Single-twitch stimulation is often used to monitor the onset of neuromuscular blockade.
- Surgical relaxationis usually adequate when fewer than two or three visible twitches of the TOF are observed in response to stimulation of the adductor pollicis muscle.
- Monitoring recoveryis useful in determining whether spontaneous recovery has progressed to a degree that allows reversal drugs to be given (preferably 4 twitches visible) and to assess the effect of these drugs (supplement with other clinical observations) (Table 20-11).
- Traditionally, a TOF of 0.7 has been considered to be the threshold below which residual weakness of the respiratory muscles could be present. Evidence suggests, however, that significant weakness and impairment of swallowing may be present at a TOF ratio of 0.9.
- A sustained head lift test may not guarantee full skeletal muscle recovery.
- The upper airway muscles used to retain a tongue depressor between the teeth are very sensitive to residual effects of muscle relaxants.
- Factors Affecting the Monitoring of Neuromuscular Blockade
- If the monitored hand is cold, the degree of paralysis will appear to be increased.
- If the monitored limb is characterized by nerve damage (from stroke, spinal cord transection,
peripheral nerve trauma), there is inherent resistance to the effect of muscle relaxants, and the degree of skeletal muscle paralysis will be underestimated.
VIII. Antagonism of Neuromuscular Blockade
In most circumstances, all efforts should be made to ensure that the patient leaves the operating room with unimpaired muscle strength (respiratory and upper airway muscles functioning normally to permit breathing, coughing, swallowing, and maintaining a patent airway). Strategies to achieve this goal include titrating the NMBDs so that no residual effect is manifest at the end of surgery, administering a reversal drug, and selective binding of NMBDs with a cyclodextrin molecule to restore neuromuscular function.
- Assessment of Neuromuscular Blockade.Spontaneous breathing (adequate to prevent hypercapnia if a patent airway is maintained) can resume even if relatively deep degrees of paralysis are present because of the relative diaphragm-sparing effect of NMBDs. Swallowing is impaired, and laryngeal aspiration may occur in the presence of vecuronium when the TOF ratio is 0.9 or below.
- Residual paralysis(neuromuscular blockade) is frequent in patients in the recovery room after surgery. The most important reason for the high incidence of residual paralysis seems to be omission of reversal.
- Clinical Importance.Residual paralysis in the recovery room is associated with significant morbidity.
- Reversal Agents.The pharmacologic principle involved is inhibition of Ach breakdown to increase its concentration of Ach at the NMJ, thus tilting the competition for receptors in favor of the neurotransmitter.
- Mechanism of Action of Anticholinesterases
- Inhibition of acetylcholinesterase by anticholinesterase drugs (neostigmine, pyridostigmine, edrophonium) results in an increase in the amount of ACh that reaches the receptor.
- Anticholinesterase drugs may also have presynaptic effects.
- Neostigmine Block.Large doses of anticholinesterases, especially if given in the absence of neuromuscular block, may produce evidence of neuromuscular
dysfunction. Although there are no clinical reports of postoperative weakness attributed to reversal agents, it seems prudent to reduce the dose of anticholinesterase agent if recovery from neuromuscular block is almost complete.
Table 20-12 Pharmacokinetics of Anticholinesterase Drugs
- Potencyratios are difficult to determine because the slopes of the edrophonium and neostigmine dose–response curves are not parallel.
- The pharmacokineticsof anticholinesterase drugs reflect the dependence of these drugs on renal clearance (Table 20-12).
- Pharmacodynamics.The onset of action of edrophonium to peak effect (1–2 minutes) is much more rapid than the onsets of action of neostigmine (7–11 minutes) and pyridostigmine (15–20 minutes).
- Recovery of neuromuscular activity reflects spontaneous recovery plus augmented (accelerated) recovery induced by the anticholinesterase drug.
- Recurarizationshould not be expected as long as the duration of the anticholinesterase drug exceeds that of the muscle relaxant.
- Factors Affecting Reversal(Table 20-13)
- The dose of anticholinesterase drug selected and the time to effective recovery are directly related to the intensity of blockade at the time of reversal (Table 20-14).
- Neostigmine is more effective than edrophonium or pyridostigmine in antagonizing intense neuromuscular blockade.
Table 20-13 Factors Affecting Reversal
- Because of the ceiling effect, there is little benefit in administering more than 0.7 mg/kg of neostigmine.
- The overall rate of recovery (spontaneous plus drug enhanced) is more rapid from atracurium or vecuronium than from pancuronium. Furthermore, the doses of antagonist drugs required to produce the same degree of antagonism are greater after administration of the long-acting than after the administration of the intermediate- and short-acting muscle relaxants.
- Recovery of neuromuscular activity occurs more rapidly with lower doses of anticholinesterase drugs in infants and children than in adults.
Table 20-14 Recommended Doses of Anticholinesterase Drugs and Anticholinergic Drugs Based on Train-of-Four Stimulation
- Anticholinesterases: Other Effects
- Cardiovascular Effects
- Anticholinesterase drugs evoke profound vagal stimulation that can be prevented by concomitant administration of an anticholinergic drug.
- Because of its rapid onset (1 minute), atropine is appropriate for use in combination with edrophonium. Glycopyrrolate (onset 2–3 minutes) may be more suitable for use with neostigmine or pyridostigmine.
- Atropine requirements are lower when combined with edrophonium (7–10 mg/kg IV) than with neostigmine (15–20 mg/kg IV).
- Other cholinergic effects ofanticholinesterase drugs include increased salivation, enhanced bowel motility (concern about increase in bowel anastomotic leakage), and an alleged increased incidence of nausea and vomiting after ambulatory surgery.
- Respiratory Effects.Anticholinesterases may cause an increase in airway resistance, but anticholinergics reduce this effect.
- Pharmacologically assisted recovery is expected in most cases because it is illusory to aim for complete recovery only by careful titration of NMBDs.
- Administration of anticholinesterase agents accelerate recovery, no matter when they are given in the course of recovery. However, there are advantages in giving reversal agents when spontaneous recovery is underway.
- If 4 twitches are not visible after TOF stimulation, it is recommended to keep the patient anesthetized and mechanically ventilated until 4 twitches reappear and then administer anticholinesterases.
- This cyclodextrin leads to restoration of normal neuromuscular function by selectively binding to rocuronium (and to a lesser extent to vecuronium and pancuronium). Because it does not bind to any known receptors, it is devoid of cardiovascular and other side effects.
- Pharmacology.If sugammadex is given upon return of the second twitch in the TOF, doses of 2 to 4 mg/kg result in return of the TOF ratio to 0.9 in about 2 minutes. The availability of sugammadex may make Sch obsolete for intubation.
- Pharmacokinetics.Sugammadex and sugammadex–rocuronium complexes are excreted unchanged via the kidney.
- For reversal of rocuronium blockade when spontaneous recovery has already started (2 to 4 twitches present), administration of 2 to 4 mg/kg will produce faster recovery than neostigmine and without cardiovascular side effects. The response of a patient who has received sugammadex who needs reexploration is unknown.
Editors: Barash, Paul G.; Cullen, Bruce F.; Stoelting, Robert K.; Cahalan, Michael K.; Stock, M. Christine
Title: Handbook of Clinical Anesthesia, 6th Edition
Copyright ©2009 Lippincott Williams & Wilkins
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