Chapter 9 Neuromuscular Blocking Drugs
Clinical uses
2. What are some clinical situations in which skeletal muscle relaxation is desired?
3. What are some methods by which skeletal muscle relaxation can be achieved without the administration of neuromuscular blocking drugs?
4. What analgesic effects do neuromuscular blocking drugs have?
5. What are some characteristics of neuromuscular blocking drugs that may influence the choice of which drug is administered for clinical use for a given patient?
Neuromuscular junction
6. What is the neuromuscular junction?
7. What events lead to the release of neurotransmitter at the neuromuscular junction? What is the neurotransmitter that is released?
8. What class of receptors is located on postjunctional membranes? What clinical effect results from the stimulation of these receptors?
9. How, and in what time course, is the action of acetylcholine terminated in the synaptic cleft? What is the clinical relevance of this?
10. With respect to the neuromuscular junction, what are the three sites at which nicotinic cholinergic receptors are located?
11. What is the role of prejunctional receptors?
12. What is the role of extrajunctional receptors? What is their effect when stimulated?
13. What is the structure of nicotinic cholinergic receptors? How is the junction of the cholinergic receptor related to its structure?
14. What is the binding site for an agonist at the nicotinic cholinergic receptor?
Depolarizing neuromuscular blocking drugs
16. What is the intubating dose of succinylcholine? What are its approximate time of onset and duration of action when administered at this dose?
17. What is the mechanism of action of succinylcholine?
18. What is phase I neuromuscular blockade?
19. What is phase II neuromuscular blockade? What is the mechanism by which it occurs? When is phase II neuromuscular blockade most likely to occur clinically?
20. What occurs clinically as a result of the opening of the nicotinic cholinergic receptor ion channel that occurs with the administration of succinylcholine?
21. How efficiently does plasma cholinesterase hydrolyze succinylcholine? Where is plasma cholinesterase produced?
22. How is the effect of succinylcholine at the cholinergic receptor terminated?
23. How is the duration of action of succinylcholine influenced by plasma cholinesterase?
24. What are some drugs, chemicals, or clinical diseases that may affect the activity of plasma cholinesterase?
25. What is atypical plasma cholinesterase? What is its clinical significance?
26. What is dibucaine? What is its clinical use?
27. What is the normal dibucaine number? For heterozygous and homozygous atypical cholinesterase patients, what is their associated dibucaine number, duration of action of an intubating dose of succinylcholine, and incidence in the population?
28. Why is succinylcholine usually not administered to children under nonemergent conditions?
29. What are some adverse cardiac rhythms that may result from the administration of succinylcholine? When and why are they likely to occur?
30. How can the potential risk of adverse cardiac rhythms associated with the administration of succinylcholine be minimized?
31. What is the mechanism by which succinylcholine may induce a hyperkalemic response with its administration? Which patients are especially at risk for this effect of succinylcholine?
32. Are renal failure patients at greater risk for a hyperkalemic response to the administration of succinylcholine?
33. What is the mechanism by which succinylcholine may induce postoperative myalgias with its administration? Which muscles are typically affected? Which patients are especially at risk for this effect of succinylcholine?
34. How might the fasciculations associated with the administration of succinylcholine be blunted?
35. What effect does the administration of succinylcholine have on intraocular pressure? What is the clinical significance of this?
36. What effect does the administration of succinylcholine have on intragastric pressure? What is the clinical significance of this?
37. What effect does the administration of succinylcholine have on masseter muscle tension? What is the clinical significance of this?
Nondepolarizing neuromuscular blocking drugs
38. What is the mechanism of action of nondepolarizing neuromuscular blocking drugs?
39. Describe the lipid solubility of nondepolarizing neuromuscular blocking drugs. How does this influence its volume of distribution and clinical effect?
40. What are some of the methods by which nondepolarizing neuromuscular blocking drugs are cleared? How does this influence its duration of action?
41. What are some drugs and physiologic states that may enhance the neuromuscular blockade produced by nondepolarizing neuromuscular blocking drugs?
42. What is the mechanism by which volatile anesthetics are believed to enhance the neuromuscular blockade produced by nondepolarizing neuromuscular blocking drugs?
43. What are some of the methods by which nondepolarizing neuromuscular blocking drugs are able to exert cardiovascular effects?
44. What is a concern regarding patients receiving long-term nondepolarizing neuromuscular blocking drugs in the intensive care unit?
45. Which patients are at risk for developing a myopathy after the administration of nondepolarizing neuromuscular blocking drugs in the intensive care unit? How might they present clinically?
Intermediate-acting nondepolarizing neuromuscular blocking drugs
48. Name some intermediate-acting nondepolarizing neuromuscular blocking drugs. What is their approximate time of onset and duration of action?
49. How is vecuronium excreted from the body? How does renal failure affect the clearance of vecuronium?
50. How does the time of onset of rocuronium compare with the time of onset of succinylcholine?
51. How is rocuronium excreted from the body? How does renal failure affect the clearance of rocuronium?
52. How are cisatracurium and atracurium structurally related?
53. How are atracurium and cisatracurium cleared from the plasma? How does renal failure affect the clearance of these drugs?
54. What is the principal metabolite of atracurium and its potential adverse physiologic effect? Which patients are especially at risk for this adverse effect?
55. What are some of the cardiovascular effects of atracurium?
56. What are some differences between cisatracurium and atracurium that make cisatracurium more desirable for clinical use?
Short-acting nondepolarizing neuromuscular blocking drugs
57. Name a short-acting nondepolarizing neuromuscular blocking drug. What is its approximate time of onset and duration of action?
58. How is mivacurium cleared from the plasma? How is the duration of action of mivacurium altered in patients who have deficiencies in plasma cholinesterase enzyme, liver disease, or renal disease?
59. Does the administration of neostigmine reverse the neuromuscular blockade produced by mivacurium?
60. What are some of the cardiovascular effects of mivacurium?
Monitoring the effects of nondepolarizing neuromuscular blocking drugs
61. What is the most common method for monitoring the effects of neuromuscular blocking drugs during general anesthesia?
62. What are two ways in which a peripheral nerve stimulator may be useful during the administration of neuromuscular blocking drugs during general anesthesia?
63. Which nerve and muscle are most commonly used to evaluate the neuromuscular blockade produced by neuromuscular blocking drugs?
64. Which nerves may be used for the evaluation of the neuromuscular blockade produced by neuromuscular blocking drugs through the use of a peripheral nerve stimulator when the arm is not available to the anesthesiologist?
65. How do the neuromuscular blocking drugs vary with regard to their time of onset at the adductor pollicis muscle, orbicularis oculi muscle, laryngeal muscles, and diaphragm?
66. What are some of the mechanical responses evoked by a peripheral nerve stimulator that are used to monitor the effects of neuromuscular blocking drugs? What are the methods to evaluate the mechanically evoked response?
67. What percent of depression of a mechanically evoked single twitch response from its control height correlates with adequate neuromuscular blockade for intubation of the trachea or for the performance of intraabdominal surgery? What approximate percent of nicotinic cholinergic receptors must be occupied by a nondepolarizing neuromuscular blocking drug to achieve this effect?
68. What is the train-of-four stimulus delivered by a peripheral nerve stimulator? What is its clinical use?
69. What is the train-of-four ratio? What is its clinical use?
70. What train-of-four ratio correlates with the complete return to control height of a single twitch response?
71. What is the train-of-four ratio during phase I neuromuscular blockade resulting from the administration of a depolarizing neuromuscular blocking drug such as succinylcholine?
72. How accurate is the estimation of the train-of-four ratio by clinicians evaluating the response visually and manually? What percent of the first twitch control height must be present before the fourth twitch is detectable?
73. What is the double burst suppression stimulus delivered by a peripheral nerve stimulator? What is its clinical use?
74. What is tetany? How might it be mechanically produced by a peripheral nerve stimulator?
75. How is the normal response to tetany altered by the administration of depolarizing and nondepolarizing neuromuscular blocking drugs?
76. What is posttetanic stimulation? What is its clinical use?
Antagonism of nondepolarizing neuromuscular blocking drugs
77. What is the mechanism by which the neuromuscular blockade produced by nondepolarizing neuromuscular blocking drugs is antagonized?
78. How are the cardiac muscarinic effects of anticholinesterases attenuated?
79. Name two factors that influence the choice of anticholinesterase drug to be administered to antagonize the neuromuscular blockade produced by nondepolarizing neuromuscular blocking drugs.
80. When might neostigmine or edrophonium be an appropriate choice of anticholinesterase drug to administer to antagonize neuromuscular blockade? What anticholinergic drug is often paired with each?
81. What are some tests that can be done to evaluate the adequacy of the recovery from the effects of neuromuscular blockade?
82. How might the residual effects of neuromuscular blockers be manifest clinically in the awake patient?
83. What are some pharmacologic or physiologic factors that may interfere with the antagonism of the neuromuscular blockade produced by neuromuscular blocking drugs?
Adverse outcomes from inadequate antagonism of neuromuscular blockade
84. What risk factors contribute to adverse respiratory events in the first hour postoperative in the postanesthetic care unit (PACU)?
85. In addition to induction of anesthesia, what is the most dangerous time for anesthetic complications in the postoperative period?
86. What is sugammadex? What is the mechanism of action of sugammadex?
87. What are the major clinical differences between sugammadex and neostigmine?
88. What are some advantages of sugammadex for the antagonism of neuromuscular blockade?
Answers*
1. Neuromuscular blocking drugs interrupt transmission of nerve impulses at the neuromuscular junction and thereby produce paresis or paralysis of skeletal muscles. (144)
Clinical uses
2. Skeletal muscle relaxation (i.e., paralysis) is desired most frequently to facilitate intubation of the trachea and provide excellent surgical conditions. Other clinical situations in which skeletal muscle relaxation is desired include to facilitate mechanical ventilation of the lungs either intraoperatively, in the intensive care unit, or during cardiopulmonary resuscitation. (144)
3. Skeletal muscle relaxation can be achieved without the administration of neuromuscular blocking drugs by the administration of high concentrations of volatile anesthetics, regional anesthesia, and by proper patient positioning on the operating table. (81, 252, 300)
4. Neuromuscular blocking drugs do not have any anesthetic or analgesic effects. The potential therefore exists for the patient to be rendered paralyzed without adequate anesthesia and subsequent unrecognized awareness during anesthesia. (144, 737)
5. Neuromuscular blocking drugs vary in their mechanism of action, speed of onset, duration of action, route of elimination, and associated side effects. These characteristics of a neuromuscular blocking drug may influence whether a specific neuromuscular blocking drug is chosen for administration to a given patient. (144)
Neuromuscular junction
6. The neuromuscular junction is the location where the transmission of neural impulses at the nerve terminal becomes translated into skeletal muscle contraction at the motor endplate. The highly specialized neuromuscular junction consists of the prejunctional motor nerve ending, a highly folded postjunctional skeletal muscle membrane, and the synaptic cleft in between. (144-146, Figure 12-1)
7. A nerve impulse conducted down the motor nerve fiber, or axon, ends in the prejunctional motor nerve ending. The resulting stimulation of the motor nerve terminal causes an influx of calcium into the nerve terminal. The influx of calcium results in a release of the neurotransmitter acetylcholine into the synaptic cleft. This is why administration of calcium briefly improves neuromuscular function. The nerve synthesizes and stores acetylcholine in vesicles in the motor nerve terminals, which is available for release with the influx of calcium. Acetylcholine released into the synaptic cleft binds to receptors in the postjunctional skeletal muscle membrane, leading to skeletal muscle contraction. (145-146, Figure 12-1)
8. Nicotinic cholinergic receptors are located on the skeletal muscle membrane, or postjunctional membrane. When acetylcholine binds to the nicotinic cholinergic receptor, there is a change in the permeability of the skeletal muscle membrane to sodium and potassium ions. The resultant movement of these ions down their concentration gradients causes a decrease in the membrane potential of the skeletal muscle cell from the resting membrane potential to the threshold potential. The resting membrane potential is the electrical potential of the skeletal muscle cell at rest, usually about − 90 mV. The threshold potential is about − 45 mV. When the threshold potential is reached, an action potential becomes propagated over the surfaces of skeletal muscle fibers. This leads to the contraction of these skeletal muscle fibers. (146, Figure 12-2)
9. Acetylcholine is hydrolyzed in the synaptic cleft by the enzyme acetylcholinesterase, or true cholinesterase. This occurs rapidly, within 15 ms. Clinically, this allows for the restoration of the membrane to its resting membrane potential. The metabolism of acetylcholine also prevents sustained depolarization of the skeletal muscle cells, and thus prevents tetany from occurring. (145, Figure 12-1)
10. Nicotinic cholinergic receptors are located in three separate sites relative to the neuromuscular junction and are referred to by their varied locations. Each of these receptors also has a different functional capacity with regard to its role in skeletal muscle contraction. The three types of nicotinic cholinergic receptors are prejunctional, postjunctional, and extrajunctional. Prejunctional receptors are located at the motor nerve terminal. Postjunctional receptors are located just opposite the prejunctional receptors in the endplate and are the most important receptors for the action of neuromuscular blocking drugs. Extrajunctional receptors are immature in form and are located throughout the skeletal muscle membrane. They are located in areas other than the endplate region of the muscle membrane as well as at the motor endplate region. (145-146, Figure 12-1)
11. Prejunctional receptors are located on the motor nerve terminal and influence the release and replenishment of acetylcholine from the nerve terminal. (145-146, Figure 12-1)
12. Extrajunctional receptors are located throughout the skeletal muscle membrane. They differ from the other two types of nicotinic cholinergic receptors both in their location and by their molecular structure. Under normal circumstances, the synthesis of extrajunctional receptors is suppressed by neural activity and has minimal contribution to skeletal muscle action. Extrajunctional receptors may proliferate under conditions of denervation, trauma, strokes, or burn injury. Conversely, when neuromuscular activity returns to normal, extrajunctional receptors quickly lose their activity. Extrajunctional receptors are stimulated more by lower concentrations of acetylcholine and depolarizing neuromuscular blocking drugs than are prejunctional or postjunctional receptors. In addition, extrajunctional receptors remain open longer and permit more ions to flow across the skeletal muscle cell membrane once activated. Clinically, this may manifest as an exaggerated hyperkalemic response when succinylcholine is administered to patients with denervation injuries. (146)
13. Nicotinic cholinergic receptors are made up of glycoproteins divided into five subunits. There are two α subunits and one each of β, γ, and δ subunits. The subunits are arranged in such a way that they form a channel in the membrane, with the binding site for the agonist being the α subunits. When the receptor becomes stimulated by the binding of an agonist or acetylcholine, the channel changes conformation such that it allows the flow of ions through the cell membrane along their concentration gradient. Extrajunctional receptors differ slightly from postjunctional nicotinic cholinergic receptors in that the γ and δ subunits of these receptors are altered from those of the postjunctional receptors. The two α subunits, however, are identical. (146, Figure 12-2)
14. The binding site for agonists at the nicotinic cholinergic receptor is the α subunit. Acetylcholine must bind to both of the two α subunits of the receptor to stimulate the receptor to change conformation and allow the flow of ions through the resulting ion channel. Nondepolarizing neuromuscular blocking drugs also bind to the α subunits of the receptor but only require that one α subunit be bound to exert their pharmacologic effect. With the binding of a nondepolarizing neuromuscular blocking drug to an α subunit on the receptor, acetylcholine is unable to bind to the receptor, the flow of ions across the channel does not occur, and the physiologic effect of skeletal muscle contraction becomes blocked. The binding of a depolarizing neuromuscular blocking drug, like acetylcholine, requires that both α subunits be bound before stimulating the receptor to change conformation and the resulting skeletal muscle contraction. Succinylcholine, a depolarizing neuromuscular blocking drug, exerts its effect in this manner. The elimination of succinylcholine is through its clearance from the plasma and requires a few minutes to occur. This accounts for its prolonged binding period on the nicotinic cholinergic receptor and subsequent skeletal muscle paralysis for the minutes after its administration. (146-148)
Structure activity relationships
15. Both depolarizing and nondepolarizing neuromuscular blocking drugs have a chemical structure similar to that of acetylcholine, which explains its pharmacologic activity at the nicotinic cholinergic receptor. Succinylcholine is two acetylcholine molecules linked together by methyl groups. The nondepolarizing neuromuscular blocking drugs are much larger and bulkier than acetylcholine but have an internal structure that is chemically related to acetylcholine and allows for interaction with the nicotinic cholinergic receptor. (146-147, Figure 12-3)
Depolarizing neuromuscular blocking drugs
16. The usual intubating dose of succinylcholine when administered intravenously is 1 to 1.5 mg/kg. Complete muscle paralysis after the administration of succinylcholine is typically within 30 to 60 seconds. The duration of action, or duration of skeletal muscle paralysis, after the administration of an intubating dose of succinylcholine is usually 5 to 10 minutes. (148)
17. Succinylcholine acts at the nicotinic cholinergic receptor through a similar mechanism as acetylcholine. Succinylcholine attaches to the two α subunits on the nicotinic cholinergic receptor and causes the ion channel in the muscle cell to open. This results in depolarization of the skeletal muscle cell. Unlike acetylcholine, succinylcholine is not hydrolyzed at the motor endplate but continues to attach to the cholinergic receptors until it is cleared from the plasma. The administration of succinylcholine therefore results in sustained depolarization of the motor endplate. The skeletal muscle paralysis associated with the administration of succinylcholine is due to the inability of the depolarized postjunctional membrane to respond to a subsequent release of acetylcholine. (148)
18. Phase I neuromuscular blockade refers to the blockade of the transmission of neuromuscular impulses caused by succinylcholine with its initial administration. This neuromuscular blockade is due to succinylcholine remaining on the receptor and the sustained depolarization of skeletal muscle cells that results. The sustained depolarization prevents the muscle cell from being able to respond to a subsequent release of acetylcholine. (149, Table 12-2)
19. Phase II neuromuscular blockade refers to the blockade of the transmission of neuromuscular impulses produced by succinylcholine after repolarization of the cell membrane has taken place, but while the cell membrane does not yet respond normally to the release of acetylcholine. Phase II neuromuscular blockade resembles the blockade produced by nondepolarizing neuromuscular blocking drugs. The mechanism of phase II neuromuscular blockade is not completely understood, but it is believed to result from the development of a nonexcitable area around the motor endplate that interferes with the spread of subsequent impulses that have been initiated by the release of acetylcholine. Phase II neuromuscular blockade is most likely to occur when the neuromuscular junction is continuously exposed to a depolarizing neuromuscular blocking drug. This may occur with a succinylcholine infusion, with the administration of a second dose of succinylcholine after the first, or when the intravenous dose of succinylcholine administered exceeds 3 to 5 mg/kg. (149, Table 12-2)
20. The sustained depolarization, and subsequent sustained opening of the cholinergic receptor ion channel, that results from the administration of succinylcholine clinically manifests as skeletal muscle fasciculations. Sustained opening of the nicotinic cholinergic receptor ion channel is also associated with leakage of potassium from the interior of cells into the plasma. The leakage of potassium ions associated with the administration of an intubating dose of succinylcholine is sufficient to increase the serum potassium level by about 0.2 to 0.5 mEq/L. (148, Table 12-2)
21. The enzyme responsible for the hydrolysis of succinylcholine is plasma cholinesterase, or pseudocholinesterase. This is in contrast to acetylcholinesterase, or true cholinesterase, the enzyme responsible for the hydrolysis of acetylcholine. Plasma cholinesterase hydrolyzes succinylcholine at a rapid rate and extremely efficiently, such that only a small fraction of succinylcholine reaches the receptor after its intravenous administration. Plasma cholinesterase is produced in the liver. (148-149, Figure 12-4)
22. The effect of succinylcholine at the cholinergic receptor is terminated by the diffusion of succinylcholine away from the neuromuscular junction and into the extracellular fluid. In the extracellular fluid succinylcholine is rapidly hydrolyzed by plasma cholinesterase. (148)
23. Plasma cholinesterase influences the duration of action of succinylcholine by limiting the amount of succinylcholine that reaches the receptor for its initial action and by hydrolyzing succinylcholine on its diffusion away from the receptor. (148)
24. Potent anticholinesterases often used in insecticides or for the treatment of myasthenia gravis, and certain chemotherapeutic drugs such as nitrogen mustard and cyclophosphamide, can significantly decrease plasma cholinesterase activity and prolong succinylcholine. Prolonged effects of succinylcholine lasting as long as 1 to 3 hours may occur. Liver disease may also result in a decrease in the amount of circulating plasma cholinesterase and a subsequent prolonged clinical effect of succinylcholine. The degree of liver disease must be severe before the synthesis of plasma cholinesterase is sufficiently decreased to result in prolonged muscle paralysis after the administration of succinylcholine, however. (148)
25. Atypical plasma cholinesterase is an abnormal genetic variant of the plasma cholinesterase enzyme that lacks the ability to hydrolyze ester bonds in drugs such as succinylcholine and mivacurium. Patients who are otherwise healthy may have atypical plasma cholinesterase enzyme. Clinically, the presence of this enzyme manifests as prolonged skeletal muscle paralysis after the administration of a conventional dose of succinylcholine. These patients may have skeletal muscle paralysis that persists for over an hour after the administration of succinylcholine. (149)
26. Dibucaine is an amide local anesthetic that greatly inhibits normal plasma cholinesterase activity, but it has limited inhibition of the activity of atypical plasma cholinesterase. This characteristic of dibucaine has led to an evaluation of the percent of inhibition of plasma cholinesterase activity by dibucaine, the result of which is referred to as the dibucaine number. By determining the dibucaine number for a given patient the diagnosis of the presence of atypical plasma cholinesterase may be established. It is important to realize that the dibucaine number reflects the quality, and not the quantity, of the circulating plasma cholinesterase enzyme in the plasma. For instance, patients with liver disease severe enough to decrease the number of circulating plasma cholinesterase enzymes would still have a normal dibucaine number. (149, Table 12-3)
27. The normal dibucaine number is 80. That is, normal plasma cholinesterase enzyme is inhibited by 80% in the presence of dibucaine. An individual heterozygous for atypical plasma cholinesterase would have a dibucaine number between 40 and 60. In these individuals a conventional dose of succinylcholine would lead to neuromuscular blockade that persisted for approximately 20 minutes. The incidence of individuals heterozygous for atypical plasma cholinesterase is about 1 in 480. An individual homozygous for atypical plasma cholinesterase would have a dibucaine number of about 20. In these individuals a conventional dose of succinylcholine would lead to neuromuscular blockade persisting for 60 to 180 minutes. The incidence of individuals homozygous for atypical plasma cholinesterase is about 1 in 3200. (149, Table 12-3)
28. Succinylcholine is usually not administered to children under nonemergent conditions. This is mostly secondary to a number of case reports of cardiac arrest in children and adolescents who were otherwise apparently healthy and had been administered succinylcholine. Hyperkalemia, rhabdomyolysis, and acidosis were frequently documented in these cases. It is believed that many of these children had undiagnosed myopathies. (149)
29. Succinylcholine may induce a wide variety of cardiac dysrhythmias with its administration. Among the most likely adverse cardiac rhythms to result from the administration of succinylcholine are sinus bradycardia, junctional rhythms, and ventricular arrhythmias. This is likely due to the similarity of the chemical structures of succinylcholine and acetylcholine. In addition to stimulating nicotinic receptors, succinylcholine may stimulate cardiac postganglionic muscarinic receptors in the sinus node of the heart and mimic the normal effect of acetylcholine at these receptors. This potential adverse effect of the administration of succinylcholine is most likely to occur when a second intravenous dose of succinylcholine is administered about 5 minutes after the first. (149-150)
30. The potential risk of adverse cardiac rhythms associated with the administration of succinylcholine may be minimized by pretreating patients before the administration of succinylcholine. The most effective pretreatment regimens include the intravenous administration of atropine or subparalyzing doses of nondepolarizing neuromuscular blocking drugs 1 to 3 minutes before administration of succinylcholine. (150)
31. A hyperkalemic response to succinylcholine in susceptible patients occurs secondary to a proliferation of extrajunctional receptors in the area of skeletal muscle after a denervation injury. These extrajunctional receptors are especially sensitive to succinylcholine. With the administration of succinylcholine to patients with a history of denervation injury there are more ion channels being opened, and more sites for the leakage of potassium out of cells during depolarization. In fact, patients with a history of denervation injury may be placed at risk of hyperkalemia sufficient to cause cardiac arrest when administered succinylcholine. Patients especially at risk are those with disease leading to skeletal muscle atrophy and those with unhealed skeletal muscle injury as produced by third-degree burns, upper motor neuron injury, and multiple trauma. Patients who have had denervation injuries are at risk of a hyperkalemic response to the administration of succinylcholine from 4 days to up to 3 to 6 months after the injury. Susceptibility to the hyperkalemic response peaks 7 to 10 days after the injury. The current recommendation is the avoidance of the administration of succinylcholine to the patient more than 24 hours after the denervation injury has occurred. (150, Figure 12-2)
32. Renal failure patients who are normokalemic can safely receive succinylcholine without being placed at risk for an exaggerated hyperkalemic response. This excludes patients with renal failure who have neuropathy secondary to uremia. (150)
33. Transient, generalized, unsynchronized skeletal muscle contractions referred to as fasciculations often accompany the administration of succinylcholine. This occurs secondary to the depolarization of the skeletal muscle membrane that occurs with the administration of succinylcholine. These fasciculations can result in skeletal muscle damage and myalgias postoperatively. The presence of myoglobinuria may be a clinical sign of skeletal muscle damage in these patients. Postoperative myalgias associated with the administration of succinylcholine most often occur in the muscles of the neck, back, and abdomen. Myalgias localized to the neck may be described as a sore throat by the patient and may be incorrectly attributed to tracheal intubation as the cause of the pain. Young, muscular adults undergoing minor surgical procedures that allow for early ambulation are most likely to complain about myalgias after the administration of succinylcholine. (150)
34. The cause of postoperative myalgias after the administration of succinylcholine has been speculated to be due to the fasciculations associated with the administration of this drug. A nondepolarizing neuromuscular blocking drug can be administered at a dose of 5% to 10% of its ED95 dose 2 to 4 minutes before the administration of succinylcholine to blunt the fasciculations. When pretreatment with a nondepolarizing neuromuscular blocking drug has been given to block fasciculations, the subsequent dose of succinylcholine should be increased by 50% to 70%. Pretreatment with a defasciculating dose of a nondepolarizing neuromuscular blocking drug has been shown to decrease the incidence of postoperative myalgias, but not abolish them completely. (150)
35. The administration of succinylcholine is associated with transient increases in intraocular pressure. The mechanism by which this occurs is not clearly understood, but it may be due to the contraction of extraocular muscles. The increase in intraocular pressure peaks 2 to 4 minutes after the administration of succinylcholine. The clinical concern regarding this effect of succinylcholine is that of the possibility of the extrusion of global contents when succinylcholine is administered to patients with open-eye injuries. Clinical experience with succinylcholine in these patients, however, has not shown this to be the case. For example, the administration of thiopental results in a decrease in intraocular pressure. When thiopental is administered before succinylcholine, the potential increase in intraocular pressure associated with succinylcholine may be attenuated. The prior administration of subparalyzing doses of nondepolarizing neuromuscular blocking drugs may also prevent succinylcholine-induced increases in intraocular pressure. In addition, the benefit of skeletal muscle paralysis associated with the administration of succinylcholine to patients with open-eye injuries far outweighs the risk of the markedly elevated intraocular pressures that are associated with bucking on an endotracheal tube. Intraoperative “bucking” with an endotracheal tube in place can increase intraocular pressure and corneal damage. (150-151)
36. The administration of succinylcholine produces increases in intragastric pressure that are unpredictable. Increases in intragastric pressure with succinylcholine administration, when they do occur, appear to correlate with the magnitude and the intensity of fasciculations. The increase in intragastric pressure is assumed to be due to fasciculation of the abdominal skeletal muscles. There is a theoretical risk of the aspiration of gastric fluid and contents with the increased intragastric pressure associated with the administration of succinylcholine. This risk appears to be increased in patients with ascites, obesity, a hiatal hernia, or an intrauterine pregnancy secondary to the altered angle of entry of the esophagus into the stomach in these patients. Because the magnitude of increase of intragastric pressure appears to be related to the intensity of fasciculations, the prior administration of subparalyzing doses of nondepolarizing neuromuscular blocking drugs may prevent the increase in intragastric pressure from occurring and decrease the theoretical risk of aspiration. (151)
37. The administration of succinylcholine can result in varying degrees of increased masseter muscle tension. In extreme cases this can result in trismus and in difficulty opening the mouth for direct laryngoscopy and intubation of the trachea. Pediatric patients are especially at risk for this complication of succinylcholine administration. Patients who develop trismus in association with the administration of succinylcholine may be susceptible to the subsequent development of malignant hyperthermia. (150)
Nondepolarizing neuromuscular blocking drugs
38. Nondepolarizing neuromuscular blocking drugs compete with acetylcholine for the binding sites on the α subunit of the nicotinic cholinergic receptor. With the binding of a nondepolarizing neuromuscular blocking drug to one or both α subunits on the receptor there are no two α subunits available for acetylcholine to bind. Subsequent depolarization in the postjunctional membrane through the actions of acetylcholine cannot occur, and skeletal muscle paralysis results. Fasciculations do not accompany the administration of nondepolarizing neuromuscular blocking drugs. (151, Table 12-6)
39. Nondepolarizing neuromuscular blocking drugs have very limited lipid solubility. This is due to the highly ionized state of nondepolarizing neuromuscular blocking drugs at physiologic pH. This limits their accessibility to the various tissues and results in a small volume of distribution. The small volume of distribution implies that neuromuscular blocking drugs are limited primarily to the extracellular fluid. Physiologically, the highly ionized state of nondepolarizing neuromuscular blocking drugs minimizes their transfer across lipid membrane barriers. This includes lipid membranes such as the blood-brain barrier, renal tubular epithelium, gastrointestinal epithelium, and placenta. Clinically, nondepolarizing neuromuscular blocking drugs therefore produce minimal central nervous system effects, undergo minimal renal tubular absorption, are ineffective when administered orally, and do not affect the fetus when administered to a parturient. (151-152)
40. Because of the hydrophilic nature of nondepolarizing neuromuscular blocking drugs, all these neuromuscular blocking drugs may be eliminated by glomerular filtration via the kidneys. When additional methods of clearance of the drugs are possible, the duration of action of the drug shortens. For example, the long-acting neuromuscular blocking drugs, such as pancuronium, undergo little or no metabolism and are primarily cleared by the kidneys. Yet, intermediate-acting and short-acting nondepolarizing neuromuscular blocking drugs are relatively independent of renal function for their clearance from the plasma. For example, vecuronium and rocuronium are cleared primarily through biodegradation in the liver, cisatracurium undergoes chemodegradation by Hofmann elimination and ester hydrolysis, and mivacurium is cleared principally by ester hydrolysis by the enzyme plasma cholinesterase. (151-152, Table 12-6)
41. There are several drugs that are often administered in the perioperative period that may enhance the neuromuscular blockade produced by nondepolarizing neuromuscular blocking drugs. These drugs include volatile anesthetics, local anesthetics, aminoglycoside antibiotics, cardiac antidysrhythmic agents, dantrolene, magnesium, lithium, tamoxifen, and calcium channel blockers. Hypothermia, hypokalemia, and decreases in pH may also prolong the action of nondepolarizing neuromuscular blocking drugs. (152)
42. Volatile anesthetics produce an enhancement of the magnitude and duration of neuromuscular blockade that is dose dependent and drug specific. Volatile anesthetics are thought to enhance the effects of nondepolarizing neuromuscular blocking drugs by directly inducing central nervous system depression and causing a corresponding decrease in skeletal muscle tone. In addition, nondepolarizing neuromuscular blocking drugs may alter the lipid membrane around the nicotinic cholinergic receptors, changing the properties of the ion channel. In this respect, volatile anesthetics may alter the sensitivity of postjunctional membranes to depolarization. (152)
43. Nondepolarizing neuromuscular blocking drugs may exert cardiovascular effects through several methods. First, they may induce the release of histamine. Second, nondepolarizing neuromuscular blocking drugs may have some direct action at cardiac postganglionic muscarinic receptors. Finally, nondepolarizing neuromuscular blocking drugs may have some direct effects on nicotinic receptors at the autonomic ganglia. The clinical significance of the cardiovascular effects produced by neuromuscular blocking drugs is minimal, however. (152, Table 12-5)
44. Most patients receiving neuromuscular blocking drugs for a prolonged period of time in the intensive care unit recover full muscle strength within a few hours of discontinuation of the drug. There have been reports of a subset of patients who, after receiving neuromuscular blocking drugs for several days or weeks, have had persistent skeletal muscle weakness after the discontinuation of the neuromuscular blocking drug. In some cases the skeletal muscle weakness has persisted for months. Weaning the patient from the mechanical ventilation of the lungs is therefore delayed. (152)
45. Risk factors for developing a myopathy secondary to the administration of nondepolarizing neuromuscular blocking drugs in the intensive care unit include patients with asthma, female patients with renal failure receiving vecuronium, the concurrent administration of high doses of corticosteroids, and the administration of large doses of neuromuscular blocking drugs for prolonged periods. Clinically, these patients may present with flaccid quadriplegia and increased creatine kinase concentrations. The pathophysiology of the myopathy is not known. (152)
Long-acting nondepolarizing neuromuscular blocking drugs
46. The principal route of clearance of pancuronium, like the other long-acting nondepolarizing neuromuscular blocking drugs, is by glomerular filtration. The clearance of all these long-acting nondepolarizing neuromuscular blocking drugs is greatly affected by renal disease, such that the plasma clearance of pancuronium in patients with renal failure is decreased by 30% to 50%. Patients with renal disease are therefore likely to exhibit prolonged neuromuscular blockade with the administration of conventional doses of pancuronium. Pancuronium is also metabolized by in the liver to a limited degree. A metabolite of pancuronium, 3-desacetylpancuronium, possesses limited muscle relaxant properties. Patients with biliary obstruction or cirrhosis of the liver may also manifest decreased plasma clearance and prolonged elimination half-times of pancuronium, although not to as great an extent as that seen with renal disease. (152)
47. The administration of pancuronium results in a modest increase in heart rate and arterial blood pressure by 10% to 15%. This effect of pancuronium is primarily due to muscarinic receptor blockade at the sinus node of the heart exerted directly by pancuronium. This selective vagal blockade of the heart is similar to the mechanism by which atropine increases heart rate. The increase in heart rate associated with the administration of pancuronium is dose-related and additive, such that subsequent doses of pancuronium will result in similar, additional increases in heart rate as previous doses. This increase in heart rate cannot be blunted or avoided through the slower injection of the drug. A minimal contributor to the increases in heart rate and blood pressure associated with the administration of pancuronium is activation of the sympathetic nervous system. Patients with altered atrioventricular conduction of cardiac impulses, such as patients with atrial fibrillation, appear to be the most likely to have marked increases in heart rate associated with the administration of pancuronium. (152-153)
Intermediate-acting nondepolarizing neuromuscular blocking drugs
48. The intermediate-acting nondepolarizing neuromuscular blocking drugs include atracurium, cisatracurium, vecuronium, and rocuronium. Their approximate time of onset is 3 to 5 minutes. Their approximate duration of action is 20 to 35 minutes, or 33% to 50% shorter than that of long-acting neuromuscular blocking drugs. The intermediate-acting neuromuscular blocking drug rocuronium stands apart from all the other muscle relaxants with respect to its time of onset, which is 1 to 2 minutes. (153, Figure 12-5, Table 12-6)
49. Vecuronium is metabolized by deacetylation in the liver to 3-, 17-, and 3,17-hydroxy metabolites. Only the 3-hydroxy metabolite has any significant neuromuscular blocking properties. Up to 60% of the injected dose of vecuronium, whether metabolized or unchanged, is excreted in the bile. Vecuronium is also partially cleared by the kidneys. Patients with renal failure may have impaired excretion of the unchanged form of vecuronium as well as the active 3-hydroxy metabolite of vecuronium. This may result in cumulative effects of vecuronium with the administration of large or repeated doses of vecuronium in renal failure patients. There are reports of prolonged neuromuscular blockade in renal failure patients in the intensive care unit being administered continuous infusions of vecuronium. (153)
50. Rocuronium has an onset time of 1 to 2 minutes at its ED95 dose, which makes it unique among the intermediate-acting nondepolarizing neuromuscular blocking drugs. In the event that a more rapid onset time is desired, rocuronium may be administered at a dose of three to four times its ED95 dose. This increased dose results in an onset time similar to that of succinylcholine. Because of the relatively increased dose of rocuronium required to produce an onset time similar to succinylcholine, when administered at this dose the duration of action of rocuronium becomes similar to that of pancuronium. (153, Figure 12-5, Table 12-6)
51. Rocuronium is mostly cleared from the plasma through the bile largely unchanged. About 30% of administered rocuronium is excreted renally. Large or repeated doses of rocuronium in patients with renal failure may theoretically produce prolonged effects of the drug, although this has not been seen clinically. (153, Table 12-6)
52. Cisatracurium is an isolated form of a stereoisomer of atracurium. (154, Figure 12-3)
53. The clearance of atracurium and cisatracurium from the plasma is completely independent of the kidneys. Two thirds of administered atracurium or cisatracurium undergoes ester hydrolysis, whereas the remaining third undergoes nonenzymatic spontaneous degradation by Hofmann elimination. Hofmann elimination is dependent on the pH and temperature of the plasma. The metabolism of these drugs is also independent of plasma cholinesterase since nonspecific plasma esterases are responsible for the ester hydrolysis. Both of the routes of metabolism for these drugs are independent of the kidneys or liver, making the duration of action of atracurium or cisatracurium unaltered in patients with hepatic or renal failure. (154, Table 12-6)
54. The principal metabolite of atracurium is laudanosine, which has no neuromuscular blocking effects. Laudanosine freely crosses the blood-brain barrier and, in high concentrations, can act as a central nervous system stimulant. Patients who have been administered continuous infusions of atracurium for several days, as in an intensive care unit setting, are especially at risk for the accumulation of the metabolite laudanosine and its central nervous system stimulatory effects. Laudanosine is primarily cleared through the liver. Patients with impaired hepatic function have a further risk of the adverse effects of laudanosine. (154)
55. The administration of atracurium can result in a transient decrease in systolic blood pressure by as much as 20%, along with facial erythema. These effects of atracurium are related to histamine release and only occur when rapidly doses of three times ED95 of atracurium are administered. (154)
56. Cisatracurium undergoes primarily Hofmann elimination to laudanosine and does not seem to undergo ester hydrolysis. In contrast to atracurium, the plasma concentrations of laudanosine after the administration of cisatracurium are very small, making it less likely to exert any central nervous system–stimulating effects. In addition, cisatracurium has minimal cardiovascular effects and does not invoke the release of histamine with its administration. (154)
Short-acting nondepolarizing neuromuscular blocking drugs
57. A short-acting nondepolarizing neuromuscular blocking drug is mivacurium. Its approximate time of onset is 3 to 5 minutes. Its approximate duration of action is 10 to 20 minutes, or 30% to 40% shorter than intermediate-acting neuromuscular blocking drugs. (154, Table 12-6)
58. Mivacurium is dependent on the enzyme plasma cholinesterase for its clearance. Patients who have either atypical plasma cholinesterase or a decreased concentration of plasma cholinesterase will have a prolonged duration of action of mivacurium in a similar manner as succinylcholine. For instance, the administration of an intubating dose of mivacurium in patients who are heterozygous for atypical plasma cholinesterase will result in a prolonged duration of effect by 30% to 50%, whereas patients who are homozygous for atypical plasma cholinesterase will have a prolonged effect for 3 to 4 hours. Although the metabolism of mivacurium is completely independent of the kidneys and liver, patients with liver failure may have a prolonged effect of mivacurium secondary to decreases in the concentration of plasma cholinesterase and a subsequent slower rate of clearance. Patients with renal failure who have been receiving continuous intravenous infusions of mivacurium may also have a mildly prolonged duration of action of mivacurium to 10 to 15 minutes. (154)
59. Neostigmine is an anticholinesterase that inhibits the activity of both plasma cholinesterase and true cholinesterase. The reversal of the neuromuscular blockade produced by mivacurium may be accomplished with the administration of neostigmine. The benefits of increasing the concentration of acetylcholine available to compete for binding sites on the nicotinic cholinergic receptor in the neuromuscular junction outweigh the inhibition of the activity of plasma cholinesterase in this circumstance, and the actions of mivacurium may be reversed. (154)
60. The administration of mivacurium rapidly and at doses of three times ED95 may result in histamine release and associated transient decreases in systemic blood pressure. (154, Table 12-6)
Monitoring the effects of nondepolarizing neuromuscular blocking drugs
61. The most common method for monitoring the effects of neuromuscular blocking drugs during general anesthesia is through the use of a peripheral nerve stimulator. The peripheral nerve stimulator works by stimulating a motor nerve to conduct an impulse. A mechanically evoked muscle response is then evaluated by the clinician. The mechanical motor response of the muscle reflects the number of muscle fibers that are blocked and provides an indication to the clinician of the degree of neuromuscular blockade. (154-155)
62. A peripheral nerve stimulator may be useful during the administration of neuromuscular blocking drugs during general anesthesia in at least two ways. First, a peripheral nerve stimulator allows the clinician to titrate the neuromuscular blocking drug to optimize skeletal muscle relaxation for surgery without unnecessarily overdosing the patient. Second, a peripheral nerve stimulator may be used as an objective means with which to judge the recovery from neuromuscular blockade at the conclusion of surgery either before or after the antagonism of a nondepolarizing neuromuscular blocking drug with an anticholinesterase drug, such as neostigmine. (154-155)
63. The ulnar nerve and adductor pollicis muscle are the nerve and muscle most commonly used for the evaluation of the neuromuscular blockade produced by neuromuscular blocking drugs through the use of a peripheral nerve stimulator. The adductor pollicis muscle is solely innervated by the ulnar nerve. This means that the only source for motor stimulation of the adductor pollicis muscle is through the mechanical stimulation of the ulnar nerve. Different muscle groups differ in their sensitivities to neuromuscular blocking drugs. The adductor pollicis muscle is more sensitive to the effects of neuromuscular blockers than are the diaphragm or upper airway muscles. (155)
64. When the arm is not available to the anesthesiologist, the facial nerve and orbicularis oculi muscle are often used for the evaluation of the neuromuscular blockade produced by neuromuscular blocking drugs through the use of a peripheral nerve stimulator. Other nerves that may be used include the median, posterior tibial, and common peroneal nerves. (155)
65. In general, the administration of nondepolarizing neuromuscular blocking drugs produces laryngeal muscle relaxation and conditions favorable for intubation of the trachea more rapidly than relaxation of the adductor pollicis muscle as measured by ulnar nerve stimulation. Facial nerve stimulation and measurement of neuromuscular blockade of the orbicularis oculi muscle more closely correlates with laryngeal muscle relaxation and vocal cord paralysis than ulnar nerve stimulation. An exception to the pattern of neuromuscular blockade onset in the various muscles is with the administration of succinylcholine. The administration of this neuromuscular blocking drug results in neuromuscular blockade at the adductor pollicis muscle and the laryngeal muscles at approximately the same time. Thus the measurement of neuromuscular blockade at the ulnar nerve provides a better indication of vocal cord paralysis when succinylcholine is administered. The diaphragm muscle appears to be resistant to the effects of neuromuscular blocking drugs, such that larger doses of drug are required to produce relaxation of the diaphragm than doses required for relaxation of either the laryngeal muscles, orbicularis oculi, or adductor pollicis muscles. (155-156, Figure 12-6)
66. Some of the mechanical responses evoked by a peripheral nerve stimulator and used to monitor the effects of neuromuscular blocking drugs include a single twitch response, a train-of-four ratio, double burst suppression, tetanus, and posttetanic stimulation. The various methods of evaluation of the mechanically evoked response vary with regard to ease and accuracy. The mechanically evoked response can be evaluated visually, manually by touch, or by recording. (154-155)
67. Depression by 90% or more of a mechanically evoked single twitch response from its control height correlates with adequate neuromuscular blockade for the performance of intraabdominal surgery or tracheal intubation. Greater than 70% of nicotinic cholinergic receptors must be occupied by a nondepolarizing neuromuscular blocking drug to achieve this. (158, Table 12-8)
68. The train-of-four stimulus delivered by a peripheral nerve stimulator is four electrical stimuli at 2 Hz each delivered every 0.5 seconds. The train-of-four stimulus is useful for the evaluation of the degree of neuromuscular blockade based on the premise that each successive electrical stimulus will further deplete stores of acetylcholine in the nerve terminal. In the presence of neuromuscular blockade produced by nondepolarizing neuromuscular blocking drugs, there will be a resultant decrease in the mechanically evoked muscle response with each stimulus. The amount of decrease in the mechanical muscle response correlates with the degree of neuromuscular blockade. Only four twitches are used in the train-of-four stimulus because any further stimulation of the nerve after the fourth does not result in any further depletion of acetylcholine stores at the nerve terminal. (158, Table 12-8)
69. The train-of-four ratio is a calculation of the height of the fourth evoked twitch response divided by the height of the first evoked twitch response of a train-of-four stimulus. For example, if the height of the fourth twitch is one half the height of the first twitch, the train-of-four ratio would be 0.5. The train-of-four ratio reflects how much fade has occurred, which correlates with the degree of neuromuscular blockade. The control, or baseline, train-of-four ratio should be 1.0 before the administration of neuromuscular blocking drugs. This corresponds to a height of the fourth mechanically evoked twitch response being equal to the height of the first evoked twitch response. (158, Table 12-8)
70. A train-of-four ratio of 0.7 or greater correlates with the complete return to the control height of a single twitch response. That is, when the height of the fourth mechanically evoked twitch response is 70% of the height of the first evoked twitch response in a train-of-four stimulus, a single twitch response will have returned to its control height. (158, Table 12-8)
71. After the administration of succinylcholine for a neuromuscular blockade, a phase II neuromuscular blockade may be reflected in the train-of-four response as a train-of-four ratio less than 0.3. The train-of-four response thus shows some fade of the fourth twitch when compared with the first twitch of the train-of-four stimulus when phase II neuromuscular blockade is present. (156, Figure 12-8)
72. Estimation of the train-of-four response by clinicians evaluating the response visually and manually is not very accurate. Although clinicians have difficulty assessing the train-of-four ratio, the assessment of the absolute number of twitches evoked by the train-of-four stimulus is much more reliable. When the first twitch is approximately 35% of the control twitch height, the fourth twitch is able to be detected. This corresponds to a train-of-four ratio of about 0.35. (156-157, Figure 12-8)
73. The double burst suppression stimulus delivered by a peripheral nerve stimulator is two bursts of three 50-Hz electrical stimuli separated by 750 milliseconds between each burst, but it is perceived by the clinician as two separate twitches. The use of the double burst suppression stimulus appears to make the estimation of the fade response easier for clinicians. It is thought that the estimation of the ratio between the two twitches is easier for clinicians because the middle two twitches of the train-of-four response are eliminated. A train-of-four ratio of 0.3 or less is most accurately detected by clinicians when using the double burst suppression stimulus. Accuracy of the estimation of a train-of-four ratio greater than 0.7 is still poor, however. (157)
74. Tetany is a continuous skeletal muscle contraction that occurs secondary to continuous stimulation of the postjunctional receptors. Tetany can be mechanically produced through the use of a peripheral nerve stimulator. The delivery of a continuous electrical stimulus of about 50 Hz for 5 seconds is frequently used in clinical anesthesia practice to induce tetany for the evaluation of neuromuscular blockade. (157-158, Figure 12-10)
75. The normal response to tetany is a sustained muscular contraction. This response is altered by the administration of neuromuscular blocking drugs. Phase I neuromuscular blockade subsequent to the administration of depolarizing neuromuscular blocking drugs, such as succinylcholine, induces a mechanical muscle contraction in response to a tetanic stimulus that is greatly decreased from the control response and does not undergo fade over time. The administration of nondepolarizing neuromuscular blocking drugs induces a mechanical muscular contraction in response to a tetanic stimulus that fades over time. (157-158, Figure 12-10)
76. Posttetanic stimulation refers to the evaluation of a train-of-four response after a tetanic stimulus has been delivered. The mechanical muscle response to a train-of-four stimulus after the delivery of a tetanic stimulus is useful during intense neuromuscular blockade when there is no evoked mechanical response to either a single twitch or a train-of-four stimulus. The clinical use of posttetanic stimulation is derived from the transient enhancement of the mechanical muscle response obtained when a train-of-four stimulus is delivered immediately after a tetanic stimulus. This enhancement is due to an increase in the available stores of acetylcholine in the nerve terminals after a tetanic stimulus and is termed posttetanic facilitation. (157, Figure 12-10)
Antagonism of nondepolarizing neuromuscular blocking drugs
77. The antagonism of the neuromuscular blockade produced by nondepolarizing neuromuscular blocking drugs is achieved through the intravenous administration of anticholinesterases. The anticholinesterases most often used for this purpose are neostigmine and edrophonium. These drugs exert their effect by inhibiting the activity of acetylcholinesterase, the enzyme that hydrolyzes acetylcholine in the neuromuscular junction. As a result of the inhibition of the hydrolysis of acetylcholine, acetylcholine accumulates in the neuromuscular junction. With more acetylcholine available at the neuromuscular junction, the competition between acetylcholine and the nondepolarizing neuromuscular blocking drug is altered such that it is more likely that acetylcholine will bind to the postjunctional receptor. In addition to increasing the amount of acetylcholine available in the neuromuscular junction to compete for sites on the nicotinic cholinergic receptors, acetylcholine also accumulates at the muscarinic cholinergic receptor sites through the same mechanism. (158)
78. Anticholinesterases increase the concentration of acetylcholine available at the muscarinic cholinergic receptors as well as at the nicotinic cholinergic receptors. This may result in profound bradycardia through the stimulation of muscarinic cholinergic receptors in the heart. To attenuate the cardiac muscarinic effects of anticholinesterases, a peripheral-acting anticholinergic such as atropine or glycopyrrolate is administered intravenously before or simultaneous with the intravenous administration of the anticholinesterase. (156, Table 12-7)
79. Two factors that influence the choice of which anticholinesterase drug to administer to antagonize neuromuscular blockade include the approximate duration of action of the nondepolarizing neuromuscular blocking drug that had been administered and the intensity of the neuromuscular blockade that exists at the conclusion of surgery. (159)
80. Neostigmine and edrophonium are the quaternary ammonium-structured anticholinesterases that are most frequently administered for the antagonism of the effects of nondepolarizing muscle relaxants. Neostigmine should be administered for the antagonism of the effects of nondepolarizing neuromuscular blocking drugs when the neuromuscular blockade is intense and/or when the neuromuscular blocking drug that had been administered is long-acting. This is primarily due to the prolonged duration of effect of neostigmine when compared with the duration of effect of edrophonium. Glycopyrrolate is often paired with neostigmine as the anticholinergic of choice because its delayed cardiac anticholinergic effects more closely parallel the time of onset of the muscarinic effects produced by neostigmine. Conversely, edrophonium has a shorter time of onset and shorter duration of action than neostigmine. Edrophonium should be administered for the antagonism of the effects of nondepolarizing neuromuscular blocking drugs when there has been adequate spontaneous recovery from the effects of these drugs and/or when the nondepolarizing neuromuscular blocking drug that had been administered was short- or intermediate-acting. Atropine is often paired with edrophonium as the anticholinergic of choice because its shorter time of onset is similar to the short onset time of edrophonium. (157, Table 12-7)
81. Confirmation of the recovery from the effects of neuromuscular blockade that have occurred either spontaneously or through the administration of anticholinesterases should be obtained before extubation of the patient’s trachea at the conclusion of general anesthesia. Often the mechanical muscle response to a train-of-four stimulus is difficult for the clinician to evaluate manually or visually. When this is the case, the evaluation of the muscular response to a continuous tetanic stimulation may be useful. A sustained muscular contraction to a continuous tetanic stimulus usually indicates a train-of-four ratio greater than 0.7 and is an indication of adequate recovery from neuromuscular blockade. Alternatively, a double burst suppression stimulus may be delivered by the peripheral nerve stimulator to facilitate the clinician’s ability to evaluate the degree of fade. Clinical tests that may also be used to evaluate the adequacy of the reversal of neuromuscular blockade include the patient’s ability to open the eyes, cough, stick out the tongue, and sustain a head lift for 5 to 10 seconds; grip strength; vital capacity; and maximal inspiratory force. Of these clinical tests, a sustained head lift is considered to be the most sensitive test to evaluate the adequacy of the recovery from neuromuscular blockade. (159)
82. Residual effects of neuromuscular blockers may manifest clinically in awake patients as diplopia, decreased hand grip strength, difficulty swallowing, and difficulty speaking. Patients may also have difficulty sustaining their minute ventilation without assistance. (159)
83. There are several pharmacologic and physiologic factors that may interfere with the antagonism of the neuromuscular blockade produced by neuromuscular blocking drugs. Physiologic factors include abnormalities in the patient’s temperature, acid-base status, electrolytes, or metabolism pathways. These may all interfere with the metabolism and clearance of the neuromuscular blocking drug. In particular, renal or liver disease may result in markedly prolonged elimination times and prolonged clinical effects of certain nondepolarizing neuromuscular blocking drugs. Pharmacologic factors include the concurrent administration of aminoglycoside antibiotics, local anesthetics, volatile anesthetics, magnesium, dantrolene, and cardiac antidysrhythmic agents. Another cause of an apparent inability to antagonize the effects of neuromuscular blocking drugs is not allowing sufficient time to pass for an anticholinesterase to begin exerting its effect. Finally, the lack of a mechanically evoked muscular response to a train-of-four stimulus is an indication that the antagonism of the neuromuscular blockade is not possible. (159)
Adverse outcomes from inadequate antagonism of neuromuscular blockade
84. Residual neuromuscular blockade, obesity, the administration of opioids, long duration of surgery, and emergency and abdominal surgery are all risk factors for patients becoming hypoxic in the immediate postoperative period. (158)
85. The most dangerous time for anesthetic complications in the postoperative period starts with the extubation of the trachea, transport to the postanesthesia care unit (PACU), and the first 30 minutes in the PACU. (158)
86. Sugammadex is a neuromuscular blocking drug antagonist that is under development, but not yet approved by the Food and Drug Administration for use in the United States due to hypersensitivity concerns. It has been approved for use in Europe and other countries. The mechanism of action of sugammadex is through encapsulation and inactivation of steroid muscle relaxants (not atracurium). (159-160)
87. Sugammadex differs from neostigmine several ways. First, it has no cardiovascular effects and does not require other drugs such as glycopyrrolate. Sugammadex, unlike neostigmine, can reverse a profound neuromuscular blockade. For example, if rocuronium, 1.2 mg/kg is given, its neuromuscular blockade can be completely reversed within minutes (e.g., 5 minutes). In this situation, neostigmine would be ineffective. (159)
88. Sugammadex confers several advantages for the antagonism of neuromuscular blockade. First, a rocuronium-sugammadex combination can be used for rapid sequence induction of anesthesia and subsequent reversal. Second, profound neuromuscular blockade can be achieved and maintained through the end of surgery and still have adequate reversal at the conclusion of surgery. Finally, the incidence of residual neuromuscular blockade can be reduced or eliminated. (159)
