The history of neuromuscular blockers, and how they came into day-to-day clinical use, is a fascinating one. Curare (Chondrodendron tomentosum) is the archetypal neuromuscular blocking agent, becoming popular in the 1930s, though it is no longer commonly used in practice in the United States [1]. Several authors describe the first "discoverer" of curare as Sir Walter Raleigh, though at least one expert disputes this idea [2,3,4]. Raleigh witnessed the natives in Guyana making a poison and applying it to the tips of their arrows when hunting monkeys. The slightest wound resulted in death to the monkey. In 1804, Charles Waterton (1782–1865) left England for his family's sugar estates in Guyana, and there he observed native Guyanese men hunting with curare. Encouraged by English scientists to find the secret of these poison arrows, Waterton brought curare back to England in 1812 for further study, thinking it might be especially useful in the treatment of rabies (then called hydrophobia) [5]. In the course of his time in Guyana, he witnessed an event that affected him profoundly: the death of a native man who was accidentally hit by his own arrow after missing the monkey at which it was aimed. His eyewitness description is [2]:

The history of neuromuscular blockers, and how they came into day-to-day clinical use, is a fascinating one. Curare (Chondrodendron tomentosum) is the archetypal neuromuscular blocking agent, becoming popular in the 1930s, though it is no longer commonly used in practice in the United States [1]. Several authors describe the first "discoverer" of curare as Sir Walter Raleigh, though at least one expert disputes this idea [2,3,4]. Raleigh witnessed the natives in Guyana making a poison and applying it to the tips of their arrows when hunting monkeys. The slightest wound resulted in death to the monkey. In 1804, Charles Waterton (1782–1865) left England for his family's sugar estates in Guyana, and there he observed native Guyanese men hunting with curare. Encouraged by English scientists to find the secret of these poison arrows, Waterton brought curare back to England in 1812 for further study, thinking it might be especially useful in the treatment of rabies (then called hydrophobia) [5]. In the course of his time in Guyana, he witnessed an event that affected him profoundly: the death of a native man who was accidentally hit by his own arrow after missing the monkey at which it was aimed. His eyewitness description is [2]:

The cells in the brain communicate with those in the rest of the body by sending and receiving small electric impulses (called action potentials) along nerves from one area of the body to another. When one wishes to move, specialized areas in the brain send action potentials along specific motor neurons that descend through the spinal cord. Bundles of neurons, running together within an anatomic sheath, are called nerves. The neurons comprising the nerves are myelinated; that is, each neuron is wrapped in a series of Schwann cells, increasing the speed of transmission of a muscle action potential along the nerve through a process called saltatory conduction[10]. There are small spaces between the Schwann cells called the nodes of Ranvier, and the underlying nerve is exposed at these points. These exposed areas of the nerve allow the action potential to skip from space to space, significantly increasing the speed of transmission of the impulse[10]. The point at which two nerves meet is called a synapse.

The neuromuscular junction is a complex of numerous anatomic structures and is itself a synapse. At any synapse, some ligand (an intracellular substance) is released from a prejunctional neuron, crosses a synaptic space, and binds with a receptor on a postjunctional neuron (or postjunctional muscle). As noted, the terminal nerve ending does not touch the muscle fiber itself. Rather, there is a small space between the two structures, referred to as the synaptic cleft or the synaptic space [10,11]. The terminal nerve ending consists of thousands of small synaptic vesicles that contain the neurotransmitter acetylcholine. When an action potential leaves the spinal cord via a lower motor neuron and travels to the terminal nerve ending, the amount of voltage within the nerve changes as the impulse passes. When the action potential (electric impulse) arrives at the prejunctional nerve terminal, the resting membrane potential (i.e., the electric "charge" inside the cell) suddenly increases from a resting level of -90 millivolts to a depolarizing level of +50 millivolts [11]. This change in voltage activates small receptors in the prejunctional neurons called voltage-gated calcium channels. These channels are specialized proteins that open and close, creating a tube through which calcium ions (Ca²⁺) can flow when open [10]. Because there is 10,000 times more calcium outside of the nerve cell than inside, Ca²⁺ rushes through these tubes into the prejunctional nerve cell [10]. The entry of calcium effects a change in the vesicles, causing them to move toward and fuse with the cell membrane. After the fusion takes place, the vesicles are opened to the extracellular space, resulting in thousands of molecules of acetylcholine being released from the prejunctional neuron and entering the synaptic space [10].

Acetylcholine is synthesized in the neuron in both the soma and the terminal nerve ending[10]. It is the product of acetyl-coenzyme-A, produced by the mitochondria, and choline from dietary sources. These substances are combined in the presence of the enzyme choline acetyl-transferase and then placed in the vesicles.

After being released from the vesicles, acetylcholine molecules travel a short distance across the synaptic cleft, where they bind to the nicotinic acetylcholine receptor (Figure 2)[11,12]. This receptor is crucially important to neuromuscular function and has been intensively studied. The receptor is a large protein that spans from the cytosol outside the muscle cell to the cytoplasm on the inside of the cell [13]. The protein has five major subunits: two alpha, two beta, and one delta. There are two acetylcholine binding sites on the receptor. Once bound, the receptor undergoes a change in shape and creates an opening through which sodium ions (Na⁺) can pass. As Na⁺ passes into the muscle cell, the electrical charge in the muscle rises, causing a muscular action potential, similar to the neuronal action potential.

The operant part of the skeletal muscle is the interdigitation of actin and myosin fibers within the muscle cell. Actin has binding sites for the myosin heads of the myosin fibers, but at rest, these are covered by a structure called the troponin-tropomyosin complex. The tropomyosin portion of this complex is tightly wound around the actin fiber and covers the actin-binding sites [10]. Once covered, the myosin heads remain quiescent, unable to bind with the sites. In the presence of increased Ca²⁺ levels, such as those that occur after an excitatory muscle potential, the binding sites are uncovered. The Ca²⁺ binds with one part of the troponin-tropomyosin complex called troponin C. Once bound, the tropomyosin undergoes a conformational change and "rolls" off the actin binding sites. Myosin heads, in the presence of magnesium (Mg²⁺) and adenosine triphosphate (ATP), bind with the actin binding sites. As the ATP dissociates into adenosine diphosphate (ADP) and a free phosphate ion, the head of the myosin assumes an acute angle, and the myosin head binds with the now-exposed actin-binding site, releasing the ADP and phosphate ion. The myosin head has been compared to a "cocked spring" [10]. Once bound to actin, the spring releases, causing the head to change to a more acute angle, thus pulling the actin fibers closer together. In the presence of ATP, the myosin releases from the actin-binding site. Ca²⁺ is actively pumped back into the sarcoplasmic reticulum and pumped outside the muscle cell, and the process is free to begin again. Indeed, the muscle stiffness called rigor mortis seen in individuals who have died is the result of a lack of ATP allowing the myosin heads to release from the actin fibers.

Some neuromuscular blockers, called depolarizing agents, have structures similar to acetylcholine. These agents bind with the neuromuscular junction, causing it to discharge and initiating random depolarization of skeletal muscle, similar to acetylcholine. The difference is that these agents remain bound to the receptor and do not allow the muscle to repolarize. In short, the muscle shortens, then relaxes, and then remains relaxed for a longer period than it would if the depolarization was caused by acetylcholine [15].

There is only one depolarizing agent currently available for use in the United States—succinylcholine[16]. As discussed, the nicotinic acetylcholine receptor has two binding sites, one on each alpha subunit. When bound to these sites, succinylcholine causes an uncontrolled depolarization of the muscle cell, resulting in random muscle movement (fasciculation). The binding of succinylcholine with these sites prevents the repolarization of the muscle, causing paralysis.

During the testing and development of neuromuscular blocking agents, a dose that results in some level of paralysis in a representative sample of patients is established. If the dose results in an effect in 95% of the patients tested, that dose is referred to as the ED₉₅ or the estimated dose at which 95% of patients receive the desired effect (i.e., paralysis) [16]. Though an agent may have an ED₉₅, there is often a significant time lapse between the time of administration and peak effect. During endotracheal intubation and airway management, time is of the essence. The prolonged onset of these agents in lower doses may be deleterious, so most agents used for endotracheal intubation are administered to patients at two to three times the ED₉₅[14,17]. This increased dose speeds the onset of action, though it is important for the practitioner to remember that the increased dose also prolongs the effect of the injected agent. Table 1 shows the typical ED₉₅ dose as well as the intubating dose of commonly used neuromuscular blocking agents [17].

There are a number of amino-steroid agents on the market today, most of them routinely used. These agents all have a quaternary amine structure, which prevents them from crossing the blood-brain barrier and interacting with cholinergic receptors in the brain. They are also highly water-soluble, allowing them to move quickly from central circulation to the peripheral neuromuscular junctions on skeletal muscle. In nearly all cases, these agents are metabolized in the liver and excreted by the kidneys.

As pancuronium undergoes 40% to 60% of its degradation in the liver, patients with cirrhosis may expect prolonged time to recovery [16]. The key to determining the duration of pancuronium's effects is a patient's hepatocyte status. Laboratory indications of destruction of hepatic parenchyma should lead to caution in the administration of pancuronium, as its action may be substantially lengthened [23]. In the presence of patients taking other drugs that undergo extensive degradation by the liver (e.g., phenytoin), the upregulation of microsomal enzymes may result in a substantial decrease in the duration of action [16,24].

Rocuronium is the most recently developed neuromuscular blocking agent, introduced in 1992 and developed as a short- to intermediate-acting nondepolarizing agent with an extremely rapid, dose-based onset (Table 3) [14,16,17]. This agent is primarily used as an induction and maintenance agent in anesthesia or when neuromuscular relaxation is needed for a comparatively short period in the non-surgical venue. Rocuronium is typically used in the prehospital environment to facilitate endotracheal intubation by paramedics in the field[35]. Its rapid onset has placed it as a nondepolarizing alternative to succinylcholine; however, doses sufficient to speed onset to this degree come with long durations of action. In the patient whose airway is difficult and in whom the chance of failure to rapidly intubate may lead to a comorbid or mortal event, succinylcholine remains the criterion standard. This circumstance, however, has changed with the introduction of sugammadex to clinical practice in the United States (as will be discussed in more detail later in this course). This novel reversal agent works by surrounding the molecules of rocuronium, precluding it from binding to the nicotinic acetylcholine receptor[36]. Following an intubating dose of rocuronium, administration of sugammadex allows the complete recovery of neuromuscular function in a shorter time than an equipotent dose of succinylcholine. This innovation has dramatically increased the use of rocuronium, making it ideal for the prehospital environment.

Elderly Patients. Rocuronium is well tolerated by the elderly population, and there have been no reports of significant change in hemodynamic variables. Elderly patients have inherent decreases in cardiac output, hepatic blood flow, and both renal blood flow and glomerular filtration rate. One might expect a longer time until onset with any agent, but the literature reports different findings. One study reveals rocuronium's onset was the same in the elderly as in younger patients, but the duration of action was markedly increased, from an average of 82 minutes in younger patients to 98 minutes in the elderly after a standard double ED₉₅ dose of the agent [25]. A second study showed that the onset of rocuronium administered at a dose of 1 mg/kg (slightly more than three times the ED₉₅) was, on average, 18 seconds longer compared with younger adult patients [47]. This 18-second difference may or may not be clinically significant to practitioners, depending on the circumstance of use. During times when gaining control of the airway in an elderly patient is crucial, this relatively short prolongation of onset may have dramatic effects on clinical outcomes. As rocuronium undergoes both hepatic and renal degradation and excretion, this prolonged effect is expected [48]. At least one source suggests that recovery from rocuronium after the administration of sugammadex as a reversal agent may also be prolonged when compared with a younger adult patient [48].

Introduced in 1980, vecuronium is an intermediate-acting nondepolarizing neuromuscular blocker that is quite potent; this can be expected, as it is a monoquaternary analogue of pancuronium. As a result, in larger doses one would expect to see prolonged duration, though in normal doses (Table 4) it is classed as intermediate-acting [15]. Further, vecuronium is unstable as an aqueous solution, so the agent is produced as a dry white powder that must be reconstituted prior to its administration [15,16,37]. Vecuronium undergoes elimination in the liver and is excreted in the bile and urine [14]. One of vecuronium's metabolites, 3-desacetyl vecuronium, is active and cleared more slowly than vecuronium, which may result in prolongation of action in patients with liver and kidney disorders.

As opposed to the amino-steroid neuromuscular blockers, there are primarily two benzylisoquinolinium-based agents on the market in the United States, and one of these (cisatracurium) is used far more than the other (atracurium). These agents have a bis-quaternary amine structure, which prevents them from crossing the blood-brain barrier and interacting with cholinergic receptors in the brain; the same properties are present in monoquaternary amino-steroids [37]. However, benzylisoquinoliniums were developed for a specific purpose, and their structure is closely related to that purpose. In the 1980s, Stenlake and colleagues developed a neuromuscular blocking agent that could be administered to patients with hepatic and renal comorbidities and still undergo predictable degradation [16,64]. The discovery of the application of the Hofmann elimination process in 1956, by which the drug "splits" into inactive parts in the presence of normal blood temperature and pH, and subsequent 25 years of testing and research resulted in the development of atracurium, followed by its cis isomer cisatracurium [15,16,65]. These agents are both classed as "intermediate-duration" nondepolarizing neuromuscular blocking agents [14,17].

Atracurium was also developed to assist in the effective treatment of patients with renal dysfunction. In a manner analogous to that of hepatic function, the Hofmann elimination aspects of the drug make it very attractive for use in the patient with kidney disease, removing renal excretion from the degradation pathway [15,16,59]. Atracurium is valued for its use in the critically ill patient, as it does not possess the accumulative properties leading to prolonged blockade, and is preferred over the amino-steroids for this class of patients [74]. One concern is the partial production of laudanosine, one of the metabolites of Hofmann elimination. This metabolite, in large doses, has rarely been associated with central nervous system disorders in the form of seizure activity [16,74]. In a study comparing the effects of atracurium in patients with renal failure against those of healthy controls, Della Rocca and colleagues found that there was no difference in onset, duration, or recovery from 25% blockade recovery to 80% blockade recovery [57]. Atracurium is also indicated in renal transplant surgery [59,75].

Trauma Patients. While the traumatically injured patient may receive atracurium acutely, those requiring prolonged mechanical ventilation in the ICU should not. The buildup of the metabolite laudanosine, which is not easily cleared by those with renal impairment or decreased glomerular filtration, may result in seizure activity [37]. In the prehospital setting, atracurium can easily be replaced by other agents that will provide a more rapid onset of muscle relaxation. Further, at the dose needed for a rapid onset, atracurium may cause histamine release accompanied by hemodynamic instability and reactive airway response that is especially deleterious in the trauma patient. In one study of 566 patients at two tertiary care centers, 287 of whom received neuromuscular blockers, atracurium was not administered to any of the patients requiring airway management, while rocuronium and succinylcholine were administered 70.4% and 29.6% of the time, respectively [35].

Post-Administration Myalgias. Patients receiving succinylcholine may complain of a diffuse musculoskeletal pain after recovering from its use. These muscle pains are believed to be the result of generalized inflammation following uncoordinated muscular fasciculations [56]. Numerous interventions have been developed to decrease this pain, which may be severe. The foremost technique is the use of a defasciculating dose of nondepolarizing agents two to three minutes before the administration of succinylcholine, resulting in visibly decreased fasciculations [16]. A meta-analysis assessed a broad compendium of possible treatments to decrease post-administration myalgias, including decreasing the succinylcholine dose and the co-administration of vitamin C, calcium gluconate, lidocaine, and aspirin and nonsteroidal analgesics [92]. Most of the treatments decreased reported pain, but none proved to be ideal. In one study of 393 patients, authors administered lidocaine, d-tubocurarine in a defasciculating dose, a combination of the two, or a placebo prior to the administration of succinylcholine [93]. The authors found that the combination of lidocaine and d-tubocurarine resulted in 8% of the patients having postoperative myalgias, compared with 41.3% reporting myalgias in the placebo group [93].

Hyperkalemia. When muscle and nerve cells depolarize, sodium ions enter the cell, followed by a release of potassium ions during repolarization [10]. The action of the sodium potassium pump then moves these ions against their concentration gradient to ensure the re-equilibration of the ions in their correct concentrations both inside and outside of the cell. However, the administration of succinylcholine, with its accompanying massive depolarization of skeletal muscle, may cause the elevation of serum potassium levels, usually about 0.5–1.0 mmol/L [16,56]. This is especially important in patients with prolonged immobility, neuromuscular weakness as a result of stroke, and/or paralysis secondary to injury [16]. These patients undergo a physiologic change in which they upregulate the number of receptors at their neuromuscular junctions [94]. A 2012 study sought to determine the degree to which hyperkalemia becomes problematic in the critically ill. In a study of 131 critically ill patients who were intubated 158 times (some requiring second intubation in the course of their care), using succinylcholine as the muscle relaxant of choice increased potassium levels an average of 0.4 mmol/L [94]. The primary impact on the elevation in potassium in this study was the length of stay in the ICU. However, in some patients, succinylcholine can cause potassium to rise precipitously. In a case study of a male adolescent (16 years of age) with Klebsiella pneumoniae-associated sepsis, the administration of succinylcholine to facilitate intubation resulted in an increase in his potassium level from 3.19 mmol/L to 8.64 mmol/L [95]. The patient developed cardiac arrest and was aggressively resuscitated. The patient's illness before intubation resulted in him being on bed rest for 15 days prior to the episode, illustrating the impact of immobility on the upregulation of the receptors [95]. Practitioners should make a careful risk/benefit analysis involving any use of succinylcholine. In each case of its use, the question is whether the short onset and, perhaps more importantly, the short duration of this agent overcome the possibility of creating a critical hyperkalemia in an immobile patient.

Masseter Muscle Spasm. One of the primary uses of succinylcholine is to temporarily paralyze the patient to ease the performance of laryngoscopy and endotracheal intubation. Occasionally, the administration of succinylcholine will result in the spasm of the masseter muscle in the jaw, resulting in a patient with a tightly clenched mouth and jaw [16,37]. This condition results in extraordinarily difficult airway manipulation. In one case study, a man became unconscious after an overdose of oral clonidine and the decision was made to intubate him [96]. The patient received 30 mg of etomidate to obtund consciousness, followed by 1.5 mg/kg of succinylcholine. With the jaw rigidly closed, two subsequent attempts at intubation failed, relieved only by the administration of the nondepolarizer vecuronium 10 mg, resulting in sufficient relaxation to allow successful intubation [96]. In a more extreme case, a man presented via ambulance to the emergency room after significant hypovolemia secondary to upper and lower gastrointestinal bleeds [97]. In the face of impending respiratory failure, rapid sequence intubation was selected, and the patient received etomidate 20 mg and succinylcholine 100 mg, after which he rapidly developed a masseter spasm so tight the mouth could not be opened nor could the mandible be moved. Following these findings, a repeat dose of succinylcholine 100 mg was administered without effect [97]. The neck was subsequently prepped and, after a failed nasal fiber optic attempt at intubation, a cricothyrotomy performed with the successful placement of a 5.0 endotracheal tube. It is vital to anticipate the possibility of masseter muscle spasm in patients receiving succinylcholine. Deepening sedation or the administration of a nondepolarizing agent will ameliorate this condition [56].

Cardiovascular Effects. The acetylcholine-based structure of succinylcholine may activate the muscarinic receptors in the parasympathetic nervous system, resulting in bradycardia and bradyarrhythmias. This is most common in patients with high vagal tone and could be of concern in patients requiring an elevated pulse rate to maintain cardiac output[16,17,99]. It is not uncommon to see these effects after large initial doses of succinylcholine or supplemental doses after an initial intubating dose (e.g., in the case of an initial failure of intubation). The slowing of heart rate may result in the generation of ventricular dysrhythmias, which are further aggravated by elevations in potassium[37]. The administration of an anticholinergic such as atropine or glycopyrrolate will ameliorate both the bradycardia and excessive secretions in the mouth and upper airway (another problem of cholinergic stimulation)[15].

Malignant Hyperthermia. Malignant hyperthermia is a rare genetic disorder occurring in both adults and children, characterized by an uncontrolled release of cellular calcium creating a hypermetabolic state [102,103]. In extreme cases, the patient's temperature can rise as high as 110 degrees Fahrenheit [102]. The syndrome is triggered by the administration of volatile anesthesia inhalation agents or succinylcholine. A prior history of masseter muscle spasm has been noted in 20% to 30% of those with malignant hyperthermia and decreases the onset time of symptoms [103]. Though symptoms can occur immediately after the administration of a triggering agent, there can also be a significant delay. One 2014 study reviewing 477 reported cases of malignant hyperthermia showed its onset from 10 minutes to 75 minutes after the administration of succinylcholine [103]. The initial onset is characterized by an unexplained tachycardia, elevation of end tidal carbon dioxide, and elevation of body temperature. A history of malignant hyperthermia is an absolute contraindication to the use of succinylcholine.

Obese Patients. Obese patients frequently have airways that are difficult to manage, whether in the inpatient environment, in the operating room, or in the field during prehospital rescue or resuscitation. Succinylcholine has been used to help facilitate endotracheal intubation in these patients primarily because of its ability to wear off quickly in the event of failed airway management, allowing the patient to breathe spontaneously [16,49]. Succinylcholine should be administered to adult patients using total body weight, rather than ideal body weight, at a dose of 1 mg/kg [33,49]. This use of total body weight to calculate dose is also appropriate for obese adolescents [107]. It is important to remember that these doses result in both rapid onset and somewhat prolonged activity, with duration increasing to approximately 12 minutes [49].

Trauma Patients. In both the inpatient emergency setting and the prehospital setting, succinylcholine has been successfully administered to facilitate intubation of the critically ill or injured patient. In the Eastern Association for the Surgery of Trauma practice guideline, succinylcholine is described as the neuromuscular blocking agent of choice for use in securing the airway via emergency intubation in the prehospital setting [108]. However, European literature has recommended rocuronium, which, with the advent sugammadex, can be readily reversed in a period as short as (or shorter than) the degradation period of succinylcholine [109].

Neuromuscular blocking agents are different from other classes of agents in many ways, but perhaps most exceptional is the ability to accurately and precisely track levels and degrees of neuromuscular blockade[15]. With most other agents, the patient's description is relied upon to determine efficacy (e.g., "My pain is less" or "My nausea is better"). Using a simple nerve stimulator (or "twitch monitor"), an anesthetized surgical patient or sedated intensive care patient can be precisely evaluated. Note that the sedation aspect in the description of these patients is important—as the frequency of the impulse rises, so does the degree of pain. An impulse of 50 Hz administered to produce tetany is quite painful, so patients being tested in such a fashion should be sedated or deemed insensate to pain secondary to severe injury or illness.

Monitoring of neuromuscular blockade could conceivably occur anywhere that a motor nerve is close enough to the skin that it may be stimulated [16]. Most practitioners, however, use either the adductor pollicis muscle in the patient's forearm and wrist (Image 2) or the orbicularis oculi muscles surrounding the eye in the face (Image 3). Both Image 2 and Image 3 show the correct placement of the electrodes on the forearm (in the case of the adductor pollicis) or over the temporal branch of the facial nerve (cranial nerve VII), stimulation of which results in twitches around the eye. In addition, Image 2 shows a comparison of the thumb in the relaxed mode and the contracted mode. The orbicularis oculi may be used if the practitioner cannot gain access to the patient's arms (e.g., due to injury or positioning for surgery). The use of the orbicularis oculi has been shown to be as effective as the adductor pollicis in determining adequate muscle relaxation for endotracheal intubation[114].

Upon release from the prejunctional neuron at the neuromuscular junction, acetylcholine rapidly crosses the synaptic space and binds with the nicotinic acetylcholine receptor on the muscle membrane. The synaptic cleft, however, is also lined with acetylcholinesterase that has the function of breaking down acetylcholine. This breakdown happens very quickly, usually within 80 to 100 microseconds [116]. In order to overcome this rapid breakdown and to allow the neurotransmitter sufficient time to build up to a level at which it can compete with the nondepolarizing drug, the acetylcholinesterase must be temporarily degraded. There are three commonly used anti-acetylcholinesterase agents that will accomplish this task: edrophonium, neostigmine, and pyridostigmine. Of these three, neostigmine is the one used most frequently for the reversal of neuromuscular blockade induced by a nondepolarizing agent.

Sugammadex is the newest reversal drug to come on the market, and it has been described as "revolutionary" [36]. It was approved for use in the United States by the FDA in 2015 [36]. Prior to this, it was used successfully in Europe for nearly a decade. Sugammadex is described as a cyclodextrin with a hydrophobic interior and hydrophilic exterior [124]. Its structure allows other hydrophobic agents to enter the center of the molecule and prevent the agent from binding with the receptor. The drug was designed to have a specific affinity for the nondepolarizing agents rocuronium and vecuronium [125]. It differs from other neuromuscular block reversal agents in that it inactivates the nondepolarizing drug while leaving acetylcholinesterase unaffected. As sugammadex combines with the amino-steroid nondepolarizers, there are fewer free nondepolarizing agent molecules available to bind with the nicotinic receptor. This in turn allows the increased binding of acetylcholine and a return to normal muscle function [36]. One of the shortcomings of this drug is that it does not work to reverse blocks from cisatracurium, atracurium, or succinylcholine [36].

Another significant problem that may occur in ICU patients receiving muscle relaxants is the phenomenon of ICU-acquired weakness. This weakness may be nerve-centered (critical illness polyneuropathy) or muscle-centered (critical illness myopathy) [140]. One study reports an incidence of between 24% and 77% in patients with stays in the ICU as short as one week, and men appear to be twice as likely to experience this as women [140,141]. The nature and role of neuromuscular blocking in aggravating or preventing this weakness is still under consideration. One study, for example, found that cisatracurium had no effect on the development or exacerbation of ICU-acquired weakness [140]. A contrary view states that the risk of myopathy increases with the concomitant administration of corticosteroids and neuromuscular blockers [138]. From this perspective, the institution of "drug-free holidays" during which neuromuscular blockers are allowed to completely wear off, as verified by the PNS, may be warranted. Their findings were echoed by other researchers, who identified prolonged neuromuscular blockade as a risk factor for prolonged weakness [141]. These researchers recommended the same drug-free holidays, as well as the use of an infusion to keep the dose at a sufficient level to allow a TOF of two twitches, with regular PNS monitoring.