Reversal (Antagonism) of Neuromuscular Blockade Miller.pdf

28 Reversal (Antagonism) of Neuromuscular Blockade GLENN MURPHY, HANS D. DE BOER, LARS I. ERIKSSON, AND RONALD D. MILLER KEY POINTS...

28 Reversal (Antagonism) of Neuromuscular Blockade GLENN MURPHY, HANS D. DE BOER, LARS I. ERIKSSON, AND RONALD D. MILLER KEY POINTS □  ppropriate reversal of a nondepolarizing neuromuscular blockade is essential to avoid adverse A patient outcomes. Complete recovery of muscle strength should be present, and the residual effects of neuromuscular blocking drugs (NMBDs) should be fully pharmacologically reversed (or spontaneously recovered). □ Sufficient recovery from neuromuscular blockade for tracheal extubation can be confirmed by an adductor pollicis train-of-four (TOF) ratio of at least 0.90 (or 1.0 if acceleromyography [AMG] is used). Quantitative neuromuscular monitoring is the only method of assessing whether a safe level of recovery of muscular function has occurred. □ Residual neuromuscular blockade is not a rare event in the postanesthesia care unit (PACU). Ap- proximately 30% to 50% of patients can have TOF ratios less than 0.90 following surgery. □ Patients with TOF ratios less than 0.90 in the PACU are at increased risk for hypoxemic events, impaired control of breathing during hypoxia, airway obstruction, postoperative pulmonary complications, symptoms of muscle weakness, and prolonged PACU admission times. Appro- priate management of neuromuscular blockade can decrease the incidence of, or eliminate, residual blockade, which will reduce the risks of these adverse postoperative events. □ Neostigmine, pyridostigmine, and edrophonium inhibit the breakdown of acetylcholine, result- ing in an increase in acetylcholine in the neuromuscular junction. However, there is a “ceiling” effect to the maximal concentration of acetylcholine that can be achieved with these drugs. Re- versal of neuromuscular blockade with anticholinesterases should not be attempted until some evidence of spontaneous recovery is present. Neostigmine in the dose range of 30 to 70 μg/ kg body weight antagonizes moderate to shallow levels of neuromuscular blockade. However, if these reversal drugs are given in the presence of full neuromuscular recovery, paradoxical muscle weakness theoretically may be induced. □ Sugammadex is a modified γ-cyclodextrin that shows a high affinity for the steroidal NMBDs rocuronium and vecuronium. Sugammadex is able to form a tight inclusion complex with either of these steroidal NMBDs, thereby inactivating the effects of rocuronium and vecuronium, resulting in rapid reversal of neuromuscular blockade. □ Sugammadex is able to reverse a moderate/shallow and a profound neuromuscular blockade with a dose of 2.0 mg/kg and 4.0 mg/kg, respectively. An immediate reversal of neuromuscular blockade induced by rocuronium is possible with a dose of sugammadex 16 mg/kg. Reversal of neuromuscular blockade by sugammadex is rapid and without many of the side effects encoun- tered with anticholinesterase drugs. □ Fumarates (gantacurium [GW280430A, AV430A], CW002, and CW011) represent a new class of NMBDs in development that are inactivated primarily via adduction of cysteine to the double bond of the compounds, resulting in inactive breakdown products. Laboratory studies have shown that the administration of exogenous l-cysteine results in complete reversal of deep neuromuscular blockade within 2 to 3 minutes. History Investigations from these same laboratories demonstrated that eserine (physostigmine)-like substances could reverse The paralytic effects of curare have been recognized since the effects of curare at the neuromuscular junction of frog the time of Sir Walter Raleigh’s voyage on the Amazon in nerve-muscle preparations.2 In the clinical setting, Ben- 1595.1 In 1935, the name d-tubocurarine was assigned nett (1940) described the use of curare in the prevention to an alkaloid isolated from a South American vine (Chon- of traumatic complications during convulsive shock ther- drodendron tomentosum). At approximately the same time, apy.3 In l942, Griffith and colleagues reported on the effects experiments from pharmacology and physiology labo- of an extract of curare in 25 surgical patients; all patients ratories in London suggested that acetylcholine was the appeared to recover fully without administration of an chemical neurotransmitter at motor nerve endings.2 antagonist such as neostigmine.4 832 Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on June 02, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved.  28 Reversal (Antagonism) of Neuromuscular Blockade 833 The importance of pharmacologic reversal of neuromus- a continued frequent incidence of residual neuromuscu- cular blockade was suggested in 1945. Specifically, use of lar blockade, more-recent surveys indicate that attitudes neostigmine or physostigmine to antagonize curare was toward reversal of neuromuscular blockade have changed recognized and was recommended to be available when- little over the intervening decades. A questionnaire sent to ever muscle relaxants were given in the operating room.5 German anesthesiologists in 2003 revealed routine reversal The first large case series examining the use of curare was with neostigmine at the end of surgery was not practiced in published by Cecil Gray in 1946.1 A crystalline extract, 75% of anesthesia departments.8 A similar survey of 1230 d-tubocurarine chloride, was administered in 1049 general senior anesthetists in France reported that pharmacologic anesthesia cases. No postoperative complications directly antagonism of neuromuscular blockade was “systematic” attributable to d-tubocurarine were noted, and physostig- or “frequent” in only 6% and 26% of surgical cases, respec- mine was administered to only two patients in the series. tively.9 In contrast, reversal of nondepolarizing NMBDs was However, in a later review article (1959) from the same routinely performed in Great Britain.10 anesthesia department, the authors concluded that “it is A large-scale, comprehensive survey of neuromuscular safer to always use neostigmine when nondepolarizing management practices in the United States and Europe was relaxants have been administered.”6 By the mid-1960s, conducted in order to better understand attitudes about significant differences in neuromuscular management doses of NMBDs, monitoring, and pharmacologic rever- existed between the United States and Europe. As noted in sal.11 Only 18% of European respondents and 34.2% of an editorial from this time, “In Great Britain the majority of respondents from the United States “always” administered anesthetists have arbitrarily adopted the attitude that the an anticholinesterase drug when a nondepolarizing relax- dangers of reversal are far less than those of latent paresis, ant was used. The findings from these surveys suggest that so that most patients receive at least some anticholines- there is little agreement about best practices related to rever- terase drug at the end of anesthesia.” In the United States, sal of neuromuscular blockade. Despite perioperative guide- however, where smaller doses of curare were used, the lines from several international and national organizations, emphasis was more on the mortality and morbidity associ- surveys from many countries reveal that most clinicians do ated with reversal drugs. Of greater importance was the use not monitor or reverse a neuromuscular blockade in the of muscle relaxants in smaller doses so that reversal drugs operating room. Surprisingly, most anesthesiologists have were not necessary.7 In fact, in the senior author’s training not witnessed obvious adverse events directly attributable (Miller), the prevailing thinking was that emphasis in anes- to incomplete recovery from neuromuscular blockade.11 thesia should be on “properly anesthetizing rather than Therefore the potential hazards of reversal of neuromuscu- paralyzing” a patient; it was commonly said that “curare is lar blockade using an anticholinesterase drug (see later) are not an anesthetic.” likely estimated to be more frequent than the risks of resid- Despite more than seven decades of research, significant ual neuromuscular blockade. In the following sections, the differences in opinion still exist regarding management of definitions, incidence, and clinical implications of residual neuromuscular blockade at the conclusion of surgery and neuromuscular blockade are reviewed. anesthesia. On a routine basis, some clinicians pharma- cologically antagonize a nondepolarizing neuromuscular RESIDUAL NEUROMUSCULAR BLOCKADE blocking drug (NMBD), whereas others antagonize neu- romuscular blockade only when obvious clinical muscle Assessment of Residual Neuromuscular Blockade weakness is present. The issue is whether clinically impor- In order to optimize patient safety, tracheal extubation in tant weakness exists when it is not clinically apparent. Will the operating room should not occur until complete recov- monitoring of neuromuscular blockade improve patient ery of muscle strength is present and the residual effects care? The aim of this chapter is to review the consequences of NMBDs have been fully reversed (or spontaneously of incomplete neuromuscular recovery, the use of anticho- recovered). Therefore methods to detect and treat residual linesterase drugs in clinical practice (benefits, risks, and muscle weakness are essential in improving postoperative limitations), and the recent developments in novel drugs to outcomes. Three methods are commonly used in the oper- reverse/antagonize residual neuromuscular blockade. ating room to determine the presence or absence of residual neuromuscular blockade: clinical evaluations for signs of muscle weakness, qualitative neuromuscular monitors Antagonism of Neuromuscular (peripheral nerve stimulators), and quantitative (objective) neuromuscular monitors. A more detailed description of Blockade: Current Management the types of neuromuscular monitors used perioperatively Practices is provided in Chapter 43. A number of survey studies have been conducted to deter- Clinical Evaluation for Signs of Muscle Weakness. mine how clinicians evaluate and manage neuromuscular Following the introduction of d-tubocurarine into clinical blockade in the perioperative period. In the late 1950s, a practice, residual paralysis and the need for neostigmine survey was sent to anesthetists in Great Britain and Ire- was determined primarily by the observation of “shallow, land.6 Forty-four percent of the respondents used neostig- jerky movements of the diaphragm” at the end of sur- mine “always” or “almost always” when d-tubocurarine gery.12 In the absence of any clinically observable respira- chloride or gallamine was used. Two thirds of respon- tory impairment, neuromuscular function was assumed dents administered 1.25 to 2.5 mg when antagonizing to be adequate, and no reversal drugs were administered. these NMBDs.6 Despite accumulating data demonstrating A peripheral nerve stimulator to assess neuromuscular Downloaded for Vicente Gonzalez ([email protected]) at Florida International University from ClinicalKey.com by Elsevier on June 02, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved. 834 SECTION II Anesthetic Physiology TABLE 28.1 Sensitivity, Specificity, Positive, and Negative Predictive Values of an Individual Clinical Test for a Train-of-Four