Publisher And Editor-in-Chief FRANK MOYA, MD Coral Gables, Florida EDITORIAL BOARD ADVISORY BOARD. Charles Barton, MSN, MEd Akron, Ohio

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2 Publisher And Editor-in-Chief FRANK MOYA, MD Coral Gables, Florida EDITORIAL BOARD ADVISORY BOARD Chuck Biddle, CRNA, PhD Richmond, Virginia Monte Lichtiger, MD Coral Gables, Florida Charles Barton, MSN, MEd Akron, Ohio Frank T. Maziarski, CRNA Seattle, Washington Linda Callahan, CRNA, PhD Klamath Falls, Oregon Nancy Gaskey-Spears, CRNA, PhD Gastonbury, Connecticut Joseph A. Joyce, CRNA, BS Winston-Salem, North Carolina Mary Jeanette Mannino, CRNA, JD Laguna Niguel, California Maria Garcia-Otero, CRNA, PhD Coral Gables, Florida Sandra Ouellette, CRNA Winston-Salem, North Carolina Carol G. Elliott, CRNA, MPA, PhD Kansas City, Kansas Linda J. Kovitch, CRNA, MSN Bedford, Massachusetts Charles Moss, CRNA, MS Westcliffe, Colorado Laura Wild, CRNA, MSN Pennington, New Jersey Associate Publishers Joan McNulty Elizabeth Moya, JD Assistant Editor Linda G. Williams Assistant Publishers Barbara McNulty Donna Scott Circulation Assistants Carrie Scott Tiffany Lazarich Myriam Montes Kimberly Gutierrez Sponsor - Frank Moya Continuing Education Programs, LLC Subscription Office - Editorial Office Current Reviews Frank Moya, M.D S.E. First Avenue 1450 Madruga Ave Ft. Lauderdale, FL Suite 207 Phone: (954) Coral Gables, FL Fax: (800) info@currentreviews.com Accreditation This program has been prior approved by the American Association of Nurse Anesthetists for 26 Class A CE credits; Code Number 33803; Expiration Date May 31, Approved by Frank Moya Continuing Education Programs, LLC. Provider approved by the California Board of Registered Nursing, Provider Number CEP 1754, for 26 contact hours and Florida Board of Nursing, Provider Number FBN 2210 for 26 contact hours. In Accordance with AANA directives, you must get 80% of the answers correct to receive one credit for each lesson and if there is a failure, there is no retaking. Disclosure Policy Frank Moya Continuing Education Programs, LLC, in accordance with the Accreditation Council for the Continuing Medical Education s (ACCME) Standards for Commercial Support, will disclose the existence of any relevant financial relationship a faculty member, the sponsor or anyone else who may be in a position to control the content of this Activity has with any commercial interest. BEFORE STARTING, PLEASE SEE LAST PAGE OF LESSON TO READ WHETHER THERE ARE ANY RELEVANT RELATIONSHIPS TO DISCLOSE AND, IF SO, THE DETAILS OF THOSE RELATIONSHIPS. Current Reviews is intended to provide it s subscribers with information that is relevant to anesthesia providers. However, the information published herein reflects the opinions of it s authors and does not represent the views of Current Reviews in Clinical Anesthesia, Current Reviews for Nurse Anesthetists, or Frank Moya Continuing Education Programs, LLC. Anesthesia practitioners must utilize their knowledge, training and experience in their clinical practice of anesthesiology. No single publication should be relied upon as the proper way to care for patients. The information presented herein does not guarantee competency or proficiency in the performance of procedures discussed. Copyright 2016 by Current Reviews. Reproduction in whole or in part prohibited except by written permission. All rights reserved. Information has been obtained from sources believed to be reliable, but it s accuracy and completeness, and that of the opinions based therein are not guaranteed. Printed in U.S.A. Current Reviews is published biweekly by Current Reviews, 1828 S.E. First Avenue, Ft. Lauderdale, FL POSTMASTER: Send address changes to Current Reviews, 1828 S.E. First Avenue, Ft. Lauderdale, FL or info@currentreviews.com.

3 Reversal of Neuromuscular Blockade: Updates and Guidelines Jeffrey B. Dobyns, DO Assistant Professor of Anesthesiology and Perioperative Medicine Associate Medical Director, Preoperative Assessment, Consultation, and Treatment Clinics University of Alabama at Birmingham School of Medicine Birmingham, Alabama LESSON OBJECTIVES Upon completion of this lesson, the reader should be able to: 1. Define postoperative residual paralysis (PORP) and discuss its incidence. 2. Identify patient, clinician, and drug risk factors for the development of PORP. 3. Associate the relevance of PORP to clinical practice. 4. Compare and contrast different monitors of neuromuscular function. 5. Discuss the consequences of inadequate reversal of neuromuscular blocking agents. 6. Review the different modes of the peripheral nerve stimulator. 7. Formulate a logical approach to the patient with PORP in the PACU. 8. Integrate strategies to reduce the incidence of PORP in clinical practice. 9. Appropriately dose neuromuscular blocking agents and reversal medications. 10. Review the side effects of the anticholinesterase medications. Current Reviews for Nurse Anesthetists designates this lesson for 1 CE contact hour in clinical pharmacology/therapeutics. Introduction Incomplete recovery from neuromuscular blockade, termed postoperative residual paralysis (PORP), is a common problem in the post-anesthesia care unit (PACU). It is estimated that approximately 40% of patients admitted to the PACU exhibit a train-offour (TOF) ratio < 0.9. These recent data also demonstrate that residual neuromuscular block is an important patient safety issue and that neuromuscular blockade management affects postoperative outcomes. A 1954 study published by Beecher and Todd reported perioperative deaths from the years , and observed a 6-fold increase in death in surgeries where neuromuscular blocking agents (NMBAs) were used. This was twice the incidence of deaths attributed to ether! The authors opined that these deaths were not attributable to overuse or misuse of the medication, which at the time included tubocurarine, metocurine, and gallamine, but rather to circulatory and respiratory failure. Considerable advancements and developments occurred over the next 50 years, and second and third generation NMBAs have much more stable hemodynamic profiles and more predictable onset and offset times. The introduction of quantitative and qualitative NMBA monitoring devices has further improved their safety and efficacy. Despite these advancements, PORP continues to be a common and undetected problem in the early postoperative period. Curr Rev Nurs Anesth 39(6):73-88,

4 Background Information Definition The definition of PORP continues to evolve, but is most simply defined as the presence of signs or symptoms of muscle weakness in the postoperative period after the intraoperative administration of an NMBA. In the 1970s, studies conducted in human volunteers established that a TOF ratio > 0.7 was associated with clinically acceptable values for vital capacity, inspiratory force, and peak expiratory flow rates. For the next 20 years, the gold standard of adequate neuromuscular blockade reversal was considered to be a TOF ratio > 0.7. More recent studies in human volunteers have demonstrated that TOF ratios of are associated with impaired airway protective reflexes, upper airway obstruction, decreased hypoxic ventilatory drive, and clinical symptoms of muscle weakness. Hypoxic ventilatory drive was shown to be decreased by vecuronium up to a TOF ratio of > 0.9. The ability to swallow was impaired when TOF ratio was < 0.9. Masseter muscle function, as assessed by the ability to hold a tongue depressor between the teeth against resistance did not return to normal until the TOF ratio was between The new gold standard indicating adequate neuromuscular blockade (NMB) reversal is now a TOF ratio > 0.9, and a TOF ratio < 0.9 is indicative of inadequate NMB reversal. Incidence The incidence of PORP varies widely, from 2-85%, depending on the definition used. In 1979, Viby-Mogenson and colleagues found that 42% of patients who were administered a long-acting NMB with reversal presented to the PACU with a TOF ratio < 0.7. Studies from the 1980s documented an incidence of 21-36% of patients with TOF ratios < 0.7 on arrival to PACU, and three large trials in the 1990s found that 30-60% of patients presented to PACU with TOF ratios < 0.9. A meta-analysis in 2007 that analyzed studies from 1979 through 2005 found that the incidence of PORP was higher in patients who received long-acting NMBAs compared to those who received intermediate-acting agents. The overall incidence was difficult to quantify because some studies defined PORP as TOF ratio < 0.7 while others used a TOF ratio < 0.9. The incidence is greater with the less stringent definition. A Portuguese study from 2013 found that 26% of patients studied arrived in the PACU with a TOF ratio of < 0.9. Rocuronium was used in 43% of patients and cisatracurium in 32%. A study from 2011 found an incidence of PORP to be 52% with rocuronium being the most commonly associated NMB. While rocuronium was most associated with PORP, the association was not statistically significant. Risk Factors for PORP Risk factors for PORP can be divided into patient risk factors, drug risk factors, and clinician risk factors (Table 1). Inter-patient variability is a considerable factor in patient response to NMBAs and makes reliably predicting peak effect and recovery time difficult. Consequently, Table 1 Risk Factors for PORP Patient Risk Factors # Inter-patient variability # Neuromuscular disease # Respiratory disease # Obstructive sleep apnea # Elderly # Morbid obesity # Female Clinician Risk Factors # Under-appreciation of PORP # Under-dosing of reversal medication Sugammadex total body weight Neostigmine total body weight # Reversal medication not given # Failure/improper use of monitor of neuromuscular function # Monitoring incorrect muscle group # Excessive/indiscriminate dosing of NMBA Nondepolarizers ideal body weight Succinylcholine total body weight # Adherence to personal and local customs for dosing and monitoring Drug Risk Factors # Long-acting versus intermediate-acting NMBA # Bolus versus infusion administration # Potentiation by other medications Inhalational anesthetics Propofol Thiazide diuretics Calcium channel blockers Anti-arrhythmic drugs Aminoglycoside antibiotics Corticosteroids Oral contraceptives Magnesium Lithium # Altered pharmacokinetics/pharmacodynamics due to patient co-morbidities Sepsis Acidosis Hypothermia Hypokalemia 76 Current Reviews for Nurse Anesthetists

5 patient risk factors are a significant contributor to PORP. In the US, anesthesia providers are limited to the use of neostigmine for reversal of NMB. Pyridostigmine is available in intravenous form but is seldom used for this purpose, so discussion here will focus on neostigmine. Neostigmine indirectly inhibits acetylcholinesterase (ACHE) at the neuromuscular junction. It also has a ceiling effect, in that once the enzyme is 100% inhibited, no further benefit is derived from increased dosing. The ceiling effect is generally reached at doses of mg/kg. If the initial reversal dose is unsuccessful, a second dose is not likely to be helpful, assuming it was properly dosed. Neostigmine is associated with a high incidence of nausea and vomiting and undesired autonomic effects. Because the time of onset and time to antagonism of block with neostigmine is not influenced by total body weight or body mass index, neostigmine can be dosed based on total body weight. Dosing based on ideal body weight with intent of minimizing side effects, in particular nausea and vomiting, may result in under-dosing and predispose to PORP. The gold standard of adequate NMB reversal is a TOF ratio of > 0.9. Clinician risk factors involve the under-appreciation of the incidence of PORP and its potential consequences, and can frequently be attributed to pressures of production and efficiency. Anesthesia providers may become complacent with the use of one or two NMBAs and forego monitoring, or may monitor inadequate muscle groups, such as the facial muscles, which do not correlate well with the recovery of upper airway muscles or the response of the adductor pollicis. Production pressures may result in reliance on subjective clinical signs such as head lift or hand grasp, both of which correlate poorly with upper airway muscle function. It is important to remember that the absence of detectable TOF fade does not guarantee the adequacy of recovered neuromuscular function. Human Factors and the Risk of PORP Several studies document that visual or tactile evaluation of the TOF ratio, such as observation of TOF number or feeling of fade in the thumb, correlate poorly with the TOF ratio measured by quantitative means, such as acceleromyography (see Modes of Peripheral Nerve Stimulation and Table 3 below). Even highly experienced clinicians and scientists are unable to detect TOF fade visually or palpably, when the quantitative measured TOF ratio exceeds 0.4. Plaud and colleagues refer to this as the zone of blind paralysis, implying that between TOF ratios of 0.4 and 0.9, residual paralysis goes undetected. This zone can be narrowed slightly with the use of double burst stimulation (DBS), but detectable fade with this modality is only to a ratio of 0.6. The specificity of TOF and DBS are good at 98-99%, but the sensitivity is poor at 11% and 14%, respectively. Posttetanic fade following a 100-Hz stimulus can be detected at a TOF ratio of , making it a somewhat more sensitive test. Roughly translated, patients may have significant residual paralysis even though the results of the TOF, DBS, and clinical signs of recovery may lead the anesthesia team to assume full recovery of neuromuscular function. PORP is a significant threat to patient safety. PORP An Underappreciated Issue of Patient Safety In July 2010, Naguib and colleagues published the results of their internet-based survey of anesthesia practitioners in the US and Europe. The survey was conducted to ascertain the clinical practice and attitudes concerning the perceived incidence and severity of PORP, and the frequency with which NMB monitoring is used in daily practice. The majority of those surveyed, both in the US and Europe, denied having ever observed a patient with clinically significant PORP in the PACU. The majority also overwhelmingly agreed that PORP is a significant issue of patient safety and that the routine use of a conventional nerve stimulator or quantitative TOF monitor would further decrease its incidence, which they believed to be < 1%. TOF monitors were reported to be widely available in the operating room. While 53% of European responders routinely used quantitative TOF monitors, only 19% of US responders did so. Conversely, 63% of US and 17% of European responders acknowledged using a conventional (qualitative) twitch monitor. The majority also acknowledged not routinely administering an ACHE inhibitor at the end of a surgery in which an NMBA had been given. When queried further, concern for nausea and vomiting from the ACHE inhibitor was the number one reason for not administering reversal, with concerns about PORP actually being third on the list behind hemodynamic effects. The majority of US responders also felt that a sustained 5-second head lift was a reliable indicator of adequate recovery. The problem of PORP and the need for routine reversal of NMBAs is not new. In 1953, Morris and colleagues advocated the routine administration of ACHE inhibitors following the intraoperative use of curare. Given the absence of conventional twitch monitors at the time, the 5-second sustained head lift was assumed to be indicative of adequate reversal, Curr Rev Nurs Anesth 39(6):73-88,

6 Table 2 Side Effects of Acetylcholinesterase (ACHE) Inhibitors Cardiovascular # Hypotension # Bradycardia # Junctional rhythm # AV block Pulmonary # Bronchorrhea # Bronchospasm # Hypoxia Gastrointestinal # Increased GI motility # Increased GI secretions # Defecation # Nausea and vomiting Eye # Lacrimation # Miosis # Decreased intraocular pressure Other # Urination # Increased sweating # Muscle fasciculations an assumption since proven inaccurate. In fact, a sustained 5-second head lift, while corresponding to maximum inspiratory pressures of cmh2o, actually correlate with a TOF ratio of 0.45 to 0.75, well below the recommended ratio of 0.9. In the following decades, considerable data has demonstrated that PORP continues to be a common and serious patient safety problem despite the availability of monitors of neuromuscular function, medication advancements, and an enhanced awareness of the issue. The unanswered question is why this preventable problem continues to occur. ASPF Position The Anesthesia Patient Safety Foundation (APSF) strongly believes that PORP is responsible for many of the adverse respiratory events seen in the PACU that are often attributed to opioids. The APSF advocates that every patient administered an NMBA should have quantitative (i.e., objective, or twitch height measurement) monitoring of block intensity during the procedure and prior to extubation. Additionally, all patients administered NMBAs should have reversal medications administered based upon the results of the quantitative monitoring. The APSF is currently working with the ASA Committee on Standards and Practice Parameters to develop evidence-based clinical practice guidelines to decrease its incidence and adverse effects. Medications Used for NMB Reversal Acetylcholinesterase Inhibitors ACHE inhibitors are not effective in reversing deep NMB. They are associated with many adverse autonomic effects due to excess acetylcholine, necessitating co-administration with an anticholinergic agent such as glycopyrrolate (Table 2). When administered in the absence of NMB, they can themselves exhibit clinical features of NMB, such as upper airway muscle impairment, genioglossus muscle weakness, impaired diaphragm function, and an increased risk of respiratory complications. The majority of anesthesia providers underestimate the incidence of PORP. Sugammadex Sugammadex is a -cyclodextrin agent that selectively binds to rocuronium and vecuronium. Its mechanism of action is by irreversible 1:1 encapsulation of the molecules of the NMBAs (rocuronium > vecuronium >> pancuronium), thereby directly inactivating them. It is ineffective against benzylisoquinolines and succinylcholine. Sugammadex binds to free rocuronium in the plasma, decreasing the free concentration, creating a concentration gradient, which promotes further movement of rocuronium away from the neuromuscular junction and back into the plasma for inactivation. The encapsulated complex is then excreted unchanged in the urine. With appropriate dosing, sugammadex is capable of reversing a deep block induced by an intubating dose of rocuronium within 3-5 minutes, even from a TOF ratio of zero, and without the adverse autonomic effects seen with the ACHE inhibitors. Several studies demonstrated that dosing sugammadex based on 2 mg/kg ideal body weight was inadequate to achieve reversal. Miller s Anesthesia therefore recommends that sugammadex be dosed based on total body weight. The rapidity of block reversal is particularly relevant in the unanticipated difficult airway or can tintubate-can t-ventilate situations. It is also beneficial in the ambulatory surgery center, where patients administered sugammadex were ready for discharge sooner than those given neostigmine. Numerous clinical trials demonstrate an advantage of sugammadex over the ACHE inhibitors for reversal of NMB. Given its mechanism of action, it seems reasonable to conclude that NMB intensity 78 Current Reviews for Nurse Anesthetists

7 need not be monitored intraoperatively. This is not the case, as studies demonstrate the occurrence of PORP can be as high as 10% in patients administered sugammadex in the absence of NMB monitoring. This underscores the need for monitoring TOF even when the use of sugammadex is anticipated, as the effectiveness of sugammadex is dependent on the dose of the NMBA. As of the time of this writing, sugammadex is not approved by the FDA for clinical use in the US. This is both surprising and disappointing to the anesthesiology community given the overwhelming positive results in clinical trials and the successful use of sugammadex in Europe and Asia since The reasons cited are continued concerns over the development of hypersensitivity and allergic reactions in certain patients, as well as possible concerns with bone healing and tooth enamel erosion. Sugammadex is not an allergen and does not stimulate histamine release. Monitors of Neuromuscular Function There are four clinically used monitors of neuromuscular function, with visual and tactile methods and electromyography being the most commonly used. Table 3 describes these monitors in greater detail. Sustained 5-second head lift does not correlate with adequate reversal of paralysis. Modes of Peripheral Nerve Stimulation Nondepolarizing NMBs In the single twitch mode, an electrical pulse is delivered at 1 Hz, and the ratio of the evoked twitch is compared with that of a twitch obtained prior to muscle relaxation. When 75% of the acetylcholine receptors on the postsynaptic membrane are occupied by an NMBA, twitch magnitude starts to decrease. When there are 100% of ACH receptors blocked, no twitch is elicited. In the train-of-four mode, four stimuli are given at a frequency of 2 Hz, potentially eliciting four twitches, so named T1-T 4. The ratio of T 4 to T 1 gives an indication of the degree of neuromuscular block. The number of elicited twitches indicates the degree of ACH receptor occupancy. Disappearance of T 4, T 3, T 2, and T 1 corresponds to receptor occupancy of 75%, 80%, 90%, and 100%. The twitches appear in reverse order as neuromuscular function recovers. Double burst stimulation (DBS) consists of two bursts of three stimuli at 50 Hz with each triple burst separated by 750 milliseconds. These will be palpable as two discrete stimuli, labeled T 1 and T 2. The ratio relates to the TOF ratio, and is easier for the practitioner to discern. Tetanic stimulation occurs at 50 Hz for 5 seconds and produces detectable fade in muscle contraction. The degree of fade is related to the extent of the NMB. In profound NMB, no response is elicited. Post-tetanic facilitation (PTF) is a stimulation, single twitch, DBS or TOF, for 5 seconds that recruits presynaptic ACH. The number of twitches subsequently obtained reflects the degree of neuromuscular block. Table 3 Monitors of Neuromuscular Function Visual and Tactile Methods # Observation and palpation of a contracting muscle group, such as hand squeeze, head lift, or response to resistance # Easiest means of monitoring the depth of blockade # Least accurate # Subjective monitor Electromyography # Use of electrodes to record the muscle potential stimulated by the PNS # Ulnar nerve is typically used # Electrodes are placed over the motor point of the adductor pollicis muscle # Most commonly used method # Subjective or objective monitor, depending on how used Acceleromyography # Relies on the physics principle that force = mass x acceleration # Would therefore be inversely proportional to the intensity of NMB # Accurate results necessitate accurate and stable positioning of the monitored digit # Objective monitor Mechanomyography # Uses a strain gauge to measure the tension generated in a muscle # Small weight is suspended from the muscle to maintain isometric contraction and the tension produced on stimulation is converted to an electrical signal # Requires splinting of the hand for accurate results # Used most frequently in research # Objective monitor Curr Rev Nurs Anesth 39(6):73-88,

8 Depolarizing NMBs The depolarizing NMBAs produce equal but diminished twitches in response to single twitch and TOF stimulation, such that the TOF ratio is always 1.0. They produce a reduced but sustained contraction with tetanic stimulation, and demonstrate neither tetanic fade nor PTF. Consequences of Inadequate NMB Reversal Poor surgical outcomes are multifactorial in nature. That being said, there is considerable evidence demonstrating a relationship between poor surgical outcomes and TOF ratios of < 0.9 on arrival to PACU. Table 4 Symptoms of Weakness Subjective Symptoms # TOF was associated with Diplopia and visual disturbances Decreased grip strength Inability to maintain incisor teeth apposition Inability to sit without assistance Severe facial weakness Difficulty speaking and drinking Generalized weakness # TOF was associated with Generalized fatigue Visual disturbances and diplopia Diplopia and visual disturbances persisted for up to 90 minutes beyond the point at which the TOF ratio had recovered to 1.0 Objective Findings # TOF < 0.9 Impaired airway protective reflexes Upper airway obstruction Decreased hypoxic ventilatory response Generalized muscle weakness Impaired hypoxic ventilatory drive Impaired swallowing Reduced contraction and discoordination of pharyngeal muscles Diminished masseter muscle function Direct Physiologic Consequences Respiratory events are the most common complication associated with PORP. The disclaimer is that upper airway obstruction and respiratory impairment in the PACU is also multifactorial, and not singularly caused by residual paralysis. Hypoxic ventilatory drive (HVD) is significantly impaired by minor degrees of residual NMB. A study in human volunteers found that HVD was reduced by 30% in patients exposed to nondepolarizing muscle relaxants titrated to a TOF ratio of 0.7 and did not recover until the TOF ratio exceeded 0.9. The mechanism of HVD suppression has been thought to be due to impairment of carotid body chemoreceptor function by neuromuscular blocking drugs, secondary to nicotinic receptor blockade in the carotid body. As previously mentioned, certain respiratory parameters such as tidal volume, vital capacity, and inspiratory and expiratory force are clinically acceptable when the TOF ratio is > 0.7. Upper airway function and the ability to protect the airway however are greatly diminished at small levels of residual paralysis. Upper airway musculature, such as the genioglossus muscle, is significantly impaired at TOF of 0.8, as evidenced by impaired tongue protrusion. Arterial oxygen saturation was maintained at TOF > 0.8. Neuromuscular function should be monitored in every patient administered a NMBA. Impaired neuromuscular transmission, even to a degree insufficient to evoke respiratory symptoms, markedly impairs upper airway dimensions and function of the upper airway dilator muscles. At a TOF ratio of 0.8, swallowing function is significantly impaired. Video radiography and computerized pharyngeal manometry monitoring during contrast bolus swallowing at TOF ratios of 0.6, 0.7, 0.8, and 0.9 demonstrated that half of the volunteers aspirated the contrast material when the TOF ratio was < 0.9. Also noted was delayed initiation of the swallowing reflex, impairment of pharyngeal muscle coordination, and reduced force of contraction of the pharyngeal constrictor muscles. Subjective Symptoms of Weakness Patients who have been affected by postoperative residual NMB generally describe it as being rather unpleasant. Table 4 describes some of the subjective symptoms and objective findings of weakness experienced and the corresponding TOF level. Increased Morbidity and Mortality Increased morbidity and mortality has been documented in anesthetized patients with PORP (Table 5). Deaths attributable to anesthesia increased 10-fold when reversal medications were not given. 80 Current Reviews for Nurse Anesthetists

9 Table 5 PORP-related Morbidity and Mortality # Death # Permanent brain damage # Pulmonary complications # Upper airway obstruction # Severe hypoxemia # Respiratory failure necessitating reintubation # Aspiration Cost Residual paralysis is costly to both the patient and the healthcare institution. Times to PACU discharge were significantly longer in patients with a TOF ratio < 0.9 on arrival to PACU. Time to discharge readiness averaged 224 minutes in patients with a TOF ratio < 0.9 on admission to PACU versus 149 minutes in those with a TOF ratio > 0.9. In a study by Dimick and colleagues that looked at patients undergoing general or vascular surgery in t he in-patient setting, the average cost of treating respiratory complications following surgery is $62,704 versus a cost of $5,015 for a procedure in which a respiratory complication does not occur. These monetary values also consider the fact that the increased PACU stay results in a prolonged stay in the OR for other patients as they await PACU availability. spontaneous and medication-facilitated recovery from the NMBA. Laryngeal Mask Airway LMAs do not necessitate NMBAs for insertion and allow for maintenance of spontaneous ventilation throughout the procedure. Many studies show that LMA use shortens the duration of the procedure without adversely affecting surgical exposure or progress. NMB Dose, Choice, and Duration of Action The choice of NMB influences postoperative outcomes. Intermediate duration NMBAs have a greater profile of patient safety and PORP when compared with longer-acting agents. The use of intermediate-acting NMBAs, however, is still associated with PORP in up to two-thirds of patients who receive them intraoperatively. Benzylisoquinoline NMBAs, such as cisatracurium, have been shown to have a more predictable duration of action when compared with steroidal agents, such as rocuronium, an association particularly notable in elderly patients. There is, however, data to suggest that the risk of pulmonary complications occurs in a dosedependent fashion and regardless of which class of NMBA is used. High doses of NMBAs at 3-4 times ED 95, as when rocuronium is used for modified and rapid sequence inductions, will prolong the duration of action by % compared with normal dosing of 1-2 times ED 95. Succinylcholine, with its short duration of action and rapid onset, carries little risk of PORP, unless the patient is positive for pseudocholinesterase deficiency. Mivacurium, a short-acing nondepolarizing Sugammadex is associated with PORP when inadequately dosed. Length of Hospitalization The length of hospitalization averaged 19 days for surgeries with postoperative respiratory complications, rather than 5 days for those procedures without respiratory complications. Strategies to Reduce PORP Table 6 lists several strategies to reduce the incidence of PORP. Regional Anesthesia One of the benefits of incorporating regional anesthesia into a balanced anesthetic technique is the ability to use lower doses of multiple medications, thereby reducing the risk of adverse side effects of each. The motor block that results from regional anesthesia may eliminate the need for NMBAs entirely. Combining regional anesthesia with NMBAs without dose reduction delays both the Table 6 Strategies to Avoid PORP # Use a peripheral nerve stimulator # Avoid total paralysis (TOF = 0) # Do not attempt reversal with neostigmine until TOF > 2 # Monitor appropriate muscle group # Any detectable fade indicates inadequate reversal # Appropriately dose NMBA and reversal agent # Avoid infusions of NMBAs # Remember that clinical tests of adequate reversal (head lift, hand squeeze) are unreliable indicators of recovery # Use LMAs when appropriate # Consider regional anesthesia when appropriate Curr Rev Nurs Anesth 39(6):73-88,

10 NMBA out of production in the US, is metabolized in the same way. Use of short-acting NMBAs translate to increased patient safety and economical advantages for the OR and ambulatory surgery center. Succinylcholine is not without other risks, in that it may be contraindicated in patients with burns or neurologic disorders, and is a known trigger of malignant hyperthermia. These risks increase the appeal of the intermediate NMBAs, such as rocuronium, over succinylcholine. While succinylcholine is dosed based on total body weight, it is recommended that nondepolarizing NMBAs be dosed based on ideal body weight, in both obese and nonobese patients. Dosing of nondepolarizing NMBAs based on total body weight results in prolonged durations of action. Table 8 Treatment of PORP # Follow the ABCs of resuscitation # Confirm residual paralysis # Give reversal if not already given # Give additional reversal if underdosed Remember ceiling effect of ACHE inhibitors # Wait it out; keeping patient sedated and amnestic # Treat/consider potentiating factors that prolong NMB # Consider giving alternative reversal agent, such as sugammadex (if available) PORP is an eradicable problem. Clinical Practice Guidelines Table 7 offers guideline suggestions for individual practice. Table 8 offers treatment steps and differential diagnoses to consider when confronted with PORP in the PACU. Table 7 Suggestions for Clinical Practice # Use NMBAs only when indicated # Individualize dose to patient and surgical indication Dose NMBAs based on ideal body weight Dose neostigmine based on total body weight Dose sugammadex based on total body weight # Use intermediate- or short-acting NMBAs # Maintain appropriate depth of intraoperative paralysis # Administer neostigmine when there is evidence of spontaneous recovery, or following a shallow level of blockade Clinically and practically, this is a TOF level of 2 or 3 # Monitor depth of NMB, even when anticipating the use of sugammadex # Tactile detection of no fade does not mean reversal can be omitted # Even a TOF ratio of 0.9 is associated with increased morbidity Summary and Conclusion Despite the large amount of published literature over the past several decades, there continues to be confusion and debate among anesthesia providers concerning the proper use of NMBAs, proper monitoring techniques, and the criteria that indicate adequacy of reversal. While at least 75% of surveyed anesthesia providers acknowledge that PORP is a significant issue, the majority considers its incidence to be less than 1%, when in reality, the incidence can be as high as 60%, depending on the definition used. Respiratory parameters such as vital capacity, tidal volume, and inspiratory force are minimally affected when the TOF ratio is > 0.7. This may lead anesthesia providers to erroneously assume that neuromuscular function has adequately recovered, and they may seek confirmation in the form of a 5- second sustained head lift and hand grasps. These clinical findings do not correlate with quantitative measures of neuromuscular function. TOF ratios below 0.9 are associated with pharyngeal muscle weakness and an increased likelihood of aspiration, airway obstruction, hypoxia, and respiratory failure. Strong arguments are made for monitoring neuromuscular block intensity and reversal in all patients administered NMBAs, regardless of clinical evidence of adequate recovery. PORP is an eradicable problem that continues to be much too common. It is a critical issue of patient safety, and as such, it is important to minimize its occurrence. It delays patient recovery, hinders the efficiency of the OR and ambulatory care centers, and is associated with greatly increased healthcare costs and length of hospitalization. References Beecher HK, Todd DP. A study of the deaths associated with anesthesia and surgery: based on a study of 82 Current Reviews for Nurse Anesthetists

11 599,548 anesthesias in ten institutions , inclusive. Annals of Surgery 1954; 140(1):2-35. Butterly A, Bittner EA, George E, Sandberg WS, Eikermann M, Schmidt U. Postoperative residual curarization from intermediate-acting neuromuscular blocking agents delays recovery room discharge. Br J Anaesth 2010; 105(3): De Baerdemaeker LE, Mortier EP, Struys MM. Pharmacokinetics in obese patients. Continuing education in anaesthesia. Critical Care & Pain 2004; 4(5): Dimick JB, Chen SL, Taheri PA, Henderson WG, Khuri SF, Campbell DA, Jr. Hospital costs associated with surgical complications: a report from the private-sector National Surgical Quality Improvement Program. Journal American College of Surgeons 2004; 199(4): Eikermann M, Fassbender P, Malhotra A, et al. Unwarranted administration of acetylcholinesterase inhibitors can impair genioglossus and diaphragm muscle function. Anesthesiology 2007; 107(4): Farhan H, Duarte-Moreno I, McLean D, Eikermann M. Residual paralysis: does it influence outcome after ambulatory surgery? Current Anesthesiology Reports 2014; 4(4): Fujimoto M, Tanahira C, Nishi M, Yamamoto T. In non-obese patients, duration of action of rocuronium is directly correlated with body mass index. Can J Anaesth 2013; 60: Kotake Y, Ochiai R, Suzuki T, Ogawa S, Takagi S, Ozaki M, et al. Reversal with sugammadex in the absence of monitoring did not preclude residual neuromuscular block. Anesth Analg 2013; 117(2): Miller, RD. Miller's Anesthesia (7th Ed.). Philadelphia, PA, Churchill Livingstone/Elsevier, Moi D. Residual neuromuscular blockade. ATOTW 290, 8/26/2013, 1-8. Morris LE, Schilling EA, Frederickson EL. The use of tensilon with curare and nitrous oxide anesthesia. Anesthesiology 1953; 14(2): Murphy GS, Brull SJ. Residual neuromuscular block: lessons unlearned. Part I: definitions, incidence, and adverse physiologic effects of residual neuromuscular block. Anesth Analg 2010; 111(1): Naguib M, Kopman AF, Ensor JE. Neuromuscular monitoring and postoperative residual curarisation: a meta-analysis. Br J Anaesth 2007; 98(3): Naguib M, Kopman AF, Lien CA, Hunter JM, Lopez A, Brull SJ. A survey of current management of neuromuscular block in the United States and Europe. Anesth Analg 2010; 111(1): Pasic E, Castorena-Arellano G, Calderón-Vidal M. Incidence and risk factors for postoperative residual paralysis. Revista Mexicana de Anestesiología 2011; 34(4): Plaud B, Debaene B, Donati F, Marty J. Residual paralysis after emergence from anesthesia. Anesthesiology 2010; 112(4): Stoelting R. Residual drug-induced muscle weakness in the postoperative period: a patient safety issue. ASA Newsletter 2015; 79(2). Viby-Mogensen J, Jorgensen BC, Ording H. Residual curarization in the recovery room. Anesthesiology 1979; 50(6): Curr Rev Nurs Anesth 39(6):73-88,

12 Jeffrey B. Dobyns, DO Dr. Dobyns is an Assistant Professor of Anesthesiology and Perioperative Medicine at the University of Alabama at Birmingham School of Medicine. In 2015, he obtained Certification in Medical Quality by the American College of Medical Quality. He graduated from Bowling Green State University with a Bachelor of Science in Biology, with a specialization in cellular and molecular biology, the Ohio University College of Osteopathic Medicine and completed residency in Anesthesiology at the University of Toledo Medical Center in Toledo, Ohio, and the University of Colorado Health Sciences Center in Denver, Colorado. Dr. Dobyns clinical interests include Vascular and Neurosurgical Anesthesia, Perioperative Medicine, and medical education. He has consistently been named one of the Top 10 Teachers of the Year. He lives with his wife and three sons in Hoover, Alabama. Tips for your Clinical Practice: Key Points # TOF ratios of are associated with impaired airway protective reflexes, upper airway obstruction, decreased hypoxic ventilatory drive, and clinical symptoms of muscle weakness. # Anesthesia providers may be deluded by monitoring inadequate muscle groups (e.g., facial muscles) which do not correlate well with the recovery of upper airway muscles. # Tactile detection of no fade does not mean that NMB does not require reversal; reversal agents should be given to all patients who have received NMBAs. # Cholinesterase inhibitors are not effective in reversing deep NMB; administer these drugs only when there is some evidence of spontaneous recovery. # Sugammadex inactivates the molecules of steroidal NMBAs by encapsulation; the encapsulated complex is excreted in the urine. # Sugammadex is devoid of the adverse autonomic effects seen with cholinesterase inhibitors. Monte Lichtiger, MD Editor, Current Reviews 84 Current Reviews for Nurse Anesthetists

13 FRANK MOYA CONTINUING EDUCATION PROGRAMS, INC. & FACULTY DISCLOSURE THIS AUTHOR S AND FMCEP S SPECIFIC DISCLOSURES: The author / faculty has indicated that there is a relevant financial interest or relationship with UpToDate. The type of relationship is as follows: royalty. The author / faculty has indicated that, as appropriate, he/she has disclosed that a product is not labeled for the use under discussion, or is still under investigation. As a matter of policy, FMCEP does not have any relevant financial interest or relationship with any commercial interest. In addition, all members of the staff, Governing Board, Editorial Board and CME Committee who may have a role in planning this activity have indicated that there is no relevant financial interest or relationship with any commercial interest. Current Reviews is intended to provide its subscribers with information that is relevant to anesthesia providers. However, the information published herein reflects the opinions of its authors. Anesthesia practitioners must utilize their knowledge, training and experience in their clinical practice of anesthesiology. No single publication should be relied upon as the proper way to care for patients. DESIGNATON OF SPECIFIC CONTENT AREAS: Current Reviews for Nurse Anesthetists (CRNA) is designed to meet the standards and criteria of the American Association of Nurse Anesthetists (AANA) for the prior-approved continuing medical education activity, Provider-Directed Independent Study, also known as home study. CRNA is an approved program provider. CRNA has designated the lessons which meet specific content areas such as pharmacology, HIV/AIDS, etc. However, only the Board of Nursing of an individual State is the final authority in the determination of whether or not these lessons meet the State s licensure requirements. Curr Rev Nurs Anesth 39(6):73-88,

14 86 Current Reviews for Nurse Anesthetists NOTES

15 Register Now! 45th Annual Refresher Course for Nurse Anesthetists Hilton Resort, Walt Disney World Village November 11-13, 2016 Orlando, Florida 20 Class A Continuing Education Credits Speakers: John Aker, CRNA, DNAP Jeffrey Dobyns, DO Girish Joshi, MB, BS, MD, FFARSCI Mark Keegan, MB, MRCPI, MSc Rainer Lenhardt, MD, MBA Jerrold Lerman, MD, FRCPC, FANZCA 1828 SE First Avenue Fort Lauderdale, FL Phone: Fax:

16 MARK ONLY THE ONE BEST ANSWER PER QUESTION ON YOUR ANSWER CARD. MARK THIS PAGE AND KEEP FOR YOUR RECORDS. 6 In accordance with AANA directives, you must get 80% of the answers correct to receive one credit for each lesson, and if there is a failure, there is no retaking. POST-STUDY QUESTIONS 1. The present gold standard indicative of adequate neuromuscular blockade reversal is: G A. TOF ratio > 0.9. G B. Strong bilateral hand grasps. G C. G D. Sustained head lift of greater than 5 seconds. No detectable fade to peripheral nerve stimulation. 2. Sugammadex is MOST effective reversing the effects of which neuromuscular blocking agent: G A. Rocuronium. G B. Pancuronium. G C. Cisatracurium. G D. Succinylcholine. 3. A short-acting neuromuscular blocking agent is: G A. Rocuronium. G B. Mivacurium. G C. Pancuronium. G D. Cisatracurium. 4. The MOST COMMON COMPLICATION (not side effect) associated with PORP is/are: G A. Nausea and vomiting. G B. Visual disturbances. G C. Permanent brain damage. G D. Respiratory complications. 5. The LEAST accurate means of monitoring neuromuscular blockade is: G A. Electromyography. G B. Acceleromyography. G C. Mechanomyography. G D. Visual and tactile methods. 6. The percentage of acetylcholine receptors blocked at a TOF count of 3 (disappearance of T 4) is: G A. 75%. G B. 80%. G C. 90%. G D. 100%. 7. A side effect of anticholinesterase inhibitors is: G A. Tachycardia. G B. Constipation. G C. Miosis. G D. Dry eye. 8. Which of the following POTENTIATES the effect of nondepolarizing NMBAs: G A. Cefazolin. G B. Phenytoin. G C. Desflurane. G D. Metoprolol. 9. Sugammadex: G A. Is not associated with PORP. G B. Potentiates neuromuscular blockade. G C. Reverses the effects of succinylcholine. G D. Should be dosed based on total body weight. 10. A TOF ratio > 0.9 on arrival to PACU is associated with: G A. Increased healthcare costs. G B. Death or permanent brain damage. G C. Earlier PACU discharge readiness. G D. Increased length of hospitalization. Moving? Please notify us at least 4 weeks before you move to your new address, so you won t miss any issues of your subscription. The post office will not forward your subscription to Current Reviews for Nurse Anesthetists. Phone: (954) Fax: (954) or (800) info@currentreviews.com