Case-Based Management of Neuromuscular Block, Reversal, and Recovery: Ensuring Optimal Outcomes

Transcription

1 Supplement to December 2015 June 2011 Volume 79 Number 3 ISSN Established in 1933, the AANA Journal is the official publication of the American Association of Nurse Anesthetists. Target Audience The target audiences for this activity include certified registered nurse anesthetists and general surgeons. Learning Objectives Upon completion of this activity, learners will have improved their ability to: Recall the incidence and complications of residual neuromuscular blockade Identify optimal techniques for assessment of neuromuscular blockade depth List patient features/comorbidities and surgical procedures which may lead to increased risk of residual neuromuscular blockade Develop effective communication strategies among surgeons, anesthesiologists, and CRNAs Compare the efficacy and safety data of currently available and emerging agents for the reversal of neuromuscular blockade Integrate strategies for reversal of neuromuscular blockade into plans for the care of patients undergoing anesthesia Case-Based Management of Neuromuscular Block, Reversal, and Recovery: Ensuring Optimal Outcomes This activity is jointly provided by AANA and MedEdicus LLC. This activity is supported through an unrestricted educational grant from Merck & Company.

2 Supplement to June 2011 Volume 79 Number 3 ISSN Established in 1933, the AANA Journal is the official publication of the American Association of Nurse Anesthetists. Faculty Mark Welliver, CRNA, DNP, ARNP Associate Professor of Professional Practice School of Nurse Anesthesia Harris College of Nursing & Health Sciences Texas Christian University Fort Worth, TX Glenn Murphy, MD (Chair) Clinical Professor NorthShore University HealthSystem Evanston Hospital Evanston, IL Aaron F. Kopman, MD Clinical Professor of Anesthesiology (retired) Weill Cornell Medical College New York, NY Sorin J. Brull, MD Professor of Anesthesiology Department of Anesthesiology Mayo Clinic, College of Medicine Jacksonville, FL Accreditation Statement This course has been prior approved by the American Association of Nurse Anesthetists. AANA Code # , Expiration Date 12/1/16, 1 Class A CE Credit. The American Association of Nurse Anesthetists is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center s Commission on Accreditation. The course will provide 1 contact hour of CNE. Provider approved by the California Board of Registered Nursing, Provider #10862 for 1 contact hour. Conflict of Interest Disclosures All presenters and planners of this continuing nursing education activity are required to disclose to the audience any significant financial relationships with the manufacturer(s) of any commercial products, goods, or services. If any conflict has been disclosed, the planners of this program assure that the content is unbiased and free of any conflict of interest. All planners, authors and content reviewers disclosed there were no commercial interest relationships to declare except for the following: Glenn Murphy, MD, has had a financial agreement or affiliation during the past year with the following commercial interests in the form of Merck & Company (consultant); Merck & Company (Speaker s Bureau). Mark Welliver, CRNA, DNP, ARNP, has had a financial agreement or affiliation during the past year with the following commercial interests in the form of Merck & Company (consultant). Instructions to Receive Credit To participate in this CNE activity you must read the objectives and article, complete a post test and evaluation. To access the post test, please visit AANALearn.com. Once you log in please follow the instructions below: 1. Use the search field to find the course CASE-BASED MANAGEMENT OF NEUROMUSCULAR BLOCK, REVERSAL, AND RECOVERY: ENSURING OPTIMAL OUTCOMES. 2. Once you find the course, open the course and click on Request button. The course will now move into the folder on the main page titled My Courses. 3. Return to the main page of AANALearn.com. 4. Click on My Courses and find the course you just selected. 5. Click on Launch on the right-hand side of the screen to access the PDF article. 6. Once you have completed reading the materials, click on Mark Complete. You must complete this before accessing the post test. 7. The Launch Test option will now appear once you mark complete and you can now click on the Launch Test to take the 10-question post test. IMPORTANT: Please be aware that a passing score of at least 80% is required and that there is no retesting for participants who score less than 80%. If you fail the test you will not receive CE credits for this course. We encourage you to refer back to the article while taking the test. 8. Once you have passed the test, the course will automatically be moved from your Active tab to your Completed tab. 9. Please click on the completed tab to access the evaluation. Once you complete the evaluation you will have access to your certificate and can print it for your records. 10. Once this step is complete your transcript will be updated within 2-3 hours. Disclosure of Unlabeled Use This educational activity might contain discussion of evidence-based and/or investigational uses of agents that are not indicated by the FDA. For additional information about approved uses, including approved indications, contraindication, and warnings, please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the planners, sponsor or publisher. System Requirements for Digital Editions If you are viewing this activity online please ensure the computer you plan to use meets the following requirements: Operating system: Windows or Macintosh Media viewing requirements: Flash Player or Adobe Supported browsers: Microsoft Internet Explorer, Firefox, Google Chrome, Safari and Opera A good Internet connection Jointly created by American Association of Nurse Anesthetists (AANA) and MedEdicus LLC, and published by AANA. Printed in the USA. Copyright 2015 AANA. All rights reserved. No part of this publication may be reproduced without written permission from the publisher. The material presented at or in any of the AANA continuing medical education activities does not necessarily reflect the views and opinions of AANA. Neither AANA nor the faculty endorse or recommend any techniques, commercial products, or manufacturers. The faculty/authors may discuss the use of materials and/ or products that have not yet been approved by the US Food and Drug Administration. All readers and continuing education participants should verify all information before treating patients or utilizing any product. 2 Supplement to AANA Journal December 2015

3 CONTENTS 4 Residual paralysis Subjective qualitative measurement of neuromuscular blockade 6 Objective quantitative measurement of neuromuscular blockade 7 Risk factors for residual paralysis Communication strategies among surgeons, anesthesiologists, and CRNAs Introduction More than 100 million doses of neuromuscular blocking agents (NMBAs) are administered in the United States every year. 1 Residual paralysis occurs in as many as 40% of surgical cases involving NMBAs. 2-5 The adverse effects of residual paralysis include respiratory complications, muscle weakness, prolonged stays in the postanesthesia care unit (PACU), and delayed extubation. 2,6,7 To explore the state of the science regarding residual paralysis, a panel of anesthesia providers familiar with current and developing technology and pharmacology was convened. A review of residual paralysis and neuromuscular monitoring is discussed, followed by case scenarios for which current and new clinical considerations are applied. 9 Emerging agents for the reversal of NMB 9 Selective relaxant binding agents Case 1: Bariatric surgery gastric stapling Case 2: Laparoscopic total abdominal hysterectomy Case 3: Transfemoral aortic valve replacement Case 4: Laparoscopic cholecystectomy 13 Conclusion Supplement to AANA Journal December

4 Case-Based Management of Neuromuscular Block, Reversal, and Recovery: Ensuring Optimal Outcomes Residual paralysis Residual paralysis has also been called residual curarization, residual neuromuscular block, and postoperative residual neuromuscular block. Residual paralysis is any level of neuromuscular block (NMB) that remains after the conclusion of anesthesia and tracheal extubation. By consensus, residual paralysis is defined as NMB measured with a train-of-four ratio (TOFr) <0.9. The target level of minimal recovery is therefore defined as TOFr 0.9. Previous to the turn of the century, a TOFr 0.7 was considered adequate recovery. Research since the 1990s has shown that a TOFr <0.9 is associated with impairment of respiratory function, airway patency, hypoxic ventilatory drive, swallowing, coughing, and other clinical signs Although clinical signs of residual paralysis can be affected by residual paralysis, these signs and symptoms are not reliable for determining adequacy of reversal. 9,12 The variability of patient abilities to perform clinical tests, such as head lift for 5 seconds, hand grasp, leg lift, teeth clenching, smile, swallow, speak, or disclose the experience of generalized weakness makes these assessments unreliable. 12 The positive predictive value of these tests to determine residual paralysis defined as TOFr <0.9 was about the same as a coin toss: 50% (Table 1). 12 As concluded by Drs. Brull and Murphy, In summary, current evidence demonstrates that frequently used clinical tests of neuromuscular function cannot reliably exclude the presence of residual paralysis unless TOFrs are < TOFrs <0.9 have been associated with impairment of respiratory function, airway patency, hypoxic ventilatory drive, swallowing, and coughing. The findings that the clinical tests used for years are unreliable for determining if muscle strength has recovered to a TOFr 0.9 are concerning. The limitation of clinical assessments should encourage the use of objective neuromuscular monitoring devices. Monitoring NMB Numerous studies have shown inconsistent knowledge and infrequent use of neuromuscular monitors Most recently and more inclusive of CRNA practice in the United States is the 2014 APSF Survey, Residual Muscle Relaxant-Induced Weakness in the Postoperative Period: Is It a Patient Safety Issue? 20 Respondents to the survey (n = 3182) included CRNAs (66%) and anesthesiologists (27%) (Table 2). 20 Although the knowledge of NMB and its complications appears better than previous surveys, room for improvement exists. Among CRNAs and anesthesiologists, 90% agreed that objective functional monitoring (twitch measurement) should be utilized routinely intraoperatively for patients receiving nondepolarizing neuromuscular blocking drugs prior to transfer to the PACU. Despite these survey findings and the American Association of Nurse Anesthetists (AANA) Standard V(e), which requires neuromuscular monitoring when NMBAs are used, the use of neuromuscular monitors in the operating room remains inconsistent and rare. Standard V Monitor, evaluate, and document the patient s physiologic condition as appropriate for the type of anesthesia and specific patient needs. When any physiological monitoring device is used, variable pitch and threshold alarms shall be turned on and audible. The CRNA should attend to the patient continuously until the responsibility of care has been accepted by another anesthesia professional. e. Neuromuscular When neuromuscular blocking agents are administered, monitor neuromuscular response to assess depth of blockade and degree of recovery. 21 Subjective (qualitative) measurement of neuromuscular blockade Peripheral nerve stimulator Although peripheral nerve stimulators (PNSs) (also known as twitch monitors) are commonly used to measure the degree of NMB, their use is by no means universal. A PNS utilizes an externally applied electrical stimulus to a peripheral nerve to elicit a corresponding muscle contraction (twitch). Ulnar nerve stimulation to assess the adductor pollicis muscle twitch is probably the most frequently used site. Response is observed by visual and tactile assessment of count and strength of the muscle twitches. PNSs provide several modes or options for nerve stimulation: single twitch, TOF, double-burst stimulation (DBS), tetanus, and, sometimes, post-tetanic count (PTC). The TOF count (TOFc) is the most frequently used mode and requires the user to count the number of responses representing the degree of NMB. 22 This assessment is inherently subjective because user s interpretations vary. Once the TOFr exceeds 0.40, most clinicians cannot detect (tactile/visual) the presence of fade (Figure 1, page 6). Thus, the absence of subjective fade does not guarantee adequate neuromuscular 4 Supplement to AANA Journal December 2015

5 Table 1. Diagnostic Attributes of the Clinical Tests: Sensitivity, Specificity, and Positive and Negative Predictive Values of an Individual Clinical Test for a TOFr <90% 12 Sensitivity Specifi city Positive Predictive Value Negative Predictive Value Inability to smile Inability to swallow Inability to speak General weakness Inability to lift head for 5 s Inability to lift leg for 5 s Inability to sustain hand grip for 5 s Inability to perform sustained tongue depressor test Sensitivity = true positive; specificity = true negative; PPV = positive test but has residual paralysis; NPV = negative test but does not have residual paralysis. Table 2. Results of APSF Survey on Muscle Weakness and Residual Neuromuscular Blockade * (n = 3182) 20 Skeletal muscle weakness in PACU due to residual neuromuscular paralysis is a rare phenomenon. 54% agreed, 41% disagreed, 5% no opinion. A TOFr >0.7 confirms the absence of significant residual neuromuscular blockade induced skeletal muscle weakness in PACU. 10% agree, 82% disagree, 8% no opinion. Normal respiratory and upper airway function in the PACU may NOT be present until TOFr is % agree, 11% disagree, 11% no opinion. There is an association between residual neuromuscular blockade and immediate (first 24 hours) pulmonary complications. 85% agree, 5% disagree, 10% no opinion. 90% agreed that objective functional monitoring (twitch measurement) should be utilized routinely intraoperatively for patients receiving nondepolarizing neuromuscular blocking drugs prior to transfer to the PACU. 80% of the survey responses supported the statement that APSF should encourage professional associations (ASA, AANA, AAAA) to consider adding Monitoring Neuromuscular Function to their standards / recommendations for the intraoperative care of those patients receiving neuromuscular blocking drugs. * Percentages might not sum to 100 due to rounding. Supplement to AANA Journal December

6 Figure 1. Comparison of Train-of-Four. 22 Note both sets have a TOFc of 4 but set B has fade. Represented in set B is a TOFr of 0.5. This means the last twitch is 50% of the fi rst twitch strength. TOFr >0.5 is not detectable by vision or touch but is graphically displayed by objective neuromuscular monitors. No Fade Equal Train-of-Four A Fade present Train-of-Four ratio 0.5 B recovery. A TOFc of 4 may represent the absence of any NMB or as much as 75% receptors that are blocked. 23,24 The PNS modes of DBS and tetanus offer only a slightly more reliable assessment of the degree of NMB. DBS exerts 2 sets of electrical bursts (50 Hz) separated by a 750-ms delay. 25 The DBS mode facilitates detection of fade by subjective evaluation if fade is present, but it, too, has an unreliable threshold for subjective detection (TOFr 0.7). 22 Considering that a TOFr 0.9 is the standard for acceptable return of motor function, TOF and PNS modes both fall short of our requirements. Similarly, the tetanus mode is unreliable. Studies by Capron, 22 Samet, 26 Dupuis, 27 and Baurain 28 found detection of fade with tetanus inconsistent. A PNS offers useful data to guide intraoperative NMB depth but is limited in its usefulness to assess low degrees of, or indicate recovery from, NMB. The human ability to detect fade with any PNS mode is varied, inconsistent, and unreliable. 22 Although counting of TOF twitches is obvious, once all 4 twitches have returned, the detection of fade is poor by tactile and visual assessment. 22 A more objective measurement tool is needed. Accelerometry/kinemyography offers a solution to the fade detection limitations of PNSs. Objective (quantitative) measurement of neuromuscular blockade Piezoelectric method Objective accelerometry measurement is more reliable than a PNS. Setup is the same as for a PNS, with electrode placement on the ulnar nerve and TOF stimulation. An accelerometer band is slid onto the thumb, which, when moved by thumb contractions, produces objective, quantified, reliable data of depth of NMB (Figure 2). Accelerometer neuromuscular monitoring uses a TOF mode that measures the ratio of the fourth twitch compared with the first twitch. This ratio of strength quantifies any fade, including that which is undetectable by tactile assessment (TOFr > ). 22 This neuromuscular monitoring technique utilizes piezoelectric crystals to measure acceleration of muscle movement. The current generated is proportional to the force applied. Newton s second law states that force is equal to mass multiplied by acceleration (F = ma). Because the mass of the thumb is constant, the acceleration is proportional to force. Thus, the force of thumb movement can be measured. The piezoelectric method relies on the unique property of these crystals that produce an electric current with movement. Accelerometry has been incorporated into neuromuscular monitors that are available clinically from several manufacturers. Kinemyography is also based on the piezoelectric method. It uses a piezoelectric polymer to measure the degree of bending of an apparatus attached to the thumb and forefinger (Figure 3A). The difference between accelerometry and kinemyography is that the former produces current based on movement, whereas the latter produces current based on polymer apparatus bending (Figure 3A). A mechanosensor is placed between the thumb and forefinger, and movement of the thumb deforms the piezoelectric polymer, generating a small current in proportion to the force applied (Figure 3A). After induction, one button starts the TOF stimulation and measurement. TOF measurement continues automatically throughout the case and provides a TOFc and TOFr when fade is present. NMB monitoring based on accelerometry or kinemyography at the ulnar nerve is consistent and reliable. It is able to quantify moderate-deep levels of NMB, as well as low levels of NMB that are undetectable by PNS assessment. Considering continued incidences of residual paralysis; the known limits of PNSs; patients with increasingly more complex problems and surgical procedures; anesthesia provider agreements for objective monitoring; and the AANA s Standard V(e), which states that neuromuscular monitoring should be used, a commitment to incorporating accelerometry/kinemyography into clinical practice should be supported. As previously stated, current evidence demonstrates that frequently used clinical tests of neuromuscular function cannot reliably exclude the presence of residual paralysis unless TOFrs are < TOFrs <0.9 may be associated with impairment of respiratory function, airway patency, hypoxic ventilatory drive, swallowing, and coughing; therefore, better assessment criteria are needed. Accelerometry and kinemyography provide more reliable measurement of NMB and return of motor function than PNS. Objective monitors are not without their limits, including a potential measurement 6 Supplement to AANA Journal December 2015

7 error of 0.15 and the need for access to the hand and wrist for intraoperative monitoring. Tucking of the patient s arms may necessitate a protective sleeve over the hand and wrist or an arm sled to allow free thumb movement during twitching. Risk factors for residual paralysis Certain patient groups and surgical procedures may contribute to increased risk of residual paralysis. These groups include the elderly, the obese, those undergoing open upper abdominal procedures that hinder postoperative respiration, and those undergoing surgeries that require deep levels of NMB. Many physiologic, pharmacologic, and disease processes also contribute to greater susceptibility to the effects of NMBAs (Table 3, page 8). 29 Judicious use of NMBAs should be considered, along with objective neuromuscular monitoring. Optimal patient-specific tailoring of NMB is best achieved through close monitoring and communication among perioperative team members. Communication strategies among surgeons, anesthesiologists, and CRNAs More than 75% of adverse incidents have been attributed, in part, to poor communication. 30 Effective communication is a crucial component of teamwork, efficiency, and safety. Effective communication requires clarity and understanding of transferred information. A common knowledge of techniques and terminology facilitates mutual understanding. For NMB, it is particularly important that the anesthesia provider clearly understand the surgeon s needs. Does she/he require immobility or actual muscle paralysis? Many times, immobility (paresis) is all that is needed, as opposed to actual paralysis. If NMB is needed, what degree or depth is desired? Will a low level of NMB suffice (TOFc 3-4), a moderate level (TOFc 1-2), or a deep level (TOFc 0, PTC 1-2)? Deep levels of NMB are not reversible by acetylcholinesterase inhibitor (CIs) and increase the incidence of residual paralysis. 31,32 On the other hand, deeper levels of NMB may be provided for key portions of a procedure, if needed, and then be allowed to recover spontaneously toward the conclusion of the surgery. Close communication with the surgeon can better coordinate the depth of NMB and dosing to allow sufficient time for an optimal degree of spontaneous recovery (TOFc 3-4) in preparation for CI reversal. Surgeon and anesthesia provider awareness of the limitations of CI reversal of NMB is important for successful case management and patient safety. Emerging agents for the reversal of NMB Although CIs such as neostigmine and edrophonium have been used to reverse NMB for more than 50 years, the incidence of residual paralysis has Figure 2. Accelerometry. Image courtesy of Mark Welliver, CRNA. Figure 3A. Kinemyography. Polymer sensor Figure 3B. Acceleromyography. Images courtesy of Sorin J. Brull, MD. Supplement to AANA Journal December

8 Table 3. Factors That May Prolong Paralysis 29 Pathophysiologic Causes Acid maltase defi ciency Guillain-Barré syndrome Nonspecifi c nutritional defi ciency Acidosis Hypercarbia Poliomyelitis Adrenocortical dysfunction Hypokalemia and hypocalcemia Pyridoxine abuse Acute intermittent porphyria Hypomagnesemia Polymyositis Amyotrophic lateral sclerosis Hypophosphatemia Renal failure (variable prolongation) Anoxia and ischemia Hypothermia Respiratory acidosis Carcinomatous polyneuropathy Motor neuron disease Sepsis Cholinesterase defi ciency or genetic variance Multiple sclerosis Thiamine defi ciency Compressive neuropathy Muscular dystrophy Trauma Critical illness polyneuropathy Myasthenia gravis Vitamin E defi ciency Diphtheria Myotonic syndromes Wound botulism Eaton-Lambert syndrome Neurofi bromatosis Pharmacologic Causes Aminoglycoside toxicity Penicillin toxicity Steroid myopathy Antihypertensives Calcium channel blockers ß-blockers Furosemide Antidysrhythmics Quinidine Procainamide Local anesthetics in large doses Antibiotics Aminoglycoside antibiotics Polymyxin B Clindamycin Tetracycline Miscellaneous Drugs Cyclosporine Steroids Volatile anesthetics Dantrolene Magnesium Lithium Azathioprine Organophosphate (poisoning) 8 Supplement to AANA Journal December 2015

9 not changed significantly from the years when longeracting NMBAs were used compared with the present reliance on intermediate-duration agents. 3,5,22,33-36 This may be partially due to our present consideration of a TOFr 0.9 as fully reversed compared with a TOFr 0.7 in the past. As previously discussed, PNSs with tactile or visual assessment are unable to determine low levels of NMB. The limits of CI reversal of NMB make this even more concerning (Table 4). 29 Indirect action of CIs by competitive antagonism does not inactivate NMBAs; rather, CIs increase the concentration of acetylcholine at the junction, making acetylcholine more likely to bind (compete) with the NMBA for the receptor binding site. Recurarization is less likely with intermediate-acting NMBAs compared with longer-acting ones. The limit of our subjective assessment, along with the limits of CI reversal of NMB, has led to the search for improved options. Selective relaxant binding agents (SRBAs) have been shown to offer improved reversal, with a notable efficacy and safety record. Selective relaxant binding agents Sugammadex is a modified cyclodextrin composed of eight repeating glucose monomers that form a cone-shaped molecule. This molecule works by encapsulating aminosteroidal NMBAs (Figure 4, page 10). A large body of literature exists both from clinical trials and worldwide experience with sugammadex. 37 Its comparison with neostigmine and edrophonium for reversal of rocuronium and vecuronium has consistently shown faster and more complete recovery of motor function. This is the pharmacologic result of sugammadex s high-affinity encapsulation of rocuronium and vecuronium molecules. The encapsulation of aminosteroidal NMBAs occurs in a 1-to-1 molecular ratio, and, once encapsulated, the complex essentially becomes a permanently bound molecule and is unable to bind to, or exert an effect on, ACh receptors. This reversal occurs within 3 to 5 minutes and can fully restore muscle function to TOFr 0.9 with proper dosing from any depth of NMB. This is in comparison with neostigmine, with which recovery times to TOFr 0.9 vary from a median of 5 to 22 minutes, with some times reported as long as 143 minutes, depending on the level of NMB from which reversal was initiated. 38,39 The faster and more complete reversal of NMB by sugammadex has made it useful for reversing high-risk patients, including elderly, obese, weakened and cachexic, those with obstructive sleep apnea, and for those undergoing upper abdominal surgeries. Sugammadex offers the option to immediately reverse high-dose rocuronium ( mg/kg) used for rapid sequence intubation (RSI) in the can t intubate, can t ventilate scenario. A caveat to this use is awareness that other drugs used to induce anesthesia will remain in effect, contributing to respiratory depression Table 4. Limitations of Cholinesterase Inhibitors 29,40-44 CIs are unable to reverse deep levels of NMB (TOFc 0) CIs do not fully reverse moderate levels of NMB (TOFc 1-2) reliably There is a ceiling effect, beyond which more CI will have no effect or can actually induce muscle weakness Can exert pharyngeal dilator muscle relaxation in the absence of NMB Side effects may include bradycardia, hypotension, bronchoconstriction, gastrointestinal hypermotility, and hypersecretions Require a concomitant anticholinergic (glycopyrrolate, atropine) Anticholinergic side effects: tachycardia, dry mouth Recovery of at least TOFc 3, and preferably more, is desirable considering the indirect action of CIs despite return of normal neuromuscular function. Sugammadex has been used to rescue incomplete CI reversal and residual paralysis found in the perioperative setting. It undergoes no metabolism and is excreted intact via urine. Originally submitted to the Food and Drug Administration (FDA) in 2008, Sugammadex has undergone additional study to evaluate potential hypersensitivity reactions. It is currently under FDA consideration for approval in the United States. Case Studies The following hypothetical clinical scenarios offer insights into some management considerations as discussed by the members of this panel. Case 1: Bariatric surgery gastric stapling 35-year-old female Height: 5 4, weight: 148 kg, body mass index (BMI): 56 kg/m 2 Past smoker Type 2 diabetes mellitus (DM): oral metformin (has not taken this morning) Active gastroesophageal reflux disease (GERD): omeprazole nightly Vital signs Blood pressure (BP): 168/88 mm Hg Heart rate (HR): 88 bpm Airway examination Decreased mouth opening (2 cm) Class II upper lip bite test (lower incisors can bite upper lip below vermillion line) Mallampati class 3 Supplement to AANA Journal December

10 Figure 4. Sugammadex encapsulation process. 37 Sugammadex carboxyl groups interact over steroidal rings A, B, C, and D, drawing the aminosteroid neuromuscular blocking agent molecule into the cavity where additional non-covalent cavity attractions hold the molecule securely in place. Reprinted with permission. Preoperative blood tests Fasting blood glucose (BG): 140 mg/dl Hemoglobin (Hgb): 14.2 g/dl K: 3.9 meq/l Surgeon desires maximal NMB (PTC of 0-1) Commentary The concerns of this case include a potential difficult airway, supermorbid obesity and associated respiratory impairment, and the surgeon s request for deep NMB. Instituting any degree of NMB before securing a patent airway with an endotracheal tube is risky. Awake fiberoptic bronchoscopy with local airway anesthesia is a cautious approach that many would consider. Once the airway is secured, NMB may be initiated with a nondepolarizing NMBA. The surgeon s desire for maximal NMB is an opportunity to discuss the risks of NMB and limitations of CI reversal. Preferably discussed preoperatively, the surgeon s needs may actually be the desire for assured immobility, abdominal muscle relaxation, and no diaphragmatic excursions. Moderate levels of NMB could be considered while allowing a greater amount of spontaneous recovery (TOFc 3-4) at the end of surgery to improve the efficacy of CI reversal. Effective doses of neostigmine are to 0.05 mg/kg Higher doses ( mg/kg) do not appear to have greater efficacy in reversing NMB. This ceiling effect, in which greater doses do not have a greater effect in reversing NMB, is the rationale for the 5-mg maximum neostigmine dose rule of thumb. Conversely, neostigmine reversal given when there are low levels of NMB may actually worsen motor function. Caldwell found that neostigmine 0.04 mg/kg, when given at a recovery of TOFr 0.9 from vecuronium-induced NMB, actually lowered the TOFr. 32 It appears that the neostigmine dosage range of effectiveness is narrower than commonly thought, as is the range of NMB that can be effectively reversed. These findings underscore the importance of the use of neuromuscular monitoring, preferably objective accelerometry/kinemyography, to optimize CI reversal of NMB. The ability to fully restore motor function is especially desirable considering the patient s comorbidities. With FDA approval, sugammadex would be useful in this clinical scenario. Sugammadex is able to fully restore motor function in 3 to 5 minutes at proper doses guided by neuromuscular monitoring Sugammadex reversal of rocuronium- or vecuronium-induced NMB may help ensure no residual paralysis, but its ability to quickly reverse NMB should not replace the appropriate caution exercised in this case scenario. The use of sugammadex to quickly reverse rocuronium-induced NMB during a RSI in this particular case, a can t intubate, can t ventilate scenario although effective, will not reverse the other induction agents. Although NMB may be fully reversed within minutes, the induction drug effects will remain and airway respirations or ventilation is not assured. Considerations: A cautious approach to airway management Anesthetic plan to assure fully restored motor function at the conclusion of surgery Objective monitoring of NMB Avoidance of deep NMB Sugammadex versus neostigmine: patient at greater risk of postoperative respiratory complications. Complete NMB reversal is mandatory before tracheal extubation. Case 2: Laparoscopic total abdominal hysterectomy 39-year-old female Height: 5 4 ; weight: 66 kg; BMI: 25 kg/m 2 ASA I Vital signs and blood chemistries unremarkable Surgeon requests deep neuromuscular block (not clearly defined) Anesthesia induction Propofol 2.5 mg/kg Fentanyl 4 μg/kg Rocuronium 0.60 mg/kg Tracheal intubation performed easily Anesthesia maintenance Desflurane/oxygen Intermittent doses of fentanyl 10 Supplement to AANA Journal December 2015

11 Depth of anesthesia monitoring: BIS monitor, values maintained at 40 to 60 Arms are tucked at side; NMB measured by visual evaluation of TOFc at facial muscles Intermittent rocuronium to keep TOFc <2 Facial nerve TOFc at closure of fascia = 2 Commentary This case represents another opportunity to clarify surgeon needs for NMB. Open abdominal cases require relaxation of the abdominal musculature. This may be achieved with volatile anesthetics as well as NMBAs. The depth of NMB in this case was measured at the facial nerve site and maintained at a TOFc <2. The TOFc was 2 at the time of fascia closure. The facial nerve monitoring site measures the corrugator supercilii/orbicularis oculi muscles, which are relatively resistant to NMB compared with other peripheral muscles, including the adductor pollicis. The concern with CI reversal based on facial nerve monitoring is that there may not be sufficient spontaneous recovery at other muscle groups. A greater degree of spontaneous recovery allows improved CI reversal of NMB. In this scenario, movement of the NM monitoring apparatus to the ulnar nerve site would better inform the CRNA to the degree of recovery and reversal dose to be considered. Adductor pollicis TOFc will be less than the count at the corrugator supercilii/orbicularis oculi. The neostigmine reversal dose for a TOFc 2 to 3 is 0.05 mg/kg, but this assumes that responses are measured at the adductor pollicis. 48 The TOFc at the adductor pollicis in this scenario would probably be 0-1. Neostigmine cannot be expected to quickly or reliably reverse NMB at this level. Waiting until a greater degree of spontaneous recovery at the adductor pollicis has occurred is recommended. 48 Considerations: Communication: What depth of NMB is actually needed? Objective monitoring of NMB Location of neuromuscular monitoring: always measure NMB at the ulnar nerve toward the end of surgery to assure sufficient degree of spontaneous recovery Sugammadex versus neostigmine: neostigmine cannot reliably reverse deep levels of NMB Timing of reversal: wait for greater spontaneous recovery of motor function before CI reversal is attempted Case 3: Transfemoral aortic valve replacement 89-year-old white female Height: 5 4 ; weight: 148 kg; BMI: 56 kg/m 2 Medical history Type 2 DM Hypertension (HTN) Chronic renal insufficiency (creatinine of 1.8 mg/dl) Chronic obstructive pulmonary disease requiring home oxygen therapy Morbid obesity (148 kg) Stroke 1 year before admission (some weakness in right arm and leg) Medications Candesartan Atenolol Albuterol Hydrochlorothiazide Metformin (stopped 2 days ago) Insulin Warfarin Vital signs BP: 148/83 mm Hg HR: 65 bpm Physical examination Decreased breath sounds bilaterally (but no wheezing) Mallampati class 2 airway Preoperative preparation 18-gauge intravenous lines started in right and left arms 20-gauge catheter placed in right radial artery No premedication Anesthesia induction Etomidate 18 mg Lidocaine 30 mg Fentanyl 50 μg Rocuronium 40 mg Anesthesia maintenance Sevoflurane 0.4% to 1.5% Phenylephrine infusion to maintain BP within 20% of baseline values 45 minutes into procedure, patient s diaphragm starts to move spontaneously Rocuronium 10 mg Fentanyl 100 μg (no other opioid administered intraoperatively) Hemodynamics stable throughout 90-minute surgery End of surgery 2 responses to TOF stimulation observed at eye with peripheral nerve stimulation Neostigmine 3 mg Glycopyrrolate 0.6 mg 8 minutes later, no fade observed with TOF stimulation Patient observed reaching for endotracheal tube and is extubated Transport to recovery room Pulse oximeter indicates decreasing oxygen saturation; patient appears to be in respiratory distress On arrival, oxygen saturation is 78%; patient appears in extreme distress Supplement to AANA Journal December

12 Commentary This case introduces multiple management concerns related to age, morbid obesity, poor cardiovascular reserve, pulmonary disease, and renal insufficiency. The situation presented here is spontaneous patient movement intraoperatively that was undesired. Rocuronium was chosen for intubation and 10 mg was readministered to re-establish diaphragmatic immobility. No mention of the degree of NMB at the time of movement was disclosed, although, at the end of surgery, facial nerve monitoring showed a TOFc 2. A neostigmine dose equal to 0.02 mg/kg was administered. On arrival at the PACU, the patient displays signs and symptoms that may indicate residual NMB. The panel critique offered the following considerations. Diaphragmatic excursions may be due to light anesthesia and CO 2 -triggered breathing. Deepening the sevoflurane anesthetic and/or the fentanyl that was administered may have sufficed. This particular surgery does not necessarily require muscle paralysis as it does assured immobility. Close monitoring of end-tidal CO 2 and depth of anesthesia may have allowed for the avoidance of deepening NMB. Immobility may also have been better accomplished with NMB management guided by accelerometry monitoring of NMB. A PNS was used at the conclusion of the case and may have offered useful intraoperative data. Monitoring of the corrugator supercilii (or orbicularis oculi) via the facial nerve correlates with diaphragmatic function, but monitoring this site at the conclusion of surgery is not advised. Determination of adequacy of spontaneous degree of recovery is best measured at the adductor pollicis muscle of the thumb via the ulnar nerve. It is likely that the TOFc at the ulnar nerve site was less than that measured at the facial nerve. Always measure NMB at the ulnar nerve toward the end of surgery to assure the degree of spontaneous recovery. Consider accelerometry/mechanomyography for NMB monitoring and recovery (target is TOFr 0.9). Considerations: Communication: Is actual paralysis or just immobility required for case? Ways to attenuate diaphragmatic excursions: NMB, opioids, lower pco 2, and deepen the anesthetic with volatile agents Objective monitoring of NMB: provides more reliable measurement of NMB, particularly fade Location of neuromuscular monitoring: always measure NMB at the ulnar nerve toward the end of surgery to assure sufficient degree of recovery Case 4: Laparoscopic cholecystectomy 42-year-old female Height: 5 6 ; weight: 72 kg; BMI: 27 kg/m 2 Medical history HTN GERD (controlled with medication) Smoker Surgical history: 2 C-sections (gravida 2, para 2) NKDA Electrocardiogram normal Medication Omeprazole 20 mg daily Lisinopril 20 mg daily Preoperative sedation: versed 2 mg intravenously Standard monitoring in operating room Anesthesia induction Lidocaine 100 mg Fentanyl 100 μg Propofol 200 mg Verified good mask ventilation Rocuronium 50 mg for NMB Facial nerve TOFc 0 after 3 minutes Intubated 7.0 ett, easily (Mallampati grade 1) Anesthesia maintenance: sevoflurane 2.5% Surgery began CO 2 insufflation 16 mm Hg pressure, FiO 2 0.4, TV 600 cc, PIP 36 cm H 2 O Vital signs stable throughout Additional 150 μg fentanyl given intraoperatively TOFc 1 on facial nerve at surgical closure Neostigmine 5 mg Glycopyrrolate 1 mg Sevoflurane discontinued; spontaneous respirations shortly thereafter; TV 450 cc with pressure support Facial nerve TOFc 4; no fade observed Head lift to command, good hand grasp, extubated Placed on 50% oxygen facemask Prepared for transport to PACU SpO 2 fell to low 80s Unable to cough strongly or clear secretions, became agitated Mask-assisted ventilations with SpO 2 rising to 95% Ulnar nerve TOFc 3 Re-induced and intubated Transferred to PACU on ventilator Extubated approximately 1 hour later Commentary This case also represents a scenario in which facial nerve monitoring provided false assurance of an acceptable degree of spontaneous recovery for neostigmine reversal. Reliance on facial nerve monitoring is insufficient for determining adequacy for reversal. The corrugator supercilii/orbicularis oculi are resistant to NMB compared with the adductor pollicis and other peripheral muscle groups. Had it been measured, the TOFc at the adductor pollicis muscle likely would have displayed no twitches compared with the TOFc of 1 found at the facial nerve. The neostigmine dose of 0.07 mg/kg was ineffective to reverse the deep level of NMB. There is evidence that neostigmine doses greater than 0.04 mg/kg to 0.05 mg/kg are unlikely to 12 Supplement to AANA Journal December 2015

13 offer any improvement on the degree of motor function CIs are unable to adequately reverse deep levels of NMB, and spontaneous recovery of TOFc to 3-4 at the ulnar nerve monitoring site is recommended. The appearance of adequate reversal indicated by no observed fade is unreliable, because the threshold for fade detection is TOFr 0.4. TOF fade (TOFr <0.9 but >0.4) that is present, representing residual paralysis, is not reliably detectable by visual or tactile assessment. Objective monitoring using accelerometry would have alerted the nurse anesthetist to the incomplete reversal of NMB. With FDA approval, sugammadex in this scenario could have allowed the avoidance of reintubation by reversing residual paralysis. Considerations: Communication: Is actual paralysis, or just immobility, required for the case? Ways to attenuate diaphragmatic excursions: NMB, increasing depth of anesthesia with volatile anesthetics, opioids, and lower pco 2 Objective monitoring of NMB displays fade that is undetectable with a PNS Location of neuromuscular monitoring: If using facial nerve monitoring intraoperatively, move neuromuscular apparatus to ulnar nerve site to determine adequacy of spontaneous recovery for effective CI reversal Sugammadex versus neostigmine: Sugammadex rescue of incomplete reversal Conclusion We are entering a new phase in anesthesia, and health care in general, in which patient outcomes and satisfaction are equally evaluated. Although we have managed anesthesia and antagonized NMB with reasonable success for many years, research continues to document the inherent limitations of our clinical and subjective assessments, along with the limited effectiveness of CI (neostigmine and edrophonium) reversal. Similarly, research has provided greater understanding and improved technologies in monitoring, managing, and reversing NMB. Work by Murphy, Brull, and others has shown a correlation of adverse respiratory events to a TOFr <0.9. Therefore, a TOFr 0.9 is worthy of consideration, especially for those patients who may be at higher risk of postoperative respiratory compromise. Communication and understanding of common terminology for NMB management, emphasizing TOFr as opposed to just TOFc, better quantifies the level of NMB and recovery for all perioperative team members. Key take-home points of this review include: Residual paralysis remains a clinical concern. Perioperative team communication of anesthetic plans and surgical needs, particularly with regard to NMB, may facilitate better management. Awareness of high-risk residual-paralysis patient populations should be conveyed to all perioperative team members. Neuromuscular monitoring is an AANA standard and should be used whenever NMBAs are used. PNSs provide useful, but limited and subjective, data compared with accelerometry/kinemyography. Accelerometry/kinemyography neuromuscular monitors provide a reliable, objective assessment of NMB depth. An ulnar nerve monitoring site should be used, especially for assessing reversibility toward the end of surgery. Avoidance of deep NMB (TOF 0) is recommended whenever possible. Greater spontaneous recovery of NMB (TOF 3-4) improves reversibility. Sugammadex can fully reverse all levels of NMB induced by rocuronium and vecuronium. References 1. Grosse-Sundrup M, Henneman JP, Sandberg WS, et al. Intermediate acting non-depolarizing neuromuscular blocking agents and risk of postoperative respiratory complications: prospective propensity score matched cohort study. BMJ. 2012;345:e 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): Murphy GS, Szokol JW, Marymont JH, Franklin M, Avram MJ, Vender JS. Residual paralysis at the time of tracheal extubation. Anesth Analg.2005;100(6): Murphy GS. Residual neuromuscular blockade: incidence, assessment, and relevance in the postoperative period. Minerva Anestesiol. 2006;72(3): Yip PC, Hannam JA, Cameron AJ, Campbell D. Incidence of residual neuromuscular blockade in a post-anaesthetic care unit. Anaesth Intensive Care. 2010;38(1): Murphy GS, Szokol JW, Avram MJ, et al. Postoperative residual neuromuscular blockade is associated with impaired clinical recovery. Anesth Analg. 2013;117(1): Murphy GS, Szokol JW, Marymont JH, et al. Intraoperative acceleromyographic monitoring reduces the risk of residual neuromuscular blockade and adverse respiratory events in the postanesthesia care unit. Anesthesiology. 2008;109(3): Eriksson LI, Lennmarken C, Wyon N, Johnson A. Attenuated ventilatory response to hypoxaemia at Supplement to AANA Journal December

14 vecuronium-induced partial neuromuscular block. Acta Anaesthesiol Scand. 1992;36(7): Kopman AF, Yee PS, Neuman GG. Relationship of the train-of-four fade ratio to clinical signs and symptoms of residual paralysis in awake volunteers. Anesthesiology. 1997;86(4): Berg H, Roed J, Viby-Mogensen J, et al. Residual neuromuscular block is a risk factor for postoperative pulmonary complications. A prospective, randomised and blinded study of postoperative pulmonary complications after atracurium, vecuronium and pancuronium. Acta Anaesthesiol Scand. 1997;41(9): Murphy GS, Szokol JW, Franklin M, Marymont JH, Avram MJ, Vender JS. Postanesthesia care unit recovery times and neuromuscular blocking drugs: a prospective study of orthopedic surgical patients randomized to receive pancuronium or rocuronium. Anesth Analg. 2004;98(1): Brull SJ, Murphy GS. Residual neuromuscular block: lessons unlearned. Part II: methods to reduce the risk of residual weakness. Anesth Analg. 2010;111(1): Grayling M, Sweeney BP. Recovery from neuromuscular blockade: a survey of practice. Anaesthesia. 2007;62(8): Fuchs-Buder T, Fink H, Hofmockel R, Geldner G, Ulm K, Blobner M. Application of neuromuscular monitoring in Germany [in German]. Anaesthesist. 2008;57(9): 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): DiMarco P, Della Rocca G, Iannuccelli F, Pompei L, Reale C, Pietropaoli P. Knowledge of residual curarization: an Italian survey. Acta Anaesthesiol Scand. 2010;54(3): Florez EL, Tafur LA, Giraldo AL. The use of neuromuscular non-depolarizing blockers and their reversal by anesthesiologists Valle del Cauca, Columbia [in Spanish]. Rev Columb Anesthesiol. 2012;40(2): Eldawlatly A, El-Tahan MR; MMM-Anaesthesia Group Collaborators. A survey of the current use of neuromuscular blocking drugs among the Middle Eastern anesthesiologists. Saudi J Anaesth. 2013;7(2): Phillips S, Stewart PA, Bilgin AB. A survey of the management of neuromuscular blockade monitoring in Australia and New Zealand. Anaesth Intensive Care. 2013;41(3): Anesthesia Patient Safety Foundation. APSF survey results: drug-induced muscle weakness in the postoperative period safety initative. Anesthesia Patient Safety Foundation Web site. newsletters/html/2014/winter/03_survey.htm. Accessed September 3, American Association of Nurse Anesthetists. Standards for Nurse Anesthesia Practice. Park Ridge, IL: AANA; professionalpractice/documents/ppm%20standards%20for%20nurse%20anesthesia%20practice. pdf. 22. Capron F, Fortier LP, Racine S, Donati F. Tactile fade detection with hand or wrist stimulation using trainof-four, double-burst stimulation, 50-hertz tetanus, 100-hertz tetanus, and acceleromyography. Anesth Analg. 2006;102(5): McCoy EP, Connolly FM, Mirakhur RK, Loan PB, Paxton LD. Nondepolarizing neuromuscular blocking drugs and train-of-four fade. Can J Anaesth. 1995;42(3): Kopman AF. Tactile evaluation of train-of-four count as an indicator of reliability of antagonism of vecuronium- or atracurium-induced neuromuscular blockade. Anesthesiology. 1991;75(4): Engbaek J, Ostergaard D, Viby-Mogensen J. Double burst stimulation (DBS): a new pattern of nerve stimulation to identify residual neuromuscular block. Br J Anaesth. 1989;62(3): Samet A, Capron F, Alla F, Meistelman C, Fuchs- Buder T. Single acceleromyographic train-of-four, 100 Hertz tetanus or double-burst stimulation: which test performs better to detect residual paralysis? Anesthesiology. 2005;102(1): Dupuis JY, Martin R, Tessonnier JM, Tetrault JP. Clinical assessment of theresponse to tetanic nerve stimulation. Can J Anaesth. 1990;37(4): Baurain M, Hennart D, Godschalx A, et al. Visual evaluation of residual curarization in anesthetized patients using one hundred-hertz, five-second tetanic stimulation at the adductor pollicis muscle. Anesth Analg. 1998;87(1): Nagelhout JJ. Neuromuscular blocking agents, reversal agents, and their monitoring. In Nagelhout JJ, Paus KL, eds. Nurse Anesthesia. 5th ed. St. Louis, MO: Saunders Imprint; 2013: The Joint Commission. Sentinel events. Comprehensive Accreditation Manual for Hospitals. January CAMH_2012_Update2_24_SE.pdf. Accessed September 3, Kim KS, Lew SH, Cho HY, Cheong MA. Residual paralysis induced by either vecuronium or rocuronium after reversal with pyridostigmine. Anesth Analg. 2002;95(6): Supplement to AANA Journal December 2015