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Provided by ASHP Supported by an educational grant from Merck

Achieving Safe and Effective Moderate to Deep Neuromuscular Blockade and Reversal in the Perioperative Setting

A Virtual Midday Symposium conducted at the 2020 ASHP Midyear Clinical Meeting and Exhibition Monday, December 7, 2020 1:00 – 2:30 pm ET

Home Study Available January 20, 2021 – May 12, 2022

FACULTY Rachel C. Wolfe, Pharm.D., M.H.A., BCCCP, Activity Chair Clinical Pharmacy Specialist Perioperative and Surgical Critical Care Barnes‐Jewish Hospital St. Louis, Missouri

Deborah Wagner, Pharm.D., FASHP Clinical Professor of Pharmacy and Anesthesiology University of Michigan Ann Arbor, Michigan

Glenn S. Murphy, M.D. Clinical Professor, Department of Anesthesiology University of Chicago Pritzker School of Medicine Director of Clinical Research NorthShore University Health System Evanston, Illinois

View faculty bios at ashpadvantage.com/nmbreversal

CE PROCESSING Participants will process CE credit online at http://elearning.ashp.org/my‐activities. CE credit will be reported directly to CPE Monitor. Per ACPE, CE credit for live Midyear activities must be claimed by February 1, 2021. CE credit for this archived activity must be claimed no later than 60 days from the date of completion.

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The American Society of Health‐System Pharmacists is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. ACPE #: 0204‐0000‐20‐436‐L01‐P

0204‐0000‐20‐436‐H01‐P

1.5 hour, application‐based

The American Society of Health System Pharmacists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The American Society of Health‐System Pharmacists designates this internet live course for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

https://www.ashpadvantage.com/nmbreversal/

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© 2020 American Society of Health-System Pharmacists, Inc. All rights reserved.2

Provided by ASHP Supported by an educational grant from Merck

Achieving Safe and Effective Moderate to Deep Neuromuscular Blockade and Reversal in the Perioperative Setting

Rachel C. Wolfe, Pharm.D., M.H.A., BCCCPClinical Pharmacy Specialist, Barnes Jewish Hospital

St. Louis, Missouri

Deborah Wagner, Pharm.D., FASHPClinical Professor of Pharmacy and Medicine, University of Michigan

Ann Arbor, Michigan

Glenn S. Murphy, M.D.Clinical Professor of Anesthesiology, University of Chicago

Evanston, Illinois

Financial Relationship DisclosureRachel Wolfe, Pharm.D.• Consultant and Speakers Bureau, MerckGlenn Murphy, M.D.• Speakers Bureau and Advisory Board, MerckDeborah Wagner, Pharm.D., FASHP• Advisory Board, Merck and Fresenius Kabi

All other planners, presenters, reviewers, ASHP staff, and others with an opportunity to control content report no financial relationships relevant* to this activity.

*As defined by the ACCME definition of commercial entity.


• Assess risk for post‐operative complications in patientsreceiving neuromuscular blocking agents (NMBAs).

• Explain the key components of neuromuscular blockade (NMB)and reversal during the intraoperative phase of care.

• Summarize the impact of residual NMB on patient and healthcare system outcomes.

• Apply strategies to improve interprofessional communicationacross the continuum of care when managing patientsreceiving NMB agents.

Learning Objectives

Pharmacology of Neuromuscular Blocking and Reversal Agents and Patient Risk

FactorsRachel C. Wolfe, Pharm.D., M.H.A., BCCCP‐Activity Chair

Clinical Pharmacy SpecialistPerioperative and Surgical Critical Care

Barnes‐Jewish HospitalSt. Louis, Missouri


• BT is a 75‐year‐old male (5’11”, 136 kg, body mass index [BMI] 41.8 kg/m2)scheduled for a laparoscopic colon resection

• PMH– Heart failure– Chronic obstructive pulmonary disease (COPD)– Hypertension– Diabetes mellitus– Obstructive sleep apnea (OSA)

• BT recently recovered from a mild case of COVID‐19 pneumonia 3 weeks ago• Preoperative O2 saturation 93%, BP 132/90 mm Hg, RR 14/min• Blood glucose 140 mg/dL

Patient Case

Postoperative Complications Associated with Neuromuscular Blockade

Rachel C. Wolfe, PharmD, MHA, BCCCPPerioperative Clinical Pharmacy Specialist

Barnes‐Jewish HospitalSt. Louis, Missouri


Postoperative Complications

Excessive sedation

Respiratory depression

Residual neuromuscular blockade

Delirium/cognitive dysfunction

Nausea/vomiting

Uncontrolled acute pain

Ileus

Bleeding

Surgical site infections

Pulmonary complications

Persistent pain

Chronic opioid use

Classification of Neuromuscular BlockersNeuromuscular Blocking Agents (NMBAs)

DepolarizingSuccinylcholine

Non-depolarizing

Aminosteroid Rocuronium

Vecuronium

Benzylisoquinolinium Mivacurium

Atracurium

Cisatracurium

© 2020 American Society of Health-System Pharmacists, Inc. All rights reserved. 6

Non‐depolarizing NMBAsAntagonize the action of acetylcholine (ACh) in a competitive manner

Bind to both presynaptic and postsynaptic receptors

Binding is dynamic with repeated association and dissociation

How Do NMBAs Compare?NMBA Metabolism Intubating

Dose (mg/kg)*Onset(min)

Recovery Begins (min)

Half‐life (min)

Succinylcholine Plasma pseudocholinesterase

0.6‐1

Why do we use NMBAs?Improves intubating conditions

Optimal surgical field conditions

Ventilation management

NMBAs: Flip Side of That Coin

NMBAs are associated with a

significant increased risk of postoperative

pulmonary complications (PPCs)

Bulka C et al. Anesthesiology. 2016; 125:647‐55.Kirmeier E et al. Lancet Respir Med. 2019; 7(2):129‐40.

Cammu G. Curr Anesthesiol Rep. 2020; 27:1‐6.


• Impairment of the normal phasic activity of genioglossus muscle– Impacts pharyngeal airway patency

• Abnormal coordination of pharyngeal and upper esophageal muscles– Impacts aspiration risk

• Impairment of the peripheral chemoreflex loop at the carotid bodies– Impacts respiratory homeostasis

Miskovic A et al. Br J Anaesth. 2017; 118:317‐34.Broens S et al. Anesthesiology. 2019; 131:467‐76.

Postoperative Respiratory Effects of NMBAs

Increased airway

resistanceUpper airway obstruction Hypoventilation

Oxygen desaturation and hypoxia

Impaired or misdirected swallowing

Inability to cough

Aspiration pneumonia Pneumonitis

Pulmonary congestion

Postoperative pneumonia

Impaired hypoxic

respiratory driveReintubation

Cammu G. Curr Anesthesiol Rep. 2020; 27:1‐6.

Postoperative Pulmonary Complications


Miskovic A et al. Br J Anaesth. 2017; 118:317‐34.Kirmeier E et al. Lancet Respir Med. 2019; 7:129‐40.

Hristovska AM et al. Cochrane Database Syst Rev. 2017; 8:CD012763.

Preoperative SpO2 ≤ 94%

ASA class ≥3

Age ≥ 60 yr

Duration of procedure > 2 hr

Emergent surgery

Intrathoracic or upper abdominal surgery

NMBA utilization

Smoking status

Poor functional health status

Severe respiratory disease (e.g., COPD)

Obstructive sleep apnea

BMI > 40 kg/m2

Chronic renal insufficiency

Congestive heart failure

History of recent respiratory infection

Male

Risk Factors for Postoperative Pulmonary Complications (PPCs)

Factors Contributing to PPCs

Aging Americans and Surgery• Americans undergo an average of 9.2 surgical procedures per lifetime– 3.4 inpatient operations– 2.6 outpatient operations– 3.2 non‐operating room invasive procedures

Lee P et al. J Am Coll Surg. 2008; 207(3):S75.


Only a Piece of the Safety & Quality Puzzle

• Safe use of neuromuscular blockade

Optimize Outcomes

Reversal StrategyDose Monitoring

PACU HandoffSelection

PACU: Post anesthesia care unit


Biro P. Anesth Analg. 2019; 128(6):1361‐1363.

Neuromuscular Blockade MonitoringDepth of Block Post‐tetanic

count (PTC)Qualitative

TOFQuantitative TOF Ratio

TOF Depiction

Complete 0 0 0Profound 1‐3 0 0Deep ≥ 4 0 0Moderate N/A 1‐3 0Shallow N/A 4, with fade 0.1 to

• Primary reversal option for succinylcholine• Not recommended for non‐depolarizing NMBAs

– Evidence indicates spontaneous reversal is associated with worse outcomes

• How often is spontaneous reversal chosen to reverse non‐depolarizing NMBAs at your institution?

Bulka C. et.al. Anesthesiology. 2016; 125:647‐655.Bronsert MR et al. Anesth Analg. 2017; 124:1476‐83.

Time

Pharmacologic Reversal

ACETYLCHOLINESTERASE INHIBITOR

NEOSTIGMINESELECTIVE RELAXANT BINDING AGENT

SUGAMMADEX


Brull SJ. Anesthesiology. 2017; 126:173‐90.Bridion (sugammadex) prescribing information. Merck and co., Inc. 2020 Jun.

Bloxoverz (neostigmine) prescribing information. Avadel Legacy Pharmaceuticals, LLC. 2017 Jan.

Depth of Block

PTC Qualitative TOF

Quantitative TOF Ratio

TOF Visual Neuromuscular Blockade Reversal Agents

Complete 0 0 0 Sugammadex 16 mg/kg (emergent reversal of rocuronium 1.2 mg/kg)

Profound 1‐3 0 0

Deep ≥ 4 0 0 Sugammadex 4 mg/kg

Moderate NA 1‐3 0 Sugammadex 2‐4 mg/kg Neostigmine 0.05‐ 0.07 mg/kg (TOF 2‐3)

Shallow NA 4, with fade 0.1 to

• Cannot reverse complete, profound, or deep block• Reversal of moderate block takes significant time• Coadministration with an anticholinergic agent

– Anticholinergic side effects (e.g., delirium, sedation, constipation, urinary retention)

• Has been associated with the following postop complications – Residual NMB– Postoperative nausea and vomiting (PONV)– Delayed return of bowel function– Bradycardia

Neostigmine: Important Considerations

Bloxoverz (neostigmine) prescribing information. Avadel Legacy Pharmaceuticals, LLC. 2017 Jan.Hristovska AM et.al. Anaesthesia. 2018;73(5):631‐641.

Sugammadex• Selective relaxant binding agent

– Distributes throughout the plasma– Encapsulates and inactivates rocuronium

and vecuronium, shifting the NMBA awayfrom the neuromuscular junction

– Complex is renally eliminated without undergoing metabolism (half‐life 2 hr)• Predictable, highly effective reversal agent

– Complete recovery in 1‐3 minutes• Able to reverse deep and moderate block• Emergent reversal induction dose is only approved for rocuronium‐induced blockade

– Affinity higher for rocuronium• No muscarinic or anticholinergic properties

Rocuroniumor

Vecuronium Sugammadex Complex

Bridion (sugammadex) prescribing information. Merck and Co., Inc. 2020 Jun.


• Drug interactions with hormonal contraceptives and ondansetron• Rare but serious adverse effects

– Marked bradycardia– Hypersensitivity reaction

• Cost: higher than the combination of neostigmine + glycopyrrolate

Sugammadex: Important Considerations

Bridion (sugammadex) prescribing information. Merck and Co., Inc. 2020 Jun.Hristovska AM et.al. Anaesthesia. 2018;73(5):631‐641.

• Not recommended in patients with creatinine clearance

• BT is transported to the OR for his laparoscopic colon resection procedure

Patient Case

Intraoperative Monitoring and Assessment/Monitoring of Patient Risk Factors

Glenn S. Murphy, M.D.Clinical Professor, Department of AnesthesiologyUniversity of Chicago Pritzker School of Medicine

Director of Clinical ResearchNorthShore University Health System

Evanston, Illinois


Objectives• Review the incidence and clinical implications of post‐

operative residual neuromuscular blockade (PRNB)• Discuss various modes of neuromuscular monitoring

and the effects on monitoring on outcomes• Examine clinical studies which have documented the

importance of reversal of neuromuscular blockade at the conclusion of surgery

BT is transported back to the OR for a 3‐hr surgery. He is given lidocaine, propofol, rocuronium 1.2 mg/kg, and fentanyl for

rapid sequence induction. General anesthesia is maintained with sevoflurane. No additional rocuronium is given. Neuromuscular

blockade is monitored at the facial nerve with a PNS (TOF stimulation). At the end of surgery, BT has 4/4 twitches (no

fade), a strong hand grip, and is able to lift his head on his own. No reversal agent was given. BT is subsequently extubated and

transported to the PACU.

PNS: peripheral nerve stimulator


Residual Neuromuscular Block: Rediscovering the Obvious

“In the United States, approximately 112,000 patients annually are at risk of adverse events associated with discharge from the operating room with residual neuromuscular blockade”

Brull SJ. Anesth Analg. 2008;107:11‐13.

Naguib M et al. Anesth Analg. 2010; 111:110‐9.

0%

20%

40%

60%

80%

100%

No Yes

Has respondent ever observed a patient exhibiting clinically significant residual NMB after the administration of a NMBA in

his/her recovery room or PACU?

Europe US

573

212156

1565


Devices to Assess Neuromuscular Blockade

• Qualitative Monitor • Quantitative monitor

• With quantitative neuromuscular monitoring– Traditional definition: TOF ratio

The RECITE US Study• Prospective observational study of the incidence of PRNB at 10 U.S. hospitals (academic and private practice)

• ASA I‐III patients undergoing abdominal surgery were assessed• TOF ratios measured immediately before extubation Results• 255 patients enrolled• Incidence PRNB: 64.7% had TOF ratio

Residual Neuromuscular Block in the Elderly: Incidence and Clinical Implications

• Data prospectively collected on 150 younger (18‐50 yr) and 150 elderly (>70 yr) patients

• TOF ratios measured on arrival to PACU• Patients examined for adverse respiratory events from

tracheal extubation until hospital discharge• Postoperative muscle weakness quantified using a

standardized exam, and PACU and hospital lengths of stay were determined

Murphy GS et al. Anesthesiology. 2015; 123:1322‐36.

Results

• Incidence of PRNB was 57.7% in elderly and 30.0% in younger patients (P

Residual Neuromuscular Blockade in the PACU: Observational Cross‐Sectional Study of a Multi‐Center

Cohort• Multi‐center study in Spain• Enrolled 763 patients from 26 centers• TOF ratios assessed at admission to PACUResults• 27% patients TOF ratio

Does qualitative neuromuscular monitoring reduce the risk of residual block or impact clinical recovery?

• 39 surgical patients randomized to TOF monitoring or no monitoring in OR

Results• No monitoring group

47% TOF ratio

• Study examined the ability of anesthesiologists to detect fade using TOF stimulation at varying levels of neuromuscular blockade

Results• Inexperienced in use of nerve stimulators

‐Unable to feel fade unless TOF ratios

Kotake Y et al. Anesth Analg. 2013; 117:345‐51.

Reversal with Sugammadex in the Absence of Monitoring

Does quantitative neuromuscular monitoring reduce the risk of residual blockade or impact clinical recovery?


3‐dimensional Acceleromyography


Comparison of the TOFscan and the TOF‐Watch SX during Recovery of Neuromuscular Function

ULoA: upper limit of agreement LLoA: lower limit of agreement


Tetragraph EMG Monitor


Intraoperative Acceleromyographic Monitoring• Reduces the risk of residual neuromuscular blockade and adverse respiratory events in the postanesthesia care unit

Acceleromyography Group Conventional TOF Group

*Degree of residual NMB classified as acceptable neuromuscular recovery=0 (TOF ratio > 0.90), mild to moderate NMB = 1 (TOF ratio 0.70‐0.90), Severe NMB=2 (TOF ratio

Intraoperative Acceleromyographic Monitoring


Tests to Detect Residual ParalysisClinical Test Reliability/Relevance

Tidal volume Not reliable

Vital capacity Not sensitive

End‐tidal CO2 Not reliable

Maximum inspiratory pressure Not sensitive

Head or leg lift test > 5 seconds Not sensitive

Tongue depressor test Reliable but difficult to implement

Plaud B et al. Anesthesiology. 2010;112:1013‐22.


Consensus Statement on Perioperative Use of Neuromuscular Monitoring

• Quantitative (objective) NMB monitoring should be used whenever a nondepolarizing NMBA is administered

The panel recognizes that replacing conventional PNS devices with quantitative monitoring equipment will take time and education. During this interim period, the use of a PNS in any patient receiving a NMBA is mandatory• Subjective or clinical tests of NMB are not predictive of adequate neuromuscular

recovery and are not sensitive to the presence of residual neuromuscular weakness; their use should be abandoned in favor of objective monitoring

• Professional organizations should develop practice standards and guidelines detailing how best to monitor and manage perioperative administration of NMBAs.

Naguib M et al. Anesth Analg. 2018; 127:71‐80.

Always reverse the effects of NMBAs


• Propensity matched study at Vanderbilt University

Design

• 1320 surgical cases who received an NMBA and reversal with neostigmine compared to 1320 cases who did not receive reversal

Method

• The incidence of pneumonia in patients receiving a NMBA was 1.79 times that of propensity matched patients who did not receive a NMBA

• The incidence of pneumonia in patients receiving a NMBA without reversal was 2.26 times that of propensity matched cases who received reversal with neostigmine

Result

Bulka C et al. Anesthesiology. 2016; 125:647‐55.

No Reversal and Respiratory Complications

Respiratory Complications without Reversal

Bronsert MR et al. Anesth Analg. 2017; 124:1476‐83.

• Retrospective study of 11,355 non‐cardiac patients from 5 VA hospitals– 8984 received NMBAs– 7047 reversed with

neostigmine• Respiratory complications

– Failure to wean, reintubation, pneumonia

• NO reversal was associated with a 70‐75% increase in odds of respiratory complications

Analysis OR/HR (95% CI) p valueRespiratory complicationsUnadjusted 4.20 (3.51‐5.03)

Neostigmine Administration After a Spontaneous Recovery to a Train‐of‐Four Ratio of 0.9 to 1.0

120 patients administered 1 X ED95 dose of rocuronium and given none thereafter (average dose 25 mg)

Average duration of the cases was 163 minutes Results

At the conclusion of surgery, 24 patients (21%) had not recovered to a TOF ratio of at least 0.9


Consider the use of sugammadex


Neostigmine Versus Sugammadex for Reversal of Neuromuscular Blockade and Effects on Reintubation for Respiratory Failure or Newly Initiated Noninvasive Ventilation: An Interrupted Time Series Design

• Adult patients undergoing general anesthesia that included reversal of neuromuscular blockade and admission ≥1 night were enrolled (7316 patients)

• Groups were determined by date of surgery: August 2015 to May 2016 (neostigmine/presugammadex), and August 2016 to May 2017 (postsugammadex)

• The primary outcome was defined as a composite of reintubation for respiratory failure (RF) or new noninvasive ventilation (NIV)

Krause M et al. Anesth Analg. 2020; 131:141‐51.

Outcome Unadjusted RatesPresugammadex Group Postsugammadex Group

Reintubation for RF or new NIV, no. (%)

209 (6.1) 164 (4.2)

Conclusions: What was done wrong in this case?• Monitored at the facial nerve‐eye muscles: The risk of PRNB can be up to

5 times higher when monitoring is conducted at the facial nerve vs. the ulnar nerve‐adductor pollicis

• PNS used as monitor vs. quantitative monitor: The incidence of PRNB can be significantly reduced by the use of quantitative monitoring; particularly important in patients at high risk for PRNB

• Not reversed: Every patient should receive a reversal agent at the end of surgery unless a quantitative monitor has demonstrated spontaneous recovery to a TOF ratio > 0.9

• Methods to reduce the risk of PRNB (quantitative monitoring, sugammadex) should always be considered in patients at risk for PRNB and subsequent complications associated with PRNB (advanced age, obesity, sleep apnea, COPD)


BT is now transported to the PACU for recovery

Addressing Post‐operative Complications and Residual Blockade

Deborah Wagner, Pharm.D., FASHPClinical Professor of Pharmacy

University of Michigan College of PharmacyClinical Professor of Anesthesiology

Michigan MedicineAnn Arbor, Michigan


Patient Arrival to PACU• Pain 9/10• Respiratory rate

Let’s Start with Patient Risk Factors

AGE

The Aging Population• In the next 4 decades, people aged ≥ 60 years will account for 22% of

the world population• Approximately 50% will require anesthesia for surgical intervention• Patients will be sicker and at greater risk for postoperative

complications• Age‐related decrease in reserve capacity of organs can affect drug

clearance– Delayed recovery from neuromuscular blocking agents– Prolonged duration of action of neostigmine

Bloom DE et al. Lancet. 2015; 385:649‐57; Sear JW. Curr Opin Anaesthesiol. 2003; 16:373‐8; McDonagh DL et al. Anesthesiology. 2011; 114:318‐29.


• Observational study of reversal practices• Significantly higher rate of PONV with neostigmine reversal than sugammadex reversal

• No significant differences in PACU or hospital LOS• Pulmonary outcomes deteriorated significantly with advanced age– Not observed in the sugammadex group

Ledowski T et al. Eur J Anaesthesiol. 2014; 31:423‐9.

Association of Postoperative Outcomes with NMB Reversal Practice

BMI / Weight


How Does Obesity Affect Drug Dosing of Reversal Agents

• Neostigmine– 30, 40, and 50 mcg/kg dose based on total body weight– 40 and 50 mcg/kg dose achieved a faster time to a TOF >0.9

• Sugammadex– Recommended dosing based on actual body weight– Use with ideal body weight

• 120 bariatric surgery patients with moderate and deep block• 39.5% and 23.4% respectively required a second dose due to TOF

Comparative Recovery Profile of Sugammadex

https://www.anesthesiologynews.com/Multimedia/Article/05‐20/Using‐Actual‐Body‐Weight‐With‐Sugammadex‐Speeds‐Reversal‐in‐Morbidly‐Obese‐Patients/58393

Duration of Surgery


Neostigmine Compared with Sugammadex in Long Surgeries

• 200 patients >70 yr undergoing surgery ≥3 hr• Neostigmine 70 mcg/kg vs. sugammadex 2 mg/kg• Primary endpoint PPCs, secondary endpoint PRNB with TOF

OSA and PACU Respiratory Complications• Pulmonary atelectasis occurs in 85‐90% of adults• Surgery alters lung mechanics• Higher risk for upper airway collapse during theperioperative period

• Hypoventilation in the PACU confounded byresidual effects of opioids, sedative hypnotics,and inhaled anesthetics

Cammu G. Current Anesthesiology Reports. 2020; 10:131‐6.

Pulmonary HistoryPneumonia/COVID‐19


Complications Associated with Residual NMB

Type of Complication Source Key Points

Death or permanent brain damage

Tiret et al.Lunn et al.Cooper et al.Arbous et al.

Postanesthetic respiratory depression;10 x increase in deaths when NMB reversal omitted

Pulmonary complications Berg et al. 3 x increase in rate of atelectasis

Upper airway obstruction, severe hypoxemia, or respiratory failure

Murphy et al. RNMB contributes to development of adverse respiratory events

Plaud B et al. Anesthesiology. 2010;112:1013‐22, Murphy GS. Anesth. 2008; 109:389‐98, Tiret L. Can J Anesth. 1986; 33:336‐44, Lunn JN Anaesthesia1983; 38: 1090‐6, Cooper Al.Anaesthesia 1989; 44: 953‐8, Arbous MS Anest. 2005; 102:257‐68, Berg H Acta Anaesth Scand 1997; 41:105‐103.

RECITE Canada Study: Incidence of Postoperative Residual NMB

Fortier L et al. Anesth Analg. 2015; 121:366‐72.

Only 36% had TOF ratio ≥ 0.9 74% reversed with neostigmine

Only 43% had TOF ratio ≥ 0.9 72% reversed with neostigmine

63.5%residualNMB

56.5% residual NMB

22%

12%11%19%

36%

NMB at Extubation

TOF < 0.6 TOF 0.6 -

Postoperative Pulmonary Complications

What is the Major Concern for BT (by the way)?

Economic Burden of PPCs annually

• Each case of bronchospasm– Adds 1 hospital day and $1,563– 1 in 14 cases results in ICU admission

• Each case of respiratory failure– Adds 8 hospital days and $24,000– 1 in 2 cases results in ICU admission

Thompson DA et al. Ann Surg. 2006;243:547‐52.Shander A et al. Crit Care Med. 2011; 39:2163‐72.

A patient safety summit was convened in Washington, DC, on December 7, 2009, to address the substantial clinical and economic costs of PPCs

92,200 additional ICU admissions584,300 additional ICU days$3.42 billion in additional costs


The Other Facts on PPCs• Rate after major surgery as high as 23%• Up to 1/3 die within first 30 days after surgery• Increased length of stay• Numerous modifiable and nonmodifiable riskfactors– Long operation times– Pancreatectomy, hepatectomy, esophagectomy,abdominal aortic aneurysm repair, lung resection

Foster C et al. J Am Coll Surg. 2019; 229:355‐65.

A Multicenter Study by the Perioperative Research Network

• PPCs can be broadly defined as conditions affectingthe respiratory tract that can adversely influence theclinical course of patients after surgery

• At least 1 PPC occurred in 401 patients (33.4%)• Patients with 1 or more PPCs, even mild ones, had

significantly increased early postoperative mortality,ICU admission, and hospital length of stay

Fernandez‐Bustamante A et al. JAMA Surg. 2017; 152(2):157‐66.


Relationship between NMB Use and PPC• 21 teaching hospitals in Spain• Patients > 18 years old with intermediate to high risk for PPC• 64.6% of patients experienced a PPC within 30 days of surgery• Risk factors

– High BMI– Low preop SpO2– High ASA status– Hypertension, diabetes mellitus, or COPD

• Pharmacologic reversal associated with a lower incidence of PPC

Garutti I et al. Eur J Anaesthesiol. 2020; 37:203‐11.

• 22,803 adult patients from 211hospitals across 28 Europeancountries

• Subsequent subgroup analysis– Extubating patients with TOF

ratio >0.95 reduced theadjusted risk of PPC by 3.5%

– Sugammadex had been given inhigher doses by 0.30 (0.13‐0.48) mg/kg in the sub‐cohortwith TOF ratio > 0.95

Key Factor Does not Apply

Key Factor Applies

OR (95% CI)

P value

Use of any NMBA

131/4001(3.3%)

152/693(8.6%)

1.86

The Stronger Study

Kheterpal S et al. Anesthesiology. 2020; 132:1371‐81.

• Matched‐cohort study from 12 MPOG hospitals• Exact matching criteria included institution, sex, age,

comorbidities, obesity, surgical procedure type, andneuromuscular blocking agent (rocuronium vs.vecuronium)

• In multivariable analysis, compared with neostigmine,sugammadex administration was associated with– 30% reduced risk of pulmonary complications

• aOR = 0.70 (95% CI 0.63 to 0.77)– 47% reduced risk of pneumonia

• aOR = 0.53 (95% CI 0.44 to 0.62)– 55% reduced risk of respiratory failure

• aOR = 0.45 (95% CI 0.37 to 0.56)

Reversal and PPCs

Kheterpal S et al. Anesthesiology. 2020; 132:1371‐81.MPOG: Multicenter Perioperative Outcomes Group


Final Decision….

Incidence of Postoperative Residual NMB

Brueckmann B et al. Br J Anaesth. 2015; 115:743‐51.

100%

0% 0% 0% 0%

57%

21%12%

4% 7%

0%10%20%30%40%50%60%70%80%90%

100%

TOF ≥0.9 TOF ≥ 0.8 to

You Choose Neostigmine• Patients receiving NMBA but no reversal are at higher

risk for PPCs• Multicenter retrospective study suggested reversal

with neostigmine reduces risk of PPC• Not administering neostigmine associated with an

increase in the odds of respiratory complications• Increased risk of PRNB in elderly and cardiovascular

effects• Strategies to use

Bulka CM et al. Anesthesiology. 2016; 125:647‐55. Bronsert MR et al. Anesth Analg. 2017;124:1476‐83. Luo J et al. Ther Clin Risk Manag. 2018; 14:2397‐406.

• Quality improvement (QI) initiative to optimize the use ofneostigmine for reversal of neuromuscular blockade– Involved change in anesthesia clinician behaviors around intraoperative management of

NMBA and emergence from anesthesia

• Evaluation of change in postoperative pulmonarycomplications, costs, and duration of hospital stay

Rudolph MI et al. Anaesthesia. 2018; 73:1067‐78.


Appropriate Reversal Can Be a TargetAppropriate Reversal Inappropriate Reversal

NMBA Dose Quintiles (x ED95 dose)

PRC rate Effect Size PRC rate Effect Size

I (Lowest) 0.39% n/a 0.43% n/aII 0.45% 1.04 (0.7‐1.6) 0.56% 1.03 (0.8‐1.3)III 0.60% 1.16 (0.8‐1.7) 0.65% 1.06 (0.8‐1.3)IV 0.63% 0.95 (0.6‐1.4) 0.89% 1.20 (1‐1.5)V (Highest) 0.91% 0.98 (0.6‐1.5) 1.49% 1.41 (1.1‐1.8)

McLean DJ et al. Anesthesiology. 2015; 122:1201‐13.

Appropriate reversal (neostigmine ≤ 0.06 mg/kg at TOF count of at least 2) Inappropriate reversal (no neostigmine administration, neostigmine administration not guided by TOF count or doses > 0.06 mg/kg)

ED95 = effective dose to produce 95% depression in twitch heightPRC = postoperative respiratory complications

Neostigmine Reversal Guide

Rudolph MI et al. Anaesthesia. 2018; 73:1067‐78.

Type of Monitoring Neostigmine Dose Qualitative Quantitative Weight‐Based 70‐kg patientNo twitch No twitch WAIT WAIT 1 twitch 1 twitch WAIT WAIT 2‐3 twitches 2‐3 twitches ~50 mcg/kg 3‐4 mg 4 twitches with fade TOF ratio 0.9 NONE NONE

Risk factors for Residual WeaknessHigh total dose of NMBA >1.5 mcg/kg rocuronium or >0.4 mg/kg cisatracurium

High dose neostigmine reversal >60 mcg/kgALWAYS DOSE NMBA AND REVERSAL ACCORDING TO MONITORING AND CLINICAL CONDITION


Clinical Outcomes

Rudolph et al. Anaesthesia. 2018; 73:1067‐78.

OutcomePre ‐QI Intervention

n= 2,937

Post ‐QI Intervention

n=9,088

AdjustedOR (95% CI)IRR (95% CI)

p‐value

PPC 220 (7. 5%) 568 (6. 3%)0.73

(0.61 ‐0.88a)0.001

Hospital LOS b

Mean ± SD5.3 ± 7.5 5.0 ± 7.2

0.91b

(0.87 ‐0.94)0.9 was 2.9 min withsugammadex 4 mg/kg and 48.8 min with neostigmine 0.07 mg/kg

• Sugammadex is associated with fewer adverse events:– Residual NMB RR 0.40 (95% CI 0.28‐0.57), NNT 13– Bradycardia RR 0.16 (95% CI 0.07‐0.34), NNT 14– PONV RR 0.52 (95% CI 0.28‐0.97), NNT 16

Hristovska AM et al. Anaesthesia. 2018; 73:631‐41.


MPOG Real‐world Utilization Patterns Of Perioperative NMB Reversal

• Aim: to identify differences in NMB reversal agent use and factorsassociated with their use after FDA approval of sugammadex (SUG)in the United States, 2015

• Retrospective observational study across 22 MPOG institutions• All adult cases between Jan 2014 and June 2018• Number of exclusions• 3 periods: pre‐SUG, 0‐6 months with SUG, > 6 months post‐SUG

Dubovoy T et al. Anesth Analg. May 2019; 128(5):827‐830.

MPOG Real‐world Utilization Patterns Of Perioperative NMB Reversal

Dubovoy T et al. Anesth Analg. May 2019; 128(5): 827‐30.


Multivariable Analysis of Sugammadex Use• Patient age OR 1.74• Male sex OR 1.34• ASA III or IV OR 1.13• Chronic pulmonary disease OR 1.11• Congestive heart failure OR 1.29• Major thoracic surgery OR 1.81• TOF 0‐1 OR 3.43• TOF 2 OR 2.59

Dubovoy T et al. Anesth Analg. May 2019; 128(5):827‐30.

In multivariate analysis, sugammadex was associated with:• 29% reduced risk of PPCs, ORadj 0.71, (0.63‐0.79, p

Michigan Medicine Outcomes : Rates of Reintubation and PPC

Total Cases at Institution

Neostigmine Cases with Composite Outcome

N (%)

Sugammadex Cases with Composite Outcome

N (%)

Unadjusted Odds Ratio

95% Confidence Interval

9,350 319 (6.8) 268 (5.7) 0.82 (0.69, 0.98)

What about Other Postoperative Outcomes?

• 584 propensity matched patients– 157 receiving sugammadex and 157 an acetylcholinesterase inhibitor– Looked at LOS, readmission, delayed discharge, oral intake, ICU

admission, and pulmonary complications– Only significant difference between groups was lower incidence of

delayed discharge with sugammadex• 1430 propensity matched comparison of sugammadex and

neostigmine on hospital stay– No reduction in 30‐day unplanned admissions

Chae YJ et al. J Clin Med. 2019; 8.pii.E97, Min B. BMC Anesth. 2020;20:178.


Conclusion

• BT was a patient at high risk for postoperativepulmonary complications (PPCs)

• Despite a TOF of 4/4 twitches patient stillneeded reversal based on his history

• Although either neostigmine or sugammadexcould be used in BT, sugammadex would bethe better choice because of his risk for PPCs.

Safe and effective neuromuscular blockade and reversal

Collaborative Strategies

Reversal StrategyDose Monitoring HandoffEducation

PACU: Post anesthesia care unit

Postop Outcomes


• Patient‐ and surgery‐specific risk factors (includingmedications and monitoring techniques) contribute to theincidence of postoperative complications

• Collaborate and take initiative– Identify patients at risk– Select the most appropriate care path– Equip clinicians with the tools (e.g., education, medications,devices) needed to achieve the best possible outcomes

Key Takeaways

Which of these practice changes will you consider making?

• Increase awareness among postanesthesia care unit (PACU) personnel about signs andsymptoms of residual NMB.

• Work with interprofessional team to develop standard handover process in PACU.

• Review access to reversal agents for moderate/deep block and rapid sequence intubation.

• Ensure appropriate use of sugammadex 16 mg/kg dose.

• Initiate a drug‐use review as step in developing guidelines for use of NMB reversal agents.

• Actively assess for risk factors associated with residual NMB in all patients who will bereceiving a neuromuscular blocking agent (NMBA).


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