Matthias Eikermann, M.D., PhD Optimal use of neuromuscular blocking agents to avoid respiratory complications Matthias Eikermann, M.D., PhD   Clinical Director, Division of Critical Care, Director of Respiratory Care Massachusetts General Hospital, Associate Professor, of Anaesthesia, Harvard Medical School, Boston, MA

Disclosures: Sponsored research - MERCK Masimo ResMed Foundation Started Calabash Biotechnology Inc.

Muscle relaxants for emergent intubation Improved respiratory outcome

The use of muscle relaxants for emergent intubation helps prevent respiratory complications

Risks associated with neuromuscular blocking agents Case report 62 y/o patient with multifocal bladder cancer scheduled for Cystoscopy/Bladder Biopsy/Fulguration. Laryngeal mask airway, sevoflurane / N2O. Fifteen minutes after insertion of endoscope, Urologist requests full paralysis. Resident gives cisatracurium 2, 4, 4 mg within 6 minutes, see anesthesia protocol. Surgeon finishes 10 minutes later

What did the resident say? Surgeon told me that the procedure will take another hour. It’s not my fault. I gave cisatracurium only – predictable recovery. The neuromuscular transmission monitor does not work – I know it because there is still no twitch, and the patient started triggering the vent – which means: Now I can give neostigmine safely. (BTW: Second twitch appears 30 minutes later.)

Blind dot

Residual paralysis in the recovery room Clinical assessment difficult Clinical evaluation after anesthesia: 68 of 72 patients appropriately recovered from NB However: Partial paralysis in 42% of patients Viby-Mogensen et al, Anesthesiology 1979

Partial paralysis: Really? “I never see that in my practice!”

MGH-data: Residual paralysis on PACU admission 43% TOF Ratio < 0.9 11% TOF Ratio < 0.7 2/33 clinical signs/sx Br J Anaes 2015, in press

- „Good twitch“ does not ensure full recovery. Calculation of ‘free’ receptor fraction from agonist’s effects Strong twitch with 80 per cent neuromuscular blockade - „Good twitch“ does not ensure full recovery. - 2 twitches (or more): then neostigmine = full recovery Waud and Waud. Anesthesiology 1972, 37:417-22.

Reversal with neostigmine Roc (■), Vec (▲), Atr (●) and Pan (□). *p<0.05, group Vec vs groups Roc and Atr **p<0.01, group Pan vs groups Vec, Roc and Atr Baurain MJ et al. Br J Anaesth. 1996;77:496–499

Consequences of residual neuromuscular blockade

60 minutes difference in recovery room length of stay TOF<90%: 60 minutes difference in recovery room length of stay

Retropalatal Retroglossal

Upper airway volume Eikermann et al. Am J Resp Crit Care Med 2007

Baseline TOF 80

Propensity matching controlled for: Age, gender, weight, body mass index, ASA physical status classification, surgical service, case duration, emergency status, use of volatile anaesthetics, nitrous oxide, opioids, neuromuscular blocking agents, neostigmine, neuromuscular transmission monitoring, charlson comorbidity index.

Results (1/2) Cohort A - Statistical findings Conclusions Cohort A: Association between use of IA-ND-NMBA & postoperative complications (n=37 158) Cohort A - Statistical findings Conclusions Outcome Not received (18 579 ) Received (18 579 ) Odds ratio (95% CI) O2 desat <90% 689 925 1.36 (1.23 to 1.51) O2 desat <80% 128 212 1.66 (1.34 to 2.07) Reintubation 108 151 1.40 (1.09 to 1.80) Death 48 55 1.15 (0.78 to 1.69) IA-ND-NMBA associated with: an increased risk of postop desat < 90% (OR 1.36, CI 1.23-1.51) an increased risk of reintubation (OR 1.40, CI 1.09-1.80) (1) IA­ND­NMBA use associated with an increased risk of postoperative desaturation < 90% & reintubation one group received neostigmine (n=18 579) the other did not (n=18 579) Grosse­Sundrup M et al. BMJ. 2012 Oct 15;345:e6329. Meyer MJ et al. BMJ. 2013 Mar 19;346:f1460

Meyer MJ et al. BMJ. 2013 Mar 19;346:f1460

Conclusion & potential weaknesses Conclusions Potential weakness of this study The use of intermediate acting neuromuscular blocking agents during anesthesia is associated with an increased risk of clinically meaningful respiratory complications, Under the conditions studied, neostigmine and qualitative neuromuscular transmission monitoring did not mitigate the increased risk of postoperative respiratory complications linked to the use of non-depolarizing neuromuscular blocking agents. Our data suggest that the strategies used in our Department to prevent residual postoperative neuromuscular blockade should be revisited. Dose-response relationship not been studied. Compound-specific effects not been investigated. Prospective study of data on file – prescription pattern may have changed over time.

Follow up studies Prospective observational trial: Respiratory effects of neostigmine reversal / effects of NMT monitoring Larger sample size trial of data on file: Dose-response relationship 3000 patients prospectively included Dose dependent effects of neostigmine on respiratory outcome? Effects of intraoperative monitoring? Is neostigmine use associated with higher TOF-ratio at PACU arrival? Dose-dependent effects of NMBA on respiratory outcome? Dose dependent effects of neostigmine on respiratory outcome? Compound-specific effects on respiratory outcome? Sugammadex trial RCT in 150 patients Sugammadex versus usual care Safety: TOF-ratio at PACU admission Surgical efficacy

Control variables Age Gender Body Mass Index (BMI) Procedure duration ASA classification Charlson Comorbidity Index (CCI) SPORC score Depth of anesthesia Age corrected MAC Use of vasopressors/hour Composite variable of all pressors corrected to norepinephrine equivalent Surgical service Admission type (in-patient/ambulatory) Emergency surgery Total number of units of packed red cells administered during surgery Total volume of intraoperative resuscitation fluid Total equivalent dose of morphine Number of intraoperative hypotensive minutes

Results – NMBA dose

Differential effects of benzylisoquinolones and steroids?

Results – neostigmine dose

Results – neostigmine dose

Neostigmine impairs respiratory muscle function in rats Eikermann et al. Anesthesiology 2007

Neostigmine increases upper airway collapsibility in humans Herbstreit, Peters, and Eikermann, Anesthesiology 2010

Background Methods Data analysis Proper use of neostigmine decreases anesthesia associated mortality In our MGH setting, neostigmine does not improve respiratory safety We would like to better understand the effects and side effects of neostigmine reversal Prospective, assessor-blinded study at MGH 3000 patients enrolled TOF-ratio measured at PACU arrival Intraoperative TOF count recorded in electronic anesthesia record analyzed. PACU and Hospital LOS P/F ratio Billing diagnoses indicating respiratory failure Mortality Regression analysis Confounder control: - surgery type - age - BMI - duration of surgery - anesthesia regimen - TOF- ratio at PACU admission

Neostigmine Dose-dependent increase in frequency of postoperative atelectasis 　None >0 to 60 >60 Neostigmine dose (mcg/kg) * The relation of neostigmine dose and the incidence of postoperative atelectasis, which increased with increasing dose of neostigmine. The incidence of atelectasis significantly differs between the three groups (i.e. patients who did not receive neostigmine, those who received minimum to 60 mcg/kg of neostigmine and those who received over 60 mcg/kg of neostigmine (p<0.001 by ANOVA). The asterisk indicates a significant increase in the incidence of atelectasis with the administration of high dose neostigmine.

“Unwarranted” Neostigmine reversal= 0/4 twitch, or no documented twitch: Increased incidence of respiratory complications. Patients who received neostigmine without proper guidance by NMT monitoring (either no documented monitoring, or a documented 0/4 as the most immediate TOF count prior to neostigmine administration) were significantly more likely to be reintubated (#; p=0.010) after correction for confounding variables. ND-NMBA: non-depolarizing neuromuscular blocking agents; TOF: train of four.

Sugammadex trial Design Randomized, active-controlled, assessor-blinded study (NCT01479764) Patients Aged ≥18 years undergoing elective abdominal surgery under general anesthesia with rocuronium-induced NMB Reversal agents Given according to randomization Sugammadex 2–4 mg/kg intravenous (IV) Usual care (neostigmine/glycopyrrolate IV) as per standard clinical practice Primary endpoint T4/T1 ratio on entry to PACU recorded by treatment-blinded personnel using TOF-Watch® SX Odds ratio of having residual NMB (T4/T1 ratio <0.9) in PACU for sugammadex vs usual care Secondary endpoints Timepoints related to perioperative patient management studied in an open-label fashion to reflect real operating room (OR) scenario Safety Assessed in a blinded manner

Patient characteristics and surgery categories 154 randomized patients 151 were treated (sugammadex n=74 and usual care n=77) 150 had a value for T4/T1 ratio at PACU entry n Demographics Characteristic Sugammadex (n=74) Usual care (n=77) Mean (SD) age, y 56.4 (12.8) 57.0 (12.7) Mean (SD) BMI, kg/m2 32.9 (8.0) 30.2 (7.0) Male, n (%) 47 (63.5) 43 (55.8) Moderate renal impairment, n (%) 5 (6.8%) 3 (3.9) ASA class ASA class Sugammadex (n=74) Usual care (n=77) Class 1 n (%) 1 (1.4) Class 2 n (%) 59 (79.7) 63 (81.8) Class 3 n (%) 14 (18.9) 14 (18.2) Surgery Most common surgeries Sugammadex (n=74) Usual care (n=77) Digestive system and spleen 37 (50.0) 35 (45.5) Urinary system, male genital organs, retro-peritoneal space 28 (37.8) 30 (39.0) Female genital organs 6 (8.1) 11 (14.3)

Patients within each interval of T4/T1 ratio at PACU entry Eight patients (10.5%) in the usual care group had T4/T1 ratio of <0.7 at PACU entry Eight usual care patients (10.5%) had a T4/T1 ratio <0.7 at PACU entry

Managing surgical neuromuscular transmission during surgery Residual NMB cannot be diagnosed by visual or tactile fade if the TOF-ratio is around 0.4. 50 Hz tetanic fade evaluation does not reliably identify residual block Deep block cannot be reversed with acetylcholinesterase inhibitors. Reversal of a NMB with neostigmine is efficacious only if partial recovery is established (TOF count >2). Neostigmine given after complete recovery of neuromuscular transmission will result in a depolarizing NMB

Anaesthesia 2009;64(S1):22

DACCPM QI Project Proposal: Twitch monitor-guided management of intraoperative neuromuscular blockade OUTLINE ------------   1. Proposed departmental QI project:  "Documentation of twitch monitoring with non-depolarizing NMB (nd-NMB) usage" 2. Background/Problem:  I would like to focus on MGH data if you have: a. What is our rate of nd-NMB usage (about 60 % of endotracheally intubated cases of cases)?  (not absolutely necessary to have) b. What fraction of our nd-NMB cases have twitch monitor use about one third with twitch documented? c. What fraction of our PACU patients have <70% TOF on admission? (11 per cent after abdominal surgery, Dick is coauthor on that paper); What fraction have <90% TOF on admission to PACU 43 per cent after abdominal surgery – Dick is co-author on that paper - attached? d. What fraction are reversed with neostigmine 75 per cent ? e. What fraction is given appropriate dose of neostigmine 42 per cent of thos who received neostigmine? 1. What fraction of patients who receive neostigmine have TOF <70% on admit to PACU? TOF>90%? g. What is the clinical consequence? Increased respiratory complication rate (pneumonia, re-intubation, pulmonary edema), prolonged PACU length of stay, prolonged hospital length of stay, a. How many QA cases of re-intubation/non-invasive PPV have we had due to residual paralysis? Don’t know b. What is the rate of airway complications associated with a. residual paralysis on PACU admit (TOF <70%; TOF<90%) Don’t know, it’s a rare event – don’t have that TOF-related data. b. inappropriate use of neostigmine clearly increased resp. complication rate, dose-dependent 3. Goal of initiative: a. Reduce the incidence of residual paralysis on admission to PACU b. Reduce the incidence of adverse clinical outcomes associated with residual postoperative paralysis 4. Components of initiative a. Infrastructure a. Ensure functional train-of-four monitor in each OR b. Education a. Case conference presenting a. the problem b. proper method of dosing neuromuscular blocking agents b. proper methods of monitoring neuromuscular blockade intraoperatively c. proper approach to reversal of nd-NMB b. Cognitive aid available in OR to serve as reference for clinicians on twitch-based NMB & reversal dosing c. Monitoring and feedback a. QI Metric: "documentation of intraoperative TOF during use of nd-NMB" b. Measurement of outcomes at 6months and 1 yr to determine efficacy of intervention w. feedback to dept c. Targetted outcomes: a. intraoperative TOF documentation during cases using nd-NMB b. incidence of inappropriate neostigmine dosing b. incidence of residual paralysis in PACU (TOF<70%; TOF<90%) c. incidence of adverse respiratory outcomes

Goals: - Reduce residual paralysis - Reduce adverse respiratory outcomes Components of Initiative Infrastructure: TOF monitor in each OR Clinical Education: - Case conference reviewing data - Online repository of literature Cognitive aid in OR and online

TOP 7 words of wisdom: Do not just ‘let it be’! Eliminate postoperative complications resulting from residual paralysis TOP 7 words of wisdom: Do not just ‘let it be’! Realize that surgical relaxation does not always require neuromuscular transmission blockade. If you apply deep neuromuscular transmission block. throughout the case, don’t expect you can reverse it with neostigmine. Measure TOF-response prior to re-administration of NMBA. Absence of visible/palpable TOF-fade or tetanic fade. does not exclude residual paralysis. A “full reversal dose” of neostigmine given after recovery induces a depolarizing block. Titrate neostigmine to TOF-count: wait until you see 2-3 twitches Quantitative neuromuscular transmission monitoring is required to exclude residual paralysis.