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Clinical Director, Division of Critical Care, Director of Respiratory Care Massachusetts General Hospital, Associate Professor, of Anaesthesia, Harvard.

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Presentation on theme: "Clinical Director, Division of Critical Care, Director of Respiratory Care Massachusetts General Hospital, Associate Professor, of Anaesthesia, Harvard."— Presentation transcript:

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

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

3 Muscle relaxants for emergent intubation Improved respiratory outcome

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

5 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 / N 2 O.  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


7 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.)

8 Blind dot

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

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

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

12 Waud and Waud. Anesthesiology 1972, 37: 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

13 Reversal with neostigmine Baurain MJ et al. Br J Anaesth. 1996;77:496–499 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

14 Consequences of residual neuromuscular blockade 14

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

16 Retropalatal Retroglossal

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

18 BaselineTOF 80


20 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.

21 Results (1/2) IA-ND-NMBA associated with:  an increased risk of postop desat < 90% (OR 1.36, CI )  an increased risk of reintubation (OR 1.40, CI ) (1) 21 Outcome Not received ( ) Received ( ) Odds ratio (95% CI) O2 desat <90% (1.23 to 1.51) O2 desat <80% (1.34 to 2.07) Reintubation (1.09 to 1.80) Death (0.78 to 1.69) (1)Grosse­Sundrup M et al. BMJ Oct 15;345:e6329. (2)Meyer MJ et al. BMJ Mar 19;346:f1460 Cohort A: Association between use of IA-ND-NMBA & postoperative complications (n=37 158)  one group received neostigmine (n=18 579)  the other did not (n=18 579) IA­ND­NMBA use associated with an increased risk of postoperative desaturation < 90% & reintubation ConclusionsCohort A - Statistical findings

22 22 (1)Meyer MJ et al. BMJ Mar 19;346:f1460

23 Conclusion & potential weaknesses Potential weakness of this study  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. Conclusions 23  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.

24 Follow up studies Larger sample size trial of data on file: Dose-response relationship  Dose-dependent effects of NMBA on respiratory outcome?  Dose dependent effects of neostigmine on respiratory outcome?  Compound-specific effects on respiratory outcome? Prospective observational trial: Respiratory effects of neostigmine reversal / effects of NMT monitoring 24  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? Sugammadex trial  RCT in 150 patients  Sugammadex versus usual care  Safety: TOF-ratio at PACU admission  Surgical efficacy

25 25

26 26 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 Control variables

27 27

28 28 Results – NMBA dose

29 Differential effects of benzylisoquinolones and steroids? 29

30 30 Results – neostigmine dose

31 31 Results – neostigmine dose

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

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

34 Background  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 34 Methods  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 Data analysis  Regression analysis  Confounder control: - surgery type - age - BMI - duration of surgery - anesthesia regimen - TOF- ratio at PACU admission

35 Neostigmine 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. *

36 “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.

37 37

38 DesignRandomized, active-controlled, assessor-blinded study (NCT ) 38 Sugammadex trial 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 Secondary endpoints Timepoints related to perioperative patient management studied in an open- label fashion to reflect real operating room (OR) scenario 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 SafetyAssessed in a blinded manner

39 154 randomized patients  151 were treated (sugammadex n=74 and usual care n=77)  150 had a value for T4/T1 ratio at PACU entry 39 Patient characteristics and surgery categories CharacteristicSugammadex (n=74)Usual care (n=77) Mean (SD) age, y56.4 (12.8)57.0 (12.7) Mean (SD) BMI, kg/m (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 classSugammadex (n=74)Usual care (n=77) Class 1 n (%)1 (1.4)0 Class 2 n (%)59 (79.7)63 (81.8) Class 3 n (%)14 (18.9)14 (18.2) Most common surgeriesSugammadex (n=74)Usual care (n=77) Digestive system and spleen37 (50.0)35 (45.5) Urinary system, male genital organs, retro-peritoneal space 28 (37.8)30 (39.0) Female genital organs6 (8.1) 11 (14.3) n Demographi cs ASA class Surgery

40 Eight usual care patients (10.5%) had a T 4 /T 1 ratio <0.7 at PACU entry 40 Patients within each interval of T 4 /T 1 ratio at PACU entry

41 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 41


43 Anaesthesia 2009;64(S1):22

44 DACCPM QI Project Proposal: Twitch monitor-guided management of intraoperative neuromuscular blockade

45 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

46 46 Eliminate postoperative complications resulting from residual paralysis TOP 7 words of wisdom: Do not just ‘let it be’! 1.Realize that surgical relaxation does not always require neuromuscular transmission blockade. 2.If you apply deep neuromuscular transmission block. throughout the case, don’t expect you can reverse it with neostigmine. 3.Measure TOF-response prior to re-administration of NMBA. 4.Absence of visible/palpable TOF-fade or tetanic fade. does not exclude residual paralysis. 5.A “full reversal dose” of neostigmine given after recovery induces a depolarizing block. 6.Titrate neostigmine to TOF-count: wait until you see 2-3 twitches 7.Quantitative neuromuscular transmission monitoring is required to exclude residual paralysis.

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