George Williams, II, MD, FCCP STICU NPO Guidelines Update George Williams, II, MD, FCCP Associate Professor http://www.memorialhermann.org/uploadedImages/_Media/News_and_Media/Press_Releases/MHRDTI.jpg?n=2850

This session is supported by an educational grant from Merck and Co This session is supported by an educational grant from Merck and Co. Handouts are available through the ASA Education Center https://education.asahq.org

Disclosures Scientific speaker for Merck® No other disclosures

Objectives Review the underlying pharmacology of neuromuscular blockade (NMB) Discuss literature regarding the effect of various types of NMB with patient outcomes Analyze trends in NMB reversal Apply pharmacologic and clinical concepts to synthesize a clinical approach to NMB reversal

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©Stan Stead, MD ©Stan Stead, MD

© Lionsgate © Lionsgate

Williams GW, Williams EW. Basic Anesthesiology Examination Review Williams GW, Williams EW. Basic Anesthesiology Examination Review. Oxford University Press. ©Williams GW, Williams EW. Basic Anesthesiology Examination Review. Oxford University Press.

Let’s Review the Menu Succinylcholine Atricurium Rocuronium Cisatricurium Vecuronium Pancuronium Review pharmacology of each of these agents Moore L et. al. Comparison of Cisatracurium Versus Atracurium in Early ARDS. Respir Care. 2017 Mar 28. Cisatracurium versus atracurium.. primary outcome was improvement in oxygenation at 72 h post-initiation of neuromuscular blocking agents, ventilator-free days at day 28, ICU and hospital LOS, hospital mortality. 76 patient There were no differences in clinical outcomes. Moore L et. al. Comparison of Cisatracurium Versus Atracurium in Early ARDS. Respir Care. 2017 Mar 28.

On the Horizon Gantacurium Onset of ~2 min, duration 12-14 minutes Not significantly changed with increased (x4) dosage 17% ↓ in BP L-cystein reversal ↓ Muscarinic effect, Bronchospasm Heerdt PM, et. al. Novel neuromuscular blocking drugs and antagonists. Curr Opin Anaesthesiol. 2015 Aug;28(4):403-10. “In the mid-1990s, our research group began evaluating novel bis-benzyltetrahydroisoquinolinium molecules for efficacy, potency, and side-effects, in particular histamine release and bronchospasm. Consistent with the previous work involving benzylisoquinoline NMBDs, these early studies identified compounds that while potent and ultrashort in duration were also histamine releasers. Ultimately, gantacurium emerged as the lead candidate, with subsequent preclinical studies performed in monkeys, dogs, cats, and guinea pigs” Heerdt PM, et. al. Novel neuromuscular blocking drugs and antagonists. Curr Opin Anaesthesiol. 2015 Aug;28(4):403-10.

On the Horizon… CW002 L-cystein reversal, again two fewer 1-benzyl methoxy groups Mild hemodynamic effects Slower reversal (11 minute ½ time) Heerdt PM, et. al. Novel neuromuscular blocking drugs and antagonists. Curr Opin Anaesthesiol. 2015 Aug;28(4):403-10. Heerdt PM, et. al. Novel neuromuscular blocking drugs and antagonists. Curr Opin Anaesthesiol. 2015 Aug;28(4):403-10.

Is Residual NMB an Issue? 44% of rocuronium patients have residual paralysis (Maybauer) 57% of cisatricurium patients as well Drug shortages Dosing variability Maybauer DM, et al. Incidence and duration of residual paralysis at the end of surgery after multiple administrations of cisatracurium and rocuronium. Anaesthesia. 2007 Jan;62(1):12-7. Howard J et al. Glycopyrrolate: It's time to review. J Clin Anesth. 2017 Feb;36:51-53. “Medication shortages have become an all-too-common inconvenience that has forced anesthesia providers to examine our administering practices. Because of these shortages, commonly used medications are at the greatest risk. Glycopyrrolate (Robinul), which has been in short supply in recent years, is one of the most widely used anticholinergic agents, especially in conjunction with the anticholinesterase neostigmine, for reversal of neuromuscular blockade (NMB) drugs.” Maybauer DM, et al. Incidence and duration of residual paralysis at the end of surgery after multiple administrations of cisatracurium and rocuronium. Anaesthesia. 2007 Jan;62(1):12-7. Howard J et al. Glycopyrrolate: It's time to review. J Clin Anesth. 2017 Feb;36:51-53.

Classic Criteria for Extubation Measurement Value for Successful Weaning Measured on ventilator: PaO2:FiO2 ratio >150 (PaO2 in mm Hg) Resting minute volume <10 L/min Negative inspiratory force −20 to −30 cmH 2 O Diaphragm ultrasound Paradoxical movements Measured during brief period of spontaneous breathing: Respiratory rate <30 breaths/min Tidal volume >4–6 ml/kg Respiratory rate : tidal volume ratio >60 breaths.l −1 Respiratory Support and Artificial Ventilation Andrew B Lumb MB BS FRCA Nunn's Applied Respiratory Physiology, Chapter 31, 451-478.e3 Respiratory Support and Artificial Ventilation Andrew B Lumb MB BS FRCA Nunn's Applied Respiratory Physiology, Chapter 31, 451-478.e3

Retrospective, 5 VA Hospitals 8,984 adult patients from 2003-2008 who received NMB 78.4% received reversal agent, 21.6% did not

Patient vs Hypothesis

Bronsert et. al. VA population only Lack of reversal associated with: Post-op respiratory complications ↑ 30 day mortality

Retrospective study, Jan 2007 to Sept 2012 AIMS + Research Patient Data Registry 48,499 included in analysis McLean DJ, et al. Dose-dependent Association between Intermediate-acting Neuromuscular-blocking Agents and Postoperative Respiratory Complications. Anesthesiology 2015; 122:1201-13

Conclusions NMBA dose dependent association with increased risk of respiratory complications Higher doses of neostigmine were associated with more frequent respiratory complications

Monitor… 24.4% - 37.2% of patients had TOF monitoring Grosse-Sundrup M, et al. Intermediate acting non-depolarizing neuromuscular blocking agents and risk of postoperative respiratory complications: prospective propensity score matched cohort study. BMJ. 2012 Oct 15;345:e6329. Murphy GS. Residual neuromuscular block: lessons unlearned. Part I: definitions, incidence, and adverse physiologic effects of residual neuromuscular block. Anesth Analg. 2010 Jul;111(1):120-8. Figure 20.12. Electrode placement to obtain contraction of the adductor pollicis muscle. The traditional method is to apply the electrodes over the course of the ulnar nerve at the wrist, with the negative electrode distal (right). An alternate method is to position the electrodes over the adductor pollicis muscle (left), the negative electrode on the palm of the hand, the positive in the same location, but on the dorsum of the hand. The device fixed to the thumb is an accelerometer. Grosse-Sundrup M, et al. Intermediate acting non-depolarizing neuromuscular blocking agents and risk of postoperative respiratory complications: prospective propensity score matched cohort study. BMJ. 2012 Oct 15;345:e6329. Murphy GS. Residual neuromuscular block: lessons unlearned. Part I: definitions, incidence, and adverse physiologic effects of residual neuromuscular block. Anesth Analg. 2010 Jul;111(1):120-8.

TOF… Location/Muscle group Visual/Tactile Accelerometry Displacement Phonomyography There are two important muscles around the eye, both supplied by the facial nerve, with major differences in response of muscles and these differences have introduced some confusion in the literature. The orbicularis oculi muscle essentially covers the eyelid, and its response to neuromuscular blocking agents is similar to that of the adductor pollicis muscle. However, the muscle that moves the eyebrow is the corrugator supercilii, and recordings at that site are similar to that of the laryngeal adductors (Fig. 20‐14), with a faster onset and more rapid recovery than at the adductor pollicis. Thus, facial nerve stimulation with inspection of the response of the eyebrow is indicated to predict intubating conditions and to monitor profound blockade.

 Agents

Neostigmine/Glycopyrolate Mechanism Recall organic chemistry Acetylcholinesterase Anticholinergic Appropriate dosage Deviation from appropriate dosing1 Similar drugs Dubovoy T, et al. Observational study on patterns of neuromuscular blockade reversal. BMC Anesthesiol. 2016 Oct 22;16(1):103. Using electronic health record data, we hypothesized that larger reversal doses are used for patients with deeper levels of neuromuscular blockade (NMB) as evidenced by the last recorded TOF measurement. We also examined if dosing regimens reflect current practice guidelines of using ideal body weight (IBW) for NMB agents and total body weight (TBW) for neostigmine 135,633 cases met inclusion criteria for the study. There was no clinically significant difference in median neostigmine dosing based on last TOF count prior to reversal administration: 37.5 mcg/kg for TOF of 4/4 vs. 37.9 mcg/kg for TOF of 0/4 for the total neostigmine dose. Significantly higher number of patients with lower TOF counts received additional neostigmine administration: 5.7 % for 0/4 vs. 1.5 % for 4/4 TOF counts. Neither neostigmine dosing nor times to extubation were affected by the depth of the neuromuscular blockade prior to reversal. The need for additional reversal, or rescue, correlated strongly with the depth of NMB. There was significant variability in neostigmine dosing across the BMI categories. Underweight patients received relatively lower NMB doses while simultaneously receiving relatively higher reversal doses, and the opposite was true for patients with BMI >40 1. Dubovoy T, et al. Observational study on patterns of neuromuscular blockade reversal. BMC Anesthesiol. 2016 Oct 22;16(1):103.

Acetylcholinesterase Physiology SLUDE B2 Acetylcholinesterase inhibitor side effects

Sugammadex FDA approved 2016 Cyclodextrin Rocuronium, Vecuronium* Steroidal NMB Dose dependent on NMB present Gaining acceptance

L-Cysteine Non-essential amino acid Compare to N-acetyl cysteine Novel isoquinoliniums (Weill Cornell) Adduction to fumarate moiety Reversal at any time Neuroexcitatory vs. neurodegeneration in excess?? Heerdt PM, et. al. Novel neuromuscular blocking drugs and antagonists. Curr Opin Anaesthesiol. 2015 Aug;28(4):403-10.

Calabadion Derivatives of Cucurbit Covers the binding site Molecular “containers” Used for drug delivery systems Covers the binding site Rapid reversal Mechanism differs from sugammadex Experimental Rats Covers the quaternary amine sites for both benzylisoquinolinium and steroidal NMBDs to prevent binding to neuromuscular nicotinic receptor Hoffmann U, et al. Calabadion: a new agent to reverse the effects of benzylisoquinoline and steroidal neuromuscular-blocking agents. Anesthesiology 2013; 119:317–325. Heerdt PM, et. al. Novel neuromuscular blocking drugs and antagonists. Curr Opin Anaesthesiol. 2015 Aug;28(4):403-10. Hoffmann U, et al. Calabadion: a new agent to reverse the effects of benzylisoquinoline and steroidal neuromuscular-blocking agents. Anesthesiology 2013; 119:317–325.

Conclusion NMB and reversal decisions directly effect outcomes Value anaylsis should be part of anesthetic decision making Landscape of reversal agents available is actively changing with more drugs on the way

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Thank you! Acknowledgements Samantha Evankovich, C-AA Program Committee Thank you!