1. George Williams, II, MD, FCCP
STICU NPO Guidelines
Update
George Williams, II, MD, FCCP
Associate Professor

2. 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

3. Disclosures
Scientific speaker for Merck®
No other disclosures

4. 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

13. ©Stan Stead, MD
©Stan Stead, MD

14. © Lionsgate
© Lionsgate

15. 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.

16. 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 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 Mar 28.

17. 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 Aug;28(4):
“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 Aug;28(4):

18. 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 Aug;28(4):
Heerdt PM, et. al. Novel neuromuscular blocking drugs and antagonists. Curr Opin Anaesthesiol Aug;28(4):

19. 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 Jan;62(1):12-7.
Howard J et al. Glycopyrrolate: It's time to review. J Clin Anesth 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 Jan;62(1):12-7.
Howard J et al. Glycopyrrolate: It's time to review. J Clin Anesth Feb;36:51-53.

20. 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, e3
Respiratory Support and Artificial Ventilation
Andrew B Lumb MB BS FRCA
Nunn's Applied Respiratory Physiology, Chapter 31, e3

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

22. Patient vs Hypothesis

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

25. 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:

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

29. 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 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 Jul;111(1):120-8.
Figure 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 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 Jul;111(1):120-8.

30. 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.

31.  Agents

32. 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 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 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 Oct 22;16(1):103.

33. Acetylcholinesterase Physiology
SLUDE B2
Acetylcholinesterase inhibitor side effects

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

35. 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 Aug;28(4):

36. 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 Aug;28(4):
Hoffmann U, et al. Calabadion: a new agent to reverse the effects of benzylisoquinoline and steroidal neuromuscular-blocking agents. Anesthesiology 2013; 119:317–325.

37. 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

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