The Latest Approaches to Reversal of Neuromuscular Blocking Agents
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1 The Latest Approaches to Reversal of Neuromuscular Blocking Agents Janay Bailey, Pharm.D. Anesthesiology 2017; 126:173-90
2 Objectives Pharmacists Determine optimal paralytic choices in knowing if reversal is an option Choose the best neuromuscular blocking reversal agent Compare differences in the effects of available reversal agents Other Participants Discover available paralytics and neuromuscular blocking agents Decide on appropriate methods to store or prepare reversal agents Utilize caution when handling neuromuscular blocking agents and their reversal
3 Pre Questions
4 Question JP is a 59 y/o male with traumatic brain injury and end stage renal disease. Which neuromuscular blocking agent is best to use for JP? A. Rocuronium B. Succinylcholine C. Cisatricurum D. Mivacurium
5 Question ET is a 49 y/o female who received vecuronium to undergo an appendectomy. She has a history of myasthenia gravis with normal renal function. Which reversal agent would be most appropriate to reverse the neuromuscular blocking agent? A. Pyridostigmine B. Sugammadex C. Neostigmine D. Edrophonium
6 Question True or false: A train of four of 90% means that a neuromuscular reversal agent is not needed.
7 Background Anesthesiology 2017; 126:173-90
8 Introduction Acetylcholinesterase inhibitors (AChE-Is) are commonly used for the reversal of neuromuscular blocking agents (NMBAs) However, the undesirable side effect profile of these reversal agents during anesthesia recovery remains a common problem Bradycardia Neuromuscular dysfunction/residual block Cholinergic crisis Post-operative nausea and vomiting Post-operative pneumonia
9 Neuromuscular Transmission Harrison's Principles of Internal Medicine, 19e; 2015
10 Indications for Neuromuscular Blocking Agents Perform rapid sequence intubation Induce muscle paralysis for certain surgical procedures (ex. abdominal) Prevent movement during fragile surgery (ex. neuro or ocular) Control ventilation
11 Neuromuscular Blocking Agents (NMBAs) Anesthesiology 2017; 126:173-90
12 Neuromuscular Blocking Agents Drug Type Dosing Half-Life OOA Aminosteroid Compounds Benzylisquinolinium Compounds Succinylcholine (Anectine, Quelicin ) Rocuronium (Zemuron ) Vecuronium (Norcuron ) Pancuronium Cisatracurium (Nimbex ) Mivacurium (Mivacron ) Atracurium (Tracrium ) Depolarizing mg/min <60 seconds < 60 seconds Nondepolarizing Nondepolarizing Nondepolarizing Nondepolarizing Nondepolarizing Nondepolarizing mg/kg minutes mcg or mg/ kg mcg or mg/ kg mcg or mg/ kg mcg or mg/ kg mcg or mg/ kg minutes minutes minutes 1-2 minutes 3-5 minutes 3-5 minutes 2-3 minutes ~ 2 minutes minutes 22 minutes 2-3 minutes
13 Neuromuscular Blocking Agents Aminosteroid Rocuronium* Vecuronium Pancuronium Benzylisquinolinium Cisatracurium Mivacurium* Atracurium
14 Aminosteroid Compounds Hibbs RE et al. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e New York, NY: McGraw-Hill
15 Benzylisquinolinium Compunds 126:173-90
16 Succinylcholine (Anectine, Quelicin ) Used to induce neuromuscular blockade for surgery and intubation Ultrashort duration Onset: minutes; Duration: 6-11 minutes Induces rapid depolarization of motor endplate Initiation dose: mg/kg; Intermittent injection mg/kg Contraindications: history of malignant hyperthermia; muscle myopathy or dystrophy; acute injury following major burns, trauma Box warning: hyperkalemic rhabdomyolysis Hibbs RE et al. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e New York, NY: McGraw-Hill
17 Rocuronium (Zemuron ) Aminosteroid Used to induce neuromuscular blockade for surgery and intubation Intermediate duration Onset: minutes; Duration: minutes Blocks acetylcholine (ACh) from binding to receptors Initiation dose: mg/kg; Intermittent injection mg/kg Adverse events: peripheral vascular resistance, tachycardia, hypertension, transient hypotension Hibbs RE. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e New York, NY: McGraw-Hill
18 Vecuronium (Norcuron ) Aminosteroid Used to induce neuromuscular blockade for surgery and intubation Intermediate duration Onset: 2-3 minutes; Duration: minutes Blocks acetylcholine (ACh) from binding to receptors Initiation dose: mg/kg; Intermittent injection mg/kg Adverse events: bradycardia, edema, circulatory shock, flushing, pruritis Hibbs RE. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e New York, NY: McGraw-Hill
19 Pancuronium Aminosteroid Used to induce neuromuscular blockade for surgery and intubation Long duration Onset: 3-4 minutes; Duration: minutes Blocks neural transmission by binding with cholinergic receptors; antimuscarinic receptor activity Initiation dose: mg/kg; Intermittent injection 0.01 mg/kg Boxed warning: Administer by individuals who are trained and familiar with the use, actions, and characteristics Adverse events: tachycardia, hypertension, increased cardiac output Hibbs RE. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e New York, NY: McGraw-Hill
20 Cisatracurium (Nimbex ) Benzylisquinolinium Used to induce neuromuscular blockade for surgery and intubation Intermediate duration Onset: 2-8 minutes; Duration: minutes Blocks neural transmission by binding with cholinergic receptors Initiation dose: mg/kg; Intermittent injection 0.03 mg/kg Preferred agent for patients with renal failure Adverse events: bradycardia, bronchospasm, hypotension, myopathy Hibbs RE. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e New York, NY: McGraw-Hill
21 Mivacurium (Mivacron ) Benzylisquinolinium Used to induce neuromuscular blockade for surgery and intubation Short duration Onset: 2-3 minutes; Duration: minutes Antagonizes ACh by competitively binding to cholinergic sites Initiation dose: mg/kg; Intermittent injection 0.1 mg/kg Adverse events: flushing, hypotension, dizziness, arrhythmia, bronchospasm Hibbs RE. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e New York, NY: McGraw-Hill
22 Atracurium (Tracrium ) Benzylisquinolinium Used to induce neuromuscular blockade for surgery and intubation Intermediate duration Onset: 3 minutes; Duration: 45 minutes Blocks neural transmission by binding with cholinergic receptors Initiation dose: mg/kg; Intermittent injection mg/kg Preferred agent for patients with renal failure Adverse events: flushing, bradycardia, bronchospasm, dyspnea, seizure Hibbs RE. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e New York, NY: McGraw-Hill
23 Neuromuscular Blocking Reversal Agents Anesthesiology 2017; 126:173-90
24 Neuromuscular Blocking Reversal Agents Drug Category Dosing Half-Life OOA Sugammadex (Bridion ) Neostigmine (Bloxiverz ) Edrophonium (Enlon, Teversol, Tensilon ) Pyridostigmine Antidote; Selective Relaxant Binding Agent Acetylcholinestera se inhibitor Acetylcholinestera se inhibitor Acetylcholinestera se inhibitor mg/kg ~ 2 hours < 3 minutes mg/kg minutes minutes 10 mg, may repeat for cumulative dose of 40 mg 126 ± 59 minutes seconds mg/kg ~1.5 hours 2-5 minutes Physostigmine Acetylcholinestera se inhibitor mg, may repeat every minutes 1-2 hours 3-8 minutes
25 Sugammadex Modified gamma cyclodextrin Specific for aminosteroid non-depolarizing NMBAs Forms a complex with neuromuscular blocking agents, therefore decreasing the amount of blocking agent available to bind to nicotinic receptors Reverse profound, deep, and moderate block Adverse effects Bradycardia, N/V, pain, hypotension, headache Not recommended in severe renal impairment (CrCl < 30 ml/minute) Monitor neuromuscular stimulation, coagulation parameters; decreases serum estrogen concentration 100 mg/ml supplied in 2 ml and 5 ml; Stored at room temperature Bridion (sugammadex) [prescribing information]. Whitehouse Station, NJ; Merck & Co, Inc: June 2017.
26 Sugammadex 126:173-90
27 Neostigmine Inhibits destruction of acetylcholine by acetylcholinesterase Administer glycopyrrolate or atropine prior to or concomitantly Reverse moderate or light block Adverse effects Cholinergic crisis, bradycardia, hypotension, dysrhythmias Reduce dose with renal function < 10 ml/min; no adjustment for dialysis Monitor electrocardiogram (ECG), blood pressure, and heart rate Supplied as 0.5 mg/ml in 10mL and 1 mg/ml in 10 ml vials Store at room temperature
28 Edrophonium Inhibits destruction of acetylcholine by acetylcholinesterase Administered with atropine or glycopyrrolate Adverse effects Cholinergic crisis, arrhythmia, convulsions, diaphoresis No renal dose adjustments necessary Monitor pre and post injection strength, heart rate, respiratory rate, and blood pressure Supplied as 10 mg/ml Store at room temperature
29 Pyridostigmine Inhibits destruction of acetylcholine by acetylcholinesterase Administered with atropine or glycopyrrolate Adverse effects Abdominal pain, diarrhea, dysmenorrhea No renal dose adjustments necessary Monitor ECG, blood pressure, heart rate, cholinergic crisis Supplied as 10 mg/ml Store in refrigerator or at room temperature
30 Physostigmine Inhibits acetylcholinesterase therefore prolonging the effects of acetylcholine Administered with atropine or glycopyrrolate Adverse effects Arrhythmias, diarrhea, diaphoresis, urinary frequency No renal dose adjustments necessary Monitor ECG, vital signs Supplied as 10 mg/ml Store at room temperature
31 Nerve Stimulation Anesthesiology 2017; 126:173-90
32 Nerve Stimulation Single Twitch Stimulation Train-of-Four (TOF) Stimulation Tetanic Stimulation Double Burst Stimulation Anesthesiology 2017; 126:173-90
33 Clinical Anesthesia 2017; 8 th ed. Single Twitch Stimulation
34 Neuromuscular Monitoring Train-of-Four (TOF) Stimulation Quantitative measure of neuromuscular blockade Four nerve stimulators Inversely proportional to posttetanic responses Residual block: train of four <0.90 Tetanic Stimulation Double Burst Stimulation Two brief tetanic bursts Detected objectively Peripheral nerve stimulators (PNSs) Qualitative neuromuscular devices Anesthesiology 2017; 126:173-90
35 Neuromuscular Monitoring Mechanomyography Electromyography Acceleromyography Kinemyography Anesthesiology 2017; 126:173-90
36 Mechanomyography Measures force of contraction of the thumb Precise and reproducible Accepted standard Complex setup so no longer commercially available Utilized in research Anesthesiology 2017; 126:173-90
37 Electromyography Measure electrical activity from nerve stimulation Most physiologic and precise measure of synaptic transmission Not commercially available Sensitive to motion and electronic noise Can record activity from any muscle Anesthesiology 2017; 126:173-90
38 Acceleromyography Measures acceleration of muscle tissue in the thimb Small, portable devices Requires appropriate electrode equipment Experienced personnel Anesthesiology 2017; 126:173-90
39 Kinemyography Quantitative device Similar to acceleromyography Measure degree of bending Easy to use Reliable Lack of availability Anesthesiology 2017; 126:173-90
40 Anesthesiology 2017; 126: Train of Four
41 Anesthesiology 2017; 126: Train of Four
42 Anesthesiology 2017; 126: Train of Four
43 Proposed Definitions of Neuromuscular Blockade Depth Anesthesiology 2017; 126: Acta Anaesthesiol Scand 2007; 51:
44 Anesthesiology 2017; 126: Recommendations for Reversal
45 Comparison of Reversal Agents Anesthesiology 2017; 126:173-90
46 Anesthesiology 2008; 109: Phase III, multicenter, randomized, parallel-group, safety assessor blinded study (Signal Study)
47 Phase III, multicenter, randomized, parallel-group, safety assessor blinded study (Signal Study) Jones RK et al. Anesthesiology 2008;109:816 24
48 Paton F et al. Br J Anaesth 2010;105:558 67
49 Paton F et al. Br J Anaesth 2010;105:558 67
50 Sacan O et al. ANESTHESIA & ANALGESIA. 2007;3:
51 Sacan O et al. ANESTHESIA & ANALGESIA. 2007;3:
52 Post Questions
53 Question JP is a 59 y/o male with traumatic brain injury and end stage renal disease. Which neuromuscular blocking agent is best to use for JP? A. Rocuronium B. Succinylcholine C. Cisatricurum D. Mivacurium
54 Question ET is a 49 y/o female who received vecuronium to undergo an appendectomy. She has a history of myasthenia gravis with normal renal function. Which reversal agent would be most appropriate to reverse the neuromuscular blocking agent? A. Pyridostigmine B. Sugammadex C. Neostigmine D. Edrophonium
55 Question True or false: A train of four of 90% means that a neuromuscular reversal agent is not needed.
56 Conclusion When choosing which neuromuscular blocking agent to use, consider the potential need for timely reversal Evaluate patient characteristics with all options Minimize side effects Use shorter-acting agents when possible Early reversal is key Neuromuscular monitoring utilization
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