The Latest Approaches to Reversal of Neuromuscular Blocking...
Transcript of The Latest Approaches to Reversal of Neuromuscular Blocking...
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The Latest Approaches to Reversal of Neuromuscular Blocking Agents Janay Bailey, Pharm.D.
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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
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Pre Questions
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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
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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
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Question True or false: A train of four of 90% means that a neuromuscular reversal agent is not needed.
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Background
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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
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Neuromuscular Transmission
Harrison's Principles of Internal Medicine, 19e; 2015
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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
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Neuromuscular Blocking Agents (NMBAs)
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Neuromuscular Blocking Agents Drug Type Dosing Half-Life OOA
Succinylcholine (Anectine®, Quelicin®)
Depolarizing mg/min <60 seconds < 60 seconds
Am
inos
tero
id
Com
pou
nds
Rocuronium (Zemuron®)
Non-depolarizing
mg/kg 84 – 144 minutes
1-2 minutes
Vecuronium (Norcuron®)
Non-depolarizing
mcg or mg/kg
65-75 minutes
3-5 minutes
Pancuronium Non-depolarizing
mcg or mg/kg
89-161 minutes
3-5 minutes
Ben
zyli
squ
inol
iniu
m
Com
pou
nds
Cisatracurium (Nimbex®)
Non-depolarizing
mcg or mg/kg
22-29 minutes
2-3 minutes
Mivacurium (Mivacron®)
Non-depolarizing
mcg or mg/kg
~ 2 minutes 1.5-3 minutes
Atracurium (Tracrium®)
Non-depolarizing
mcg or mg/kg
22 minutes 2-3 minutes
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Neuromuscular Blocking Agents
Aminosteroid
• Rocuronium* • Vecuronium • Pancuronium
Benzylisquinolinium
• Cisatracurium • Mivacurium* • Atracurium
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Aminosteroid Compounds
Hibbs RE et al. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e New York, NY: McGraw-Hill
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Benzylisquinolinium Compunds
https://aneskey.com/neuromuscular-blocking-drugs-and-reversal-agents/2017; 126:173-90
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Succinylcholine (Anectine®, Quelicin®) • Used to induce neuromuscular blockade for surgery and intubation
• Ultrashort duration
• Onset: 0.8-1.4 minutes; Duration: 6-11 minutes
• Induces rapid depolarization of motor endplate
• Initiation dose: 0.3-1.5 mg/kg; Intermittent injection 0.04-0.07 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
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Rocuronium (Zemuron®) • Aminosteroid
• Used to induce neuromuscular blockade for surgery and intubation
• Intermediate duration
• Onset: 0.5-2 minutes; Duration: 36-73 minutes
• Blocks acetylcholine (ACh) from binding to receptors
• Initiation dose: 0.4-1.2 mg/kg; Intermittent injection 0.1-0.2 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
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Vecuronium (Norcuron®) • Aminosteroid
• Used to induce neuromuscular blockade for surgery and intubation
• Intermediate duration
• Onset: 2-3 minutes; Duration: 25-40 minutes
• Blocks acetylcholine (ACh) from binding to receptors
• Initiation dose: 0.04-0.28 mg/kg; Intermittent injection 0.01-0.015 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
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Pancuronium • Aminosteroid
• Used to induce neuromuscular blockade for surgery and intubation
• Long duration
• Onset: 3-4 minutes; Duration: 85-100 minutes
• Blocks neural transmission by binding with cholinergic receptors; antimuscarinic receptor activity
• Initiation dose: 0.04-0.1 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
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Cisatracurium (Nimbex®) • Benzylisquinolinium
• Used to induce neuromuscular blockade for surgery and intubation
• Intermediate duration
• Onset: 2-8 minutes; Duration: 45-90 minutes
• Blocks neural transmission by binding with cholinergic receptors
• Initiation dose: 0.15-0.2 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
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Mivacurium (Mivacron®) • Benzylisquinolinium
• Used to induce neuromuscular blockade for surgery and intubation
• Short duration
• Onset: 2-3 minutes; Duration: 15-21 minutes
• Antagonizes ACh by competitively binding to cholinergic sites
• Initiation dose: 0.15-0.25 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
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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: 0.3-0.5 mg/kg; Intermittent injection 0.08-0.2 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
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Neuromuscular Blocking Reversal
Agents
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Neuromuscular Blocking Reversal Agents Drug Category Dosing Half-Life OOA
Sugammadex (Bridion®)
Antidote; Selective Relaxant Binding Agent
mg/kg ~ 2 hours < 3 minutes
Neostigmine (Bloxiverz ®)
Acetylcholinesterase inhibitor
mg/kg 42-60 minutes 10-30 minutes
Edrophonium (Enlon®, Teversol®, Tensilon®)
Acetylcholinesterase inhibitor
10 mg, may repeat for cumulative dose of 40 mg
126 ± 59 minutes 30-60 seconds
Pyridostigmine Acetylcholinesterase inhibitor
mg/kg ~1.5 hours 2-5 minutes
Physostigmine Acetylcholinesterase inhibitor
0.5-2 mg, may repeat every 10-30 minutes
1-2 hours 3-8 minutes
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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.
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Sugammadex
https://aneskey.com/a-history-of-neuromuscular-block-and-its-antagonism/2017; 126:173-90
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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
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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
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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
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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
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Nerve Stimulation
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Nerve Stimulation • Single Twitch Stimulation
• Train-of-Four (TOF) Stimulation
• Tetanic Stimulation
• Double Burst Stimulation
Anesthesiology 2017; 126:173-90
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Single Twitch Stimulation
Clinical Anesthesia 2017; 8th ed.
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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
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Neuromuscular Monitoring • Mechanomyography
• Electromyography
• Acceleromyography
• Kinemyography
Anesthesiology 2017; 126:173-90
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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
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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
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Acceleromyography • Measures acceleration of muscle tissue in the thimb
• Small, portable devices
• Requires appropriate electrode equipment
• Experienced personnel
Anesthesiology 2017; 126:173-90
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Kinemyography • Quantitative device
• Similar to acceleromyography
• Measure degree of bending
• Easy to use
• Reliable
• Lack of availability
Anesthesiology 2017; 126:173-90
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Train of Four
Anesthesiology 2017; 126:173-90
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Train of Four
Anesthesiology 2017; 126:173-90
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Train of Four
Anesthesiology 2017; 126:173-90
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Proposed Definitions of Neuromuscular Blockade Depth
Anesthesiology 2017; 126:173-90 Acta Anaesthesiol Scand 2007; 51:789–808
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Recommendations for Reversal
Anesthesiology 2017; 126:173-90
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Comparison of Reversal Agents
An
esth
esio
logy
201
7; 1
26:1
73-9
0
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Phase III, multicenter, randomized, parallel-group, safety assessor– blinded study (Signal Study)
Anesthesiology 2008; 109:816–24
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Phase III, multicenter, randomized, parallel-group, safety assessor– blinded study (Signal Study)
Jones RK et al. Anesthesiology 2008;109:816–24
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Paton F et al. Br J Anaesth 2010;105:558–67
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Paton F et al. Br J Anaesth 2010;105:558–67
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Sacan O et al. ANESTHESIA & ANALGESIA. 2007;3:569-574
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Sacan O et al. ANESTHESIA & ANALGESIA. 2007;3:569-574
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Post Questions
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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
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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
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Question True or false: A train of four of 90% means that a neuromuscular reversal agent is not needed.
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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