the latest approaches to reversal of neuromuscular blocking...
TRANSCRIPT
The Latest Approaches to Reversal of Neuromuscular Blocking Agents Janay Bailey, Pharm.D.
An
esth
esio
logy
201
7; 1
26:1
73-9
0
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
Pre Questions
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
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
Question True or false: A train of four of 90% means that a neuromuscular reversal agent is not needed.
Background
An
esth
esio
logy
201
7; 1
26:1
73-9
0
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
Neuromuscular Transmission
Harrison's Principles of Internal Medicine, 19e; 2015
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
Neuromuscular Blocking Agents (NMBAs)
An
esth
esio
logy
201
7; 1
26:1
73-9
0
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
Neuromuscular Blocking Agents
Aminosteroid
• Rocuronium* • Vecuronium • Pancuronium
Benzylisquinolinium
• Cisatracurium • Mivacurium* • Atracurium
Aminosteroid Compounds
Hibbs RE et al. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e New York, NY: McGraw-Hill
Benzylisquinolinium Compunds
https://aneskey.com/neuromuscular-blocking-drugs-and-reversal-agents/2017; 126:173-90
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
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
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
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
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
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
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
Neuromuscular Blocking Reversal
Agents
An
esth
esio
logy
201
7; 1
26:1
73-9
0
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
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.
Sugammadex
https://aneskey.com/a-history-of-neuromuscular-block-and-its-antagonism/2017; 126:173-90
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
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
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
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
Nerve Stimulation
An
esth
esio
logy
201
7; 1
26:1
73-9
0
Nerve Stimulation • Single Twitch Stimulation
• Train-of-Four (TOF) Stimulation
• Tetanic Stimulation
• Double Burst Stimulation
Anesthesiology 2017; 126:173-90
Single Twitch Stimulation
Clinical Anesthesia 2017; 8th ed.
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
Neuromuscular Monitoring • Mechanomyography
• Electromyography
• Acceleromyography
• Kinemyography
Anesthesiology 2017; 126:173-90
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
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
Acceleromyography • Measures acceleration of muscle tissue in the thimb
• Small, portable devices
• Requires appropriate electrode equipment
• Experienced personnel
Anesthesiology 2017; 126:173-90
Kinemyography • Quantitative device
• Similar to acceleromyography
• Measure degree of bending
• Easy to use
• Reliable
• Lack of availability
Anesthesiology 2017; 126:173-90
Train of Four
Anesthesiology 2017; 126:173-90
Train of Four
Anesthesiology 2017; 126:173-90
Train of Four
Anesthesiology 2017; 126:173-90
Proposed Definitions of Neuromuscular Blockade Depth
Anesthesiology 2017; 126:173-90 Acta Anaesthesiol Scand 2007; 51:789–808
Recommendations for Reversal
Anesthesiology 2017; 126:173-90
Comparison of Reversal Agents
An
esth
esio
logy
201
7; 1
26:1
73-9
0
Phase III, multicenter, randomized, parallel-group, safety assessor– blinded study (Signal Study)
Anesthesiology 2008; 109:816–24
Phase III, multicenter, randomized, parallel-group, safety assessor– blinded study (Signal Study)
Jones RK et al. Anesthesiology 2008;109:816–24
Paton F et al. Br J Anaesth 2010;105:558–67
Paton F et al. Br J Anaesth 2010;105:558–67
Sacan O et al. ANESTHESIA & ANALGESIA. 2007;3:569-574
Sacan O et al. ANESTHESIA & ANALGESIA. 2007;3:569-574
Post Questions
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
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
Question True or false: A train of four of 90% means that a neuromuscular reversal agent is not needed.
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