The Latest Approaches to Reversal of Neuromuscular Blocking …cbshpharm.org/wp-content/uploads/2016/08/NMBAs-Reversal... · 2018-06-26 · Neuromuscular Monitoring • Train-of-Four

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

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

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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

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)

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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

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

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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

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

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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

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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