PAST, PRESENT, AND FUTURE OF

NEUROMUSCULAR REVERSAL AGENTS

Jennifer Bradley, BS, BSN, SRNA

OBJECTIVES• Review anticholinesterase agents: history,

mechanism of action, dosing

• “When” to reverse: TOF monitoring, adequate return of muscular function, acceleromyography

• Discuss issues with current reversal agents

• Review of Sugammadex: mechanism of action, current research, impact on future practice , update of FDA approval status

HISTORY

• Physostigmine (prototype)- derived from the Calabar bean of the physostigma veneosum plant in West Africa

• 1864-The pure alkaloid (physostigmine) was isolated by Jobste and Hesse

• 1877-First therapeutic drug use was to treat glaucoma

• 1900- A physiologist in Vienna performed experiments on dogs paralyzed with curare-observed respiratory recovery with physostigmine

HISTORY

• Physostigmine (prototype)- derived from the Calabar bean of the physostigma veneosum plant in West Africa

• 1864-The pure alkaloid was isolated by Jobste and Hesse and named physostigmine

• 1877-First therapeutic drug use was to treat glaucoma

• 1900- A physiologist in Vienna performed experiments on dogs paralyzed with curare-observed respiratory recovery with physostigmine

HISTORY

• 1931-Neostigmine was introduced into therapeutics for GI tract stimulation and symptomatic treatment of myasthenia gravis

• 1946-Neuromuscular blocking agents (NMBA) were established in England’s anesthesia practice- anticholinesterases were only suggested

• 1950’s (mid)-Incomplete surgical recovery and high incidence of morbidity/mortality led to use of reversal agents in anesthesia

CHOLINESTERASE INHIBITORS (BASIC

PRINCIPLES)• Currently the primary clinical use of cholinesterase

inhibitors is to reverse nondepolarizing muscle blockade

• Acetylcholine (ACh) is the neurotransmitter for the:• entire parasympathetic nervous system• parts of the sympathetic nervous system• select neurons in the central nervous system• somatic nerves innervating skeletal muscle

• Neuromuscular transmission is blocked when nondepolarizing muscle relaxants (NDMR) compete with acetylcholine to bind to nicotinic cholinergic receptors

MECHANISM OF ACTION

• The cholinesterase inhibitors indirectly increase the amount of acetylcholine available to compete with the NDMR by reversibly binding to inactivate the acetylcholinesterase enzyme

• Acetylcholinesterase is responsible for the rapid hydrolysis of the neurotransmitter (ACh) acetylcholine to choline and acetic acid

• Neostigmine, physostigmine, pyridostigmine, and edrophonium follow this generic mechanism; increasing the availability of acetylcholine at the neuromuscular junction (NMJ) to compete with the NDMR

MECHANISM OF ACTIONCONTINUED

• The mechanism of action of these drugs not only increases neuromuscular transmission but elicits muscarinic side effects

• Cellular goal of reversing the neuromuscular blockade:• maximize nicotinic transmission• minimize muscarinic side effects

• Reversal of blockade depends on: • Pharmacokinetics-of the NDMR and the anticholinesterase

MUSCARINIC SIDE EFFECTS OF

CHOLINESTERASE INHIBITORS

Organ System Muscarinic Side Effects

CardiovascularDecreased heart rate, bradyarrhythmias

PulmonaryBronchospasm, bronchial secretions

Cerebral Diffuse excitation

GastrointestinalIntestinal spasm, increased salivation, nausea

Genitourinary Increased bladder tone

Ophthalmological Pupillary constriction

Unwanted muscarinic side effects are minimized by prior or concomitant administration of

anticholinergic medications, such as atropine sulfate or glycopyrrolate(Robinul)

STRUCTURES

PHYSOSTIGMINE• Structure: Tertiary amine, a carbamate group. but no

quaternary ammonium. Lipid soluble and the only clinically available cholinesterase inhibitor that freely passes the blood-brain barrier

• Dosing: The recommended dosage is 0.01-0.03 mg/kg.• Physostigmine (0.04 mg/kg) has been shown to be effective in

preventing postoperative shivering

• Packaging: Packaged as a solution containing 1 mg/mL

• Effects: Onset, 1-2min with the duration of action 45-60min

• Metabolism: Plasma esterases

PHYSOSTIGMINE

• Anticholinergic Choice: Not typically needed. Bradycardia is infrequent in the recommended dosage range, but atropine should be immediately available

• Other Factors: Ability to antagonize morphine-induced respiratory depression

• Effective in the treatment of central anticholinergic toxicity caused by overdoses of atropine or scopolamine

• Reverses some of the CNS depression and delirium associated with use of benzodiazepines and volatile anesthetics

NEOSTIGMINE• Structure: Consists of a carbamate moiety (covalent

bonding) and a quaternary ammonium group (lipid insoluble) to prevent passage through the blood brain barrier (BBB)

• Dosing: Most potent: 0.03-0.08 mg/kg (up to 5 mg in adults)

• Packaging: Most commonly packaged in a 10 mL vial of a 1 mg/mL solution ( although 0.5 mg/mL and 0.25 mg/mL concentrations are also available)

• Effects: 5-7 min, peak at 10 min, BUT may take 15-30 minutes for full effect Duration: >1 hr

• Metabolism: 50% hepatic, ~ 25% Renal ~ 25% plasma esterases

NEOSTIGMINE• Anticholinergic choice: Glycopyrollate’s onset and

duration (0.2 mg glycopyrrolate per 1 mg of neostigmine) is similar to that of neostigmine and is associated with less tachycardia than is experienced with atropine (0.4 mg of atropine per 1 mg of neostigmine)

• Factors to consider: The duration of action is prolonged in geriatric patients

• Reported that neostigmine crosses the placenta, resulting in fetal bradycardia

• Neostigmine is also used to treat myasthenia gravis, flaccid bladder, and paralytic ileus

PYRIDOSTIGMINE• Structure: Pyridostigmine is similar to neostigmine but

the quaternary ammonium is incorporated into the phenol ring. Pyridostigmine shares neostigmine’s covalent binding to acetylcholinesterase and its lipid insolubility

• Dosing: 20% as potent as neostigmine and may be administered in doses up to 0.25 mg/kg (up to a total of 20 mg in adults)

• Packaging: It is available as a solution of 5 mg/mL

• Effects: Slowest onset of action(10-20 minutes) and longest duration (>2 h)

• Metabolism: 75% hepatic

PYRIDOSTIGMINE

• Anticholinergic choice: Glycopyrollate (0.05 mg per 1 mg of pyridostigmine) or atropine (0.1 mg per 1 mg of pyridostigmine) to prevent bradycardia

• Glycopyrrolate is preferred because its slower onset of action better matches that of pyridostigmine, and results in less tachycardia

EDROPHONIUM• Structure: Lacks a carbamate group, therefore it relies on

noncovalent bonding to the acetylcholinesterase enzyme. The quaternary ammonium group limits lipid solubility

• Dosing: Less than 10% as potent as neostigmine. The recommended dosage is 0.5-1 mg/kg

• Packaging: Available as a solution containing 10 mg/mL; it is available with atropine as a combination drug (Enlon-Plus; 10 mg edrophonium and 0.14 mg atropine per 10mLvial). Max 40mg

• Effects: Most rapid onset of action (30-60s) and the shortest duration of action of all the cholinesterase inhibitors (20-40 minutes)

• Metabolism: 30% Hepatic, ~ 70% Renal

EDROPHONIUM

• Anticholinergic Choice: Edrophonium’s rapid onset is well matched to atropine (0.014 mg of atropine per 1 mg of edrophonium)(preferred)

• Glycopyrrolate (0.007-0.1 mg per 1 mg of edrophonium) can also be used, but it should be given several minutes prior to edrophonium

• Facts: Reduced doses should not be used, longer acting muscle relaxants may outlast the effects of edrophonium

• In equipotent doses, muscarinic effects of edrophonium are less pronounced – approximately 50% less dose of anticholinergic typically needed

ANTICHOLINESTERASES

Agent

Dose(mg/kg)

PeakAntagonism(min)

Duration of

Antagonism (min)

Dosage of Atropine(mcg/kg)

Dose of Robinul

(mcg/kg)

Metabolism and

Comments

Edrophonium(Tensilon)

0.5-1.0 30-60s 40-60 7-14 7-10 30% hepatic*

Neostigmine(Prostigmin)

0.03-0.08

(up to 5mg)

5-7 55-75 14-40 1-2 50% hepatic**

Pyridostigmine

(Mestinon)

0.25 10-15 80-130 15-20 10 75% hepatic***

ANTICHOLINESTERASESDOSING

Cholinesterase Inhibitor

Usual Dose of Cholinesterase Inhibitor

Recommended Anticholinergic

Usual Dose of Anticholinergic per 1 mg of Cholinesterase Inhibitor

Neostigmine0.04-0.08 mg/kg

Glycopyrrolate 0.2 mg

Pyridostigmine 0.1-0.25 mg/kg Glycopyrrolate 0.05 mg

Edrophonium 0.5-1 mg/kg Atropine 0.014 mg

Physostigmine0.01-0.03 mg/kg

Usually not necessary

NA

ADDITIONAL INFO

• In excessive doses, acetylcholinesterase inhibitors can potentiate a nondepolarizing neuromuscular blockade

• These drugs also prolong the depolarization blockade of succinylcholine

• Prolonged action of a nondepolarizing muscle relaxant from renal or hepatic insufficiency will likely be accompanied by a corresponding increase in the duration of action of a cholinesterase inhibitor

ADDITIONAL INFO

• The time required to fully reverse a nondepolarizing block depends on several factors:

• choice and dose of cholinesterase inhibitor administered

• the muscle relaxant being antagonized

• the extent of the blockade before reversal

• Recommended: A reversal agent should be routinely given to patients who have received NDMR- unless full reversal can be demonstrated or the postoperative plan includes continued intubation

FACTORS THAT POTENTIATE

NEUROMUSCULAR BLOCKADEDrugs

•Volatile anesthetics•Antibiotics: Aminoglycosides• clindamycin,• neomycin• polymyxin B• tetracycline •,Dantrolene•Verapamil•Furosemide•Lidocaine

Electrolytes and acid-base disorders•Hypermagnesemia•Hypocalcemia•Hypokalemia•Respiratory acidosis

Temperature•Hypothermia

HALF-WAY VIDEO

REVERSAL CONSIDERATIONS:

MONITORING BLOCKADE

• Monitoring the depth of paralysis when using NDMR is an important part of standard practice when considering reversal

• Train-of-Four (TOF) stimulation was introduced in 1970 by Ali and colleagues

• There are different patterns of stimulation possible with the TOF monitor

TOF MONITORING BASICS

• Single Stimulus: Simplest-single impulse every 10seconds

• TOF stimulation: 4 impulses over 2 seconds ( at 2Hz) and relating the ratio of the last twitch (T4) to the first twitch (T1)

• Tetanic Stimulation: 50hz ( 50 stimuli per second) or 100Hz for 5 seconds

• Post-tetanic facilitation (PTC): 50Hz stimulus for 5 seconds followed in 3 seconds by repetitive single twitches at 1 Hz

• Double Burst: Initial burst of 2 (0.2-ms) impulses at 50 Hz followed by an identical stimulation in 750ms

TOF MONITORING

•Optimal placement: black electrode (-) closest proximity to the nerve, red (+) electrode distal monitoring to reach maximum twitch height

•Most commonly monitored nerve is the ulnar contraction of the adductor pollicis muscle of the thumb (extubating conditions)

•Opthalmic branch of the facial nerve contraction of the orbicularis occuli (intubating conditions)

•Peroneal nerve (near the fibular head)dorsiflection of the ankle

•Posterior tibial nerve (behind knee)plantar flexion of the big toe

APPROPRIATE TIME TO REVERSE BASED ON

NERVE STIMULATION

• Neuromuscular blockade can be reversed when there is at least ONE twitch with TOF stimulation-but the recommendation is a MINUMUM of 2 TOF twitches

• It is important to remember that only ONE of the alpha subunits of the post-junctional receptor needs to be occupied by NDMB to inhibit function and TWO Ach molecules are required to stimulate the receptor

Test ResultsPercentage of Receptors Occupied

Tidal Volume >5 ml/kg 80

Single twitch* Return to baseline 75-80

Train of four (4/4) No fade 70-75

Sustained tetanus(50 Hz, 5 seconds)**

No fade 70

Vital capacity >20 ml/kg 70

Double-burst stimulation

No fade 60-70

Sustained tetanus(100 Hz, 5 seconds)**

No fade 50

Inspiratory force >-40 cm H20 50

Head lift Sustained 5 seconds 50

Hand grip Return to baseline 50

Sustained bite Sustained clenching of a tongue depressor

50

Tests of Return of Neuromuscular Function

RETURN OF NEUROMUSCULAR

FUNCTION• In general, the higher the frequency of stimulation, the

greater the sensitivity of the test (100-Hz tetany > 50-Hz tetany>TOF > single-twitch height)

• Clinical signs of adequate reversal also vary in sensitivity (sustained head lift/ hand grip > inspiratory force > vital capacity > tidal volume)

• The suggested end points of recovery are sustained tetanus for 5 sec in response to a 100-Hz stimulus in anesthetized patients or sustained head or leg lift in awake patients

• Other methods for assessing recovery from neuromuscular blockade, such as acceleromyography, may help reduce the incidence of residual blockade

ACCELEROMYOGRAPHY• Easy to use, relatively inexpensive and provides more

quantitative information regarding TOF ratio

• The device is usually attached to the tip of the thumb and a digital readout is obtained (TOF ratio)

• The setup is sensitive to inadvertent displacement of the thumb and careful positioning and placement of the hand is important

• The operating concept is the knowledge that acceleration is measured by the TOF

• According to Newton's law, acceleration is proportional to force if mass remains unchanged

ACCELEROMYOGRAPHY

• Studies addressing post op residual blockade have begun to look at the potential benefit using acceleromyography

• Acceleromyography studies have shown a significant decrease in the incidence of TOF <0.9

• In a 2011 study that looked at 115 post-op patients 14.5% of those measured with acceleromyography had residual blockade versus 50% of patients monitored with the conventional TOF monitor

ISSUES ENCOUNTERED WITH REVERSAL

• Residual paralysis remains a serious clinical concern despite intermediate acting NMBA

• Studies have shown that after a single dose of NMBA 37% of patients have shown residual paralysis

• It is estimated that approximately 30%-60% of PACU patients have a TOF<0.9

• Remember: There is an upper limit to the amount of acetylcholinesterase inhibition that is possible at the neuromuscular junction

ISSUES ENCOUNTERED WITH REVERSAL

• Clinically evident events have occurred in 1%-3% of patients with TOF< 0.9

• 0.8-6.9% of these events result in serious respiratory complications

• In a case control study of 42 critical respiratory events in the PACU, patients with mean TOF <0.62 accounted for 74% of the adverse events (P<0.0001)

• Remember: muscles of the hypoglossal area are among the last to recover, which also increases the aspiration risk in these patients

ISSUES ENCOUNTERED WITH REVERSAL

• Think of the patients: muscle weakness due to residual blockade can be uncomfortable/frightening

• Unwanted events may also occur during transport between the OR and PACU

• Ultimately, patients with residual blockade may have longer PACU stays or require re-intubation

PROBLEMS WITH NEOSTIGMINE/GLYCOPYRROLATE

COMBINATIONS

• Ineffective at reversing profound blockade

• Cardiac arrhythmias

• Combination of two powerful cardiovascular drugs• Is the calculated reversal appropriate for each patient• Errors? • Inability to appropriately match two drugs

CHARACTERISTICS OF AN IDEAL REVERSAL

AGENT• Quickly and completely reverses NDMB regardless of the

depth of blockade

• Achieve reversal without side effects (minimal)

• Provides the possibility to continue full paralysis until the end of the procedure

• Serve as an alternative to succinylcholine for rapid sequence induction

• Has the potential to decrease the incidence of post-op residual blockade

SELECTIVE RELAXANT BINDING AGENT

• Sugammadex (Bridion)-first in class using a novel mechanism of action

• Approved in the European Union in 2008

• Currently approved in >50 countries, with >5million vials sold

• Awaiting approval from US FDA

SUGAMMADEX

• Sugammadex is in the family of cyclic dextrose units used as solubilizing agents since 1953

• Modfied gamma-cyclodextrine-comprised of 8 sugar molecules that form a rigid ring with a central lipophilic cavity

• Initially discovered when a compound was needed to increase the solubility of rocuronium in a specific media

• Observed permanent binding of the rocuronium molecule to the center of the sugammadex molecule in a 1:1 ratio

MECHANISM OF ACTION

• Hydrophobic interactions trap the drug in the cyclodextrine cavity forming a tight a water-soluble complex in a 1:1 ratio (encapsulation)

• A concentration gradient is created with no free unbound NMBA in the plasma as compared to the extravascular compartment

• Favors movement of NDMB (rocuronium or veuronium) into the plasma where they are rapidly encapsulated

• Terminates the NDMR’s action and restrains the drug in extracellular fluid where it cannot interact with nicotinic acetylcholine receptors

MOA VIDEO

GENERAL FINDINGS

• Extensive research and numerous clinical trials have evaluated the safety, efficacy, and usefulness of sugammadex

• A metaanalysis including 18 randomized controlled trials (RTC’s) demonstrated that sugammadex can reverse rocuronium induced blockade faster than neostigmine at all levels of blockade in a dose dependent manner

• In trials of immediate reversal sugammadex (16mg/kg) was administered 3 minutes after profound blockade by rocuronium and showed faster recovery than patients who underwent spontaneous recovery from succinylcholine

DOSING Available: 2mL or 5mL vials (100mg/mL) Elimination: 24h clearance unchanged via kidneys

Dose Sugammadex Indication Mean Recovery time to TOF 0.9

16mg/kg Immediate Reversal after 1.2 mg/kg rocuronium

1.5 minutes

4mg/kg Routine reversal of deep neuromuscular block (PTC 1-2)

3 minutes

2mg/kg Routine reversal of moderate block (T2 appearance)

2 minutes

RESEARCH FINDINGS• In a 2012 RCT by Geldner et al, researchers evaluated 140

patients randomized into neostigmine versus sugammadex groups to evaluate blockade recovery time• Found that those who received sugammadex recovered 3.4 times

faster (CI:95%) • 94% of sugammadex patients recovered within 5 minutes versus

20% of the neostigmine patients

• In a 2011 RCT by Kadoi et al, researchers evaluated recovery times of ECT patients who received succinylcholine for muscle relaxation versus rocuronium and sugammadex• Found that sugammadex 16mg/kg administered 3 minutes after

rocuronium showed faster return to TOF 0.9 and faster return to respirations (CI 99%)

• Sugammadex 8mg/kg showed recovery times equivalent to succinylcholine

• Sugammadex 4mg/kg showed slower recovery times compared to succinylcholine

DRAWBACKS• Hypersensitivity reactions: variable from rashes,

bronchospasm, hypotension, to anaphylactic reaction

• Cyclodextrines are prominent molecules with daily exposures, leading to the possibility of cross sensitivity

• Case reports have shown allergic reactions in patients who have received sugammadex for the first time

• Reviews of published approval studies and retrospective data have shown the incidence to be < 1%

• The British Journal of Anesthesia discussed three case reports of suspected hypersensitivity and reported occurrence of 1-3500 to 1-13,000 cases

DRAWBACKS

•Inability to reverse benzylquinolones

•Recurrence of neuromuscular blockade (when inadequate dose used)

•Small risk of QT prolongation, nausea, prolonged bleeding times (with use of 16mg/kg dose)

•Not suggested to use when a patient is taking fusidic acid or toremifene ( potential for delayed recovery )

•Not to be used in patients with highly impaired renal function: dialysis or creatinine clearance <30mL/min

FUTURE PRACTICE• Sugammadex has the potential to allow full blockade to

remain until the “last stich” and ensure complete reversal even at post-tetanic counts

• Importance in Can’t Intubate Can’t Ventilate cases where a difficult airway was unrecognized and rocuronium or vecuronium was used at induction

• Ability to replace succinylcholine in rapid sequence inductions and ECT’s

• New research showing its efficacy in patients who are typically not candidates for neuromuscular blockade

• Safer cardiac profile-concurrent administration of anticholinergic is not required

FDA APPROVAL STATUS

• Since its approval in 2008 for use in the European Union, Merck has sought US FDA approval

• Sugammadex was denied approval in 2008 and was re-submitted to the FDA for approval in January 2013

• September 2013 the FDA requested the Merck researchers to “re-do” their hypersensitivity trials

• Currently Merck is conducting new hypersensitivity trials with hopes for approval in January 2015

• Final Obstacle: Cost $$

SUMMARY

• Anesthesia is a continually evolving field with new standards, monitoring techniques, medications, and management styles

• To improve current standards we must understand our current methods and recognize areas that can be improved upon

• Though sugammadex is not yet available in the US, it is on the horizon

• Sugammadex carries the potential to impact our practice and provide choice with reversal agents

REFERENCES

• Duke, James. "Chapter 13 Muscle Relaxants AndMonitoring of Relaxant Activity." Anesthesia Secrets. Philadelphia, PA: Mosby/Elsevier, 2011. 95-104. Print.

• Geldner, G., M. Niskanen, P. Laurila, V. Mizikov, M. Hübler, G. Beck, H. Rietbergen, and E. Nicolayenko. "A Randomised Controlled Trial Comparing Sugammadex and Neostigmine at Different Depths of Neuromuscular Blockade in Patients Undergoing Laparoscopic Surgery*." Anaesthesia 67.9 (2012): 991-98. Print.

• Godai, K., M. Hasegawa-Moriyama, T. Kuniyoshi, T. Kakoi, K. Ikoma, S. Isowaki, A. Matsunaga, and Y. Kanmura. "Three Cases of Suspected Sugammadex-induced Hypersensitivity Reactions." British Journal of Anaesthesia 109.2 (2012): 216-18. Print.

• Kadoi, Yuji, Hiroko Hoshi, Akiko Nishida, and Shigeru Saito. "Comparison of Recovery times from Rocuronium-induced Muscle Relaxation after Reversal with Three Different Doses of Sugammadex and Succinylcholine during Electroconvulsive Therapy." Journal of Anesthesia 25.6 (2011): 855-59. Print

• Kirkland, Matt L., John J. Nagelhour, and Mark D. Welliver. "Deep Neuromuscular Blockade: Exploration and Perspectives on Multidisciplinary Care." AANA Journal (2013): 2+. Print.

• "Merck Sharp & Dohme Limited." Bridion 100 Mg/ml Solution for Injection. MSD, 25 Oct. 2013. Web. https://www.medicines.org.uk/emc/medicine/21299/SPC/Bridion+100+mg+ml+solution+for+injection/ 10 Mar. 2014,

REFERENCES

• Chapter 12. Cholinesterase Inhibitors & Other Pharmacologic Antagonists to Neuromuscular Blocking Agents. In: Butterworth JF, IV, Mackey DC, Wasnick JD. eds. Morgan & Mikhail's Clinical Anesthesiology, 5e. New York: McGraw-Hill; 2013. http://accessanesthesiology.mhmedical.com/content.aspx?bookid=564&Sectionid=42800543.Accessed March 10, 2014.

• Murphy, Glen S., Joseph W. Szokol, Michael J. Avram, Steven B. Greenberg, Jesse H. Marymont, Jeffery S. Vender, Jayla Gray, Elizabeth Landry, and Dhanesh K. Gupta. "Intraoperative Acceleromyography Monitoring Reduces Symptoms of Muscle Weakness and Improves Quality of Recovery in the Early Postoperative Period." Survey of Anesthesiology 56.3 (2012): 150-51. Print.

• Sadleir, P.H.M, T. Russell, R.C. Clarke, E. Maycock, and P.R. Platt. "Intraoperative Anaphylaxis to Sugammadex and a Protocol for Intradermal Skin Testing." Anesthesia Intensive Care 42 (2014): 93-96. Web

• Schaller, Stefan J., and Heidrun Fink. "Sugammadex as a Reversal Agent for Neuromuscular Block: An Evidence Based Review." Core Evidence: Dove Medical Press, Ltd 8 (2013): 57-67. Print.

• Taylor P. Chapter 10. Anticholinesterase Agents. In: Brunton LL, Chabner BA, Knollmann BC. eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e. New York: McGraw-Hill; 2011. http://accessanesthesiology.mhmedical.com/content.aspx?bookid=374&Sectionid=41266216. Accessed March 10, 2014.

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