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Past, present, and future of neuromuscular reversal agents

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

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Past, present, and future of neuromuscular reversal agents

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  1. Past, present, and future of neuromuscular reversal agents Jennifer Bradley, BS, BSN, SRNA

  2. 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

  3. History • Physostigmine (prototype)- derived from the Calabar bean of the physostigmaveneosum 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

  4. history • Physostigmine (prototype)- derived from the Calabar bean of the physostigmaveneosum 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

  5. 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

  6. 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

  7. 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 • Acetylcholinesteraseis responsible for the rapid hydrolysis of the neurotransmitter (ACh) acetylcholine to choline and acetic acid • Neostigmine, physostigmine, pyridostigmine, and edrophoniumfollow this generic mechanism; increasing the availability of acetylcholine at the neuromuscular junction (NMJ) to compete with the NDMR

  8. 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

  9. Muscarinic Side effects of Cholinesterase inhibitors Unwanted muscarinic side effects are minimized by prior or concomitant administration of anticholinergic medications, such as atropine sulfate or glycopyrrolate(Robinul)

  10. Structures

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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

  19. Anticholinesterases

  20. AnticholinesterasesDosing

  21. 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

  22. 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

  23. Factors that Potentiate Neuromuscular blockade

  24. Half-way video

  25. 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

  26. 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

  27. 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

  28. 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

  29. Tests of Return of Neuromuscular Function

  30. 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 for5 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

  31. 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

  32. 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 TOFmonitor

  33. 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

  34. 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

  35. 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

  36. 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

  37. 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

  38. 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

  39. 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

  40. 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

  41. Moa video

  42. 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

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

  44. 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

  45. 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

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