Neuromuscular Blockers (PDF)

NEUROMUSCULAR BLOCKERS AND REVERSAL NRAN 80424 SPRING 2024 RON ANDERSON, M.D. 1 2023 ASA Practice Guideline 2 2023 ASA Practice Guidelines for Monitoring and Antagonism of Neuromuscular Blockade Highlights This practice guideline provides evidence-based recommendations on the management of neuromusc...

NEUROMUSCULAR BLOCKERS AND REVERSAL NRAN 80424 SPRING 2024 RON ANDERSON, M.D. 1 2023 ASA Practice Guideline 2 2023 ASA Practice Guidelines for Monitoring and Antagonism of Neuromuscular Blockade Highlights This practice guideline provides evidence-based recommendations on the management of neuromuscular monitoring and antagonism of neuromuscular blocking agents. The objective is to guide practice that will enhance patient safety by reducing residual neuromuscular blockade. It is recommended to use quantitative neuromuscular monitoring at the adductor pollicis and to confirm a recovery of train-of-four ratio greater than or equal to 0.9 before extubation. Sugammadex is recommended from deep, moderate, and shallow levels of neuromuscular blockade that is induced by rocuronium or vecuronium. Neostigmine is a reasonable alternative from minimal blockade (train-of-four ratio in the range of 0.4 to less than 0.9). Patients with adequate spontaneous recovery to train-of-four ratio greater than or equal to 0.9 can be identified with quantitative monitoring, and these patients do not require pharmacological antagonism. KEY POINTS Many different conditions are associated with change in the makeup of the nicotinic acetylcholine receptors (NAChRs) and will effect response to both depolarizing and non-depolarizing neuromuscular blockers An increase in the “immature” forms of NAChRs may result in excessive potassium release following administration of a depolarizing NMB Both succinylcholine and the non-depolarizing neuromuscular blockers act via binding the alpha subunits of the NAChRs 4 KEY POINTS Other than the distinction between depolarizing and non-depolarizing, the neuromuscular blockers are typically classified based on onset and duration of action Succinylcholine results in the fastest onset with the least variability and shortest duration of the NMBs. Monitoring of the typical succinylcholine block reveals no fade on train-of-four monitoring, and no post-tetanic facilitation There are significant side effects with all neuromuscular blockers, with distinct differences between succinylcholine and the non-depolarizing NMBs 5 KEY POINTS Succinylcholine is a trigger for malignant hyperthermia which may occur due to mutation in the ryanodine receptor resulting in excessive calcium release While widely used previously, it is now believed that routine use of succinylcholine in otherwise healthy children is contraindicated Non-depolarizing neuromuscular block results from competitive antagonism of Ach binding the NAChR. Monitoring of non-depolarizing block reveals fade with repetitive stimulation and the presence of posttetanic facilitation 6 KEY POINTS As a general rule, decreased potency results in more rapid onset of neuromuscular block The volatile anesthetics produce a dose-dependent potentiation of the neuromuscular blockers resulting in a reduction in necessary dosage and prolongation of effect Clinical assessment of recovery from neuromuscular blockade is unreliable at best and predisposes the patient to residual postoperative neuromuscular blockade and a marked increase in morbidity 7 KEY POINTS Even the use of a nerve stimulator, in the absence of objective measurement, results in a marked increase in the likelihood of residual paralysis and the associated complications Various muscles have differing sensitivity to, and recovery from, neuromuscular block and monitoring at particular sites may under- or over estimate onset and recovery from block The non-depolarizing neuromuscular blockers may be antagonized with an anticholinesterase which results in increased levels of ACh at the NMJ to compete with the NMB drug for the alpha subunit of the NAChR 8 KEY POINTS The anticholinesterases are paired with an antimuscarinic for reversal of neuromuscular blockade to prevent the unwanted muscarinic effects of increased acetylcholine. It is important to match the appropriate antimuscarinic with the anticholinesterase to match the onset of effect The selective relaxant binding agent (SRBA) sugammadex encapsulates and renders ineffective the aminosteroidal NMBs, in particular rocuronium and vecuronium The availability of sugammadex changes the way we think about a difficult airway scenario, CICO, and certain neuromuscular disorders, in that recovery from neuromuscular block with rocuronium and sugammadex may be more rapid than spontaneous recovery from succinylcholine 9 KEY POINTS Significant consequences exist for patients with inadequate reversal of muscle relaxant at the conclusion of surgery Prolonged use of neuromuscular blockade in the ICU is associated with multiple concerns, including myopathy, polyneuropathy, and the potential for hyperkalemic arrest following use of succinylcholine for emergent reintubation 10 OUTLINE Anatomy and Physiology Review Pharmacology Depolarizing Neuromuscular Blockers Non-depolarizing Neuromuscular Blockers Aminosteroids Isoquinoliniums Drug Interactions and Altered Responses to Neuromuscular Blockers Monitoring Neuromuscular Blockade Reversal of Neuromuscular Blockade Anticholinesterases Selective Binding Agents Inadequate Reversal of Neuromuscular Blockade 11 ANATOMY AND PHYSIOLOGY REVIEW The Neuromuscular Junction Presynaptic Events Postsynaptic Events Receptor Regulation 12 NEUROMUSCULAR JUNCTION BARASH FUNDAMENTALS 13 THE NICOTINIC ACETYLCHOLINE RECEPTOR (nAChR) IMMATURE (fetal) RECEPTOR BARASH MATURE (adult) RECEPTOR BARASH 14 NICOTINIC Ach RECEPTOR ISOFORMS Mature (ε) Confined to the end-plate region of the muscle membrane Immature (γ) May be expressed anywhere in the muscle membrane α7 Expressed throughout the muscle membrane in response to denervation, immobility, sepsis, or burn injury Choline, a breakdown product of acetylcholine and succinylcholine acts as a full agonist at the α7 receptor Prolonged presence of agonist (choline) does not produce desensitization of the α7 receptor 15 NICOTINIC Ach RECEPTORS Muscle prior to innervation Only γ and α7 receptors present Dispersed widely throughout muscle Beginnings of innervation Start to see ε receptors appear “Mature” innervated muscle Only ε receptors present Only at the NMJ Denervated muscle Return of γ and α7 receptors widely dispersed 16 DENERVATED MUSCLE MILLER 17 RECEPTOR REGULATION Upregulation Increase in number of “immature” Ach receptors (and α7 subunit receptors), both junctional and extrajunctional in response to decreased stimulation of the NMJ Immobilization CVA Spinal cord injury Prolonged use of NDPNMB in ICU setting Severe burns Severe infection/sepsis Some neuromuscular diseases Downregulation Secondary to presence of excess agonist over time Anticholinesterase use for myasthenia gravis Organophosphate poisoning 18 RECEPTOR REGULATION MILLER Table 34-12 19 EFFECTS OF RECEPTOR CHANGE ON NMB DRUGS Upregulation Which primarily means an increase in “immature” receptor types Increased sensitivity to ACh and succinylcholine Sodium/potassium channels may remain open much longer Resistance to non-depolarizers Increased expression of α7 receptors Partial agonist effect of some NDMRs at “immature” receptors Downregulation Resistance to succinylcholine Sensitivity to non-depolarizers 20 DISEASE STATES and nAChR UP-REGULATION Impaired neural traffic Infection/Sepsis The α7 nicotinic Ach receptor appears to play an important role in moderating the inflammatory response in sepsis, particularly abdominal sepsis Agonism of this receptor reduces organ system damage in abdominal sepsis Upregulation of “immature” α7 NAChRs occurs in this setting May lead to hyperkalemia following use of succinylcholine Critical Illness Polyneuropathy (CIP) Incidence > 50% in multi-organ system failure My be compounded by the use of NMBDs to immobilize patients in ICU 21 DISEASE STATES and nAChR REGULATION Burns Increased expression of fetal and α7 nicotinic ACh receptors Occurs throughout the entire muscle membrane as described for denervation injury Persists throughout the healing process until new tissue has regrown and infection controlled Safe to use succinylcholine during the first 24-48 hours postburn Conservative approach Avoid succinylcholine after 24 hours and for at least 1 year afterwards Non-depolarizers Resistance to all NDPNMBs in burns >30% TBSA beginning at 1 week post-injury and peaking at ~ 5-6 weeks Onset is delayed Can be partially overcome with increased doses Recovery from NDPNM Block is more rapid 22 PHARMACOLOGY Definitions Depolarizing Neuromuscular Blockers Succinycholine Non-depolarizing Neuromuscular Blockers Aminosteroids Isoquinolinium 23 DEFINITIONS ED50 and ED95 Dosages required to reduce single twitch height by 50% and 95% from baseline Onset time Time from administration to disappearance of single twitch Inversely related to dose Duration of Action Directly related to dose DUR 25% Time from administration to return to 25% of baseline twitch height DUR 0.90 or total duration of action Time from administration to return of TOF ratio to 0.90 24 ONSET OF ACTION MILLER 25 DEPOLARIZING NEUROMUSCULAR BLOCKERS SUCCINYLCHOLINE 26 DEPOLARIZING NMB = SUCCINYLCHOLINE MILLER 27 DEPOLARIZING NMB AT NEUROMUSCULAR JUNCTION BARASH FUNDAMENTALS 28 SUCCINYLCHOLINE Acts like acetylcholine to activate the nACh receptor, opening a channel which allows Na+ influx and K+ efflux resulting in depolarization of the postsynaptic membrane activating the excitation-contraction sequence Failure of acetylcholinesterase to degrade succinylcholine results in a longer period of depolarization and, ultimately, desensitization resulting in flaccid paralysis Ultimately hydrolyzed in the plasma by pseudocholinesterase (aka plasma cholinesterase or butyrylcholinesterase) 29 SUCCINYLCHOLINE BARASH 30 SUCCINYLCHOLINE Characteristics of succinylcholine blockade Fastest onset Shortest duration Most reliable Dose-dependent reduction in single twitch height Lack of fade on train-of-four (TOF) monitoring Does not exhibit post-tetanic facilitation Phase II block may result from: Large bolus dose (> 10x ED95) Repeated boluses Prolonged infusion Phase II block exhibits fade on TOF and post-tetanic facilitation 31 SUCCINYLCHOLINE BARASH 32 SUCCINYLCHOLINE – PHASE II BLOCK BARASH 33 SUCCINYLCHOLINE ED95 Clinical Duration Typical intubating dose Metabolism ~ 0.3 mg/kg 1.0 – 1.5 mg/kg Onset ~ 60 seconds 7-12 minutes In plasma, by butyrylcholinesterase en route to and after diffusion away from the NMJ 34 BUTYRYLCHOLINESTERASE ACTIVITY Affected by many things: Liver disease Pregnancy Advanced age Malnutrition Drugs e.g. esmolol, echothiophate, MAOIs, metoclopramide, many others BUT Little effect on duration of succinylcholine block So rarely clinically significant 35 BUTYRYLCHOLINESTERASE ACTIVITY MILLER 36 ATYPICAL BUTYRYLCHOLINESTERASE/ DIBUCAINE # Butyrylcholinesterase Incidence Homozygous typical Dibucaine Number Duration of Block 70-80 Normal Heterozygous atypical 1:480 50-60 Increased 50-100% Homozygous atypical 1:3200 20-30 4-8 hours qDibucaine q Local anesthetic which inhibits normal butyrylcholinesterase to a greater extent than it does atypical cholinesterase q Multiple other variants of atypical cholinesterase exist, but this is most common and of most importance to us 37 SUCCINYLCHOLINE SIDE EFFECTS Bradydysrhythmias – resulting from generalized stimulation of autonomic ganglia and muscarinic receptors in the SA node Sinus bradycardia More likely in children with greater vagal tone May occur in adults following a second dose ~ 5 minutes after the initial dosing Preventable with antimuscarinic pretreatment Junctional (nodal) rhythm AV nodal pacing rhythm appears as SA node is suppressed More likely following a second dose Ventricular dysrhythmias Due to: Increased catecholamine levels related to succinylcholine administration Decreased threshold for catecholamine-induced dysrhythmias Ventricular escape beats may appear with slowing of SA and AV node conduction 38 SUCCINYLCHOLINE SIDE EFFECTS Fasciculations Disorganized muscle contractions may or may not be related to myalgias ~80% incidence in the absence of a defasciculating dose of NDPNMB Requires increased succinylcholine dose Slows onset of the succinylcholine Myalgias More common in: Women Minor procedures Ambulatory (outpatient) surgery Most effectively prevented with NSAID pretreatment 39 SUCCINYLCHOLINE SIDE EFFECTS Increased Intragastric Pressure Increased, but offset by a concurrent increase in lower esophageal sphincter tone Increased Intraocular Pressure (IOP) Transient increase by up to 15mm Hg Attenuated by lidocaine and opioid + Concern over extrusion of ocular contents with an open globe injury Has not been reported Increased ICP Attenuated by a defasciculating dose of NDPNMB 40 INCREASED INTRAOCULAR PRESSURE BARASH 41 SUCCINYLCHOLINE SIDE EFFECTS Hyperkalemia Typically results in an ~ 0.5 mEq/L increase in serum potassium Potentially much greater increases in denervation, burn injury, sepsis, ARF, and severe trauma as discussed earlier Potential association with: Beta blockade use in pediatrics Statin use “Black Box” Warning Succinylcholine administration may result in rhabdomyolysis and fatal hyperkalemia in children with myotonia and muscular dystrophies, which may be undiagnosed FDA states succinylcholine should only be used for emergency intubation 42 SUCCINYLCHOLINE SIDE EFFECTS Masseter Spasm (Trismus) Jaw muscle rigidity in association with limb muscle flaccidity following administration of succinylcholine >80% of the time not associated with rigidity of other muscles In association with rigidity of other muscles this is an early warning of MH MHAUS Suggests: Close observation of patient with masseter spasm for at least 12 hours Follow CK and urine myoglobin at 6 hour intervals for 36 hours Miller: Currently, no indication exists to change to a “non-triggering” anesthetic in instances of isolated masseter spasm BUT…… 43 SUCCINYLCHOLINE CONTRAINDICATIONS Malignant Hyperthermia Multiple inheritance patterns with variable expression Effects the ryanodine receptor resulting in excessive Ca++ release Hypermetabolism with metabolic and respiratory acidosis Hyperkalemia Rhabdomyolysis Hyperthermia Widely varying degree of response Variation in onset from immediate to several hours Triggers Volatile anesthetics Succinylcholine Addition of succinylcholine to volatile anesthetic markedly increases the incidence of MH relative to volatile anesthetics alone 44 SUCCINYLCHOLINE CONTRAINDICATIONS Atypical or Deficient Psuedocholinesterase Relative or absolute? States of Receptor Upregulation Previously discussed Severe acidosis and hypovolemia Reports of fatal hyperkalemia in this setting Hyperkalemia Baseline > 5.5 mEq/L Pediatrics Undiagnosed skeletal muscle myopathy 45 The routine administration of succinylcholine to healthy children should be discontinued. In apparently healthy children, intractable cardiac arrest with hyperkalemia, rhabdomyolysis, and acidosis may develop after succinylcholine administration, particularly in children with unsuspected muscular dystrophy of the Duchenne type. MILLER 46 SUCCINYLCHOLINE CONTRAINDICATIONS Non-depolarizing Neuromuscular Block Increased incidence of hyperkalemic cardiac arrest in ICU patients given succinylcholine for emergent intubation, likely related to upregulation of “immature” receptors from: Prolonged immobilization Prolonged use of non-depolarizing NMBs Following use of anticholinesterase drugs Neostigmine and pyridostigmine inhibit butyrlcholinesterase Duration of succinylcholine NMB will be significantly increased if given after an anticholinesterase 90 minutes following neostigmine, butyrylcholinesterase activity is still sevoflurane > isoflurane > halothane > nitrous oxide Proposed mechanisms Inhibition of postsynaptic nAChRs Central effect on α motorneurons and interneuronal synapses Increase affinity of NMB for receptor 84 DRUG INTERACTIONS WITH NEUROMUSCULAR BLOCKERS Antibiotics Aminoglycosides (especially streptomycin and neomycin) Polymixins, lincomycin, clindamycin Primarily inhibit prejunctional release of Ach Also impair sensitivity of postjunctional receptor to ACh Tetracyclines Postjunctional effect only Cephalosporins and penicillins No effect Potentiation of neuromuscular blockade by antibiotics is exacerbated by: Hypercarbia Acidosis Hypothermia 85 DRUG INTERACTIONS WITH NEUROMUSCULAR BLOCKERS Local Anesthetics Potentiate the effects of both succinylcholine and the nondepolarizers May prolong duration of action Do not speed onset Anticonvulsants (phenytoin, carbamazepine) Acute administration potentiates the non-depolarizers Chronic administration increases clearance and shortens duration of NDPNMBs Slight prolongation of block with succinylcholine 86 DRUG INTERACTIONS WITH NEUROMUSCULAR BLOCKERS Magnesium Markedly potentiates the non-depolarizers More rapid onset Prolonged recovery time Impairs reversal with anticholinesterases Presynaptic Magnesium-induced impairment of Ca++ channels reduces Ach release Postsynaptic Magnesium decreases membrane excitability by inhibiting postsynaptic potentials Hypercalcemia Decreased sensitivity to non-depolarizers due to increased presynaptic release of ACh 87 DRUG INTERACTIONS WITH NEUROMUSCULAR BLOCKERS Lithium Potentiates both succinylcholine and the non-depolarizers Requires a reduction in dose and careful titration when appropriate Corticosteroids Long-term therapy in the critically ill concurrent with neuromuscular blockade markedly increases the incidence of critical illness myopathy Dantrolene Blocks excitation-contraction coupling by blocking release of Ca++ from the sarcoplasmic reticulum, thereby prolonging non-depolarizing neuromuscular block Antiestrogenic drugs (Tamoxifen) may potentiate the non-depolarizing NMBs 88 ALTERED RESPONSE TO NEUROMUSCULAR BLOCKING DRUGS Critical Illness Myopathy Diffuse flaccid weakness sometimes including the diaphragm and facial muscles Associated with: Prolonged immobilization Prolonged neuromuscular blockade Particularly with aminosteroid NMBs, but also reported with benzylisoquinoliniums Corticosteroid use Possible mechanisms Selective muscle atrophy related to upregulation of corticosteroid receptors in immobilized muscle Development of antibodies to nACh receptors in sepsis 89 ALTERED RESPONSE TO NEUROMUSCULAR BLOCKING DRUGS Hypothermia Prolongs duration Decreased receptor sensitivity and mobilization of Ach Decreased strength of muscle contraction Decreased renal and hepatic perfusion Impairment of Hoffman elimination (temperature dependent) Elderly Patients Decreased volume of distribution for NMBs Decreased total body water Decreased plasma proteins Decreased metabolism of NMBs Decreased cardiac output Decreased liver blood flow and GFR 90 ALTERED RESPONSE TO NEUROMUSCULAR BLOCKING DRUGS Acidosis and Hypercarbia Impairs reversal of non-depolarizing block with anticholinesterase Hypokalemia Potentiates non-depolarizing block Impairs reversal of non-depolarizing block with anticholinesterase Hypermagnesemia Prolongs duration due to inhibition of Ca++ channels Hepatorenal dysfunction Impaired metabolism and prolonged duration of the aminosteroid NMBs in particular 91 BARASH 92 MONITORING OF NEUROMUSCULAR BLOCKADE Inadequacy of Clinical Signs of Recovery Nerve Stimulator Single Twitch Train of Four Tetanus and Post-tetanic Facilitation Double Burst Electromyography Mechanomyography Acceleromyography Kinemyography Differential Muscle Sensitivity Clinical Application 93 INADEQUACY OF CLINICAL SIGNS OF RECOVERY Clinical tests of reversal of neuromuscular blockade 5-second head lift Grip strength Negative inspiratory force (NIF or NIP) Tidal volume Vital capacity Leg lift Resist removal of tongue blade from clenched teeth 94 INADEQUACY OF CLINICAL SIGNS OF RECOVERY Over 40% of patients managed clinically (without objective neuromuscular monitoring) will have residual paralysis in the PACU Residual paralysis is considered to be a TOF ratio < 0.9 Postoperative mortality increased 90-fold if residual paralysis results in emergent tracheal reintubation postoperatively and an ICU stay Essentially zero risk and minimal cost associated with neuromuscular monitoring, but significant risk to not doing so 95 INADEQUACY OF CLINICAL SIGNS OF RECOVERY BARASH/ MILLER(BASICS) 96 NERVE STIMULATION AND MONITORING Peripheral nerve stimulator Delivers an electrical current via electrodes allowing a visual evaluation of response by the anesthesia provider Various strength, duration and patterns of current are used Single twitch (ST) Train of Four (TOF) Tetanus Allowing evaluation of post-tetanic count (PTC) and post-tetanic facilitation Double Burst stimulation (DBS) Neuromuscular monitor Delivers an electrical current in the same way, but also measures an objective motor response by EMG, MMG, AMG, or KMG 97 PERIPHERAL NERVE STIMULATOR 98 NEUROMUSCULAR MONITORS 99 100 NERVE STIMULATION AND MONITORING Single Twitch Useful only in determining onset of neuromuscular block, not recovery Requires establishing a baseline of current which will produce a maximal motor response Done with slowly increasing current at a low frequency BARASH 101 NERVE STIMULATION AND MONITORING Train-of-four ratio (TOF) Four single twitches delivered at 2 Hz TOF ratio is amplitude of T4 amplitude of T1 No baseline required since we are comparing T4 to T1 Lack of need to deliver a supramaximal current to assure maximum response allows use of a lower current More comfortable in a patient who is awakening Presence or absence of fade allows us to distinguish between non-depolarizing and depolarizing block Well-described relationship between TOF ratio and receptor occupancy by a non-depolarizing NMB 102 NERVE STIMULATION AND MONITORING Train-of-four ratio (TOF) and train-of-four count (TOFC) versus receptor occupancy by non-depolarizing NMB ~ 2/3 of receptors may be blocked with no decrement in TOF ratio 70-75% of receptors blocked – begin to see fade of T4 75-80% of receptors blocked – T4 disappears (TOFC = 3) 80-85% of receptors blocked – T3 disappears (TOFC = 2) 85-90% of receptors blocked – T2 disappears (TOFC = 1) >95% of receptors blocked – T1 disappears Following sustained tetanus some portion of the train of four may reappear, albeit with fade 103 NERVE STIMULATION AND MONITORING BARASH 104 NERVE STIMULATION AND MONITORING BARASH 105 NERVE STIMULATION AND MONITORING BARASH 106 NERVE STIMULATION AND MONITORING Tetanus Current supplied at frequencies > 30 Hz produced sustained contraction Tetanus fades (or disappears) in the presence of non-depolarizing block In a similar fashion as fade in the TOF ratio Tetanic stimulation is delivered for 5 seconds Non-depolarizing block will produce post-tetanic facilitation Mechanism = increased Ach present at the NMJ following the tetanic stimulation lasting for 1-3 minutes Depolarizing block will not produce PTF Post-tetanic count (single twitches delivered 3 seconds after tetanus at 1 Hz) Inversely proportional to depth of block Useful in evaluating ability to reverse with an anticholinesterase or determining sugammadex dose 107 CHARACTERISTICS OF NEUROMUSCULAR BLOCK DEPOLARIZING BLOCK NON-DEPOLARIZING BLOCK 108 NERVE STIMULATION AND MONITORING BARASH 109 NERVE STIMULATION AND MONITORING BARASH 110 NERVE STIMULATION AND MONITORING BARASH 111 NERVE STIMULATION AND MONITORING Double burst stimulation Two short bursts of current separated by 750 milliseconds DBS3,3 is two bursts of 3 stimuli each while DBS3,2 is a burst of three followed by a burst of 2 Fade of DBS3,3 is identical to fade of TOF Improves subjective evaluation of fade versus TOF Able to visualize or feel fade in DBS at a TOF ratio < 0.6 versus < 0.4 in standard TOF monitoring Somewhat uncomfortable for the waking patient 112 NERVE STIMULATION AND MONITORING BARASH 113 BARASH 114 NERVE STIMULATION AND MONITORING Monitoring of response Even with nerve stimulation, subjective monitoring is inadequate if the TOF ratio is >0.6. We desire a TOF ratio of >0.9 to assure adequate neuromuscular recovery Objective monitoring modalities Typically stimulate the ulnar nerve/ adductor pollicis muscle Electromyography (EMG) Measures the action potential Mechanomyography (MMG) Force of thumb adduction Acceleromyography (AMG) Acceleration of thumb adduction Kinemyography Type of mechanomyography with a mechanosensory placed between the thumb and index finger 115 DETECTION OF FADE MILLER 116 ADEQUATE DEPTH OF BLOCK What are we trying to achieve? Intubation Relaxation of abdominal muscles Diaphragmatic paralysis Depth of neuromuscular block Moderate block Two or more twitches on TOF Deep block One or more responses on post-tetanic count Intense block No response on post-tetanic count 117 ADEQUATE DEPTH OF BLOCK Moderate (1-2 TOF at APM) Adequate for most surgical procedures Deep (0 TOF at APM) (1-2 PTC at APM) Return of diaphragmatic movement possible Intense (0 PTC) Diaphragmatic/ laryngeal muscle paralysis Ideal intubating conditions BARASH 118 DIFFERENTIAL MUSCLE SENSITIVITY Adductor pollicis muscle Most commonly used Delayed onset relative to diaphragm and laryngeal muscles Decreased tissue blood flow Delayed recovery relative to diaphragm and laryngeal muscles Due to greater sensitivity of APM Flexor hallucis brevis Similar to APM Facial Orbicularis oculi (moves eyelid) Similar to APM Corrugator supercilia Similar to diaphragm and laryngeal muscles 119 DIFFERENTIAL MUSCLE SENSITIVITY MILLER 120 BARASH 121 Train of Four Monitoring Reversal Agent and Dose after Rocuronium and Vecuronium TOF-R > 0.9 (Objective Monitoring) Reversal not required 4 twitches without Fade Sugammadex 2 mg/kg or neostigmine 20 mcg/kg (max 5 mg) 4 twitches with Fade Sugammadex 2 mg/kg or neostigmine 40-50 mcg/kg (max 5 mg) 2-3 twitches Sugammadex 2 mg/kg or neostigmine 60 mcg/kg (max 5 mg) 1 twitch Sugammadex 4 mg/kg neostigmine not recommended Post-tetanic twitches only Sugammadex 4 mg/kg neostigmine not recommended No post-tetanic twitches following high dose rocuronium (CICO) Sugammadex 16 mg/kg neostigmine not recommended Neostigmine dose based on actual body weight Sugammadex dose based on actual body weight; not recommended with CrCl < 30 ml/min Sugammadex binds hormonal contraceptives – alternative form of non-hormonal contraception for 7 days needed Train of Four Monitoring Reversal Agent and Dose after Cisatracuriuim TOF-R > 0.9 (Objective Monitoring) Reversal not required 4 twitches without Fade Neostigmine 20 mcg/kg (max 5 mg) 4 twitches with Fade Neostigmine 40-50 mcg/kg (max 5 mg) 2-3 twitches Neostigmine 60 mcg/kg (max 5 mg) 123 BARASH 124 ELECTRODE PLACEMENT Adductor pollicis muscle Stimulate ulnar nerve Negative electrode 2 cm proximal to wrist crease Positive electrode 3-5 cm proximal to negative electrode Flexor hallucis brevis Stimulate medial plantar nerve (branch of the tibial) Posterior to the medial malleolus Orbicularis oculi and corrugator supecilii Stimulate facial nerve Positive electrode in front of the ear at the level of the mastoid process Negative electrode above + distal on the facial nerve 125 ELECTRODE PLACEMENT ADDUCTOR POLLICIS 126 ELECTRODE PLACEMENT FLEXOR HALLIUCIS BREVIS 127 ELECTRODE PLACEMENT ORBICULARIS OCULI CORRUGATOR SUPERCILII 128 REVERSAL OF NEUROMUSCULAR BLOCKADE Anticholinesterases Neostigmine Edrophonium Selective Binding Agents Sugammadex 129 REVERSAL WITH ANTICHOLINESTERASE Mechanism Inhibition of acetylcholinesterase increases the concentration of Ach at the NMJ allowing greater competition with a non-depolarizing NMB Available anticholinesterases Quatenary structure Edrophonium Neostigmine Pyridostigmine Used primarily for treatment of myasthenia gravis Tertiary Physostigmine Not used for NMB reversal due to ability to cross B-B-B 130 REVERSAL WITH ANTICHOLINESTERASE Edrophonium Hydrogen bond to enzyme Weak attachment Neostigmine/ pyridostigmine Carbamylation of enzyme Stronger attachment Organophosphates Phosphorylation of enzyme “Irreversible” attachment 131 NEOSTIGMINE Inhibition of acetylcholinesterase by neostigmine is concentration-dependent, but…. Very high concentrations of neostigmine may directly block the Ach receptor Dosage > 70 μg/kg is not recommended A ceiling effect exists such that a very dense block can not be antagonized Administration of excessive neostigmine when recovery is near complete may result in weakness and upper airway collapse Acetylcholinesterase throughout the body is inhibited resulting in a need to coadminister and anticholinergic to avoid excessive parasympathetic effect 132 NEOSTIGMINE Factors Affecting Reversal Depth of block Dose of anticholinesterase Duration of NDPNMB Anesthetic type Age Depth of block Recommended not to attempt reversal of a deep block Will not be faster than waiting for partial spontaneous resolution prior to giving reversal May predispose to respiratory compromise later Should have at least 3 twitches on TOF prior to attempting reversal with an anticholinesterase 133 NEOSTIGMINE Dose of anticholinesterase 20-70 μg/kg depending on degree of block 60-70 μg/kg of neostigmine is considered a “full reversal dose” Near-complete spontaneous recovery 20 μg/kg Complete spontaneous recovery Even a small dose may induce weakness Maximum dose 70 μg/kg Doses greater than this may induce weakness through block of receptors 134 NEOSTIGMINE Duration of NDPNMB Reversal is more effective and complete with the intermediate-acting than with the long-acting neuromuscular blockers Anesthetic type IV agents Minimal to no effect Inhalational agents potentiate neuromuscular block and prolong reversal Desflurane > sevoflurane > isoflurane > halothane > nitrous oxide Age Reversal is faster and more complete in children Slower in elderly 135 NEOSTIGMINE Other considerations Neostigmine is most commonly paired with glycopyrrolate Onset matches that of neostigmine Less tachycardia than atropine Doesn’t cross blood-brain barrier Association with prolonged QT (and potentially torsade de pointes) Muscarinic effects also include Increased salivation Minimized with use of an antimuscarinic Increased bowel motility Less affected by an antimuscarinic Debate, but no conclusive association with an increase in PONV 136 EDROPHONIUM Anticholinesterase forming an ionic bond with acetylcholinesterase Weaker binding than seen with neostigmine Use should be limited to reversing a shallow block Relative to neostigmine Much more rapid onset Shorter time to peak effect Similar, only slightly shorter duration of action Typically administered with atropine rather than glycopyrrolate due to its rapid onset Prolonged impairment of baroreflex sensitivity 137 ANTIMUSCARINIC DOSING WITH AN ANTICHOLINESTERASE Neostigmine most commonly paired with glycopyrrolate, usually at a ratio of ~5:1 E.g. Neostigmine 3-5 mg + glycopyrrolate 0.6-1.0 mg Neostigmine dose 20-70 μg/kg (supplied as 1.0 mg/ml) Glycopyrrolate 20-25% of the neostigmine dose (supplied as 0.2 mg/ml) Edrophonium most commonly paired with atropine Edrophonium dose 0.5-1.0 mg/kg (supplied as 10 mg/ml) Atropine at 10-20 μg/kg (check your concentration) Some advocate split dosing into smaller increments to reduce heart rate changes These antimuscarinic doses may be adjusted depending on patient’s underlying heart rate, etc 138 139 SUGAMMADEX A selective relaxant binding agent (SRBA) Eight-membered ring which encapsulates steroidal NMBAs Affinity for the steroidal NMBAs Rocuronium > vecuronium >> pancuronium = pipecuronium Effective in reversing the effects of rocuronium and vecuronium Affinity for vecuronium is 1/3 that for rocuronium Higher potency of vecuronium means less molecules are present that need to be encapsulated, so efficacy of reversal is similar Mechanism: NMB in plasma is bound, reducing the free NMB concentration in plasma Concentration gradient now exists such that NMB at the NMJ moves back into the plasma, reversing the block 140 SUGAMMADEX Highly water soluble – volume of distribution approximates the ECF Minimal metabolism Excreted primarily by kidneys T1/2 ~100 minutes Sugammadex/NMB (roc or vec) complex excreted by kidneys Re-establishment of rocuronium block following reversal with sugammadex Recommendation is to wait 24 hours before re-administering rocuronium May be acceptable sooner in the absence of high-dose sugammnadex reversal 141 SUGAMMADEX Dosing and Onset Based on total body weight Moderate block (TOFC > 2) 2 mg/kg Reversal to TOF >0.9 in 2-4 minutes Deep block (PTC >1, TOF = 0) 4 mg/kg Mean reversal time = 2.9 minutes Profound block (PTC = 0, TOF = 0) 16 mg/kg 2-4 minutes More rapid than spontaneous reversal from succinylcholine 142 SUCCINYLCHOLINE versus ROCURONIUM/SUGAMMADEX BARASH 143 SUGAMMADEX- SIDE EFFECTS Hemodynamic None Hypersensitivity reactions (anaphylaxis) 1:3500 – 1:20,000 Coagulation Minimal, brief increase in PT and PTT lasting < 60 minutes No increase noted in perioperative bleeding Hypothermia (mild) Slight increase in reversal time (< 1 minute) Interference with oral contraception Equivalent to missing one dose Alternative means of birth control suggested for one week after sugammadex 144 SUGAMMADEX – OTHER CONSIDERATIONS Special populations Recovery of neuromuscular function may be prolonged in: Elderly (age > 75 years) BMI > 40 Pulmonary, cardiac or renal disease Recurarization May occur in the presence of suboptimal dosing PONV Reduced with sugammadex relative to an anticholinesterase Pulmonary complications Reduced with sugammadex relative to an anticholinesterase 145 SUGAMMADEX – OTHER CONSIDERATIONS Expense ~ $90/200 mg vial vs 0.90 in 95% of patients in the absence of reversal Median time to reversal to a TOF ratio >0.90 from a TOFC of 2-4 with neostigmine is 15-20 minutes Exceeding the maximum dose limits of anticholinesterase (60-80 mcg/kg neostigmine or 1.0-1.5 mg/kg edrophonium) provides no further benefit 154 MILLER The incidence of residual neuromuscular blockade after a single intubating dose of intermediate-duration nondepolarizing relaxant (rocuronium, vecuronium, or atracurium). Partial paralysis rate (percent) according to the delay between the administration of muscle relaxant and the arrival in the postanesthesia care unit (PACU). Partial paralysis was defined as a train-of-four (TOF) ratio less than 0.70 or less than 0.90. n = number of patients. *Significantly different from TOF 2 days More common in: Asthmatic patients receiving high-dose steroids Renal failure More common with the steroidal neuromuscular blockers Association of prolonged use of neuromuscular blockers with: Critical Illness Myopathy (CIM) Critical Illness Polyneuropathy (CIP) When neuromuscular blockade is necessary in the ICU Neuromuscular monitoring should be used Periodic return of muscle function should be allowed 159 MILLER 160 INTUBATING CONDITIONS IN THE ABSENCE OF NMB Adequate intubating conditions are usually, but not always attainable in the absence of neuromuscular blocker usage. 161 BARASH 162 SOURCES Barash Clinical Anesthesia 8th edition 2017 Miller Miller’s Anesthesia 9th edition 2020 Barash Clinical Anesthesia Fundamentals 2015 Flood Stoelting’s Pharmacology and Physiology in Anesthetic Practice 6th edition 2022 Pardo/Miller Basics of Anesthesia 7th edition 2018 163