Overview of Non-Depolarizing Neuromuscular Blockers and NDNMB Reversal

Taylor Johnson MD

Overview of Non-Depolarizing Neuromuscular Blockers and NDNMB Reversal

Taylor Johnson MD

Learning Objectives:

At the conclusion of this activity, participants should be able to:

1. Describe the physiology of the neuromuscular junction as it pertains to Non-Depolarizing Neuromuscular Blockers (NDNMBs) and neuromuscular blockade reversal
2. Explain the basic pharmacodynamics and pharmacokinetics of rocuronium
3. Explain Train of Four monitoring and how it affects practice/outcomes
4. Compare options for neuromuscular blockade reversal and monitoring with regard to efficacy and safety

Non-Depolarizing Neuromuscular Blockers

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Mechanism of Action

• Reversible competitive inhibitors that bind to nicotinic acetylcholine receptor (nAChR)
• An antagonist that leaves fewer receptors available for ACh to bind → muscle relaxation

Examples

• Short-acting: mivacurium
• Intermediate-acting: rocuronium, vecuronium, atracurium, cisatracurium
• Long-acting: pancuronium

Non-Depolarizing Neuromuscular Blockers

IMAGE

Mechanism of Action

• Reversible competitive inhibitors that bind to nicotinic acetylcholine receptor (nAChR)
• An antagonist that leaves fewer receptors available for ACh to bind → muscle relaxation

Examples

• Short-acting: mivacurium
• Intermediate-acting: rocuronium, vecuronium, atracurium, cisatracurium
• Long-acting: pancuronium

Rocuronium

Molecular structure: quaternary ammonium aminosteriod

Onset: 1-2 minutes

Duration: 20-35 minutes

Elimination: predominantly hepatobiliary

Warnings/Precautions:

(1) residual neuromuscular weakness → increase risk for postoperative respiratory dysfunction, leading to hypoxia, need for re-intubation, and longer hospital stay

(2) Anaphylaxis reaction

Contraindications: rocuronium induced anaphylaxis

Jain A, Wermuth HR, Dua A, et al. Rocuronium. [Updated 2022 May 5]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK539888/

Rocuronium (cont.)

Clinical Relevance

Facilitation of tracheal intubation

• Dose:
• Based on ideal body weight
• MEN: 50 + (0.91 x [height (cm) - 152.4])
• Ex. 6 ft male - 77 kg
• WOMEN: 45.5 + (0.91 x [height (cm) - 152.4])
• Ex. 5’5 female - 57 kg
• 0.6 mg/kg (standard induction dose)
• 1.2 mg/kg (rapid sequence induction dose)
• 0.04 mg/kg (precurarization dose)*

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• Consider certain patient populations
• THINK patient with altered mental status, CT shows midline shift presenting for emergent crani = GOAL is to avoid increasing intracranial pressures, maintain cerebral perfusion pressure
• THINK patient with aortic stenosis = GOAL is to AVOID tachycardia and maximize diastolic filling

Continuous skeletal muscle relaxation during surgery

Allows controlled ventilation

*Should be given 90 seconds prior to succinylcholine for maximum effect

Butterworth, J. F., IV,, Mackey, D. C., & Wasnick, J. D. (2018). Morgan & Mikhail's clinical anesthesiology (Sixth edition.). New York: McGraw-Hill Education

Rocuronium (cont.) - Clinical Relevance

Drug Interactions

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Monitoring Rocuronium - Train of Four

Routine use of peripheral nerve stimulators (PNS) is strongly encouraged by the Anesthesia Patient Safety Foundation (APSF) to monitor the depth of neuromuscular blockade during surgery and after reversal

Train of Four (TOF)

• A sequence of four stimuli at a frequency of 2 Hz every 0.5 sec are delivered.
• The comparison of amplitude of such stimuli (the last = TOF 4 and the first = TOF 1)
• Ulnar nerve path at distal forearm stimulate adductor pollicis response
• Facial nerve at eye stimulate orbicularis oculi muscle

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Naguib, M., Brull, S.J. and Johnson, K.B. (2017), Conceptual and technical insights into the basis of neuromuscular monitoring. Anaesthesia, 72: 16-37. https://doi.org/10.1111/anae.13738

McLean DJ, Diaz-Gil D, Farhan HN, Ladha KS, Kurth T, Eikermann M. Dose-dependent Association between Intermediate-acting Neuromuscular-blocking Agents and Postoperative Respiratory Complications. Anesthesiology. 2015 Jun;122(6):1201-13.

Monitoring Rocuronium - Train of Four

Train of Four (TOF)

• T4/T1 ratio indicates quantitative depth of anesthesia
• An awake individual with no muscular pathology = TOF ratio will be 100% (1.0)
• Under paralysis from NDNMB, the amplitude starts to “fade” until T4 = 0
• Post-tetanic twitch = TOF count is 0, a 5-sec 50 Hz tetanic stimulus will allow for a short lived muscle response

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Glenn S. Murphy, Sorin J. Brull; Quantitative Neuromuscular Monitoring and Postoperative Outcomes: A Narrative Review. Anesthesiology 2022; 136:345–361 doi: https://doi.org/10.1097/ALN.0000000000004044

Naguib M, Brull SJ, Kopman AF, Hunter JM, Fülesdi B, Arkes HR, Elstein A, Todd MM, Johnson KB. Consensus Statement on Perioperative Use of Neuromuscular Monitoring. Anesth Analg. 2018 Jul;127(1):71-80. doi: 10.1213/ANE.0000000000002670. PMID: 29200077.

Train of Four

Re-dosing based on TOF

• Depth of neuromuscular block for surgical anesthesia = 2/4 twitches
• If 0/4 twitches, do not administer more muscle relaxant
• Should not be based off of elapsed time, clinical response, patient weight

Fortier LP, McKeen D, Turner K, de Médicis É, Warriner B, Jones PM, Chaput A, Pouliot JF, Galarneau A. The RECITE Study: A Canadian Prospective, Multicenter Study of the Incidence and Severity of Residual Neuromuscular Blockade. Anesth Analg. 2015 Aug;121(2):366-72

Jahangiri, F. R. (2018, Sept)). Train of Four (TOF) Monitoring: Are We Doing It The Right Way?

(2nd ed.). Charleston, SC: CreateSpace Independent Publishing.

NDNMB Reversal Agents

Neostigmine

• Mechanism of Action:
• Competitive cholinesterase inhibitor
• Dose:
• Based on NDNMB used and twitch response
• 0.03 mg/kg - 0.07 mg/kg
• Maximum total dosage is 0.07 mg/kg or up to a total of 5 mg
• Onset:
• Within 10 to 20 mins can achieve TOF ratio of 90%

• Adverse Effects:
• Most common adverse reactions during treatment: bradycardia, nausea and vomiting
• Bradycardia: atropine or glycopyrrolate should be administered prior to lessen risk
• Caution: coronary artery disease, cardiac arrhythmias, recent acute coronary syndrome, myasthenia gravis
• Neuromuscular dysfunction
• Contraindications
• Peritonitis
• Mechanical obstruction of intestinal tract

RECITE - Residual Curarization and its Incidence at Tracheal Extubation

RECITE - Residual Curarization and its Incidence at Tracheal Extubation

64.7% of 255 patients undergoing abdominal surgery in US had TOF ratios <0.9 despite reversal with neostigmine + qualitative monitoring. This is common complication when sugammadex and quantitative monitoring is not used.

NDNMB Reversal Agents

Sugammadex - A modified gamma-cyclodextrin

*Initial US approval 2015

• Mechanism of Action:
• encapsulate steroidal neuromuscular blocking drugs
• Dose:
• Based on actual body weight
• 2 mg/kg when TOF is >= 2
• 4 mg/kg when TOF is <2
• 8-16 mg/kg with profound block induced by rocuronium at RSI dose (ie. 1.2 mg/kg)

Figure: Rocuronium encapsulated by sugammadex. Image contributed by Dr Ronnie Palin and John MaClean at Merck

Bridion (sugammadex). Prescribing information. Merck; 2015. https://www.merck.com/product/usa/pi_circulars/b/bridion/bridion_pi.pdf.

Sugammadex

• Onset:
• Average reversal time of 3 minutes in rocuronium induced neuromuscular blockade
• Elimination:
• Renal excretion in unchanged form
• Adverse Effects:
• Marked bradycardia (usually within minutes)
• 3rd degree AVB, asystole, hypotension, coronary vasospasm
• Most common (reported >10% of adults) - nausea/vomiting, hypotension, headache
• Patients must use an additional, non-hormonal method of contraception for 7 days following sugammadex administration

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• Re-administration of neuromuscular blocking agent: waiting times should be based on dose of sugammadex given and the renal function of the patient *Consider nonsteroidal NMB

Mitchell C, Lobaz S. An Overview of Sugammadex. World Federation Of Societies Of Anaesthesiologists. 2016 June;332

Sugammadex Use in Special Populations

Pediatrics:

• 2 mg/kg when TOF count is 2 is recommended in children age 2 to 17
• Not endorsed in neonates or infants, despite safe use in a small number of case reports
• Immediate reversal in pediatric population has not been studied (ie. 16 mg/kg dose after large rocuronium dosing)
• Most common adverse reactions (reported in > 10% of pediatric patients 2 to 17 years of age) = pain, nausea/vomiting.

Elderly (> 75 yrs of age)

• Recommended dose = same as younger adult patients
• *normal organ function
• Slower onset of action likely secondary to decreased cardiac output

Bridion (sugammadex). Prescribing information. Merck; 2015. https://www.merck.com/product/usa/pi_circulars/b/bridion/bridion_pi.pdf.

Sugammadex Use in Special Populations

Chronic Kidney Disease:

• Not recommended in patients with a creatinine clearance < 30 ml/min
• No dose adjustment needed for mild to moderate renal impairment (CrCl >=30 and <= 80 ml/min)

Should I use it “off-label” or should I not?

• 2020 historical cohort study published in Canadian Journal of Anesthesia - 219 patients with CKD stage 5
• The efficacy and safety profile of sugammadex in CKD patients suggest no increased risk to hypersensitivity reactions with slightly increased time to recovery (3.1 min vs. 1.9 min)
• No patient experienced hypersensitivity reaction
• 3 required reintubation
• 2 developed hypoxemia not requiring intubation
• This study agrees with several smaller published studies.

Paredes S, Porter SB, Porter IE 2nd, Renew JR. Sugammadex use in patients with end-stage renal disease: a historical cohort study. Can J Anaesth. 2020 Dec;67(12):1789-1797. English. doi: 10.1007/s12630-020-01812-3. Epub 2020 Sep 18. PMID: 32949009.

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Panhuizen IF, Gold SJ, Buerkle C, et al. Efficacy, safety and pharmacokinetics of sugammadex 4 mg kg−1 for reversal of deep neuromuscular blockade in patients with severe renal impairment. Br J Anaesth 2015; 114: 777-84.

Efficacy of NMB Reversal Options

Sugammadex

• Reverses only rocuronium and vecuronium
• Co-administration of medication not required to prevent adverse drug events
• Effectively reverses induction doses of rocuronium
• Reverses ALL depths of NMB within approximately 3 minutes
• Residual NMB rarely observed

Neostigmine

• Reverses ALL nondepolarizing NMB
• Requires co-administration of an anticholinergic agent (glycopyrrolate) to prevent bradycardia
• Cannot reverse induction dose of rocuronium
• Does not adequately reverse profound or deep NMB; most effective for light to minimal NMB
• Residual NMB is prevalent due to competitive nature and ceiling effect

Hristovska AM, Duch P, Allingstrup M, Afshari A. Efficacy and safety of sugammadex versus neostigmine in reversing neuromuscular blockade in adults. Cochrane Database Syst Rev. 2017 Aug 14;8(8):CD012763. doi: 10.1002/14651858.CD012763. PMID: 28806470; PMCID: PMC6483345.

Bridion (sugammadex) prescribing information. Merck and Co., Inc. 2017 Jun. Bloxoverz (neostigmine) prescribing information. Avadel Legacy Pharmaceuticals, LLC. 2017 Ja

Reversal Efficacy: Moderate to Deep Block

Reversal Efficacy: Moderate to Deep Block

Safety of NMB Reversal Options

Sugammadex

• Lower incidence of residual NMB
• Lower incidence of PONV
• Severe bradycardia can occur
• Higher incidence of hypersensitivity and anaphylaxis
• Drug interactions: hormonal contraceptives

Neostigmine

• Higher incidence of residual NMB
• Higher incidence of PONV
• Higher incidence of bradycardia (despite anticholinergic administration)
• Lower incidence of hypersensitivity and anaphylaxis
• No relevant drug-drug interactions

Min KC et al. Br J Anaesth. 2018; 121:749‐57. De Kam P‐J et al. Br J Anaesth. 2018; 121:758‐67. Hristovska AM et al. Cochrane Database Syst Rev. 2017; 8:CD012763

Key Points

1. Rocuronium is based on ideal body weight
2. APSF strongly encourages routine use of peripheral nerve stimulators
3. Do NOT re-dose based off of elapsed time, clinical response, patient weight. INSTEAD check TOF count.
4. Sugammadex 2 mg/kg (TOF >=2) vs. 4 mg/kg (TOF < 2)
5. Sugammadex in ESRD - not FDA approved when CrCl < 30 ml/min
6. If using neostigmine for reversal in ESRD - dose: 0.07 mg/kg up to 5 mg; for every 1 mg of neostigmine give 0.2 mg glycopyrrolate first.