Neuromuscular Blocking Agents in Adult Patients

Full update June 2022

The FAQ below reviews common questions about neuromuscular blocking agents relating to place in therapy, patient monitoring and care, ICU-acquired weakness, other adverse effects, interactions, and reversal agents. A chart comparing properties of the available neuromuscular blocking agents including onset of action, dosing, and routes of elimination is also included.

Question

Answer/Pertinent Information

What are the different types of neuromuscular blocking agents?

Depolarizing:5

  • MOA: nicotinic receptor agonist, opening ion-gated channels
  • Available product: succinylcholine

Non-depolarizing:5

  • MOA: competitive nicotinic receptor antagonist, preventing acetylcholine from binding
  • Two different classes of non-depolarizing NMBAs:
    • benzylisoquinolinium (e.g., atracurium, cisatracurium)1
    • aminosteroid (e.g., pancuronium, rocuronium, vecuronium)1

When is it appropriate to use neuromuscular blocking agents?

  • Some long-standing uses for NMBAs include: rapid sequence intubation, facilitating breathing synchronization with mechanical ventilation, ablation of muscle spasms associated with tetanus, and decreasing oxygen consumption.3
  • Use in ARDS has been controversial. Current evidence supports continuous infusion for up to 48 hours for moderate to severe ARDS in cases where ongoing deep sedation for protective ventilation is required.16
    • Cisatracurium continuous infusion has been safely used in the treatment of acute ARDS with improved oxygenation and reduced 28-day mortality without increasing risk of ICU-acquired weakness [Evidence Level A-2].8
  • Though not used frequently, there are limited data for NMBA use in the treatment of other conditions:
    • status asthmaticus:
      • Avoid routine use of NMBAs in patients with status asthmaticus due to potential for prolonged mechanical ventilation and risk of ICU-acquired weakness [Evidence Level B-3].5
      • NMBAs can be considered in life-threatening situations (e.g., profound hypoxemia, respiratory acidosis, hemodynamic compromise) [Evidence Level C].5
    • shivering due to therapeutic hypothermia:
      • Reserve use of NMBAs when shivering persists after trying other options (e.g., acetaminophen, magnesium), with adequate analgesia and sedation.1,2
      • In patients undergoing therapeutic hypothermia post-cardiac arrest, protocols that favor as-needed NMBAs on top of basal sedation are associated with improved functional outcomes as opposed to escalating sedation in an effort to limit NMBA use [Evidence Level B-3].4
      • Use of NMBAs may mask seizures associated with hypothermia.5

How do you choose a neuromuscular blocking agent?

  • Consider cisatracurium for continuous infusion in patients with liver or kidney impairment, patients receiving systemic corticosteroids, and patients with ARDS, therapeutic hypothermia, or traumatic brain injury (due to favorable outcomes).10,13
    • Neither atracurium nor cisatracurium rely on the liver or kidney for elimination.13
    • Whether atracurium is associated with more hypotension than cisatracurium is unclear.14
  • The chart below provides a comparison of the individual properties of the available products including onset of action, dosing, and routes of elimination to aid in appropriate selection.

How should neuromuscular blocking agents be monitored?

  • Combine clinical monitoring (e.g., hand grip, sustained head or leg lift, respirations) with PNS and TOF.5,6
    • Several factors may impact the accuracy of TOF monitoring:5
      • body temperature: possible reduced accuracy with therapeutic hypothermia
      • peripheral edema: may block landmarks when evaluating TOF in the adductor pollicis (muscle in hand that adducts the thumb)
      • site evaluated (orbicularis oculi [face muscle that closes the eyelids] vs adductor pollicis): may be affected by differences in blood flow to these areas.
      • staff training and experience with equipment
    • Be aware that ventilator synchrony-based titration of cisatracurium in ARDS resulted in less drug use vs TOF-based titration [Evidence Level B-3].7
  • Data are lacking to support the use of electroencephalogram parameters to assess sedation with use of NMBAs.5

Are neuromuscular blocking agents associated with ICU-acquired weakness?

  • The data linking NMBAs to ICU-acquired weakness are conflicting and may depend on the indication for NMBAs as well as concomitant medications.
    • ARDS: Cisatracurium continuous infusion for up to 48 hrs had no effect on the incidence of ICU-acquired weakness (RR, 1.09; 95% CI, 0.76 to 1.56; p=0.63) in patients with ARDS [Evidence Level A-2].8
    • sepsis: Occurrence of ICU-acquired weakness was not different in mechanically ventilated patients treated with NMBAs (0.28%) compared to controls (0.17%) in mechanically ventilated patients with severe sepsis, but most patients received a NMBA for only one day (p = 0.48).9
    • status asthmaticus: NMBA use with corticosteroids has been associated with a higher incidence of ICU-acquired weakness, but switching to a sedation-based protocol from an NMBA-based protocol did not reduce risk of weakness [Evidence Level B-3].10
  • Minimize the risk of ICU-acquired weakness by incorporating physiotherapy, avoiding concomitant high-dose steroids, and limiting duration of NMBA use to <48 hours, when possible.5

What other adverse effects may be seen with neuromuscular blocking agents?

  • NMBAs can mask evidence of seizure activity.5
  • Hypotension due to histamine release is dose-dependent and most commonly seen with atracurium and succinylcholine.3,6
  • Tachycardia is most commonly seen with pancuronium and rocuronium.3
  • Tachyphylaxis can occur with NMBA use.3,6
    • Bolus dosing may reduce incidence, compared to continuous infusions.3,6
    • If tachyphylaxis develops, a trial of another NMBA is warranted.3,6

What general care measures should be used with neuromuscular blocking agents?

  • Use analgesics and sedatives prior to and during use of NMBAs to achieve deep sedation.5,16
  • Use methods to prevent unplanned extubation (e.g., proper sedation, restraints).5
  • Use structured physiotherapy regimens to prevent complications of immobility with continuous infusions.5
  • Ensure proper eye care (e.g., lubrication, eye closure) to prevent ulceration, infection, and scarring.5
  • Consider VTE prophylaxis, due to immobility.6

Which drugs/conditions interact with neuromuscular blocking agents?

  • Some conditions may lead to an altered response to NMBAs. These patients might be more sensitive to potential drug interactions.
    • Patients with the following may be more sensitive to the effects of NMBAs: acidosis, advanced age, hypokalemia, hypothermia, and myasthenia gravis.5
    • Conversely, patients with burn injuries may be resistant to NMBA effects and require higher doses.5
  • Drugs that may increase non-depolarizing NMBA activity include: lidocaine, antimicrobials (e.g., aminoglycosides, clindamycin, polymyxin B, tetracycline), antiarrhythmics (e.g., procainamide, quinidine), magnesium, calcium channel blockers, beta-blockers, immunosuppressives (e.g., cyclophosphamide, cyclosporin), dantrolene, diuretics, and lithium.3
  • Drugs that may decrease non-depolarizing NMBA activity include: phenytoin, carbamazepine, theophylline, and ranitidine.3

Which products should be used to reverse neuromuscular blocking agents?

Reversal of NMBAs is rarely necessary in the ICU but is more commonly seen in the operating room.5

  • neostigmine: acetylcholinesterase inhibitor, increasing acetylcholine levels.11
    • Typically given after some TOF recovery due to ceiling effect.11,12
    • Given with a muscarinic blocker (e.g., atropine, glycopyrrolate) to reduce adverse effects (e.g., bradycardia, respiratory secretions).11
  • sugammadex (Bridion): forms complex with rocuronium and vecuronium, preventing receptor binding.

What storage and dispensing practices can improve neuromuscular blocking agent safety?

  • Automated dispensing cabinet (ADC) safety considerations:
    • Limit NMBAs to ADCs to areas where patients can be ventilated (e.g., ICU, emergency department).15
    • Store the NMBA in a locked-lidded ADC pocket or sealed rapid sequence intubation kit.15
    • If possible, require five letters to be typed into the ADC.15
    • Add the brand and generic name to the ADC med list.15
    • Add “paralytic agent” to the drug name in the ADC.18
    • Require and independent double-check for overrides.15
    • Require confirmation in the ADC that the patient is ventilated before NMBA removal from an ADC.15
    • Take steps to ensure distraction-free removal of meds from ADC.15
    • See our checklist, Automated Dispensing Cabinet Safety, for general best practices.
  • Pharmacy safety practices:
    • Add a label such as, “Warning: causes respiratory arrest. Patient must be ventilated” on storage bins, vials, syringes, or bags containing NMBAs, including on the administration port.15,17
    • Have processes for timely and secure return and destruction of unused NMBA bags or syringes.17
    • Question orders for NMBAs outside of ICU or surgical areas.17 Require NMBA orders in the ICU to be part of an intubation order set.17
    • Remove the NMBA from the med list when the patient is moved to the floor so that it cannot be re-ordered.17

Abbreviations: ADC = automated dispensing cabinet; ARDS = acute respiratory distress syndrome; ICU = intensive care unit; IV = intravenous; MOA = mechanism of action; NMBA = neuromuscular blocking agent; PNS = peripheral nerve stimulator; TOF = train of four.

--Continue for a Comparison of Neuromuscular Blocking Agents--

Comparison of Neuromuscular Blocking Agents

Dosing in chart may differ from product labeling

NMBA

Onset and Duration of Action

ADULT Dosinga

Eliminationb/Active Metabolites

Atracurium(generics)

Intermediate-acting

Onset:6,19

  • Three to five minutes

Duration:6,19

  • 20 to 35 minutes

Reduce twitch height:6 0.2 mg/kg IV

Intubation:6 0.4 to 0.5 mg/kg IV

Bolus:6 0.1 mg/kg IV

Continuous infusion:6 5 to 20 mcg/kg/min IV

Elimination:6 plasma esterase and Hofmann elimination

Active metabolite:6 laudanosine (may cause central nervous system toxicity [e.g., seizures])

Cisatracurium (Nimbex, generics)

Intermediate-acting

Onset:6

  • Three to five minutes

Duration:6

  • 20 to 35 minutes

Reduce twitch height:6 0.05 mg/kg IV

Intubation:6 0.1 to 0.2 mg/kg IV

Bolus:0.15 to 0.2 mg/kg IV

Continuous infusion:1 to 3 mcg/kg/min IV

Elimination:6 Hofmann elimination

Active metabolite:6 none

Pancuronium (generics)

Long-acting

Onset:6

  • Three to five minutes

Duration:6

  • 60 to 90 minutes

Reduce twitch height:6 0.07 mg/kg IV

Intubation:6 0.1 mg/kg IV

Bolus:6 0.02 mg/kg IV

Continuous infusion:6 0.8 to 1.7 mcg/kg/min IV

Elimination:6 kidney more than liver

Active metabolite:6 3-desacetyl-pancuronium

(50% potency)

Rocuronium (generics)

Intermediate-acting

Onset:6,19

  • One to two minutes

Duration:6,19

  • 20 to 35 minutes
  • 60 to 80 minutes (with rapid sequence)1

Reduce twitch height:6 0.3 mg/kg IV

Intubation:2,21 0.6 to 1.2 mg/kg IV

Bolus:6 0.1 mg/kg IV

Continuous infusion:8 to 12 mcg/kg/min IV

Elimination:6 liver more than kidney

Active metabolite:6 none

Succinylcholine (Anectine, Quelicin, generics)

Short-acting

Onset:6,19

  • <1 minute

Duration:6,19

  • Five to ten minutes

Reduce twitch height:6 0.5 to 0.6 mg/kg IV

Intubation:6 0.5 to 1 mg/kg IV

Bolus:6 1 mg/kg IV

Continuous infusion:not recommended

Elimination:6 plasma cholinesterase

Active metabolite:6 none

Vecuronium (generics)

Intermediate-acting

Onset:6

  • Three to five minutes

Duration:6,19

  • 20 to 35 minutes

Reduce twitch height:6 0.05 mg/kg IV

Intubation:6 0.08 to 0.1 mg/kg IV

Bolus:6 0.02 mg/kg IV

Continuous infusion:6 0.8 to 1.7 mcg/kg/min IV

Elimination:6 liver slightly more than kidney

Active metabolite:3-desacetyl-vecuronium (50% to 70% potency)

  1. Use ideal body weight, lean body weight, or adjusted body weight when calculating most NMBA doses for obese patients.20 Choose ideal body weight if overdosing is more of a concern than underdosing.20 Use actual body weight when calculating succinylcholine doses.20
  2. Hofmann elimination involves methylation of a quaternary amine to create a tertiary amine and an alkene.

References

  1. Renew JR, Ratzlaff R, Hernandez-Torres V, et al. Neuromuscular blockade management in the critically Ill patient. J Intensive Care. 2020 May 24;8:37. doi: 10.1186/s40560-020-00455-2.
  2. Madden LK, Hill M, May TL, et al. The Implementation of Targeted Temperature Management: An Evidence-Based Guideline from the Neurocritical Care Society. Neurocrit Care. 2017 Dec;27(3):468-487.
  3. Murray MJ, Cowen J, DeBlock H, et al. Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient. Crit Care Med. 2002 Jan;30(1):142-56.
  4. May TL, Riker RR, Fraser GL, et al. Variation in Sedation and Neuromuscular Blockade Regimens on Outcome After Cardiac Arrest. Crit Care Med. 2018 Oct;46(10):e975-e980.
  5. Murray MJ, DeBlock H, Erstad B, et al. Clinical Practice Guidelines for Sustained Neuromuscular Blockade in the Adult Critically Ill Patient. Crit Care Med. 2016 Nov;44(11):2079-2103.
  6. deBacker J, Hart N, Fan E. Neuromuscular Blockade in the 21st Century Management of the Critically Ill Patient. Chest. 2017 Mar;151(3):697-706.
  7. DiBridge JN, Rivosecchi RM, McVerry BJ, et al. Comparison of three cisatracurium dosing strategies in acute respiratory distress syndrome: A focus on drug utilization and improvement in oxygenation. J Crit Care. 2021 Dec;66:166-172.
  8. Hua Y, Ou X, Li Q, Zhu T. Neuromuscular blockers in the acute respiratory distress syndrome: A meta-analysis. PLoS One. 2020 Jan 21;15(1):e0227664. doi: 10.1371/journal.pone.0227664.
  9. Steingrub JS, Lagu T, Rothberg MB, et al. Treatment with neuromuscular blocking agents and the risk of in-hospital mortality among mechanically ventilated patients with severe sepsis. Crit Care Med. 2014 Jan;42(1):90-6.
  10. Kesler SM, Sprenkle MD, David WS, Leatherman JW. Severe weakness complicating status asthmaticus despite minimal duration of neuromuscular paralysis. Intensive Care Med. 2009 Jan;35(1):157-60.
  11. Pani N, Dongare PA, Mishra RK. Reversal agents in anaesthesia and critical care. Indian J Anaesth. 2015 Oct;59(10):664-9.
  12. Bowman WC. Neuromuscular block. Br J Pharmacol. 2006 Jan;147 Suppl 1(Suppl 1):S277-86.
  13. Szakmany T, Woodhouse T. Use of cisatracurium in critical care: a review of the literature. Minerva Anestesiol. 2015 Apr;81(4):450-60.
  14. VanderWeide LA, Abdel-Rasoul M, Gerlach AT. The Incidence of hypotension with continuous infusion atracurium compared to cisatracurium in the Intensive Care Unit. Int J Crit Illn Inj Sci. 2017 Apr-Jun;7(2):113-118.
  15. ISMP. Safety enhancements every hospital must consider in wake of another tragic neuromuscular blocker event. January 17, 2019. https://www.ismp.org. (Accessed May 15, 2022).
  16. Alhazzani W, Belley-Cote E, Møller MH, et al. Neuromuscular blockade in patients with ARDS: a rapid practice guideline. Intensive Care Med. 2020 Nov;46(11):1977-1986.
  17. ISMP. Paralyzed by mistakes-reassess the safety of neuromuscular blockers in your facility. June 16, 2016. https://www.ismp.org. (Accessed May 15, 2022).
  18. ISMP. Criminalization of human error and a guilty verdict: a travesty of justice that threatens patient safety. April 7, 2022. https://www.ismp.org. (Accessed May 15, 2022).
  19. Greenberg SB, Vender J. The use of neuromuscular blocking agents in the ICU: where are we now? Crit Care Med. 2013 May;41(5):1332-44.
  20. Erstad BL, Barletta JF. Dosing of neuromuscular blocking agents in patients with obesity: A narrative review. Anaesth Intensive Care. 2021 Mar;49(2):98-104.
  21. Tran DT, Newton EK, Mount VA, et al. Rocuronium versus succinylcholine for rapid sequence induction intubation. Cochrane Database Syst Rev. 2015 Oct 29;2015(10):CD002788.

Cite this document as follows: Clinical Resource, Neuromuscular Blocking Agents in Adult Patients. Pharmacist’s Letter/Prescriber’s Letter. June 2022. [380618]