Non-depolarizing Neuromuscular Blockers

Article Author:
Derek Clar
Article Editor:
Mark Liu
Updated:
3/23/2019 1:38:23 AM
PubMed Link:
Non-depolarizing Neuromuscular Blockers

Indications

Non-depolarizing neuromuscular blockers (nNMBs) are administered as primary therapy in facilitating endotracheal intubations and adjuvant therapy in the perioperative maintenance of anesthesia and care of the critically ill patient. Primarily nNMBs (rocuronium, vecuronium, pancuronium, atracurium, cisatracurium, mivacurium) are used to facilitate airway management and decrease the risk of laryngeal injury during regular and emergent intubations.[1] nNMBs can decrease hoarseness secondary to intubation via decreasing incidence of vocal cord injuries.[2] As an adjunctive therapy to intravenous (IV) or inhaled anesthetics, nNMBs has also been found to improve outcomes of mechanical ventilation in patients with poor lung compliance who are critically ill and/or being treated in the perioperative setting.[3] This combination in the perioperative setting can also facilitate access to the thoracic and abdominal cavities by depressing voluntary or reflex muscle movement.[4]

FDA-Approved Indications

  • Endotracheal intubation: Primary; improve intubation outcomes, facilitates airway management
  • Surgical procedures: Adjunctive; combined with anesthetics, improves surgical field prep
  • Mechanical ventilation: Adjunctive; improves outcomes in mechanical ventilation   

Currently, there are no FDA off-label indications.

Mechanism of Action

nNMBs are classified as competitive acetylcholine (ACh) antagonists which directly bind to the alpha subunits of nicotinic receptors on the postsynaptic membrane. In normal cases, transmission of impulses from the primary motor cortex to the motor endplates occurs via ACh release from the presynaptic terminal, diffusion across the synaptic membrane, and binding to the nicotinic receptor of the postsynaptic membrane. Binding of the receptor then activates its sodium (Na+) channel domain allowing the influx of Na+ and depolarizing the motor endplate from a resting membrane potential of -100 mV to +40 mV depolarized potential. The depolarizing signal would reach the sarcoplasmic membrane which would signal a release of calcium ions (Ca2+) that facilitates muscular contraction.[5] nNMBs fit into this metabolic process by blocking ACh binding to the alpha subunits on nicotinic receptors and maintains the polarized motor endplate. This metabolic process leads to muscular paralysis, a favorable condition to have in patients who are undergoing perioperative procedures.

These agents are differentiated into 2 subcategories, classified structurally and clinically based on drug reversal patterns[6]:

  • Steroidal: Rocuronium, vecuronium, pancuronium  
  • Benzylisoquinolinium: Atracurium, cisatracurium, mivacurium

Although slight differences in clinical effects like the steroidal agents possessing more vagolytic activity and benzylisoquinolines causing more histamine reactions, both subtypes have the same mechanism of action. However, due to the recent development of Sugammadex, clinical reversal algorithms now differ.[7]

Administration

nNMBs are administered via IV route. All agents have individualized dosing[8]

  • Rocuronium: IV 0.45 to 0.90 mg/kg for intubation and IV 0.15 mg/kg boluses for maintenance. IV 0.40 mg/kg also used in cases which reversal achieved within 25 minutes after intubation
  • Vecuronium: IV 0.08 to 0.12 mg/kg used for intubation. Intraoperatively IV 0.04 mg/kg given initially followed by increments of 0.01 mg/kg every 15 to 20 minutes
  • Pancuronium: IV 0.08 to 0.12 mg/kg used for intubation within 2 to 3 minutes. Intraoperatively IV 0.04 mg/kg given initially followed by increments of 0.01 mg/kg every 20 to 40 minutes
  • Atracurium: IV 0.5 mg/kg given for intubation. Intraoperatively, following succinylcholine administration, 0.25 mg/kg can initially be given with maintenance doses of 0.1 mg/kg every 10 to 20 minutes
  • Cisatracurium: IV 0.1 to 0.15 mg/kg administered within 2 min. prior to intubation. Maintenance infusion administered at IV 1.0 to 2.0 mcg/kg per minute
  • Mivacurium: IV 0.2 mg/kg for intubation, with maintenance infusion rate of 4 to 10 mcg/kg per minute

Adverse Effects

The common adverse reaction for which to monitor is the effects of nNMB induced histamine release. Studies have shown that benzylisoquinolinium nNMBs (atracurium, mivacurium) have the highest incidence of all nNMBs to induce histamine reactions in the perioperative setting. Effects of histamine reaction include hemodynamic instability (tachycardia, hypotension), bronchospasm, and urticaria.[6] Slow injection rates and pretreatment with an anti-histamine are found to decrease the severity and/or incidence of these reactions.[9]

The common drug interaction monitored is the co-administration of nNMBs and inhaled anesthetics (desflurane, sevoflurane, isoflurane, enflurane, halothane, NO). Inhaled anesthetics augment nNMB activity so that dosing of nNMB must be reduced to accommodate. If dosing is not reduced, then the risk of a residual blockade and ensuing pulmonary distress increases.[1] Other categories of drug interactions are differentiated by either augmenting or eliciting resistance of activity[9]:

  • Augments: Antibiotics (aminoglycosides, clindamycin, tetracycline), antiarrhythmics (quinidine, calcium channel blockers), dantrolene, ketamine, local anesthetics, magnesium sulfate 
  • Resistance: Anti-convulsants (phenytoin, valproic acid, carbamazepine), cholinesterase inhibitors (neostigmine, pyridostigmine)

Contraindications

There are both contraindications and cautions when administering nNMBs. The contraindications include[9]:

  • Conditions that exhibit resistance: Cerebral palsy, burn injuries, hemiplegia (on the affected side), peripheral nerve injury, severe chronic infections of botulism or tetani
  • Conditions that exhibit hypersensitivity: ALS, autoimmune disorders (SLE, polymyositis, dermatomyositis), Guillain-Barre, Duchenne type muscular dystrophy, myasthenia gravis

Factors to be cautious of when administering include[9]:

  • Hypothermia: Prolongs blockade by decreasing metabolism and elimination
  • Respiratory acidosis: Potentiates neuromuscular blockade and antagonizes reversal
  • Electrolyte abnormalities: Hypokalemia and hypocalcemia potentiate blockade; in preeclamptic patients who are taking magnesium sulfate can present with hypermagnesemia which also potentiates blockades
  • Hepatic disease/failure: Decreases clearance and increase volume of distribution
  • Renal failure: Decreases clearance, though prolongation of blockade varies

Monitoring

Train-of-four (TOF) is the standard of monitoring a patient’s blockade status during perioperative and postoperative periods. TOF involves four 2-Hz stimulations to specific muscle groups to assess the extent of the blockade and, in a prognostic sense, how the patient will react when maintenance of the blockade is withdrawn. Normally performed on the adductor pollicis muscle via stimulation of the ulnar nerve, the response desired is a twitch that indicates the contraction of a specific muscle. The 4 twitches are quantified so that a normal TOF should be TOF greater than or equal to 1, meaning the muscle has improved contraction on each stimulation so that the fourth is much stronger than the first.[10] This would indicate that no more nNMB is required and that reversal should receive a standard dose. However, if TOF is less than 0.9, then this would indicate that post-residual blockade and postoperative complications have a higher risk of occurring. The main complication of concern is respiratory distress due to residual blockade of the diaphragm and laryngeal muscles. If TOF less than 0.7 this would indicate persistent blockade.[6] Both situations described would mean that the nNMB be discontinued, a higher dose of reversal agent required, and/or that the patient should remain on mechanical ventilation until the blockade is reversed enough for spontaneous respirations.[8]

Toxicity

When metabolized and eliminated, most nNMBs undergo either an ester hydrolysis process performed by non-specific esterases at the synaptic cleft or by the Hoffman elimination which is a spontaneous non-enzymatic breakdown which occurs at physiologic pH. For atracurium and cisatracurium, from their Hoffman’s elimination produces the metabolite Laudanosine. This metabolite, if allowed to build up like in cases of hepatic failure, can cause central nervous system (CNS) excitation to the point of seizure activity.[11] Pancuronium which is normally eliminated via deacetylation by hepatocytes can increase in volume of distribution in cases of both cirrhosis and renal failure. Due to pancuronium’s feature of inducing high vagal blockade activity, in excess can cause hypertension, tachycardia, and increase the risk of producing ventricular arrhythmias in those who are predisposed to them and/or those already taking tricyclic antidepressants.[12] Both vecuronium and rocuronium are relatively less concerning for their toxic effect with vecuronium showing potentiation of opioid-induced bradycardia in some cases and rocuronium exhibiting mild vagal blockade abilities.[9]

In the event of overdose or perioperative reversal of nNMB activity:

Originally, all neuromuscular blockers were reversed via acetylcholinesterase inhibitors (neostigmine, edrophonium, pyridostigmine).[13] Reversal occurs by these agents blocking acetylcholinesterase enzymes present in the synaptic cleft and function to break down ACh. When these enzymes are blocked, increased concentration of ACh at the postsynaptic membrane out-competes the antagonists and restores the function of the Na+ channels and restores muscle contraction. Giving only neostigmine, clinically the most relevant of the acetylcholinesterase inhibitors, causes increased parasympathetic effects; the most worrisome of these effects being bronchospasm and laryngeal collapse. Glycopyrrolate, an anti-muscarinic agent, was added to this regimen to alleviate these effects.[9]

Now sugammadex, a steroidal nNMB binder, is implemented in the algorithm since it has shown to reverse the effects of nNMBs with less incidence of laryngeal collapse. Sugammadex works to bind nNMB molecules in a 1:1 ratio, the binding producing a concentration gradient in the synaptic cleft, increasing the diffusion of these molecules away from the postsynaptic membrane.[6] Sugammadex was originally designed for the reversal of the steroidal nNMBs, while the neostigmine/glycopyrrolate combination is still being used for the reversal of benzylisoquinolinium nNMBs.[13]

Enhancing Healthcare Team Outcomes

Non-depolarizing neuromuscular blockers are often administered to assist endotracheal intubations and provide adjuvant therapy in the perioperative maintenance of anesthesia and care of the critically ill patient. The physician, nurse anesthetist, and nurses must work together in a team approach to assure safe intubations with the best possible patient outcome. [Level V]


References

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[2] Lundstrøm LH,Duez CH,Nørskov AK,Rosenstock CV,Thomsen JL,Møller AM,Strande S,Wetterslev J, Avoidance versus use of neuromuscular blocking agents for improving conditions during tracheal intubation or direct laryngoscopy in adults and adolescents. The Cochrane database of systematic reviews. 2017 May 17     [PubMed PMID: 28513831]
[3] Lieutaud T,Billard V,Khalaf H,Debaene B, Muscle relaxation and increasing doses of propofol improve intubating conditions. Canadian journal of anaesthesia = Journal canadien d'anesthesie. 2003 Feb     [PubMed PMID: 12560300]
[4] Adam JM,Bennett DJ,Bom A,Clark JK,Feilden H,Hutchinson EJ,Palin R,Prosser A,Rees DC,Rosair GM,Stevenson D,Tarver GJ,Zhang MQ, Cyclodextrin-derived host molecules as reversal agents for the neuromuscular blocker rocuronium bromide: synthesis and structure-activity relationships. Journal of medicinal chemistry. 2002 Apr 25     [PubMed PMID: 11960492]
[5] Errando CL,Garutti I,Mazzinari G,Díaz-Cambronero Ó,Bebawy JF, Residual neuromuscular blockade in the postanesthesia care unit: observational cross-sectional study of a multicenter cohort. Minerva anestesiologica. 2016 Dec     [PubMed PMID: 27232277]
[6] Zafirova Z,Dalton A, Neuromuscular blockers and reversal agents and their impact on anesthesia practice. Best practice     [PubMed PMID: 30322460]
[7] Zoremba N,Schälte G,Bruells C,Pühringer FK, [Update on muscle relaxation : What comes after succinylcholine, rocuronium and sugammadex?] Der Anaesthesist. 2017 May     [PubMed PMID: 28289767]
[8] Palsen S,Wu A,Beutler SS,Gimlich R,Yang HK,Urman RD, Investigation of intraoperative dosing patterns of neuromuscular blocking agents. Journal of clinical monitoring and computing. 2018 Aug 9     [PubMed PMID: 30094585]
[9] Smith G,Goldman J, General Anesthesia for Surgeons null. 2018 Jan     [PubMed PMID: 29630251]
[10] 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. Anesthesia and analgesia. 2018 Jul     [PubMed PMID: 29200077]
[11] Sakuraba S,Hosokawa Y,Kaku Y,Takeda J,Kuwana S, Laudanosine has no effects on respiratory activity but induces non-respiratory excitement activity in isolated brainstem-spinal cord preparation of neonatal rats. Advances in experimental medicine and biology. 2010     [PubMed PMID: 20217344]
[12] Kandukuri DS,Phillips JK,Tahmindjis M,Hildreth CM, Effect of anaesthetic and choice of neuromuscular blocker on vagal control of heart rate under laboratory animal experimental conditions. Laboratory animals. 2018 Jun     [PubMed PMID: 28862524]
[13] Bulka CM,Terekhov MA,Martin BJ,Dmochowski RR,Hayes RM,Ehrenfeld JM, Nondepolarizing Neuromuscular Blocking Agents, Reversal, and Risk of Postoperative Pneumonia. Anesthesiology. 2016 Oct     [PubMed PMID: 27496656]