Nondepolarizing Neuromuscular Blockers

Mechanism of Action

nNMBs classify as competitive acetylcholine (ACh) antagonists, which directly bind to the alpha subunits of nicotinic receptors on the postsynaptic membrane. Under normal circumstances, the 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. The receptor binding 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 maintaining the polarized motor endplate. This metabolic process leads to muscular paralysis, a favorable condition for patients undergoing perioperative procedures.

These agents differentiate into two 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 possess more vagolytic activity and benzylisoquinolines, causing more histamine reactions, both subtypes have the same mechanism of action. However, clinical reversal algorithms now differ due to the recent development of sugammadex.[7]

Administration

nNMBs administration is via the 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 minutes before 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 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. The effects of histamine reaction include hemodynamic instability (tachycardia, hypotension), bronchospasm, and urticaria.[6] Slow injection rates and pretreatment with an anti-histamine will decrease the severity and/or incidence of these reactions.[9]

The primary drug interaction to monitor is the co-administration of nNMBs and inhaled anesthetics (desflurane, sevoflurane, isoflurane, enflurane, halothane, NO). Inhaled anesthetics augment nNMB activity so that the dosing of nNMB must be reduced to accommodate. If there is no reduction in dosing, 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: anticonvulsants (phenytoin, valproic acid, carbamazepine), cholinesterase inhibitors (neostigmine, pyridostigmine)

Contraindications

Contraindications [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

Cautions [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 for 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 withdrawing the maintenance of the blockade. Normally performed on the adductor pollicis muscle via stimulation of the ulnar nerve, the response desired is a twitch that indicates a specific muscle contraction. The four 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 reaction would indicate that no more nNMB is required and that reversal should receive a standard dose. However, if TOF is less than 0.9, 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 is less than 0.7, this would indicate persistent blockade.[6] Both situations described would mean that the nNMB must be discontinued, or a higher dose of a reversal agent is necessary, and/or that the patient should remain on mechanical ventilation until the blockade reverses 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 that occurs at physiologic pH. For atracurium and cisatracurium, their Hoffman elimination produces the metabolite laudanosine. If allowed to build up like in cases of hepatic failure, this metabolite 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 the volume of distribution in cases of both cirrhosis and renal failure. Due to pancuronium’s action of inducing high vagal blockade activity, an excess can cause hypertension and tachycardia and increase the risk of producing ventricular arrhythmias in those predisposed to them/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

Initially, all neuromuscular blockers were reversed via acetylcholinesterase inhibitors (neostigmine, edrophonium, pyridostigmine).[13] The reversal occurs by these agents blocking acetylcholinesterase enzymes present in the synaptic cleft and function to break down ACh. When these enzymes are blocked, an 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 been 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 initially designed for the reversal of the steroidal nNMBs, while the neostigmine/glycopyrrolate combination is still in use 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 critically ill patients. These drugs paralyze muscles and make it difficult to breathe. Thus, no alert patient should ever receive these agents. To ensure the safety of these drugs, the physician, nurse anesthetist, and nurses must work together in a team approach to assure safe intubations with the best possible patient outcome. When administering non-depolarizing agents, resuscitative equipment must be at the bedside for immediate intubation. Nurses who manage patients in the ICU should be familiar with the dosage and potential adverse effects. The pharmacist should always double-check the drug dosage before dispensing it to the nurse. Only through open communication and interprofessional teamwork can the patient's safety be ensured with nNMBs.[14] [Level 5]