Continuing Education Activity

Cisatracurium besylate is an intermediate-acting, non-depolarizing neuromuscular blocking drug (NMBD). Cisatracurium has a benzylisoquinolinium structure and is the 1R cis-1-prime R cis isomer of atracurium. As an NMBD, it has found use as an adjunct to general anesthesia facilitating tracheal intubation and providing skeletal muscle relaxation during surgery. It may also be used to provide skeletal muscle relaxation to facilitate mechanical ventilation in an intensive care unit setting, but must be used with sedation. This activity reviews indications, mechanism of action, administration, contraindications, monitoring, and toxicity associated with cisatracurium, and the role of the interprofessional team in caring for patients who have received cisatracurium.

Objectives:

• Identify indications for use of cisatracurium.
• Describe the potential side effects of cisatracurium.
• Outline the recommended doses and recommended reversal medications for cisatracurium.
• Explain the importance of detailed handoffs and interpersonal communication with other professionals involved in the management of the patient that received cisatracurium.

Indications

Cisatracurium besylate is an intermediate-acting, non-depolarizing neuromuscular blocking drug (NMBD). Cisatracurium has a benzylisoquinolinium structure and is the 1R cis-1’R cis isomer of atracurium. Metocurine and d-tubocurarine are also in the benzylisoquinolinium class.[1] As an NMBD, it has found use as an adjunct to general anesthesia facilitating tracheal intubation and providing skeletal muscle relaxation during surgery.  It may also function to provide skeletal muscle relaxation to facilitate mechanical ventilation in an intensive care unit setting, but its use requires sedation.[2][3]

Mechanism of Action

Cisatracurium, like the other NMBDs, binds to the nicotinic cholinergic receptor at the muscle motor end-plate but is not capable of inducing the conformational change necessary for ion channel opening. Because acetylcholine cannot bind to its receptors, no end-plate potential can develop. Cisatracurium acts as a competitive antagonist to acetylcholine; acetylcholinesterase inhibitors such as neostigmine antagonize this action.

The neuromuscular blocking potency of cisatracurium is roughly three times that of atracurium.[4] The clinically beneficial duration of action and rate of spontaneous recovery from equipotent doses of the two drugs are similar. Continuous infusion or repeated administration of maintenance doses of cisatracurium for up to 3 hours does not correlate with the development of tachyphylaxis or cumulative neuromuscular blocking effects.

Cisatracurium undergoes organ-independent Hofmann elimination—a chemical process dependent on pH and temperature—to form the monoquaternary acrylate metabolite and laudanosine. Patients with hypothermia, which typically occurs in surgeries needing cardiopulmonary bypass and therapeutic hypothermia, may need a lower dose of cisatracurium. Alternatively, a persistently febrile patient in ARDS on cisatracurium drip may require higher doses of this medication.[5] Neither of these byproducts has any neuromuscular blocking activity.[6][7][8] The liver and kidney both play a minor role in the elimination of cisatracurium but are primary pathways for the elimination of metabolites. Therefore, the half-life of metabolites is longer in patients with kidney or liver dysfunction, and metabolite concentrations may be higher after long-term administration. More importantly, the values of laudanosine are significantly lower in healthy surgical patients who receive cisatracurium infusions than in patients receiving infusions of atracurium, making cisatracurium a better choice for long-term use in the ICU.

The following lists diseases that can lead to hypersensitivity to NMBDs:

• Amyotrophic lateral sclerosis
• Autoimmune disorders
  • Systemic lupus erythematosus
  • Polymyositis
  • Dermatomyositis
• Familial periodic paralysis hyperkalemia
• Guillain-Barre syndrome
• Muscular dystrophy (Duchenne type)
• Myasthenia gravis
• Myasthenic syndrome
• Myotonia
  • Dystrophic
  • Congenital
  • Paramyotonia

 The following lists diseases that can lead to a resistance to NMBDs:

• Burn injury
• Cerebral palsy
• Hemiplegia (on the affected side)
• Muscular denervation (peripheral nerve injury)
• Severe chronic infection
  • Tetanus
  • Botulism

Administration

Cisatracurium is administered intravenously. The typical dose for intubation is 0.15 to 0.2 mg/kg. After this typical dose, ideal intubating conditions are generally achievable in between 1.5 and 2 minutes. The clinically effective duration of an intubating dose lasts 55 to 65 minutes. Maintenance dosing by bolus is 0.02 mg/kg. Maintaining paralysis via infusion with cisatracurium is at 1 to 3 mcg/kg/min, although it is important to adjust the dosing based on peripheral nerve monitoring.[9]

Adverse Effects

Adverse effects are uncommon with the use of cisatracurium. Adverse reactions occurred at a rate of less than 1% and include bradycardia, hypotension, bronchospasm, rash, anaphylaxis, prolonged neuromuscular blockade, and myopathy.[10]

No clinically relevant alterations in the recovery profile were observed in patients with renal dysfunction or end-stage liver disease, making cisatracurium a good choice in a patient with either of these diseases.

Contraindications

Cisatracurium is contraindicated if there is a known hypersensitivity. Caution is advisable in patients with myasthenia gravis or myasthenic syndrome, as a profound effect may occur.

Severe anaphylactic reactions to NMBDs, including cisatracurium, have been reported. Precautions are also advisable in those patients with a history of prior anaphylactic reactions to neuromuscular blocking agents as there are reports of cross-reactivity in the neuromuscular blocking agent drug class, with both depolarizing and non-depolarizing agents.

Cisatracurium should be kept refrigerated at 2 to 8 degrees Celsius and protected from light to preserve potency. The rate of loss of potency is as high as 5% per month at 25 degrees Celsius. Once removed from refrigeration to room temperature storage, it should be used within 21 days.

Monitoring

The standard of care for monitoring while using all NMBDs is to use peripheral nerve stimulation. The most common locations to place the electrodes are over the facial nerve on the lateral face, the ulnar nerve at the medial wrist, or the posterior tibial nerve at the medial ankle. Stimulation of these nerves will cause muscular contraction of the orbicularis oculi, adductor pollicis, and flexor hallucis longus, respectively. Peripheral nerve stimulation measuring a twitch response should serve to measure the depth of muscle paralysis. The most common pattern to test nerve stimulation is with a train of four (TOF), but sustained tetanus and double burst stimulation (DBS) is another option. TOF stimulation is four repetitive electrical impulses of 2 Hz in 2 seconds. In the presence of NMBDs, repetitive stimulation causes a diminished release of acetylcholine at the neuromuscular junction, leading to a decreased amplitude of muscle contraction. With the return of the TOF ratio to 0.9, esophageal tone and pharyngeal coordination returned toward baseline.[11][12][13]

Toxicity

Overdose with cisatracurium may result in neuromuscular blockade beyond the time needed for surgery and anesthesia. The primary treatment is the maintenance of sedation, a patent airway, and controlled ventilation until recovery of neuromuscular function is assured. It is important to note that there should be no attempt at reversal if there is evidence or suspicion of complete neuromuscular blockade. Once recovery from blockade begins, from the evidence of peripheral nerve stimulation, the neuromuscular blockade may be reversed with an anticholinesterase agent (e.g., neostigmine) in conjunction with an anticholinergic agent (e.g., glycopyrrolate). As in the case of other nondepolarizing neuromuscular blocking agents, the more full the neuromuscular blockade at the point of reversal, the longer the time required for recovery of neuromuscular function. A typical dose of neostigmine is 0.4 to 0.8 mg/kg, in conjunction with 0.2 mg glycopyrrolate for every 1 mg of neostigmine.

Enhancing Healthcare Team Outcomes

Cisatracurium should be administered only by adequately trained individuals (anesthesiologist, nurse anesthetist, intensivist, emergency physician) familiar with its actions, characteristics, and hazards. The drug should not be administered absent personnel and facilities for resuscitation, and life support and an antagonist for cisatracurium must be immediately available. Cisatracurium dosing should be individualized, and a peripheral nerve stimulator should be used to measure neuromuscular function during the administration of cisatracurium to monitor drug effect, to determine the need for additional doses, and to confirm recovery from neuromuscular block. Cisatracurium has no known effects on consciousness or pain threshold, so to avoid patient distress, a neuromuscular block should not be induced before unconsciousness. The use of this medication is safest when used by an interprofessional team monitoring the patient. [Level 5]