Cisatracurium

Mechanism of Action

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

The neuromuscular blocking potency of cisatracurium is roughly 3 times that of atracurium.[5] 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 require a lower dose of cisatracurium. Alternatively, a persistently febrile patient in ARDS on a cisatracurium drip may necessitate higher doses of this medication.[6] Neither of these byproducts has any neuromuscular blocking activity.[7][8][9]

The liver and kidney both play a minor role in eliminating cisatracurium but are primary pathways for removing 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

Pharmacokinetics

The parent drug of cisatracurium is responsible for its neuromuscular blocking activity. After IV bolus administration, a 2-compartment open model best describes the cisatracurium plasma concentration-time profile. 

Distribution

Cisatracurium has a large molecular weight and high polarity. The drug has a volume of distribution at a steady state (VSS) of 145 mL/kg. As cisatracurium rapidly degraded at physiologic pH, plasma protein binding of cisatracurium has not been studied successfully. 

Elimination

Elimination based on a chemical process due to temperature and pH (Organ-independent Hofmann elimination) is the key pathway for cisatracurium elimination. The kidney and liver play a minor role in cisatracurium elimination; however, they are primary pathways for metabolite elimination. Therefore, metabolite half-life is longer in patients with renal or hepatic impairment. In studies of healthy surgical patients, average clearance values ranged from 4.5 to 5.7 mL/min/kg for cisatracurium. In studies of healthy surgical patients, the average half-life of cisatracurium ranged from 22 to 29 minutes.

Metabolism

The degradation of cisatracurium was mainly independent of liver metabolism. Suggestions have been made that cisatracurium undergoes Hofmann elimination to form laudanosine based on in vitro experiments. Laudanosine metabolite has been noted to cause transient hypotension and cerebral excitatory effects in higher doses when administered to several animal species. However, the relationship between laudanosine concentrations and CNS excitation has not been established in humans.

Excretion

According to a study involving 6 healthy male patients, most of the administered dose of 14C-cisatracurium (approximately 95%) was found in their urine, while 4% was in their feces. Furthermore, less than 10% of the excreted dose in the urine remained in its parent form.

Administration

Cisatracurium is administered intravenously. The typical dose for intubation is 0.15 to 0.2 mg/kg. After this usual dose, ideal intubating conditions are generally achievable 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 adjusting the dosing based on peripheral nerve monitoring is important.[10]

Specific Patients Population

Hepatic impairment: Hepatic impairment analysis of cisatracurium was summarized from a study of 11 healthy adult patients undergoing elective surgery and 13 patients undergoing liver transplantation with end-stage liver disease. A slightly larger distribution volume is observed in liver transplant patients due to a slightly faster rate of cisatracurium plasma clearances. There was no difference in half-life, keo, or EC50 values between patient groups. Approximately one minute faster neuromuscular blockade response was observed in liver transplant patients than in healthy adult patients who received 0.1 mg/kg of cisatracurium. However, half-life values of metabolites are longer in patients with hepatic disease, and higher concentrations may be observed after long-term administration of cisatracurium.

Renal impairment: Renal impairment analysis of cisatracurium was summarized from a study of 13 healthy adult patients undergoing elective surgery and 15 patients with end-stage renal disease. No significant difference was observed in PK/PD parameters of cisatracurium between healthy adults and end-stage renal disease patients. Approximately one minute slower response to block 90% neuromuscular was observed in end-stage renal disease patients than in healthy adult patients who received 0.1 mg/kg of cisatracurium. There were no differences in recovery rates or cisatracurium durations between healthy adults and end-stage renal disease patients.

However, half-life values of metabolites are longer in patients with end-stage renal disease, and higher concentrations may be observed after long-term administration of cisatracurium. Based on Population PK analyses, patients with creatinine clearances less than 70 mL/min had a slower equilibration rate between plasma concentrations and the effect of the neuromuscular block than normal renal function patients. There was no clinically significant change in the cisatracurium recovery profile in patients with renal impairment. 

Pregnancy: No well-controlled and adequate studies of cisatracurium have been conducted in pregnant women. The risk of major congenital abnormalities and miscarriage is unknown in the indicated population. Using magnesium salts to manage preeclampsia or eclampsia during pregnancy may enhance the effect of neuromuscular blocking agents. Recommendations for administering cisatracurium for prolonged neuromuscular blockade in critically ill pregnant patients are unavailable due to lack of evidence.[4]

Breastfeeding: The presence of cisatracurium in human milk is unknown. The health and developmental benefits of breastfeeding must be considered before initiating the clinical use of cisatracurium in breastfeeding women. The recommendation is to monitor any potential negative impacts on the breastfed infant that may arise from cisatracurium or the mother's underlying medical condition.[1][11] Generally, neuromuscular blocking medicines may be used in lactating females depending on their physical characteristics and poor oral bioavailability.[12]

Pediatric patients: The effect of cisatracurium in pediatric patients was summarized from a population PK/PD study of 12 healthy pediatric patients of 2 to 12 years old and 12 healthy adult patients. Higher clearance was observed in healthy pediatric patients (5.89 mL/min/kg) compared to healthy adult patients (4.57 mL/min/kg). The minor difference in the PK/PD parameters of cisatracurium may be due to a shorter duration of neuromuscular blockade action and a faster time to onset in pediatric patients.

Older patients: The effect of cisatracurium in older patients was summarized from a study of 12 healthy older patients and 12 healthy adult patients who received a single IV cisatracurium dose of 0.1 mg/kg. Cisatracurium plasma clearances were unaffected by age; however, a slightly larger volume of distribution was observed in older patients than in young patients, which may lead to slightly longer half-life values for cisatracurium. The equilibration rate between the plasma cisatracurium concentrations and neuromuscular blockade was slower in older than young patients. There are only minor differences in pharmacokinetics and pharmacodynamic parameters of cisatracurium between older and young patients.

Adverse Effects

Adverse effects are uncommon with the use of cisatracurium. Adverse reactions occurred at a rate of less than 1% and included bradycardia, hypotension, bronchospasm, rash, anaphylaxis, prolonged neuromuscular blockade, and myopathy.[13]

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 for patients with either of these diseases.

Contraindications

Cisatracurium is contraindicated if there is a known hypersensitivity. Caution is advised 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 depolarizing and nondepolarizing agents.

Cisatracurium should be kept refrigerated at 2 to 8 °C and protected from light to preserve potency. The potency loss rate is as high as 5% monthly at 25°C. 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 causes muscular contraction of the orbicularis oculi, adductor pollicis, and flexor hallucis longus, respectively. Peripheral nerve stimulation measuring a twitch response should 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.[14][15][16]

Toxicity

Overdose with cisatracurium may result in neuromuscular blockade beyond the time needed for surgery and anesthesia. The primary treatment is maintaining sedation, a patent airway, and controlled ventilation until recovery of neuromuscular function is assured. 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 (eg, neostigmine) in conjunction with an anticholinergic agent (eg, glycopyrrolate). As with 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 0.03 to 0.07 mg/kg, in conjunction with 0.2 mg glycopyrrolate for every 1 mg of neostigmine.[17]

Enhancing Healthcare Team Outcomes

Cisatracurium should be administered only by adequately trained individuals (ie, anesthesiologist, nurse anesthetist, intensivist, emergency physician) familiar with its actions, characteristics, and hazards. The drug should not be administered without the presence of 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 the drug's effect. This monitoring will determine the need for additional doses and 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. This medication is most effective and safest when used with an interprofessional team administering the drug and monitoring the patient.