Overview
Cisatracurium besylate is an intermediate-acting, nondepolarizing neuromuscular blocking drug (NMBD). It is used as an adjunct to general anesthesia during surgery to aid tracheal intubation and skeletal muscle relaxation. It is also used in an intensive care unit along with sedation to facilitate mechanical ventilation. The injection is used to aid tracheal intubation in adults, patients with neuromuscular disease, geriatric patients, and patients with end-stage renal disease. Compared to other neuromuscular blocking agents, it has an immediate onset of action.
After approval from the FDA (US Food and Drugs Administration), Cisatracurium besylate was marketed by Zydus Cadila, a global pharmaceutical company under the trade name Nimbex. Liva Pharmaceuticals Limited, an entirely-owned subsidiary company of Candila Healthcare Limited, manufactures Cisatracurium besylate injection.
How Does Cisatracurium Besylate Work?
Cisatracurium besylate is a neuromuscular junction-blocking drug. It works by binding to the nicotinic cholinergic receptor at the muscle motor end plate. As acetylcholine cannot bind to its receptors, end plate potential does not develop. Therefore, Cisatracurium acts as a competitive antagonist to acetylcholine. The neuromuscular blocking potential of Cisatracurium is about three times that of Atracurium. Repeated administration or continuous infusion of maintenance doses of Cisatracurium besylate for up to three hours does not cause collective neuromuscular blocking effects or tachyphylaxis (a sudden and rapid decrease in response to an administered drug).
Cisatracurium undergoes an organ-independent Hofmann elimination (elimination of amines to form alkenes). It is a chemical process that depends on pH and temperature to form metabolites like monoquaternery acrylate and laudanosine. Therefore, patients with hypothermia may require a lower dose of the drug. Hypothermia occurs in surgeries that need cardiopulmonary bypass or therapeutic hypothermia. However, a persistently febrile patient with acute respiratory distress syndrome (ARDS) on a Cisatracurium drip may require higher doses of the drug.
The liver and kidney are the primary pathways for eliminating Cisatracurium metabolites. Therefore, the half-life of the metabolites is higher in patients with kidney or liver dysfunction. Also, the concentration of metabolites can be higher after long-term administration. Therefore, Cisatracurium is a better choice in long-term ICU (intensive care unit) patients when compared to Atracurium, as the values of metabolites, especially laudanosine, are significantly lower in healthy surgical patients.
What Are the Indications and Uses of Cisatracurium Besylate Injection?
Cisatracurium besylate injection is indicated:
-
As an adjunct to general anesthesia to aid tracheal intubation in pediatric patients (one month to 12 years of age) and adults.
-
To aid in skeletal muscle relaxation for mechanical ventilation or during surgical procedures in adults in an ICU.
-
To help in skeletal muscle relaxation in pediatric patients older than two during surgical procedures through infusion.
Limitations of Use:
Cisatracurium besylate is not used for rapid endotracheal intubation, as its onset of action takes a longer time. Drug use is not recommended in neonates.
Description:
Cisatracurium besylate is a nondepolarizing skeletal muscle relaxant recommended for intravenous administration. It is one of the ten isomers of atracurium besylate and constitutes about 15 % of the mixture. Compared to other neuromuscular blocking agents, Cisatracurium has an immediate onset of action. Cisatracurium besylate injection is a sterile, non-pyrogenic aqueous solution available in 5 mL, 10 mL, and 20 mL vials.The pH is adjusted from 3.25 to 3.65 with benzenesulfonic acid.
The 5 mL and 10 mL vials contain Cisatracurium besylate equivalent to 2 mg/mL Cisatracurium. 20 mL vial contains 10 mg/mL of Cisatracurium, which is intended only for ICU use. The 5 mL and 20 mL vials are single-dose vials and do not contain benzyl alcohol. In contrast, the 10 mL vial is multiple-dose and contains 0.9 % benzyl alcohol as a preservative. Therefore, complications of benzyl alcohol toxicity must be considered before administering large patient doses of 10 mL vials.
Cisatracurium loses its potency at about 5 % every year. Therefore, it is recommended to refrigerate the medicine from 2 degrees Celsius to 8 degrees Celsius to prevent it from losing its potency. The drug must be used within 21 days if moved from cold storage to average room temperature.
Chemical Name:
[1R-[1α,2α(1'R*,2'R*)]]-2,2'-[1,5- pentanediylbis[oxy(3-oxo-3,1-propanediyl)]]bis[1-[(3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro6,7-dimethoxy-2-methylisoquinolinium] dibenzenesulfonate.
Molecular Formula:
C65H82N2O18S2 is the molecular formula of Cisatracurium as the besylate salt.
Molecular Weight:
1243.5
Dosage and Administration:
Important instructions regarding dosage and administration of Cisatracurium besylate injection include:
-
Cisatracurium besylate injection is recommended for intravenous use only.
-
The injection must be administered in carefully adjusted doses by a clinician who is well acquainted with the drug's actions and possible complications.
-
The injection must be administered only in setups with immediately available personnel and facilities to handle emergencies for resuscitation and life support, like oxygen therapy, tracheal intubation, and artificial ventilation and an antagonist of Cisatracurium besylate.
-
It is recommended to use a peripheral nerve stimulator to measure the neuromuscular function during the administration of the drug to monitor the drug effects, the need for additional doses, and confirm recovery from the block.
-
Cisatracurium besylate has no known effects on the consciousness, pain threshold, and cerebration of the patient. However, the neuromuscular block must not be induced before inducing unconsciousness.
Cisatracurium besylate is administered intravenously. The typical dose to be administered for intubation is 0.15 to 0.2 mg/kg. After administration, ideal conditions for intubation are achieved within 1.5 to 2 minutes and lasts for 55 to 65 minutes. The maintenance dose by bolus is 0.02 mg/kg. Maintaining paralysis through infusion through Cisatracurium besylate is 1 to 3 mcg/kg/min (micrograms per kilogram per minute), though it is recommended to adjust the dosing based on peripheral nerve monitoring.
What Is the Recommended Dosage for Performing Tracheal Intubation?
Tracheal Intubation in Adults:
Before selecting the initial injection bolus dose, factors like the anticipated length of surgery, age and renal function of the patient, co-induction agents (Fentanyl and Midazolam), and depth of anesthesia must be considered. The recommended starting dose is 0.15 mg/kg to 0.2 mg/kg administered by intravenous bolus injection. This is in conjunction with a propofol/nitrous oxide/oxygen-induced intubation technique or a thiopental/nitrous oxide/oxygen induction-intubation technique. Doses up to 0.4 mg/kg have been administered safely to healthy patients and patients with serious cardiovascular disease by bolus intravenous injection.
Patients With Neuromuscular Diseases:
The maximum recommended initial bolus dose of Cisatracurium besylate in patients with neuromuscular disorders like myasthenia gravis (an autoimmune disorder characterized by weakness of the skeletal muscles) and carcinomatosis is 0.02 mg/kg.
Geriatric Patients and Patients With End-Stage Renal Disease:
As the time to neuromuscular blockade in geriatric patients and patients with end-stage renal disease is one minute slower compared to younger patients and patients with normal renal function, it is recommended to consider waiting an extra minute before attempting tracheal intubation. Also, a peripheral nerve stimulator must be used to assess the adequacy of muscle relaxation and the timing and amounts of subsequent doses.
Tracheal Intubation in Pediatric Patients:
Infants Between 1 to 23 Months of Age:
Pediatric patients between 1 to 23 months can be administered 0.15 mg/kg over five to ten seconds during a stable opioid, nitrous oxide, or oxygen anesthesia. Injection Cisatracurium besylate produced maximum neuromuscular blockade in about two minutes, with a clinically effective block time of 43 minutes (that included 25 % of recovery).
Pediatric Patients of 2 to 12 Years of Age:
The weight-based recommended dose of Cisatracurium besylate injection in patients between two to 12 years of age is 0.1 to 0.15 mg/kg, administered for five to ten seconds. A dose of 0.1 mg/kg when administered with a stable opioid, nitrous oxide, or oxygen anesthesia produced maximum neuromuscular blockade in an average of 2.8 minutes, with a clinically effective dose for 28 minutes, whereas a dose of 0.15 mg/kg produced maximum neuromuscular blockade in an average of 3 minutes, with a clinically effective dose for 36 minutes.
Recommended Maintenance Bolus Dose in Adult Surgical Procedures:
The requirement for a maintenance bolus dose must be decided based on clinical criteria like the response to peripheral nerve stimulation. The recommended maintenance bolus dose of the injection is 0.03 mg/kg. However, smaller or larger doses may be preferred based on the required duration of action.
The first maintenance bolus dose must be administered starting:
-
40 to 50 minutes after an initial dose of 0.15 mg/kg Cisatracurium besylate injection.
-
50 to 60 minutes after an initial dose of 0.2 mg/kg Cisatracurium besylate injection.
Cases of long surgical procedures that use inhalational anesthetics like nitrous oxide or oxygen at 1.25 MAC level for at least 30 minutes, less frequent, or low bolus doses of Cisatracurium besylate injection must be considered. However, no maintenance dose adjustment is required when the initial dose is administered shortly after initiating volatile anesthetics or in patients receiving propofol anesthesia.
Dosage in Burn Patients:
Studies show that burn patients have decreased resistance to nondepolarizing neuromuscular blocking agents. Therefore, increasing the injection dose for intubation and maintenance must be considered.
Dosage for Continuous Infusion:
Continuous infusion of Cisatracurium besylate injection may be required in adult and pediatric patients above two years of age undergoing prolonged surgical procedures if they have a spontaneous recovery from the initial bolus dose. Also, it may be necessary to re-administer a bolus dose before starting the maintenance dose to quickly re-establish the neuromuscular blockade.
In patients who have recovery of neuromuscular function after the initial dose, the recommended initial dose of infusion is 3 mcg/kg/min. The dose must be reduced to 1 to 2 mcg/kg/min to maintain a continuous neuromuscular blockade. The peripheral nerve stimulation must be assessed, and if there is no response, the infusion may be discontinued until a response is initiated. The level of neuromuscular stimulation must be evaluated to titrate the infusion dose appropriately.
The infusion rate of Cisatracurium besylate must be reduced by 30 to 40 % when administered during stable isoflurane anesthesia for at least 30 minutes. When administering isoflurane or other inhalational anesthetics for longer durations, a more significant reduction in Cisatracurium besylate injection rate may be required.
Patients Undergoing Coronary Artery Bypass Graft Surgery:
The infusion rate of Cisatracurium besylate injection must be reduced to half in patients undergoing CABG with induced hypothermia when compared to patients with normothermia.
Continuous Infusion for Mechanical Ventilation for Adults in the Intensive Care Unit:
A continuous infusion of Cisatracurium besylate injection can be administered for adult patients admitted to an intensive care unit who require prolonged mechanical ventilation and skeletal muscle relaxation. The recommended infusion rate in adult patients in ICU is 3 mcg/kg/min.
How Is Cisatracurium Besylate Injection Prepared?
-
Cisatracurium besylate injection is colorless to mild yellow or a greenish-yellow solution.
-
Before administration, it must be visually inspected for any discoloration or particulate matter.
-
If the injection contains visible particulates or is cloudy, it must not be used.
-
The injection may be diluted to 0.1 mg/mL in one of the following solutions:
-
5 % dextrose injection, USP.
-
0.9 % Sodium chloride injection, USP.
-
5 % dextrose and 0.9 % Sodium chloride injection, USP.
-
-
The diluted solutions can be stored at room temperature or in the refrigerator for 24 hours. Unused portions must be discarded.
-
Cisatracurium besylate injection can also be diluted to 0.1 or 0.2 mg/mL in Lactated Ringer's and 5 % dextrose injection.
What Are the Dosage Forms and Strengths?
Cisatracurium besylate injection USP is a clear solution. It is available in the following strengths:
-
10 mg per 5 mL (2 mg/mL) in single-dose vials that is equivalent to 2.68 mg/mL of Cisatracurium besylate.
-
200 mg per 20 mL (10 mg/mL) in single-dose vials that is equivalent to 13.38 mg/mL of Cisatracurium besylate. Also, it is intended for administration as an infusion only in a single patient in the ICU.
What Are the Contraindications for Cisatracurium Besylate Injection Use?
Cisatracurium besylate is contraindicated in cases of known hypersensitivity. In patients with myasthenic syndrome or myasthenia gravis, the drug must be used cautiously as a profound effect can occur. Severe anaphylactic reactions with Cisatracurium besylate have been reported. Caution must be exercised in patients with a previous history of anaphylactic reactions to neuromuscular blocking agents. Reports suggest a cross-reactivity in the neuromuscular blocking agent drug class with both non-depolarizing and depolarizing agents.
What Are the Warnings and Precautions?
Risk of Seizure:
Studies have shown that laudanosine, an active metabolite of Cisatracurium besylate injection, causes seizures in animals. Also, patients with hepatic and renal impairment who were administered Cisatracurium for extended periods were at a higher risk of seizures due to higher metabolite concentrations. Therefore, during the long-term administration of the drug, the levels must be monitored with a nerve stimulator, and the doses must be titrated accordingly.
Residual Paralysis:
Patients with myasthenia gravis, myasthenic syndrome, and carcinomatosis are at an increased risk of developing residual paralysis. Therefore, to prevent complications, extubation is recommended solely after the patient completely recovers from the neuromuscular blockade. In addition, the use of reversal agents must be considered, especially in patients at an increased risk of residual paralysis.
Anaphylaxis and Hypersensitivity Reactions:
Severe and fatal anaphylactic reactions have been reported using Cisatracurium besylate injections. In addition, bronchospasm (a sudden contraction of muscles of the airway), laryngospasm (a sudden contraction of the vocal cords), wheezing, rashes, and itching occurred in pediatric patients who were administered Cisatracurium besylate injection. Therefore, precautions like the availability of immediate emergency treatment must be taken to administer the injection to patients with a previous history of anaphylactic reactions to neuromuscular blocking agents.
Risk Due to Inadequate Anesthesia:
Neuromuscular blockade in a patient with adequate sedation or anesthesia can cause distress to the patient. Therefore, patients must be constantly monitored to ensure an adequate level of sedation.
Risk of Death Due to Errors in Handling the Medication:
Cisatracurium besylate injection can cause paralysis, leading to respiratory arrest and death. Therefore, care must be taken while handling injectables in a critical care setting. The injection must be administered only after appropriately checking the dosage and labeling of the injection.
Infection Risk:
A 20 mL vial of Cisatracurium besylate is recommended for single use. It must not be used multiple times, as it does not contain a preservative and poses a risk of infection.
Potentiation of Neuromuscular Blockade:
Drugs like local anesthetics, inhalational anesthetics, antibiotics, lithium, magnesium, quinidine, and procainamide and conditions like serum electrolyte imbalances or acid-base imbalance can potentiate the actions of Cisatracurium besylate.
Resistance to Neuromuscular Blockade:
Certain drugs like Phenytoin and Carbamazepine that are administered for the long term can reduce the effect of Cisatracurium besylate.
Malignant Hyperthermia:
As malignant hyperthermia can occur without triggering factors, the doctor must be prepared to treat it when under general anesthesia and NMBD (neuromuscular blocking drugs).
Adverse Effects:
Adverse reactions are less common with Cisatracurium besylate use, with only about 1 % reported adverse effects. The common adverse effects that were noted included:
-
Hypotension.
-
Bradycardia (slow heart rate).
-
Anaphylaxis (a severe allergic reaction).
-
Bronchospasm (a sudden contraction of muscles of the airway).
-
Rash.
-
Myopathy (muscle weakness and loss of muscle function).
-
Prolonged neuromuscular blockade (failure of neuromuscular transmission).
However, the recovery profile of patients with hepatic or renal impairment did not show any clinically relevant alterations, thereby making drug use safe in such patients.
What Is the Clinical Pharmacology of Cisatracurium Besylate?
Mechanism of Action:
Cisatracurium besylate works by antagonizing acetylcholine by binding competitively to cholinergic receptors on the motor end plate. Acetylcholinesterase inhibitors like Neostigmine antagonize this action.
Pharmacodynamics:
When the dose of Cisatracurium besylate injection is doubled, the clinically effective duration of the block increases by approximately 25 minutes. However, the rate of recovery is independent of the dose. The duration of action of an initial dose of Cisatracurium besylate was minimally altered when administered with 1.25 MAC isoflurane or enflurane on an exposure between 15 to 30 minutes. It was observed that the required maintenance doses were low, and reduced infusion rates of Cisatracurium besylate were required when isoflurane or enflurane anesthesia was greater than 30 minutes. The average rate of infusion decreased by 30 to 40 %.
The onset, duration of action, and recovery of Cisatracurium injection with propofol/oxygen or propofol/nitrous oxide/oxygen anesthesia were similar to those of opioid/nitrous oxide/oxygen anesthesia. Repeated administration of maintenance doses or continuous infusion of Cisatracurium did not impact the recovery rate. Also, it did not cause tachyphylaxis or cumulative neuromuscular effects.
Pediatric patients treated with the same weight-based doses achieved neuromuscular blockade in a faster time and had an early rate of recovery. In addition, Cisatracurium besylate injection did not impact the heart rate or mean arterial pressure in healthy or cardiac patients when administered 0.1 mg/kg 0.4 mg/kg over five to ten minutes.
Pharmacokinetics:
The neuromuscular blocking effects of Cisatracurium besylate is due to the parent drug.
Distribution:
The drug's volume of distribution is limited due to its high polarity and large molecular weight. Cisatracurium has a rapid degradation at physiological pH. Therefore, its binding to plasma proteins is impacted. Inhibition of degradation requires non-physiological conditions like pH and temperature associated with changes in protein binding.
Elimination:
The predominant pathway of elimination of Cisatracurium besylate is an organ-independent Hofmann elimination, a chemical process that depends on pH and temperature. The liver and kidneys have a major role in eliminating Cisatracurium besylate injections and only a minor role in eliminating the parent drug.
Metabolism:
The degradation of Cisatracurium besylate was largely by Hofmann elimination to form laudanosine and monoquaternary acrylate metabolite. Both metabolites are not neuromuscular blocking agents. The monoquaternery metabolite undergoes hydrolysis to form monoquaternary alcohol metabolite (MQA). Laudosine metabolizes to desmethyl metabolites conjugate with glucuronic acid to be excreted in the urine.
The relation between laudanosine concentration and CNS excitation has not been reported in humans. However, animal studies have shown transient hypotension and cerebral excitation. The peak plasma concentrations of laudanosine and MQA metabolite were 6 % and 11 % during continuous infusions of Cisatracurium besylate.
Excretion:
About 95 % of the drug was excreted as conjugated metabolites in urine and about 4 % in feces. Less than 10 % was excreted in the form of the parent drug in urine.
What Are the Drug Interactions?
The following drug interactions were reported:
Succinylcholine:
Succinylcholine, when administered prior to Cisatracurium besylate, can decrease the time of onset of action of Cisatracurium but does not affect the duration of action.
Inhalational Anesthetics:
Administration of inhalational anesthetics with nitrous oxide or oxygen for more than 30 minutes can prolong the duration of action of both the initial and maintenance doses of Cisatracurium which potentiates the neuromuscular blockade.
Phenytoin and Carbamazepine:
These drugs resist the neuromuscular blocking action of Cisatracurium and may require higher infusion rates.
Antibiotics, Lignocaine, Procainamide, Lithium, and Magnesium salts:
The above drugs prolong the neuromuscular blocking action of Cisatracurium besylate.
Propofol:
Co-administration of propofol does not impact the dosage or duration of action of Cisatracurium. Also, the injection is not compatible with propofol for Y-site administration.
What is the Use of Cisatracurium Besylate in Specific Populations?
Pregnancy:
There is no adequate clinical data available on the effects of Cisatracurium besylate injection in pregnant women. However, studies on rats (animal studies) did not show any significant harmful effects on the organogenesis of the fetus when exposed to a human starting dose of 0.2 mg/kg. In addition, the action of neuromuscular blocking agents was found to be enhanced by magnesium salts that were used to treat preeclampsia or eclampsia during pregnancy.
Lactation:
It is not known whether Cisatracurium can occur in breast milk. However, the use of the drug must be decided based on the health benefits of breastfeeding, potential adverse effects on the breastfed child, and the mother's clinical need for the injection.
Pediatric Patients:
The safety and effectiveness of Cisatracurium injection in infants younger than one month are not established. However, drug use in patients above one month up to 12 years of age has been found to aid tracheal intubation when co-administered with inhalational anesthetics and also provide skeletal muscle relaxation during surgical procedures. In addition, the duration of action of the drug can be increased in case of prolonged surgeries by maintaining an infusion rate.
Geriatric Use:
The time to achieve neuromuscular blockade is one minute more in older patients. Therefore, increasing the interval between administering Cisatracurium and attempting intubation must be considered. However, no differences were noted in the drug's safety and effectiveness in geriatric and younger patients.
Patients With Renal Impairment:
The time to 90 % blockade was one minute less when Cisatracurium injection was administered in end-stage renal disease patients. Therefore, increasing the interval between administering Cisatracurium and attempting intubation must be considered.
Patients With Hepatic Impairment:
The time to achieve maximum neuromuscular blockade was one minute faster in liver transplant patients compared to healthy adults receiving 0.1 mg/kg Cisatracurium besylate injection.
Monitoring:
The standard way to monitor when using Cisatracurium besylate and other NMBDs is by using peripheral nerve stimulation. Electrodes are commonly placed over the facial nerve on the lateral skin, the ulnar nerve at the medial wrist, or the posterior tibial nerve at the medial ankle. Stimulation of these nerves causes muscular contraction of orbicularis oculi, adductor pollicis, and flexor hallucis longus, respectively. A twitch response determines the depth of muscle paralysis. The nerve stimulation is measured by the train of four (TOF), sustained tetanus, or double burst stimulation (DBS). TOF stimulation is most common and involves four repetitive impulses of 2 Hz (Hertz) in two minutes. In the presence of repetitive stimulation, Cisatracurium causes a diminished release of acetylcholine at the neuromuscular junction, causing a decreased amplitude of muscle contraction. With the return of the TOF ratio to 0.9, esophageal tone and pharyngeal coordination returned to baseline.
Toxicity:
Overdose of Cisatracurium leads to extended neuromuscular blockade. The primary treatment includes maintaining a patent airway, sedation, and controlled ventilation until the blockade is recovered. An attempt to reverse the neuromuscular blockade must be attempted only after signs of recovery, as peripheral nerve stimulation occurs. Anticholinesterase agents like Neostigmine and anticholinergic agents like Glycopyrrolate are administered for reversal. A typical dose of Neostigmine is0).4 to 0.8 mg/kg, in conjunction with 0.2 mg Glycopyrrolate for every 1 mg of Neostigmine.
