CISATRACURIO EN VADEMECUM

	CISATRACURIO
	Description: Cisatracurium is a nondepolarizing neuromuscular blocker that is considered intermediate in onset and duration of action relative to other neuromuscular blockers. It is one of several isomers of atracurium (see separate monograph) and is three times as potent as atracurium. Both cisatracurium and atracurium are often used in patients with multisystem organ failure since their metabolism is independent of hepatic or renal function. Unlike atracurium, cisatracurium does not cause dose-related increases in histamine release. Thus, like vecuronium and doxacurium, cisatracurium can be used safely in patients with cardiovascular disease. Clinical uses include skeletal muscle relaxation, facilitation of tracheal intubation in combination with general anesthesia, and skeletal muscle relaxation in ICU patients requiring mechanical ventilation. Mechanism of Action: Like other nondepolarizing agents, cisatracurium binds competitively to (but does not activate) nicotinic receptors on the motor end-plate to antagonize the action of acetylcholine, resulting in blockade of neuromuscular transmission. Skeletal muscle relaxation proceeds in a predictable order, starting with muscles associated with fine movements, e.g., eyes, face, and neck. These effects are followed by muscle relaxation of the limbs, chest, and abdomen and, finally, the diaphragm. The effects of cisatracurium are antagonized by acetylcholinesterase inhibitors such as neostigmine. Cisatracurium has no dose-related effects on mean arterial blood pressure (MAP) or heart rate following doses ranging from 2ï¿½8 times ED95 (> 0.1 to > 0.4 mg/kg) in healthy adult patients or in patients with serious cardiovascular disease. Unlike atracurium, cisatracurium does not cause dose-related elevations in histamine plasma concentrations. Pharmacokinetics: Cisatracurium is administered intravenously. The volume of distribution is limited by its large molecular weight and high polarity. The binding of cisatracurium to plasma proteins has not been successfully studied due to its rapid degradation at physiologic pH. Cisatracurium undergoes organ-independent Hofmann elimination (a pH and temperature-dependent chemical process) to form the monoquaternary acrylate metabolite and laudanosine, neither of which has any neuromuscular blocking activity. The monoquaternary acrylate metabolite undergoes hydrolysis by non-specific plasma esterases to form the monoquaternary alcohol (MQA) metabolite. Laudanosine is further metabolized to desmethyl metabolites which are conjugated with glucuronic acid and excreted in the urine. During IV infusions of cisatracurium, peak plasma concentrations of laudanosine and the MQA metabolite are approximately 6% and 11% of the parent compound, respectively. Peak concentrations of laudanosine are significantly lower in healthy surgical patients receiving infusions of cisatracurium than in patients receiving infusions of atracurium (Cmax = 60 ng/ml vs 342 ng/ml). Mean clearance values for cisatracurium range 4.5ï¿½5.7 ml/min/kg in healthy surgical patients. Pharmacokinetic modeling suggests that 80% of the clearance is accounted for by Hofmann elimination and the remaining 20% by renal and hepatic elimination. Approximately 95% of a dose is recovered in the urine (mostly as conjugated metabolites) and 4% in the feces; less than 10ï¿½15% of the dose is excreted as unchanged drug. The mean elimination half-life of cisatracurium is 22ï¿½29 minutes. The mean elimination half-life for laudanosine is 3.1 hours. The average ED95 (dose required to produce 95% suppression of the adductor pollicis muscle twitch response to ulnar nerve stimulation) of cisatracurium is 0.05 mg/kg (range: 0.048ï¿½0.053) in adults receiving opioid/nitrous oxide/oxygen anesthesia. The average ED95 for atracurium under similar conditions is 0.17 mg/kg. After a cisatracurium dose of 0.1 mg/kg (2 times ED95), time to 90% block is 3.3 minutes (range: 1ï¿½8.7 min) and time to 95% recovery is about 64 minutes (range: 25ï¿½93 min). In children, cisatracurium has a lower ED95 (0.04 mg/kg) than in adults. At 0.1 mg/kg during opioid anesthesia, cisatracurium had a faster onset and shorter duration of action in children than in adults. Recovery during reversal also is faster in children than in adults. In adult patients, the time to maximum block is up to 2 minutes longer for equipotent doses of cisatracurium compared to atracurium. The clinically effective duration of action and rate of spontaneous recovery from equipotent doses of cisatracurium and atracurium are similar. For cisatracurium, the rate of spontaneous recovery of neuromuscular function after infusion is independent of the duration of the infusion and comparable to the rate of recovery following initial doses. In one study in which cisatracurium or vecuronium infusion was administered for up to 6 days during mechanical ventilation in the ICU, patients treated with cisatracurium recovered neuromuscular function following termination of the infusion in about 55 minutes (range: 20ï¿½270 min); those treated with vecuronium recovered in 178 minutes (range: 40 min to 33 hours).
	Indications...Dosage For neuromuscular blockade, as an adjunct to general anesthesia, to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation in the ICU: ï¿½for endotracheal intubation: NOTE: Because of its intermediate onset of action, cisatracurium is not recommended for rapid sequence endotracheal intubation (i.e., where intubation is rapidly performed to minimize the time the airway is unprotected). Intravenous dosage: Adults: Doses of 0.15 mg/kg IV and 0.2 mg/kg IV, as components of a propofol/nitrous oxide/oxygen induction-intubation technique, may produce generally good or excellent conditions for tracheal intubation in 2 and 1.5 minutes, respectively. The clinically effective durations of action for 0.15 mg/kg IV and 0.2 mg/kg IV during propofol anesthesia are 55 minutes (range: 44ï¿½74 min) and 61 minutes (range: 41ï¿½81 min), respectively. Lower doses may result in a longer time for the development of satisfactory intubation conditions. The presence of co-induction agents (e.g., fentanyl, midazolam) and the depth of anesthesia are factors that can influence intubation conditions. In two intubation studies using thiopental or propofol and midazolam and fentanyl as co-induction agents, excellent intubation conditions were most frequently achieved with a 0.2 mg/kg dose compared to a 0.15 mg/kg dose of cisatracurium (manufacturer product literature). Doses up to 0.4 mg/kg IV (8 times ED95) have been administered safely to healthy adult patients and patients with serious cardiovascular disease. These doses are associated with longer clinically effective durations of action. Adults with myasthenia gravis: In patients with neuromuscular disease such as myasthenia gravis, use of a peripheral nerve stimulator and a dose not more than 0.02 mg/kg IV is recommended to assess the level of neuromuscular blockade and to monitor dosage requirements. Children 2ï¿½12 years: 0.1 mg/kg IV over 5ï¿½10 seconds during either halothane or opioid anesthesia. When administered during stable opioid/nitrous oxide/oxygen anesthesia, 0.1 mg/kg IV of cisatracurium produces maximum neuromuscular block in an average of 2.8 minutes (range: 1.8ï¿½6.7 min) and clinically effective block for 28 minutes (range: 21ï¿½38 min). ï¿½maintenance of neuromuscular blockade during prolonged surgical procedures: Intravenous dosage: Adults and children >= 2 years: Maintenance doses of 0.03 mg/kg IV sustain neuromuscular blockade for about 20 minutes. Maintenance dosing is generally required 40ï¿½50 minutes following an initial dose of 0.15 mg/kg IV and 50ï¿½60 minutes following an initial dose of 0.2 mg/kg IV. For shorter or longer durations of action, smaller or larger maintenance doses may be administered. Cisatracurium can also be given as a continuous IV infusion for maintenance of neuromuscular blockade. Infusion of cisatracurium should only be initiated after spontaneous recovery from the initial bolus dose. An initial infusion rate of 3 ï¿½g/kg/min IV may be required to rapidly counteract the spontaneous recovery of neuromuscular function. Thereafter, a rate of 1ï¿½2 ï¿½g/kg/min IV should be adequate to maintain continuous neuromuscular blockade in the range of 89ï¿½99% in most pediatric and adult patients under opioid/oxygen anesthesia. Reduction of the infusion rate by 30ï¿½40% should be considered when cisatracurium is administered during stable isoflurane or enflurane anesthesia (with nitrous oxide/oxygen at the 1.25 MAC level). Greater reductions in the infusion rate may be required with longer durations of administration of isoflurane or enflurane. Adults with myasthenia gravis: In patients with neuromuscular disease such as myasthenia gravis, use of a peripheral nerve stimulator and a dose not more than 0.02 mg/kg IV is recommended to assess the level of neuromuscular blockade and to monitor dosage requirements. ï¿½to maintain adequate neuromuscular blockade in patients undergoing coronary artery bypass surgery: Intravenous dosage: Adults: The rate of infusion of atracurium required in patients undergoing CABG surgery with induced hypothermia (25 degreesï¿½28 degreesC) is approximately half the rate required during normothermia. Based on the structural similarity between cisatracurium and atracurium, a similar effect on the infusion rate of cisatracurium may be expected. ï¿½to provide adequate neuromuscular blockade in mechanically ventilated patients in the intensive care unit: Intravenous dosage: Adults: An infusion rate of 3 ï¿½g/kg/min (range: 0.5ï¿½10.2 ï¿½g/kg/min) IV should provide adequate neuromuscular blockade. There may be wide interpatient variability in dosage requirements and these may increase or decrease with time. Following recovery from neuromuscular block, readministration of a bolus dose may be necessary to quickly reestablish NMB prior to reinstitution of the infusion. Adults with myasthenia gravis: In patients with neuromuscular disease such as myasthenia gravis, use of a peripheral nerve stimulator and a dose not more than 0.02 mg/kg IV is recommended to assess the level of neuromuscular blockade and to monitor dosage requirements. Patients with renal impairment: Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed. Intermittent hemodialysis: The effects of hemofiltration, hemodialysis, and hemoperfusion on plasma levels of cisatracurium and its metabolites are unknown.
	Contraindications Cisatracurium has no known effect on consciousness, pain threshold, or cerebration. To avoid distress to the patient, neuromuscular block should not be induced before unconsciousness. Patients with conditions that impair neuromuscular function can experience prolonged or exaggerated neuromuscular block with nondepolarizing agents. These conditions include myasthenia gravis, myasthenic syndrome associated with small cell carcinomatosis (Lambert-Eaton syndrome; originally associated with lung cancer), myopathy, or any other neuromuscular disease. Cisatracurium should be used with extreme caution in patients with these conditions; the use of a peripheral nerve stimulator and a cisatracurium dose of not more than 0.02 mg/kg is recommended to assess the level of neuromuscular block and to monitor dosage requirements. Patients with hemiparesis or paraparesis may demonstrate resistance to cisatracurium in the affected limbs. To avoid inaccurate dosing, neuromuscular monitoring should be performed on a non-paretic limb. Neuromuscular blocking agents can cause respiratory paralysis as a result of respiratory depression and should be used with caution in patients with pulmonary disease such as COPD. Because of its intermediate onset of action, cisatracurium is not recommended for rapid sequence endotracheal intubation. Patients with burns have been shown to develop resistance to nondepolarizing neuromuscular blocking agents, including atracurium. The extent of altered response depends upon the size of the burn and the time elapsed since the burn injury. Although cisatracurium has not been studied in burn patients, due to its structural similarity to atracurium, the possibility of increased dosage requirements and a shortened duration of action must be considered if cisatracurium is administered to burn patients. Pathophysiologic states that potentiate the pharmacological actions of nondepolarizing neuromuscular blockers may increase the risk of prolonged neuromuscular block. These states include dehydration, electrolyte imbalance (hypokalemia, hypocalcemia, hyponatremia or hypermagnesemia) and severe acid/base imbalance (respiratory acidosis or metabolic alkalosis). No data are available to support the use of cisatracurium by intramuscular administration. Patients with a familial history of malignant hyperthermia (MH) should be treated with great caution. Because malignant hyperthermia can develop in patients receiving general anesthesia, with or without triggering factors (e.g. succinylcholine), this condition should be monitored for routinely in anesthetized patients. The condition can be precipitated by the use of halogenated anesthetics; and concomitant neuromuscular blocking agents may be a contributory factor. The 10 ml multiple-dose vials of Nimbexï¿½ contain benzyl alcohol. In neonates or other patients with benzyl alcohol hypersensitivity, benzyl alcohol has been associated with an increased incidence of neurological and other complications, which are sometimes fatal. Single-use vials of cisatracurium do not contain benzyl alcohol.
	Cisatracurium is classified as FDA pregnancy risk category B. There are no adequate and well controlled studies in pregnant women. Teratology testing in pregnant rats treated with doses of cisatracurium equivalent to 8ï¿½20 times the human ED95 revealed no maternal or fetal toxicity or teratogenic effects. However, because animal studies are not always predictive of human response, cisatracurium should only be used during pregnancy if clearly needed. It is not known whether cisatracurium is excreted in human milk. Caution should be exercised following administration of cisatracurium to a woman who is breast-feeding. Safety and effectiveness of cisatracurium have not been studied in children less than 2 years of age.
	Interactions Cisatracurium has been used safely following varying degrees of recovery from succinylcholine-induced neuromuscular block. Following an intubating dose of succinylcholine, administration of 0.1 mg/kg of cisatracurium produced >= 95% neuromuscular block. The time to onset of maximum block following cisatracurium is about 2 minutes faster with prior administration of succinylcholine. Prior administration of succinylcholine appears to have no effect on the duration of neuromuscular block following initial or maintenance bolus doses of cisatracurium, however, infusion requirements of cisatracurium may be slightly greater than when succinylcholine is not administered prior to cisatracurium. Isoflurane or enflurane administered with nitrous oxide/oxygen to achieve 1.25 MAC (minimum alveolar concentration) may prolong the clinically effective duration of action of cisatracurium. The magnitude of these effects may depend on the duration of administration of the inhalation anesthetics. Fifteen to 30 minutes of exposure to 1.25 MAC isoflurane or enflurane had minimal effects on the duration of action of initial doses of cisatracurium and therefore, no adjustment to the initial dose should be necessary when cisatracurium is administered shortly after initiation of volatile agents. In long surgical procedures during isoflurane or enflurane anesthesia, less frequent maintenance dosing or lower maintenance doses of cisatracurium may be necessary. The average infusion rate requirement may be decreased by as much as 30ï¿½40%. Other inhalation anesthetics (e.g., halothane) also may potentiate the neuromuscular blocking effect of cisatracurium. Amphotericin B, cisplatin, and diuretics can cause hypokalemia which may enhance the neuromuscular blocking activity of cisatracurium. Polypeptide antibiotics such as bacitracin, capreomycin, polymyxin B, and vancomycin may affect presynaptic and postsynaptic myoneural function and potentiate the neuromuscular blocking action of nondepolarizing agents such as cisatracurium. Aminoglycosides may enhance the neuromuscular blocking effect of cisatracurium by producing a presynaptic inhibition of acetylcholine release and a postsynaptic reduction of sensitivity of the postjunctional membrane to acetylcholine. Other drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as cisatracurium include: clindamycin, colistimethate, lidocaine, lithium, local anesthetics, magnesium salts, quinidine, procainamide, and tetracyclines. Chronic administration of phenytoin or carbamazepine may antagonize the neuromuscular blocking action of nondepolarizing agents. While the effects of phenytoin or carbamazepine therapy on the action of cisatracurium are unknown, slightly shorter durations of neuromuscular block may be anticipated and infusion rate requirements may be higher. Some evidence exists that calcium-channel blockers prolong neuromuscular blockade, but further data are required to confirm this observation. Cholinesterase inhibitors antagonize the effects of nondepolarizing neuromuscular blockers such as cisatracurium. In clinical studies, propofol had no effect on the duration of action or dosing requirements for cisatracurium.
	Adverse Reactions Adverse events associated with use of cisatracurium are uncommon. The following adverse effects were judged to have a possible causal relationship to administration of cisatracurium in controlled clinical trials: sinus bradycardia (0.4%), hypotension (0.2%), flushing (0.2%), bronchospasm (0.2%), and maculopapular rash (0.1%). Little information is available on the plasma concentrations and clinical consequences of cisatracurium metabolites that may accumulate during days to weeks of cisatracurium administration. Laudanosine, a major biologically active metabolite without neuromuscular blocking activity, produces transient hypotension and cerebral excitatory effects (generalized muscle twitching and seizures) when administered to animals. There have been rare reports of seizures in ICU patients who have received atracurium or other agents. However, these patients usually had predisposing conditions (e.g., cranial trauma, cerebral edema). Thus, there are insufficient data to determine whether or not laudanosine contributes to seizures in ICU patients. Because cisatracurium is three times more potent than atracurium and lower doses are required, the corresponding laudanosine concentrations following cisatracurium are one-third those that would be expected following an equipotent dose of atracurium. Malignant hyperthermia is associated mainly with the use of succinylcholine and halogen anesthetics. Because of the potentially fatal outcome, however, all patients undergoing anesthesia with administration of neuromuscular blockers such as cisatracurium should be considered at risk. Prolonged neuromuscular blockade can occur with cisatracurium (post-marketing experience), which could potentially result in muscle paralysis, apnea, or respiratory depression. In one study in ICU patients in which train-of-four neuromuscular monitoring was used, there were two reports of prolonged recovery (167 and 270 min) among 28 patients administered cisatracurium and 13 reports of prolonged recovery (range: 90 mins to 33 hours) among 30 patients administered vecuronium. Inadequate neuromuscular block has also been reported with cisatracurium (post-marketing data). Hypersensitivity reactions have been reported with cisatracurium, including anaphylactic or anaphylactoid reactions, which in rare cases were severe.
	PRESENTACION Cisatracurium Nimbexï¿½
	REFERENCIAS
	Monografía revisada el 17 de Febrero de 2012.Equipo de redacciï¿½n de IQB (Centro colaborador de La Administraciï¿½n Nacional de Medicamentos, alimentos y Tecnologï¿½a Mï¿½dica -ANMAT - Argentina). .