Nondepolarizing Skeletal Neuromuscular Blocking Agent
Action And Clinical Pharmacology: Cisatracurium is an intermediate-acting, nondepolarizing neuromuscular blocking agent for i.v. administration. Cisatracurium, 1 of 10 isomers of atracurium besylate, constitutes approximately 15% of that mixture. Cisatracurium binds competitively to cholinergic receptors on the motor end-plate to antagonize the action of acetylcholine, resulting in block of neuromuscular transmission. This action is antagonized by acetylcholinesterase inhibitors such as neostigmine and edrophonium.
Pharmacodynamics: The average ED95 (dose required to produce 95% suppression of the adductor pollices muscle twitch response to ulnar nerve stimulation) of cisatracurium is 0.05 mg/kg (range: 0.048 to 0.053 mg/kg) in adults receiving opioid/nitrous oxide/oxygen anesthesia. For comparison, the average ED95 for atracurium when also expressed as the parent biscation is 0.17 mg/kg under similar anesthetic conditions. When the dose of cisatracurium is doubled, the clinically effective duration of block increased by approximately 25 to 35 minutes. Once recovery begins, the rate of recovery is independent of dose.
The neuromuscular blocking potency of cisatracurium is approximately 3-fold that of atracurium besylate. At equipotent doses, the time to maximum block of cisatracurium is up to 2 minutes longer than that of atracurium besylate. The clinically effective duration of action and rate of spontaneous recovery from equipotent doses of cisatracurium and atracurium besylate are similar.
The neuromuscular blocking effect of cisatracurium administered by infusion is potentiated by potent inhalation anesthetics. 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 initial and maintenance doses, and decrease the average infusion rate requirement of cisatracurium. The magnitude of these effects may depend on the duration of administration of the volatile agents. 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 enflurane or isoflurane anesthesia, less frequent maintenance dosing, lower maintenance doses, or reduced infusion rates of cisatracurium may be necessary. As for atracurium, the average infusion rate requirement for cisatracurium may be decreased under these circumstances by as much as 30 to 40%.
The onset, duration of action, and recovery profiles of cisatracurium during propofol/oxygen or propofol/nitrous oxide/oxygen anesthesia are similar to those during opioid/nitrous oxide/oxygen anesthesia.
Intubation Conditions: When administered during the induction of adequate anesthesia using propofol, nitrous oxide/oxygen, and coinduction agents (e.g., fentanyl, midazolam), good or excellent conditions for tracheal intubation occurred in 67/71 (94%) patients in 1.5 to 2.0 minutes following 0.15 mg/kg (3´ED95) cisatracurium and in 69/80 (87%) patients in 1.5 minutes following 0.2 mg/kg (4´ED95) cisatracurium. Favorable intubation conditions, within 2 minutes, were achieved less frequently with a cisatracurium dose of 0.1 mg/kg (2´ED95).
Maintenance Doses: Repeated administration of maintenance doses or a continuous infusion of cisatracurium for up to 3 hours is not associated with development of tachyphylaxis or cumulative neuromuscular blocking effects. The time needed to recover from successive maintenance doses does not change with the number of doses administered as long as partial recovery is allowed to occur between doses. Maintenance doses can therefore be administered at relatively regular intervals with predictable results. The rate of spontaneous recovery of neuromuscular function after infusion is independent of the duration of infusion and comparable to the rate of recovery following initial doses.
Anticholinesterase Antagonism: The neuromuscular block produced by cisatracurium is readily antagonized by anticholinesterase agents once recovery has started. As with other non-depolarizing neuromuscular blocking agents, the more profound the neuromuscular block at the time of reversal, the longer the time required for recovery of neuromuscular function.
Children: In children (2 to 12 years) cisatracurium has a lower ED95 than in adults (0.04 mg/kg, halothane/nitrous oxide/oxygen anesthesia). At 0.1 mg/kg during opioid anesthesia, cisatracurium had a faster onset and shorter duration of action in children than in adults. Recovery following reversal is faster in children than in adults.
Hemodynamics Profile: Cisatracurium had no dose-related effects on mean arterial blood pressure (MAP) or heart rate (HR) in healthy adult ASA class 1 or 2 patients, after administration over 5 to 10 seconds at the following doses: 2´ED95 (0.10 mg/kg), n=153; 4´ED95 (0.20 mg/kg), n=15; 5´ED95 (0.25 mg/kg), n=14 or 8´ED95 (0.40 mg/kg), n=15.
The safety of 2´ED95 (0.1 mg/kg) cisatracurium, administered over 5 to 10 seconds, was evaluated in the following number of patients with cardiovascular disease: New York Heart Association(NYHA) Class I-III: n=45; (NYHA) Class IV: n=16.
No clinically significant effects on MAP or HR were noted in this patient population at this dose. However, the number of NYHA Class IV patients contributing data was limited.
In a double-blind comparative study involving patients undergoing coronary artery bypass grafting (CABG), there were no clinically significant differences in the hemodynamic effects following equipotent doses of up to 0.3 mg/kg cisatracurium (NYHA Class I-III, n=37) or vecuronium (NYHA Class I-III, n=31; NYHA Class IV, n=1). There is no information regarding the safety of cisatracurium doses above 0.1 mg/kg (2´ED95) in NYHA class IV patients.
Doses greater than 6´ED95 have not been studied in patients with cardiovascular disease.
Cisatracurium, at therapeutic doses of 2 to 4 times the ED95 (0.1 to 0.2 mg/kg), administered over 5 to 10 seconds, does not cause dose-related elevations in mean plasma histamine concentration. Clinical experience with initial bolus doses greater than 0.2 mg/kg is limited in this regard (0.25 mg/kg, n=15; 0.40 mg/kg, n=15).
No clinically significant changes in MAP or HR were observed following administration of doses up to 0.1 mg/kg cisatracurium over 5 to 10 seconds in children (2 to 12 years) receiving either halothane/nitrous oxide/oxygen or opioid/nitrous oxide/oxygen anesthesia.
Pharmacokinetics: Following i.v. administration of cisatracurium, plasma concentrations of cisatracurium are best described by a 2-compartment open model. Cisatracurium undergoes degradation in the body at physiological pH and temperature by organ-independent Hofmann elimination to form laudanosine and the monoquaternary acrylate metabolite. Laudanosine is further metabolized to many components which are eliminated in the urine. The monoquaternary acrylate metabolite undergoes hydrolysis by nonspecific plasma esterases to form the monoquaternary alcohol metabolite. Cisatracurium does not appear to undergo direct hydrolysis by nonspecific plasma esterases. Organ-independent Hofmann elimination appears to be the predominant pathway for the elimination of cisatracurium. The liver and the kidney play a minor role in the elimination of cisatracurium but are primary routes for elimination of the metabolites.
Tests in which the monoquaternary alcohol metabolite or the monoquaternary acrylate was administered to cats suggest that metabolites are unlikely to produce clinically significant neuromuscular, autonomic, or cardiovascular effects following administration of cisatracurium. Laudanosine, a biologically active metabolite of cisatracurium without neuromuscular blocking activity, produces transient hypotension and, in higher concentrations, cerebral excitatory effects when administered in several species of animals. The relationship between CNS excitation and laudanosine concentrations in humans has not been established. Because cisatracurium is 3 times more potent than atracurium and lower doses are required, maximum concentrations of laudanosine following infusions of cisatracurium to surgical patients were lower (5-to 8-fold) than following atracurium besylate. After adjusting for differences in doses, the AUC for laudanosine was significantly lower following cisatracurium administration than following atracurium besylate administration (i.e., less laudanosine may be formed following cisatracurium than following atracurium besylate). The clinical relevance of this finding is unknown.
Plasma cisatracurium concentrations and neuromuscular block data from 261 patients in 6 studies were combined to develop population estimates of the pharmacokinetic/ pharmacodynamic parameters for cisatracurium in healthy adult patients. The plasma clearance was 4.6 mL/min/kg and the volume of distribution at steady-state was 145 mL/kg in healthy adult patients receiving opioid/nitrous oxide/oxygen anesthesia. Results from population pharmacokinetic/pharmacodynamic analyses and from conventional pharmacokinetic analyses of cisatracurium in healthy adult patients and in patient subpopulations (e.g., geriatric, pediatric, obese) are described below.
Dose Proportionality: Conventional pharmacokinetic analysis from a study of 10 healthy adult patients receiving 0.1 mg/kg (2´ED95) cisatracurium and 10 healthy adult patients receiving 0.2 mg/kg (4´ED95) cisatracurium indicated no statistically significant differences in the pharmacokinetic parameters between the 2 groups. In addition, population pharmacokinetic/pharmacodynamic analyses revealed no statistically significant effect of dose on plasma clearance between 0.1 mg/kg and 0.4 mg/kg (2´ to 8´ED95) doses of cisatracurium. The pharmacokinetics are linear between these doses of cisatracurium (i.e., plasma concentrations are approximately proportional to dose).
Geriatrics: The results of conventional pharmacokinetic analysis from a study of 12 healthy elderly patients (³65 years) and 12 healthy young adult patients (18 to 50 years) receiving a single i.v. dose of 0.1 mg/kg (2´ED95) cisatracurium are summarized in Table III. Plasma clearance of cisatracurium was not affected by age; however, the volume of distribution was slightly larger in elderly patients than in young patients, resulting in a slightly longer half-life for cisatracurium. The time to maximum block was approximately 1 minute slower in elderly patients than in young patients. These minor differences in pharmacokinetics of cisatracurium between elderly and young adult patients were not associated with clinically significant differences in the recovery profile of cisatracurium.
Hepatic Diseases: Organ-independent Hofmann elimination is the predominant pathway for the elimination of cisatracurium. The slightly larger volume of distribution in liver transplant patients was associated with slightly higher plasma clearance of cisatracurium. The parallel changes in these parameters resulted in no difference in half-life.
The time to maximum block was approximately 1 minute faster in liver transplant patients than in healthy adult patients. These minor differences in pharmacokinetics were not associated with clinically significant changes in the recovery profile of cisatracurium.
The time to maximum block was approximately 1 minute faster in liver transplant patients than in healthy adult patients receiving 0.1 mg/kg cisatracurium. These minor differences in pharmacokinetics were not associated with clinically significant changes in the recovery profile of cisatracurium.
The t1/2 values of metabolites are longer in patients with hepatic disease and concentrations may be higher after long-term administration.
Renal Disease: Results from a conventional pharmacokinetic study of 13 healthy adult patients and 15 patients with end-stage renal disease (ESRD) undergoing elective surgery are summarized in Table V. The pharmacokinetics of cisatracurium were similar in healthy adult patients and ESRD patients.
The time to 90% block was approximately 1 minute slower in ESRD patients following 0.1 mg/kg cisatracurium. There was no difference in the duration or rate of recovery between ESRD and healthy adult patients.
The t1/2 values of metabolites are longer in patients with renal failure and concentrations may be higher after long-term administration.
Population pharmacokinetic analysis revealed that patients with creatinine clearances 70 mL/min had a slower rate of equilibration between plasma concentrations and neuromuscular block than patients with normal renal function; therefore, the predicted time to 90% T1 suppression may be slightly slower in patients with renal dysfunction. There was no clinically significant alteration in the recovery profile of cisatracurium in patients with renal dysfunction. The recovery profile of cisatracurium is unchanged in the presence of renal or hepatic failure, which is consistent with predominantly organ-independent elimination.
Children: Population pharmacokinetic analysis of cisatracurium revealed a plasma clearance of 5.9 mL/kg/min and a volume of distribution at steady-state of 125 mL/kg in 20 healthy pediatric patients during halothane anesthesia. These minor differences were associated with a faster time to onset and a shorter duration of cisatracurium-induced neuromuscular block in pediatric patients.
Other Patient Factors: Population pharmacokinetic/pharma- codynamic analysis revealed that gender and obesity were associated with statistically significant effects on the pharmacokinetics and/or pharmacodynamics of cisatracurium; these factors were not associated with clinically significant alterations in the predicted onset or recovery profile of cisatracurium. The use of inhalation anesthesia (i.e., enflurane or isoflurane) was associated with statistically significant effects on the pharmacokinetics and pharmacodynamics of cisatracurium. These changes were associated with a slightly faster predicted time to 90% suppression for patients under inhalation anesthesia, but there were no clinically significant alterations in the predicted recovery profile of cisatracurium.
Indications And Clinical Uses: As an adjunct to general anesthesia, to facilitate nonemergency endotracheal intubation, and to provide skeletal muscle relaxation during surgery or mechanical ventilation.
Contra-Indications: Patients known to have an allergic hypersensitivity to cisatracurium, atracurium besylate or other bis-benzylisoquinolinium agents. Use of cisatracurium from vials containing preservative is contraindicated in patients with a known hypersensitivity to benzyl alcohol.
Manufacturers’ Warnings In Clinical States: Cisatracurium should be administered in carefully adjusted dosage by or under the supervision of experienced clinicians who are familiar with the drug’s actions and the possible complications of its use. The drug should not be administered unless personnel and facilities for resuscitation and life support (tracheal intubation, artificial ventilation, oxygen therapy), and an antagonist of cisatracurium are immediately available. It is recommended that a peripheral nerve stimulator be used to measure neuromuscular function during the administration of cisatracurium in order to monitor drug effect, determine the need for additional doses, and confirm recovery from neuromuscular block.
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.
Cisatracurium injection is acidic (pH 3.25 to 3.65) and should not be mixed with alkaline solutions having a pH greater than 8.5 (e.g., barbiturate solutions). Cisatracurium is also hypotonic and must not be administered into the infusion line of a blood transfusion.
The 10 mL multiple dose vials of cisatracurium contain benzyl alcohol. In newborn infants, benzyl alcohol has been associated with an increased incidence of neurological and other complications which are sometimes fatal. Single use vials (20 mL) of cisatracurium do not contain benzyl alcohol. Cisatracurium has not been studied in children less than 2 years old.
Intensive Care Unit: To reduce the possibility of prolonged neuromuscular blockade and other complications that might occur following long-term use in the ICU, cisatracurium or any other neuromuscular relaxant should be administered in carefully adjusted doses by or under the supervision of experienced clinicians who are familiar with its actions and with appropriate peripheral nerve stimulator muscle monitoring techniques.
In patients with neuromuscular disease such as myasthenia gravis or myasthenic (Eaton-Lambert) syndrome, small doses of nondepolarizing neuromuscular blocking agents may have profound effects. In these patients, and patients with conditions in which prolonged neuromuscular blockade is a possibility (e.g., neuromuscular disease, carcinomatosis, severe cachexia or debilitation), the use of a peripheral nerve stimulator and a first dose of not more than 0.02 mg/kg cisatracurium is recommended to assess the level of neuromuscular block and to monitor dosage requirements.
Precautions: General: Because of its intermediate onset of action, cisatracurium is not recommended for rapid sequence endotracheal intubation.
Recommended doses of cisatracurium have no clinically significant effects on heart rate; therefore, cisatracurium will not counteract the bradycardia produced by many anesthetic agents or by vagal stimulation.
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. Cisatracurium has not been studied in patients with burns; however, based on its structural similarity to atracurium, the possibility of increased dosing requirements and shortened duration of action must be considered if cisatracurium is administered to burn patients.
Patients subjected to hypothermia may necessitate a reduction in the rate of infusion of cisatracurium (see Dosage).
Patients with hemiparesis or paraparesis also may demonstrate resistance to nondepolarizing neuromuscular blocking agents in affected limbs. To avoid inaccurate dosing, neuromuscular monitoring should be performed on the nonparetic limb.
Acid-base and/or serum electrolyte abnormalities may potentiate or antagonize the action of neuromuscular blocking agents. The action of neuromuscular blocking agents may be enhanced by magnesium salts administered for the management of toxemia of pregnancy.
As cisatracurium has not been studied in patients with asthma or a history of severe anaphylactic reactions, it should be administered with caution to these patient groups.
No data are available to support the use of cisatracurium by i.m. injection.
Malignant Hyperthermia (MH): In a study of MH-susceptible pigs, cisatracurium besylate did not trigger MH. Cisatracurium has not been studied in MH-susceptible patients. Because MH can develop in the absence of established triggering agents, the clinician should be prepared to recognize and treat MH in any patient undergoing general anesthesia.
Long-Term Use in the Intensive Care Unit (ICU): There is limited information regarding the safety and efficacy of long-term infusion of cisatracurium during mechanical ventilation in the ICU (up to 2 days n=37, 2 to 4 days n=19, 4 to 6 days n=12) and no information on its use beyond 6 days. Thus dosage recommendations cannot be made at this time. In rare cases, long-term use of neuromuscular blocking drugs to facilitate mechanical ventilation in ICU settings has been associated with prolonged paralysis and/or skeletal muscle weakness that is first noted during attempts to wean patients from the ventilator. In these patients, the actions of the neuromuscular blocking agent may be enhanced by other drugs (e.g., broad spectrum antibiotics, narcotics and/or steroids) or by conditions such as acid-base or electrolyte imbalance, hypoxic episodes of varying duration, or extreme debilitation. Additionally patients immobilized for extended periods frequently develop symptoms consistent with disuse muscle atrophy. The recovery picture may vary from regaining movement and strength in all muscles to initial recovery of movement of the facial muscles and small muscles of the extremities then to the remaining muscles. In rare cases, recovery may involve an extended period of time or even require rehabilitation. Therefore, when there is a need for long-term mechanical ventilation, the benefits to risk ratio of neuromuscular blockade must be considered. The syndrome of critical illness polyneuropathy associated with sepsis and multiorgan failure may be associated with prolonged muscle paralysis, but can also occur without the use of muscle relaxants. Thus, the role of muscle relaxants in the etiology of prolonged paralysis in the ICU is not known with certainty. Continuous infusion or intermittent bolus dosing to support long-term mechanical ventilation has not been studied sufficiently to support dosage recommendations.
Whenever the use of cisatracurium or any neuromuscular blocking agent is contemplated in the ICU, it is recommended that a peripheral nerve stimulator be used to continuously monitor neuromuscular transmission during administration and recovery. Additional doses of cisatracurium or any other neuromuscular blocking agent should not be given before there is evidence of the return of the first twitch response to peripheral nerve stimulation. If no response is elicited, the infusion should be discontinued until a response returns.
Renal and Hepatic Disease: No clinically significant alterations in the recovery profile were observed in patients with renal dysfunction or in patients with end-stage liver disease following a 0.1 mg/kg (2´ED95) dose of cisatracurium. The onset time was approximately 1 minute faster in patients with end-stage liver disease and approximately 1 minute slower in patients with renal dysfunction than in healthy adult control patients.
Pregnancy: Teratogenic Effects: Teratology testing in rats revealed no maternal or fetal toxicity or teratogenic effects. There are no adequate and well-controlled studies of cisatracurium in pregnant women. Because animal studies are not always predictive of human response, cisatracurium should be used during pregnancy only if clearly needed.
Labor and Delivery: The use of cisatracurium during labor, vaginal delivery, or cesarean section has not been studied in humans and it is not known whether cisatracurium administered to the mother has effects on the fetus. Doses of 0.2 or 0.4 mg/kg (4 or 8Â´ human ED95) cisatracurium given to female beagles undergoing cesarean section resulted in negligible levels of cisatracurium in umbilical vessel blood of neonates and no deleterious effects on the pups.
Lactation : It is not known whether cisatracurium besylate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised following administration of cisatracurium to a nursing woman.
Children: Cisatracurium has not been studied in children under 2 years of age (see Pharmacology for clinical experience and Dosage for recommendations for use in children 2 to 12 years of age).
Geriatrics: Cisatracurium was safely administered during clinical trials to 130 elderly (³65 years) patients, including a subset of patients with significant cardiovascular disease (see Precautions, General).
Minor differences in the pharmacokinetics of cisatracurium between elderly and young adult patients are not associated with clinically significant differences in the recovery profile of cisatracurium following a single 0.1 mg/kg (2´ED95) dose; the time to maximum block is approximately 1 minute slower in elderly patients (see Pharmacology, Pharmacokinetics).
The effects of hemofiltration, hemodialysis, and hemoperfusion on plasma levels of cisatracurium and its metabolites are unknown.
Drug Interactions: Succinylcholine: The use of cisatracurium prior to succinylcholine, for the purpose of attenuating succinylcholine-induced side effects, has not been studied.
The use of cisatracurium following varying degrees of recovery from succinylcholine-induced neuromuscular block has been assessed in a limited number of patients. Administration of 0.1 mg/kg (2´ED95) cisatracurium at 10% (n=15) or 95% recovery (n=15) following an intubating dose of succinylcholine (1 mg/kg) produced ³95% neuromuscular block. The time of onset of maximum block following cisatracurium is approximately 2 minutes faster with prior administration of succinylcholine. Prior administration of succinylcholine had no effect on the duration of neuromuscular block following initial or maintenance bolus doses of cisatracurium. Cisatracurium infusion requirements were comparable or slightly greater in patients who received succinylcholine prior to the cisatracurium infusions, in contrast to patients who did not receive succinylcholine.
Other nondepolarizing Muscle Relaxants: Although not studied systematically in clinical trials, no drug interactions were observed when vecuronium, pancuronium, or atracurium were administered following varying degrees of recovery from single doses or infusions of cisatracurium.
Inhalation Anesthetics: 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 initial and maintenance doses of cisatracurium, and decrease the average infusion rate of cisatracurium. The magnitude of these effects may depend on the duration of administration of the volatile agents. 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. Hence, no adjustment to the initial dose should be necessary when cisatracurium is administered shortly after initiation of volatile agents. In long surgical procedures during enflurane or isoflurane anesthesia, less frequent maintenance dosing, lower maintenance doses, or reduced infusion rates of cisatracurium may be necessary. The average infusion rate requirement may be decreased by as much as 30 to 40%.
I.V. Anesthetics: In clinical studies, propofol had no effect on the duration of action or dosing requirements for cisatracurium.
Anticonvulsants: Resistance to the neuromuscular blocking action of nondepolarizing neuromuscular blocking agents has been demonstrated in patients chronically administered phenytoin or carbamazepine. While the effects of chronic 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.
Other drugs: The neuromuscular blocking action of nondepolarizing agents such as cisatracurium may be enhanced by certain antibiotics (e.g., aminoglycosides, tetracyclines, bacitracin, polymyxins, lincomycin, clindamycin, colistin, and sodium colistemethate), magnesium salts, lithium, local anesthetics, procainamide, and quinidine.
Drug/Laboratory Test Interactions : None known.
Adverse Reactions: Observed in Clinical Trials of Surgical Patients: Adverse experiences were uncommon among the 908 surgical patients who received cisatracurium in conjunction with other drugs in U.S. and European clinical studies in the course of a wide variety of procedures in patients receiving opioid, propofol, or inhalation anesthesia. The following adverse experiences were judged by investigators during the clinical trials to have a possible causal relationship to cisatracurium. (incidence less than 1%): Cardiovascular: flushing (0.2%), hypotension (0.2%) and bradycardia (0.4%).
Respiratory: bronchospasm (0.2%).
Dermatological: rash (0.1%).
Observed During Clinical Practice: In addition to events reported from clinical trials, the following events have been identified during post-approval use of cisatracurium besylate in conjunction with one or more anesthetic agents in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events are reported due to their seriousness, frequency of reporting, or potential causal relationship to cisatracurium besylate.
General: Hypersensitivity reactions including anaphylactic or anaphylactoid responses which, in some cases were severe.
Musculoskeletal: Prolonged neuromuscular block, inadequate neuromuscular block.
Symptoms And Treatment Of Overdose: Symptoms: Overdosage with neuromuscular blocking agents may result in neuromuscular block beyond the time needed for surgery and anesthesia. tag_Treatment
Treatment: The primary treatment is maintenance of a patent airway and controlled ventilation until recovery of normal neuromuscular function is assured. Once recovery from neuromuscular block begins, further recovery may be facilitated by administration of an anticholinesterase agent (e.g., neostigmine, edrophonium) in conjunction with an appropriate anticholinergic agent (see Antagonism of Neuromuscular Block below). A peripheral nerve stimulator should be used to monitor recovery.
Antagonism of Neuromuscular Block: Antagonists (such as neostigmine and edrophonium) should not be administered when complete neuromuscular block is evident or suspected. The use of a peripheral nerve stimulator to evaluate recovery and antagonism of neuromuscular block is recommended. The time required for anticholinesterase-mediated recovery is longer for reversals attempted at deeper levels of blockade.
Administration of 0.04 to 0.07 mg/kg neostigmine at approximately 10% recovery from neuromuscular block (range: 0 to 15%) produced 95% recovery of the muscle twitch response and a T4:T1 ratio ³70% in an average of 9 to 10 minutes. The time from 25% recovery of the muscle twitch response to a T4:T1 ratio ³70% following these doses of neostigmine averaged 7 minutes. The mean 25 to 75% recovery index following reversal was 3 to 4 minutes.
Administration of 1.0 mg/kg edrophonium at approximately 25% recovery from neuromuscular block (range: 16 to 30%) produced 95% recovery and a T4:T1 ratio ³70% in an average of 3 to 5 minutes.
Patients administered antagonists should be evaluated for evidence of adequate clinical recovery (e.g., 5-second head lift and grip strength). Ventilation must be supported until no longer required.
The onset of antagonism may be delayed in the presence of debilitation, cachexia, carcinomatosis, and the concomitant use of certain broad spectrum antibiotics, or anesthetic agents and other drugs which enhance neuromuscular block or separately cause respiratory depression (see Precautions, Drug Interactions). Under such circumstances the management is the same as that of prolonged neuromuscular block (see Overdose).
Dosage And Administration: Should be administered only by i.v. route. This drug should be administered by or under the supervision of experienced clinicians familiar with the use of neuromuscular blocking agents. Dosage must be individualized in each case.
To avoid patient distress, cisatracurium should not be administered prior to the induction of unconsciousness. It should not be mixed in the same syringe or administered simultaneously through the same needle with alkaline solutions (e.g., barbiturate solutions).
Individualization of Dosages: The dosage information provided below is intended as a guide only. Doses should be individualized and a peripheral nerve stimulator should be used to measure neuromuscular function during administration in order to monitor drug effect, to determine the need for additional doses, and to confirm recovery from neuromuscular block. The use of a peripheral nerve stimulator will permit the most advantageous use of cisatracurium, minimize the possibility of overdosage or underdosage, and assist in the evaluation of recovery.
Adults: Initial Doses: One of 2 intubating doses may be chosen, based on the desired time to intubation and the anticipated length of surgery. Doses of 0.15 mg/kg (3´ED95) and 0.20 mg/kg (4´ED95), as components of a propofol/nitrous oxide/oxygen induction-intubation technique, each may produce generally good or excellent conditions for tracheal intubation in 1.5 to 2 minutes. The clinically effective durations of action for 0.15 and 0.20 mg/kg of cisatracurium during propofol anesthesia are 55 minutes (range: 44 to 74 minutes) and 61 minutes (range: 41 to 81 minutes), respectively. Lower doses may result in a longer time for the development of satisfactory intubation conditions. In addition to the dose of the neuromuscular blocking agent, the presence of coinduction agents (e.g., fentanyl and midazolam) and the depth of anesthesia are factors that can influence intubation conditions. Doses of cisatracurium up to 8 times the ED95 (0.40 mg/kg) have been administered to a limited number of healthy adult patients (n=15) and the larger doses are associated with a longer clinically effective duration of action (see Pharmacology).
Cardiovascular Disease: Doses of up to 0.3 mg/kg (6´ED95) were found to have no significant hemodynamic effects in patients with cardiovascular disease (NYHA Class I-III)(see Pharmacology). However, doses higher than 0.1 mg/kg (2´ED95) have not been studies in NYHA Class IV patients. At a dose of 0.1 mg/kg an extension of the interval between administration of cisatracurium and the intubation attempt may be required to achieve satisfactory intubation conditions.
Geriatrics and Renal Failure Patients: Because a slower time to onset of complete neuromuscular block was observed in elderly patients and in patients with renal failure, extending the interval between administration of cisatracurium and the intubation attempt for these patients may be required to achieve adequate intubation conditions.
Maintenance Doses: A dose of 0.03 mg/kg is recommended for maintenance of neuromuscular block during prolonged surgical procedures. Maintenance doses of 0.03 mg/kg each sustain neuromuscular block for approximately 20 minutes. Although maintenance dosing is generally required 40 to 50 minutes following an initial dose of 0.15 mg/kg (3´ED95), and 50 to 60 minutes following an initial dose of 0.20 mg/kg (4´ED95), the need for maintenance doses should be determined by clinical criteria. For a shorter or longer duration of action, smaller or larger maintenance doses may be administered.
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 initial and maintenance doses. The magnitude of these effects may depend on the duration of administration of the volatile agents. 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; 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 enflurane or isoflurane anesthesia, less frequent maintenance dosing or lower maintenance doses of cisatracurium may be necessary.
No adjustments to the initial dose of cisatracurium are required when used in patients receiving propofol anesthesia.
Children: Initial Doses: The recommended dose for children 2 to 12 years of age is 0.10 mg/kg administered over 5 to 10 seconds during either halothane or opioid anesthesia. When administered during stable opioid/nitrous oxide/oxygen anesthesia, 0.10 mg/kg produces maximum neuromuscular block in an average of 2.8 minutes (range: 1.8 to 6.7 minutes) and clinically effective block for an average of 28 minutes (range: 21 to 38 minutes). Cisatracurium has not been studied in children under 2 years of age.
Special Conditions: Based on the known action of cisatracurium and other neuromuscular blocking agents, the following factors should be considered when administering cisatracurium.
Renal and Hepatic Disease: Doses for patients with renal disease or hepatic disease are as recommended for healthy adult patients. However, see Precautions.
Drugs or Conditions Causing Potentiation of, or Resistance to, Neuromuscular Block: Persons with certain pre-existing conditions or receiving certain drugs may require individualization of dosing (see Precautions).
Burns: Patients with burns have been shown to develop resistance to nondepolarizing neuromuscular blocking agents, and may require individualization of dosing (see Precautions).
Hypothermia: The rate of infusion of atracurium required to maintain adequate surgical relaxation in patients undergoing coronary artery bypass surgery with induced hypothermia (25 to 28°C) 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.
Use by Continuous Infusion: Infusion in the Operating Room (OR): After administration of an initial bolus dose, a diluted solution can be administered by continuous infusion to adults and children (³ 2 years of age) for maintenance of neuromuscular block during extended surgical procedures. Infusion should be individualized for each patient. The rate of administration should be adjusted according to the patient’s response as determined by peripheral nerve stimulation. Accurate dosing is best achieved using a precision infusion device.
Infusion should be initiated only after early evidence of spontaneous recovery from the initial bolus dose. An initial infusion rate of 3 g/kg/min may be required to rapidly counteract the spontaneous recovery of neuromuscular function. Thereafter, a rate of 1 to 2 g/kg/min should be adequate to maintain continuous neuromuscular block in the range of 89 to 99% in most pediatric and adult patients under opioid/nitrous oxide/oxygen anesthesia.
Reduction of the infusion rate by up to 30 to 40% should be considered when cisatracurium is administered during stable isoflurane or enflurane anesthesia (administered with nitrous oxide/oxygen to achieve 1.25 MAC). Greater reductions in the infusion rate of cisatracurium may be required with longer durations of administration of isoflurane or enflurane.
Spontaneous recovery from neuromuscular block following discontinuation of cisatracurium infusion may be expected to proceed at a rate comparable to that following administration of a single bolus dose.
Infusion Rate Tables: The amount of infusion solution required per minute will depend upon the concentration of cisatracurium in the infusion solution, the desired dose and the patient’s weight. The contribution of the infusion solution to the fluid requirements of the patient also must be considered.
Stability and Storage Recommendation: Cisatracurium slowly loses potency with time at a rate of approximately 5% per year under refrigeration (5°C). Cisatracurium should be stored under refrigeration (2 to 8°C) and protected from light to preserve potency. Protect from freezing.
The rate of loss in potency increases to approximately 5% per month at 25°C. If removed from refrigeration to room temperature storage (25°C), cisatracurium must be used within 21 days, even if rerefrigerated.
Parenteral Products: Y-site Administration: Cisatracurium Injection is acidic (pH=3.25 to 3.65) and may not be compatible with alkaline solution having a pH greater than 8.5 (e.g., barbiturate solutions).
Studies have shown that cisatracurium injection is compatible with: 5% Dextrose Injection USP; 0.9% Sodium Chloride Injection USP; 5% Dextrose and 0.9% Sodium Chloride Injection USP; Sufenta Injection, diluted as directed; Alfenta Injection, diluted as directed; Sublimaze Injection, diluted as directed; Versed Injection, diluted as directed; Droperidol Injection USP, diluted as directed.
Cisatracurium Injection is not compatible with Diprivan Injection or Toradol Injection for Y-site administration. Studies of other parenteral products have not been conducted.
Dilution Stability: Cisatracurium Injection diluted to 0.1 mg/mL in 5% Dextrose Injection USP, 0.9% Sodium Chloride Injection USP, or 5% Dextrose and 0.9% Sodium Chloride Injection USP, may be stored either under refrigeration or at room temperature for 24 hours without significant loss of potency. Dilutions to 0.1 mg/mL in 5% Dextrose and Lactated Ringer’s Injection may be stored under refrigeration for 24 hours.
Cisatracurium Injection should not be diluted in Lactated Ringer’s Injection USP due to chemical instability.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Solutions which are not clear, or contain visible particulates, should not be used.
Availability And Storage: 2 mg/mL: Each mL of a sterile, nonpyrogenic, aqueous solution, colorless to slightly yellow or greenish-yellow, contains: cisatracurium 2 mg (as besylate). Nonmedicinal ingredients: benzyl alcohol (see Warnings concerning newborn infants) and water for injection. Multidose vials of 10 mL.
10 mg/mL: Each mL of a sterile, nonpyrogenic, aqueous solution, colorless to slightly yellow or greenish-yellow, contains: cisatracurium 10 mg (as besylate). Nonmedicinal ingredients: water for injection. Benzyl alcohol-free. Single dose vials of 20 mL.
Store under refrigeration (2 to 8°) and protect fom light to preserve potency. Protect from freezing.
NIMBEX® Glaxo Wellcome Cisatracurium Besylate Nondepolarizing Skeletal Neuromuscular Blocking Agent