A client who experienced an intracranial hemorrhage is receiving Cisatracurium

Published online by Cambridge University Press:  05 June 2014

Daniel HanleyAffiliation:

Division of Brain Injury Outcomes, Johns Hopkins University Medical Institutions, Baltimore, Maryland

A. David MendelowAffiliation:

Department of Neurosurgery, University of Newcastle upon Tyne

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Print publication year: 2014

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CLINICAL PHARMACOLOGY

Mechanism Of Action

NIMBEX binds competitively to cholinergic receptors on the motor end-plate to antagonize the action of acetylcholine, resulting in blockade of neuromuscular transmission. This action is antagonized by acetylcholinesterase inhibitors such as neostigmine.

Pharmacodynamics

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: 0.048 to 0.053) in adults receiving opioid/nitrous oxide/oxygen anesthesia.

The pharmacodynamics of various NIMBEX doses administered over 5 to 10 seconds during opioid/nitrous oxide/oxygen anesthesia are summarized in Table 5. When the NIMBEX dose is doubled, the clinically effective duration of blockade increases by approximately 25 minutes. Once recovery begins, the rate of recovery is independent of dose.

Isoflurane or enflurane administered with nitrous oxide/oxygen to achieve 1.25 MAC (Minimum Alveolar Concentration) prolonged the clinically effective duration of action of initial and maintenance NIMBEX doses, and decreased the average infusion rate requirement of NIMBEX. The magnitude of these effects depended 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 NIMBEX.
• In surgical procedures during enflurane or isoflurane anesthesia greater than 30 minutes, less frequent maintenance dosing, lower maintenance doses, or reduced infusion rates of NIMBEX were required. The average infusion rate requirement was decreased by as much as 30% to 40% [see DRUG INTERACTIONS].

The onset, duration of action, and recovery profiles of NIMBEX during propofol/oxygen or propofol/nitrous oxide/oxygen anesthesia were similar to those during opioid/nitrous oxide/oxygen anesthesia (see Table 5).

Repeated administration of maintenance NIMBEX doses or a continuous NIMBEX infusion for up to 3 hours was not associated with development of tachyphylaxis or cumulative neuromuscular blocking effects. The time needed to recover from successive maintenance doses did not change with the number of doses administered when partial recovery occurred between doses. The rate of spontaneous recovery of neuromuscular function after NIMBEX infusion was independent of the duration of infusion and comparable to the rate of recovery following initial doses (see Table 5).

Pediatric patients including infants generally had a shorter time to maximum neuromuscular blockade and a faster recovery from neuromuscular blockade compared to adults treated with the same weight-based doses (see Table 5).

Table 5. Pharmacodynamic Dose Response* of NIMBEX During Opioid/Nitrous Oxide/Oxygen Anesthesia

Hemodynamics Profile

NIMBEX had no dose-related effects on mean arterial blood pressure (MAP) or heart rate (HR) following doses ranging from 0.1 mg/kg to 0.4 mg/kg, administered over 5 to 10 seconds, in healthy adult patients (see Figure 1) or in patients with serious cardiovascular disease (see Figure 2).

A total of 141 patients undergoing coronary artery bypass graft (CABG) surgery were administered NIMBEX in three active-controlled clinical trials and received doses ranging from 0.1 mg/kg to 0.4 mg/kg. While the hemodynamic profile was comparable in both the NIMBEX and active control groups, data for doses above 0.3 mg/kg in this population are limited.

Figure 1. Maximum Percent Change from Preinjection in HR and MAP During First 5 Minutes after Initial 4 × ED95 to 8 × ED95 NIMBEX Doses in Healthy Adults Who Received Opioid/Nitrous Oxide/Oxygen Anesthesia (n = 44)

Figure 2. Percent Change from Preinjection in HR and MAP 10 Minutes After an Initial 4 × ED95 to 8 × ED95 NIMBEX Dose in Patients Undergoing CABG Surgery Receiving Oxygen/Fentanyl/Midazolam/Anesthesia (n = 54)

No clinically significant changes in MAP or HR were observed following administration of doses up to 0.1 mg/kg NIMBEX over 5 to 10 seconds in 2- to 12-year-old pediatric patients who received either halothane/nitrous oxide/oxygen or opioid/nitrous oxide/oxygen anesthesia. Doses of 0.15 mg/kg NIMBEX administered over 5 seconds were not consistently associated with changes in HR and MAP in pediatric patients aged 1 month to 12 years who received opioid/nitrous oxide/oxygen or halothane/nitrous oxide/oxygen anesthesia.

Pharmacokinetics

The neuromuscular blocking activity of NIMBEX is due to parent drug. Cisatracurium plasma concentration-time data following IV bolus administration are best described by a twocompartment open model (with elimination from both compartments) with an elimination halflife (t½β) of 22 minutes, a plasma clearance (CL) of 4.57 mL/min/kg, and a volume of distribution at steady state (Vss) of 145 mL/kg.

Results from population pharmacokinetic/pharmacodynamic (PK/PD) analyses from 241 healthy surgical patients are summarized in Table 6.

Table 6. Key Population PK/PD Parameter Estimates for Cisatracurium in Healthy Surgical Patients* Following 0.1 (2 × ED95) to 0.4 mg/kg (8 × ED95) of NIMBEX

The magnitude of interpatient variability in CL was low (16%), as expected based on the importance of Hofmann elimination. The magnitudes of interpatient variability in CL and volume of distribution were low in comparison to those for keo and EC50. This suggests that any alterations in the time course of NIMBEX-induced neuromuscular blockade were more likely to be due to variability in the PD parameters than in the PK parameters. Parameter estimates from the population PK analyses were supported by noncompartmental PK analyses on data from healthy patients and from specific populations.

Conventional PK analyses have shown that the PK of cisatracurium are proportional to dose between 0.1 (2 × ED95) and 0.2 (4 × ED95) mg/kg cisatracurium. In addition, population PK analyses revealed no statistically significant effect of initial dose on CL for doses between 0.1 (2 × ED95) and 0.4 (8 × ED95) mg/kg cisatracurium.

Distribution

The volume of distribution of cisatracurium is limited by its large molecular weight and high polarity. The Vss was equal to 145 mL/kg (Table 6) in healthy 19- to 64-year-old surgical patients receiving opioid anesthesia. The Vss was 21% larger in similar patients receiving inhalation anesthesia.

The binding of cisatracurium to plasma proteins has not been successfully studied due to its rapid degradation at physiologic pH. Inhibition of degradation requires nonphysiological conditions of temperature and pH which are associated with changes in protein binding.

Elimination

Organ-independent Hofmann elimination (a chemical process dependent on pH and temperature) is the predominant pathway for the elimination of cisatracurium. The liver and kidney play a minor role in the elimination of cisatracurium but are primary pathways for the elimination of metabolites. Therefore, the t½β values of metabolites (including laudanosine) are longer in patients with renal or hepatic impairment and metabolite concentrations may be higher after long-term administration [see WARNINGS AND PRECAUTIONS].

The mean CL values for cisatracurium ranged from 4.5 to 5.7 mL/min/kg in studies of healthy surgical patients. The compartmental PK modeling suggests that approximately 80% of the cisatracurium CL is accounted for by Hofmann elimination and the remaining 20% by renal and hepatic elimination. These findings are consistent with the low magnitude of interpatient variability in CL (16%) estimated as part of the population PK/PD analyses and with the recovery of parent and metabolites in urine.

In studies of healthy surgical patients, mean t½β values of cisatracurium ranged from 22 to 29 minutes and were consistent with the t½β of cisatracurium in vitro (29 minutes). The mean ± SD t½β values of laudanosine were 3.1 ± 0.4 and 3.3 ± 2.1 hours in healthy surgical patients receiving NIMBEX (n = 10).

Metabolism

The degradation of cisatracurium was largely independent of liver metabolism. Results from in vitro experiments suggest that cisatracurium undergoes Hofmann elimination (a pH and temperature-dependent chemical process) to form laudanosine [see WARNINGS AND PRECAUTIONS] and the monoquaternary acrylate metabolite, neither of which has any neuromuscular blocking activity. The monoquaternary acrylate undergoes hydrolysis by non-specific plasma esterases to form the monoquaternary alcohol (MQA) metabolite. The MQA metabolite can also undergo Hofmann elimination but at a much slower rate than cisatracurium. Laudanosine is further metabolized to desmethyl metabolites which are conjugated with glucuronic acid and excreted in the urine.

The laudanosine metabolite of cisatracurium has been noted to cause transient hypotension and, in higher doses, cerebral excitatory effects when administered to several animal species. The relationship between CNS excitation and laudanosine concentrations in humans has not been established [see WARNINGS AND PRECAUTIONS].

During IV infusions of NIMBEX, peak plasma concentrations (Cmax) of laudanosine and the MQA metabolite were approximately 6% and 11% of the parent compound, respectively. The Cmax values of laudanosine in healthy surgical patients receiving infusions of NIMBEX were mean ± SD Cmax: 60 ± 52 ng/mL.

Excretion

Following 14C-cisatracurium administration to 6 healthy male patients, 95% of the dose was recovered in the urine (mostly as conjugated metabolites) and 4% in the feces; less than 10% of the dose was excreted as unchanged parent drug in the urine. In 12 healthy surgical patients receiving non-radiolabeled cisatracurium who had Foley catheters placed for surgical management, approximately 15% of the dose was excreted unchanged in the urine.

Special Populations

Geriatric Patients

The results of conventional PK analysis from a study of 12 healthy elderly patients and 12 healthy young adult patients who received a single IV NIMBEX dose of 0.1 mg/kg are summarized in Table 7. Plasma clearances of cisatracurium were not affected by age; however, the volumes of distribution were slightly larger in elderly patients than in young patients resulting in slightly longer t½β values for cisatracurium.

The rate of equilibration between plasma cisatracurium concentrations and neuromuscular blockade was slower in elderly patients than in young patients (mean ± SD keo: 0.071 ± 0.036 and 0.105 ± 0.021 minutes-1, respectively); there was no difference in the patient sensitivity to cisatracurium-induced block, as indicated by EC50 values (mean ± SD EC50: 91 ± 22 and 89 ± 23 ng/mL, respectively). These changes were consistent with the 1-minute slower times to maximum block in elderly patients receiving 0.1 mg/kg NIMBEX, when compared to young patients receiving the same dose. The minor differences in PK/PD parameters of cisatracurium between elderly patients and young patients were not associated with clinically significant differences in the recovery profile of NIMBEX.

Table 7. Pharmacokinetic Parameters* of Cisatracurium in Healthy Elderly and Young Adult Patients Following 0.1 mg/kg (2 × ED95) of NIMBEX (Isoflurane/Nitrous Oxide/Oxygen Anesthesia)

Patients With Hepatic Impairment

Table 8 summarizes the conventional PK analysis from a study of NIMBEX in 13 patients with end-stage liver disease undergoing liver transplantation and 11 healthy adult patients undergoing elective surgery. The slightly larger volumes of distribution in liver transplant patients were associated with slightly higher plasma clearances of cisatracurium. The parallel changes in these parameters resulted in no difference in t½β values. There were no differences in keo or EC50 between patient groups. The times to maximum neuromuscular blockade were approximately one minute faster in liver transplant patients than in healthy adult patients receiving 0.1 mg/kg NIMBEX. These minor PK differences were not associated with clinically significant differences in the recovery profile of NIMBEX.

The t½β values of metabolites are longer in patients with hepatic disease and concentrations may be higher after long-term administration.

Table 8. Pharmacokinetic Parameters* of Cisatracurium in Healthy Adult Patients and in Patients Undergoing Liver Transplantation Following 0.1 mg/kg (2 × ED95) of NIMBEX (Isoflurane/Nitrous Oxide/Oxygen Anesthesia)

Patients With Renal Impairment

Results from a conventional PK study of NIMBEX in 13 healthy adult patients and 15 patients with end-stage renal disease (ESRD) who had elective surgery are summarized in Table 9. The PK/PD parameters of cisatracurium were similar in healthy adult patients and ESRD patients. The times to 90% neuromuscular blockade were approximately one minute slower in ESRD patients following 0.1 mg/kg NIMBEX. There were no differences in the durations or rates of recovery of NIMBEX between ESRD and healthy adult patients.

The t½β values of metabolites are longer in patients with ESRD and concentrations may be higher after long-term administration.

Population PK analyses showed 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; this change was associated with a slightly slower (~ 40 seconds) predicted time to 90% T1 suppression in patients with renal impairment following 0.1 mg/kg NIMBEX. There was no clinically significant alteration in the recovery profile of NIMBEX in patients with renal impairment. The recovery profile of NIMBEX is unchanged in the presence of renal or hepatic failure, which is consistent with predominantly organindependent elimination.

Table 9. Pharmacokinetic Parameters* for Cisatracurium in Healthy Adult Patients and in Patients With End-Stage Renal Disease (ESRD) Who Received 0.1 mg/kg (2 × ED95) of NIMBEX (Opioid/Nitrous Oxide/Oxygen Anesthesia)

Intensive Care Unit (ICU) Patients

The PK of cisatracurium and its metabolites were determined in six ICU patients who received NIMBEX and are presented in Table 10. The relationships between plasma cisatracurium concentrations and neuromuscular blockade have not been evaluated in ICU patients.

Limited PK data are available for ICU patients with hepatic or renal impairment who received NIMBEX. Relative to NIMBEX-treated ICU patients with normal renal and hepatic function, metabolite concentrations (plasma and tissues) may be higher in NIMBEX-treated ICU patients with renal or hepatic impairment [see WARNINGS AND PRECAUTIONS].

Table 10. Parameter Estimates* for Cisatracurium and Metabolites in ICU Patients After Long-Term (24-48 Hour) Administration of NIMBEX

Pediatric Population

The population PK/PD of cisatracurium were described in 20 healthy pediatric patients ages 2 to 12 years during halothane anesthesia, using the same model developed for healthy adult patients. The CL was higher in healthy pediatric patients (5.89 mL/min/kg) than in healthy adult patients (4.57 mL/min/kg) during opioid anesthesia. The rate of equilibration between plasma concentrations and neuromuscular blockade, as indicated by keo, was faster in healthy pediatric patients receiving halothane anesthesia (0.1330 minutes-1) than in healthy adult patients receiving opioid anesthesia (0.0575 minutes-1). The EC50 in healthy pediatric patients (125 ng/mL) was similar to the value in healthy adult patients (141 ng/mL) during opioid anesthesia. The minor differences in the PK/PD parameters of cisatracurium were associated with a faster time to onset and a shorter duration of cisatracurium-induced neuromuscular blockade in pediatric patients.

Sex And Obesity

Although population PK/PD analyses revealed that sex and obesity were associated with effects on the PK and/or PD of cisatracurium; these PK/PD changes were not associated with clinically significant alterations in the predicted onset or recovery profile of NIMBEX.

Use Of Inhalation Agents

The use of inhalation agents was associated with a 21% larger Vss, a 78% larger keo, and a 15% lower EC50 for cisatracurium. These changes resulted in a slightly faster (~ 45 seconds) predicted time to 90% T1 suppression in patients who received 0.1 mg/kg cisatracurium during inhalation anesthesia than in patients who received the same dose of cisatracurium during opioid anesthesia; however, there were no clinically significant differences in the predicted recovery profile of NIMBEX between patient groups.

Drug Interaction Studies

Carbamazepine And Phenytoin

The systemic clearance of cisatracurium was higher in patients who were on prior chronic anticonvulsant therapy of carbamazepine or phenytoin [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].

Clinical Studies

Skeletal Muscle Relaxation For Intubation Of Adult Patients

The efficacy of NIMBEX to provide skeletal muscle relaxation to facilitate tracheal intubation during surgery was established in six studies in adult patients. In all these studies patients had general anesthesia and mechanical ventilation.

• NIMBEX doses between 0.15 and 0.2 mg/kg were evaluated in 240 adults. Maximum neuromuscular blockade generally occurred in within 4 minutes for this dose range.
• When administered during induction using thiopental or propofol and co-induction agents (i.e., fentanyl and midazolam), excellent to good intubating conditions were generally achieved within 2 minutes (excellent intubation conditions most frequently achieved with the 0.2 mg/kg dose of NIMBEX).
• Following the induction of general anesthesia with propofol, nitrous oxide/oxygen, and coinduction agents (e.g., fentanyl and midazolam), good or excellent conditions for tracheal intubation occurred in 96/102 (94%) patients in 1.5 to 2 minutes following NIMBEX doses of 0.15 mg/kg and in 97/110 (88%) patients in 1.5 minutes following NIMBEX doses of 0.2 mg/kg.

In Study 1, the clinically effective duration of action for 0.15 and 0.2 mg/kg NIMBEX using propofol anesthesia was 55 minutes (range: 44 to 74 minutes) and 61 minutes (range: 41 to 81 minutes), respectively.

In Studies 2 and 3, NIMBEX doses of 0.25 and 0.4 mg/kg were evaluated in 30 patients under opioid/nitrous oxide/oxygen anesthesia and provided 78 (66-86) and 91 (59-107) minutes of clinical relaxation, respectively.

In Study 4, two minutes after fentanyl and midazolam were administered, patients received thiopental anesthesia. Intubating conditions were assessed at 120 seconds following administration of 0.15 mg/kg or 0.2 mg/kg of NIMBEX in 51 patients (see Table 11).

Table 11. Intubating Conditions at 120 Seconds after NIMBEX Administration with Thiopental Anesthesia in Adult Surgery Patients in Study 4

Excellent intubating conditions were more frequently achieved with the 0.2 mg/kg dose (60%) than the 0.15 mg/kg dose (31%) when intubation was attempted 120 seconds following NIMBEX.

Study 5 evaluated intubating conditions after 3 and 4 × ED95 (0.15 mg/kg and 0.20 mg/kg) following induction with fentanyl and midazolam and either thiopental or propofol anesthesia. This study compared intubation conditions produced by these doses of NIMBEX after 90 seconds. Table 12 displays these results.

Table 12. Intubating Conditions at 90 Seconds after NIMBEX Administration with Thiopental or Propofol Anesthesia in Study 5

Excellent intubating conditions were more frequently observed with the 0.2 mg/kg dose when intubation was attempted 90 seconds following NIMBEX.

Skeletal Muscle Relaxation For Intubation Of Pediatric Patients

The efficacy of NIMBEX to provide skeletal muscle relaxation to facilitate tracheal intubation was established in studies in pediatric patients aged 1 month to 12 years old. In these studies, patients had general anesthesia and mechanical ventilation.

In Study 6, a NIMBEX dose of 0.1 mg/kg was evaluated in 16 pediatric patients (ages 2 years to 12 years) during opioid anesthesia. When administered during stable opioid/nitrous oxide/oxygen anesthesia, maximum neuromuscular blockade was achieved in an average of 2.8 minutes (range: 1.8 to 6.7 minutes) with a clinically effective block for 28 minutes (range: 21 to 38 minutes).

In Study 7, a NIMBEX dose of 0.15 mg/kg was evaluated in 50 pediatric patients (ages 1 month to 12 years) during opioid anesthesia. When administered during stable opioid/nitrous oxide/oxygen anesthesia, maximum neuromuscular blockade was achieved in an average of about 3 minutes (range: 1.5 to 8 minutes) with a clinically effective block for 36 minutes (range: 29 to 46 minutes) in 24 patients ages 2 to 12 years. In 27 infants (1 to 23 months), maximum neuromuscular block was achieved in about 2 minutes (range: 1.3 to 4.3 minutes) with a clinically effective block for about 43 minutes (range: 34 to 58 minutes) with this dose.

Study 7 also evaluated intubating conditions in 180 pediatric patients (ages 1 month to 12 years) after administration of NIMBEX doses of 0.15 mg/kg following induction with either halothane (with halothane/nitrous oxide/oxygen maintenance) or thiopentone and fentanyl (with thiopentone/fentanyl nitrous oxide/oxygen maintenance). Table 13 displays the intubating conditions by type of anesthesia, and pediatric age group. Excellent or good intubating conditions were produced 120 seconds following 0.15 mg/kg of NIMBEX in 88/90 (98%) of patients induced with halothane and in 85/90 (94%) of patients induced with thiopentone and fentanyl. There were no patients for whom intubation was not possible, but there were 7/120 patients aged 1 year to 12 years old for whom intubating conditions were described as poor.

Table 13. Intubating Conditions at 120 Seconds* in Pediatric Patients Ages 1 Month to 12 Years Old in Study 7

Skeletal Muscle Relaxation In ICU Patients

Long-term infusion (up to 6 days) of NIMBEX during mechanical ventilation in the ICU was evaluated in two studies.

Study 8 was a randomized, double-blind study using presence of a single twitch during train-offour (TOF) monitoring to regulate dosage. Patients treated with NIMBEX (n = 19) recovered neuromuscular function (T4:T1 ratio ≥ 70%) following termination of infusion in approximately 55 minutes (range: 20 to 270).

In Study 9, NIMBEX patients recovered neuromuscular function in approximately 50 minutes (range: 20 to 175; n = 34).

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