The Study of Pharmacokinetics and Pharmacodynamics of Cisatracurium

Study Overview
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Brief Summary
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Pathophysiological changes influenced by multiple factors in critically ill patients, has a significant impact on pharmacokinetics (PK) and pharmacodynamics (PD) of cisatracurium. In order to understand better and find an appropriate dosing regimen, the purpose of this study is to investigate the PK and PD of a loading dose cisatracurium in critically ill patients. Cisatracurium, nondepolarizing neuromuscular blocking agents (NMBAs), are commonly used in intensive care units because of a lesser effect on hemodynamic parameters and a reduction in mortality rate in ARDS patients. Loading dose recommended in clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient is 0.1-0.2 mg/kg. Then, maintenance dose of 1-3 mcg/kg/min is followed regarding indications, such as ARDS. However, this recommended loading dose might not be adequate in critically ill patients, the study in this specific population might be needed.

Detailed Description
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Neuromuscular blocking agents (NMBAs) are commonly used in critically ill patients, especially in adult respiratory distress syndrome (ARDS). Use of NMBAs to facilitate mechanical ventilation, to control patient/ventilator asynchrony and to reduce uncontrolled muscle tone in special conditions including tetanus, therapeutic hypothermia, and status epilepticus were increasingly found in current clinical practice. Cisatracurium, 1Rcis-1'Rcis isomer of atracurium, is benzylisoquinolium nondepolarizing NMBAs which is three to five folds higher potency than atracurium besylate. The degradation of cisatracurium by hofmann elimination and ester hydrolysis in plasma generates laudanosine and a monoquaternary acrylate metabolite. Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient published in year 2016 strongly recommended cisatracurium due to a reduction in incidence of prolonged blockade, cardiovascular related adverse events and anaphylactic reactions. Moreover, recent evidence showed that early use of cisatracurium in early severe ARDS patients led to a significant reduction in mortality. Regarding pharmacokinetics and pharmacodynamics of cisatracurium in critically ill patients, there were multiple factors affected cisatracurium blood concentration and neuromuscular blockade actions. Several reports demonstrated that pathophysiological changes, such as age, hypothermia/ hyperthermia, electrolyte imbalance and acid-base disturbances, had a significant impact on PK and PD of cisatracurium. Currently, there were an increasing data of slow response and less paralysis effect in critically ill patients receiving standard dose of cisatracurium. These may be explained by inadequate drug concentration at target organ, therefore, treatment failures regarding recommended dose of cisatracurium has been reported. Consequently, higher cisatracurium dose with higher drug concentration level might overcome a problem of inadequate level and therapeutic failure while receiving a standard dose of cisatracurium (a loading dose of 0.1-0.2 mg/kg, followed by a maintenance dose of 1-3 mcg/kg/min)

Official Title
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The Study of Pharmacokinetics and Pharmacodynamics of a Loading Dose Cisatracurium in Critically Ill Patients

Conditions
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Critical Illness, Respiratory Distress Syndrome, Adult, Neuromuscular Blockade, Respiratory Failure, Paralysis, ARDS, Human

Intervention / Treatment
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* Drug: cisatracurium


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age greater than 18 years Admission for ICU care Require paralysis with cisatracurium as part of their clinical care Patients or legal representatives who are able to understand and are willing and able to give their signed informed consent before any trial-related procedures are performed Exclusion Criteria: Lactating women Pregnancy women Documented history of hypersensitivity to cisatracurium Pre-existing neuromuscular disease Patients with burn lesions Currently diagnosed of hypothermia condition (tympanic body temperature ≤ 36 °C) Patients currently receiving intravenous bolus or push of cisatracurium within 24 hours or receiving intravenous continuous infusion of cisatracurium within 48 hours prior to enrollment Patients who have to receive intravenous continuous infusion of cisatracurium within 30 minutes after given intravenous bolus of 0.2 mg/ kg cisatracurium

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cisatracurium<br>Patients who require paralysis with cisatracurium as part of their clinical care in ICU | Drug: cisatracurium<br>* A single dose of 0.2 mg/kg intravenous bolus cisatracurium will be administered and blood samples will be taken before and at least 7 occasions post dose (at 1, 5, 10, 12, 15, 20, 30, and/or 60 minutes after a single bolus).<br>* Other names: Nimbex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total plasma concentration-time data | Data will be collected in case-record form and managed by Microsoft Office Excel. Statistical analyses will be performed using SPSS. | Pre-dose through 60 minutes post-dose | 
| Patient-ventilator asynchrony - time data | Data will be collected in case-record form and managed by Microsoft Office Excel. Statistical analyses will be performed using SPSS. | Pre-dose through 60 minutes post-dose | 
| The degree of neuromuscular block by train-of-four-watch monitor - time data | Data will be collected in case-record form and managed by Microsoft Office Excel. Statistical analyses will be performed using SPSS. | Pre-dose through 60 minutes post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to maximum concentration | Analysis of time to maximum concentration will be performed with a nonlinear mixed-effects population modelling approach as implemented in NONMEM software. | Pre-dose through 60 minutes post-dose | 
| Half-life | Analysis of half-life will be performed with a nonlinear mixed-effects population modelling approach as implemented in NONMEM software. | Pre-dose through 60 minutes post-dose | 
| Clearance | Analysis of clearance will be performed with a nonlinear mixed-effects population modelling approach as implemented in NONMEM software. | Pre-dose through 60 minutes post-dose | 
| Elimination rate constant | Analysis of elimination rate constant will be performed with a nonlinear mixed-effects population modelling approach as implemented in NONMEM software. | Pre-dose through 60 minutes post-dose | 
| Time to maximum block | Data will be collected in case-record form and managed by Microsoft Office Excel. Statistical analyses will be performed using SPSS. | Pre-dose through 60 minutes post-dose | 
| Percentage of maximum block | Data will be collected in case-record form and managed by Microsoft Office Excel. Statistical analyses will be performed using SPSS. | Pre-dose through 60 minutes post-dose | 
| Time to patient-ventilator synchrony | Data will be collected in case-record form and managed by Microsoft Office Excel. Statistical analyses will be performed using SPSS. | Pre-dose through 60 minutes post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Critical care, Neuromuscular Blocking Agents, Pharmacodynamics, Pharmacokinetics, Physiological Effects of Drugs