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The Study of Pharmacokinetics and Pharmacodynamics of Cisatracurium

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ClinicalTrials.gov Identifier: NCT03337373
Recruitment Status : Completed
First Posted : November 9, 2017
Last Update Posted : March 6, 2019
Sponsor:
Information provided by (Responsible Party):
Panadda Panusitthikorn, Mahidol University

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Critical Illness Respiratory Distress Syndrome, Adult Neuromuscular Blockade Respiratory Failure Paralysis ARDS, Human Drug: cisatracurium Phase 4

Detailed Description:

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)


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 10 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: The Study of Pharmacokinetics and Pharmacodynamics of a Loading Dose Cisatracurium in Critically Ill Patients
Actual Study Start Date : December 15, 2017
Actual Primary Completion Date : August 31, 2018
Actual Study Completion Date : August 31, 2018


Arm Intervention/treatment
Experimental: Cisatracurium
Patients who require paralysis with cisatracurium as part of their clinical care in ICU
Drug: cisatracurium
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).
Other Name: Nimbex




Primary Outcome Measures :
  1. Total plasma concentration-time data [ Time Frame: Pre-dose through 60 minutes post-dose ]
    Data will be collected in case-record form and managed by Microsoft Office Excel. Statistical analyses will be performed using SPSS.

  2. Patient-ventilator asynchrony - time data [ Time Frame: Pre-dose through 60 minutes post-dose ]
    Data will be collected in case-record form and managed by Microsoft Office Excel. Statistical analyses will be performed using SPSS.

  3. The degree of neuromuscular block by train-of-four-watch monitor - time data [ Time Frame: Pre-dose through 60 minutes post-dose ]
    Data will be collected in case-record form and managed by Microsoft Office Excel. Statistical analyses will be performed using SPSS.


Secondary Outcome Measures :
  1. Time to maximum concentration [ Time Frame: Pre-dose through 60 minutes post-dose ]
    Analysis of time to maximum concentration will be performed with a nonlinear mixed-effects population modelling approach as implemented in NONMEM software.

  2. Half-life [ Time Frame: Pre-dose through 60 minutes post-dose ]
    Analysis of half-life will be performed with a nonlinear mixed-effects population modelling approach as implemented in NONMEM software.

  3. Clearance [ Time Frame: Pre-dose through 60 minutes post-dose ]
    Analysis of clearance will be performed with a nonlinear mixed-effects population modelling approach as implemented in NONMEM software.

  4. Elimination rate constant [ Time Frame: Pre-dose through 60 minutes post-dose ]
    Analysis of elimination rate constant will be performed with a nonlinear mixed-effects population modelling approach as implemented in NONMEM software.

  5. Time to maximum block [ Time Frame: Pre-dose through 60 minutes post-dose ]
    Data will be collected in case-record form and managed by Microsoft Office Excel. Statistical analyses will be performed using SPSS.

  6. Percentage of maximum block [ Time Frame: Pre-dose through 60 minutes post-dose ]
    Data will be collected in case-record form and managed by Microsoft Office Excel. Statistical analyses will be performed using SPSS.

  7. Time to patient-ventilator synchrony [ Time Frame: Pre-dose through 60 minutes post-dose ]
    Data will be collected in case-record form and managed by Microsoft Office Excel. Statistical analyses will be performed using SPSS.


Other Outcome Measures:
  1. Bispectral index (BIS) - time data [ Time Frame: Pre-dose through 60 minutes post-dose ]
    Data will be collected in case-record form and managed by Microsoft Office Excel. Statistical analyses will be performed using SPSS.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03337373


Locations
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Thailand
Faculty of Medicine Ramathibodi Hospital
Bangkok, Thailand, 10400
Sponsors and Collaborators
Mahidol University

Publications:

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Responsible Party: Panadda Panusitthikorn, Principal Investigator, Mahidol University
ClinicalTrials.gov Identifier: NCT03337373     History of Changes
Other Study ID Numbers: 06-60-07
First Posted: November 9, 2017    Key Record Dates
Last Update Posted: March 6, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Panadda Panusitthikorn, Mahidol University:
Critical care
Neuromuscular Blocking Agents
Pharmacodynamics
Pharmacokinetics
Physiological Effects of Drugs
Additional relevant MeSH terms:
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Respiratory Distress Syndrome, Newborn
Respiratory Distress Syndrome, Adult
Respiratory Insufficiency
Acute Lung Injury
Paralysis
Critical Illness
Lung Diseases
Respiratory Tract Diseases
Respiration Disorders
Infant, Premature, Diseases
Infant, Newborn, Diseases
Disease Attributes
Pathologic Processes
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Lung Injury
Cisatracurium
Atracurium
Neuromuscular Blocking Agents
Neuromuscular Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Neuromuscular Nondepolarizing Agents
Nicotinic Antagonists
Cholinergic Antagonists
Cholinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action