- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03337373
The Study of Pharmacokinetics and Pharmacodynamics of Cisatracurium
The Study of Pharmacokinetics and Pharmacodynamics of a Loading Dose Cisatracurium in Critically Ill Patients
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.
Study Overview
Status
Conditions
Intervention / Treatment
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)
Study Type
Enrollment (Actual)
Phase
- Phase 4
Contacts and Locations
Study Locations
-
-
-
Bangkok, Thailand, 10400
- Faculty of Medicine Ramathibodi Hospital
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Basic Science
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Cisatracurium
Patients who require paralysis with cisatracurium as part of their clinical care in ICU
|
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 Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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.
|
Pre-dose through 60 minutes post-dose
|
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.
|
Pre-dose through 60 minutes post-dose
|
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.
|
Pre-dose through 60 minutes post-dose
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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.
|
Pre-dose through 60 minutes post-dose
|
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.
|
Pre-dose through 60 minutes post-dose
|
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.
|
Pre-dose through 60 minutes post-dose
|
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.
|
Pre-dose through 60 minutes post-dose
|
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.
|
Pre-dose through 60 minutes post-dose
|
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.
|
Pre-dose through 60 minutes post-dose
|
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.
|
Pre-dose through 60 minutes post-dose
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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.
|
Pre-dose through 60 minutes post-dose
|
Collaborators and Investigators
Sponsor
Publications and helpful links
General Publications
- Papazian L, Forel JM, Gacouin A, Penot-Ragon C, Perrin G, Loundou A, Jaber S, Arnal JM, Perez D, Seghboyan JM, Constantin JM, Courant P, Lefrant JY, Guerin C, Prat G, Morange S, Roch A; ACURASYS Study Investigators. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010 Sep 16;363(12):1107-16. doi: 10.1056/NEJMoa1005372.
- Greenberg SB, Vender J. The use of neuromuscular blocking agents in the ICU: where are we now? Crit Care Med. 2013 May;41(5):1332-44. doi: 10.1097/CCM.0b013e31828ce07c.
- Dieye E, Minville V, Asehnoune K, Conil C, Georges B, Cougot P, Fourcade O, Conil JM. Pharmacodynamics of cisatracurium in the intensive care unit: an observational study. Ann Intensive Care. 2014 Feb 11;4(1):3. doi: 10.1186/2110-5820-4-3.
- Liu X, Kruger PS, Weiss M, Roberts MS. The pharmacokinetics and pharmacodynamics of cisatracurium in critically ill patients with severe sepsis. Br J Clin Pharmacol. 2012 May;73(5):741-9. doi: 10.1111/j.1365-2125.2011.04149.x.
- Murray MJ, DeBlock H, Erstad B, Gray A, Jacobi J, Jordan C, McGee W, McManus C, Meade M, Nix S, Patterson A, Sands MK, Pino R, Tescher A, Arbour R, Rochwerg B, Murray CF, Mehta S. Clinical Practice Guidelines for Sustained Neuromuscular Blockade in the Adult Critically Ill Patient. Crit Care Med. 2016 Nov;44(11):2079-2103. doi: 10.1097/CCM.0000000000002027.
- Gainnier M, Roch A, Forel JM, Thirion X, Arnal JM, Donati S, Papazian L. Effect of neuromuscular blocking agents on gas exchange in patients presenting with acute respiratory distress syndrome. Crit Care Med. 2004 Jan;32(1):113-9. doi: 10.1097/01.CCM.0000104114.72614.BC.
- Forel JM, Roch A, Marin V, Michelet P, Demory D, Blache JL, Perrin G, Gainnier M, Bongrand P, Papazian L. Neuromuscular blocking agents decrease inflammatory response in patients presenting with acute respiratory distress syndrome. Crit Care Med. 2006 Nov;34(11):2749-57. doi: 10.1097/01.CCM.0000239435.87433.0D.
- Murray MJ, Cowen J, DeBlock H, Erstad B, Gray AW Jr, Tescher AN, McGee WT, Prielipp RC, Susla G, Jacobi J, Nasraway SA Jr, Lumb PD; Task Force of the American College of Critical Care Medicine (ACCM) of the Society of Critical Care Medicine (SCCM), American Society of Health-System Pharmacists, American College of Chest Physicians. Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient. Crit Care Med. 2002 Jan;30(1):142-56. doi: 10.1097/00003246-200201000-00021. No abstract available.
- Welch RM, Brown A, Ravitch J, Dahl R. The in vitro degradation of cisatracurium, the R, cis-R'-isomer of atracurium, in human and rat plasma. Clin Pharmacol Ther. 1995 Aug;58(2):132-42. doi: 10.1016/0009-9236(95)90190-6.
- McManus MC. Neuromuscular blockers in surgery and intensive care, Part 1. Am J Health Syst Pharm. 2001 Dec 1;58(23):2287-99. doi: 10.1093/ajhp/58.23.2287. Erratum In: Am J Health Syst Pharm 2002 Jan 1;59(1):16.
- Panusitthikorn P, Suthisisang C, Tangsujaritvijit V, Nosoongnoen W, Dilokpattanamongkol P. Pharmacokinetics and pharmacodynamics studies of a loading dose of cisatracurium in critically ill patients with respiratory failure. BMC Anesthesiol. 2022 Jan 22;22(1):32. doi: 10.1186/s12871-022-01571-2.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Pathologic Processes
- Nervous System Diseases
- Respiratory Tract Diseases
- Respiration Disorders
- Lung Diseases
- Neurologic Manifestations
- Disease Attributes
- Infant, Newborn, Diseases
- Lung Injury
- Infant, Premature, Diseases
- Respiratory Insufficiency
- Critical Illness
- Paralysis
- Respiratory Distress Syndrome
- Respiratory Distress Syndrome, Newborn
- Acute Lung Injury
- Physiological Effects of Drugs
- Peripheral Nervous System Agents
- Neuromuscular Agents
- Neuromuscular Blocking Agents
- Cisatracurium
Other Study ID Numbers
- 06-60-07
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Paralysis
-
Neurotrigger LtdRecruitingParalysis | Paralysis; Eye | Paralysis; BellIsrael
-
Assistance Publique - Hôpitaux de ParisCompletedUnilateral Diaphragmatic ParalysisFrance
-
University Hospital, RouenUniversity Hospital, CaenCompleted
-
Seoul National University HospitalCompleted
-
Lawson Health Research InstituteSuspended
-
University of MinnesotaCompleted
-
Ben-Gurion University of the NegevCompleted
-
Brigham and Women's HospitalCompletedPhrenic Nerve ParalysisUnited States
-
Shenzhen People's HospitalUnknownPhrenic Nerve ParalysisChina
-
Ajou University School of MedicineWithdrawnPhrenic Nerve ParalysisKorea, Republic of
Clinical Trials on cisatracurium
-
Lawson Health Research InstituteUniversity of Western Ontario, CanadaUnknownPostcardiac Arrest Therapeutic HypothermiaCanada
-
University Hospital, Clermont-FerrandUnknownTraumatic Brain Injury | Intracranial HypertensionFrance
-
Massachusetts General HospitalNational Heart, Lung, and Blood Institute (NHLBI)CompletedAcute Respiratory Distress SyndromeUnited States
-
Tianjin Nankai HospitalNot yet recruitingIntra-abdominal Hypertension
-
Assistance Publique Hopitaux De MarseilleGlaxoSmithKlineCompleted
-
Fudan UniversityCompletedC.Delivery; Surgery (Previous), Gynecological
-
Northwell HealthTerminatedTotal Knee ReplacementUnited States
-
Tanta UniversityRecruitingAcute Lung Injury/Acute Respiratory Distress Syndrome (ARDS) | Respiratory Distress Syndrome, PediatricEgypt
-
Digestive Care, Inc.St. Louis UniversityTerminatedExocrine Pancreatic Insufficiency
-
Second Affiliated Hospital of Xi'an Jiaotong UniversityUnknown