The Study of Pharmacokinetics and Pharmacodynamics of Cisatracurium

Critical Illness Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03337373
• Other study ID #: 06-60-07
• Status: Completed
• Phase: Phase 4
• Start date: December 15, 2017
• Est. completion date: August 31, 2018

Study information

• Verified date: March 2019
• Source: Mahidol University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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)

Recruitment information / eligibility

• Status: Completed
• Enrollment: 10
• Est. completion date: August 31, 2018
• Est. primary completion date: August 31, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acute Lung Injury
• ARDS, Human
• Critical Illness
• Neuromuscular Blockade
• Paralysis
• Respiratory Distress Syndrome, Adult
• Respiratory Distress Syndrome, Newborn
• Respiratory Failure
• Respiratory Insufficiency

Intervention

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).

Locations

Country	Name	City	State
Thailand	Faculty of Medicine Ramathibodi Hospital	Bangkok

Sponsors (1)

Lead Sponsor	Collaborator
Mahidol University

Country where clinical trial is conducted

Thailand, 

References & Publications (10)

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. — View Citation

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. — View Citation

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. — View Citation

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. Review. — View Citation

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. — View Citation

McManus MC. Neuromuscular blockers in surgery and intensive care, Part 1. Am J Health Syst Pharm. 2001 Dec 1;58(23):2287-99. Review. Erratum in: Am J Health Syst Pharm 2002 Jan 1;59(1):16. — View Citation

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. — View Citation

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. Review. — View Citation

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, Guérin 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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Bispectral index (BIS) - 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
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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