The Study of Pharmacokinetics and Pharmacodynamics of Cisatracurium

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

Study Description

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)

Study Design

• 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

Arms and Interventions

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

Outcome Measures

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.

Eligibility Criteria

• 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

Contacts and Locations

Locations

Thailand

Faculty of Medicine Ramathibodi Hospital

Bangkok, Thailand, 10400

Sponsors and Collaborators

Mahidol University

More Information

Publications:

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. Review.

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.

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.

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.

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.

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.

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.

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.

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.

• 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
• Last Update Posted: March 6, 2019
• Last Verified: March 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• 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:

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