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Pharmacokinetic and Pharmacodynamic Modelling of Norepinephrine in Patients Under Target Controlled Infusions (TCI) for Anaesthesia (NOR-PHARM)

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ClinicalTrials.gov Identifier: NCT03454204
Recruitment Status : Recruiting
First Posted : March 5, 2018
Last Update Posted : August 18, 2020
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Tracking Information
First Submitted Date February 26, 2018
First Posted Date March 5, 2018
Last Update Posted Date August 18, 2020
Actual Study Start Date June 27, 2018
Estimated Primary Completion Date June 27, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: March 2, 2018)
PLASMATIC DOSAGES [ Time Frame: 1 day ]
Relationship between exposure and the effect (desired-effectiveness or undesirable-toxicity) of norepinephrine during hypotension induced by anaesthetic drugs in a pharmacokinetic model (PLASMATIC DOSAGES) and pharmacodynamic model (HEMODYNAMIC EFFECTS MODELISED)
Original Primary Outcome Measures Same as current
Change History
Current Secondary Outcome Measures Not Provided
Original Secondary Outcome Measures Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Pharmacokinetic and Pharmacodynamic Modelling of Norepinephrine in Patients Under Target Controlled Infusions (TCI) for Anaesthesia
Official Title Pharmacokinetic and Pharmacodynamic Modelling of Norepinephrine in Patients Under Target Controlled Infusions (TCI) for Anaesthesia : Plasma Concentration and "Site Effect"
Brief Summary Currently, administration of norepinephrine diluted at 5 µg/ml bolus or continuous infusion is common during sympatholysis hypotension of TCI following the elimination of hypovolemia or anesthetic overdosage. Continued intravenous administration must meet hemodynamic goals within a narrow time frame. Depending on the intensity of hypotension the dosage is variable. It is adjusted in real time while it is excessive or insufficient at times. Therefore, the development of modeling should predict the kinetic and hemodynamic effects based on dosage and individual.
Detailed Description

Main objective Establish a pharmacokinetic relationship between plasma concentration and the effect of norepinephrine in patients under concentration-target intravenous anesthesia by identifying significant covariates during general anesthesia.

Primary Evaluation Criteria Relationship between exposure and the effect (desired-effectiveness or undesirable-toxicity) of norepinephrine during hypotension induced by anaesthetic drugs in a pharmacokinetic model (PLASMATIC DOSAGES) and pharmacodynamic model (HEMODYNAMIC EFFECTS MODELISED)

Experimental design This is a single-center, "non-interventional" study.

Population concerned The study involves major patients who have benefited from intraoperative hemodynamic optimization with norepinephrine (as noradrenaline tartrate) for maintaining blood pressure under general anaesthesia in neurosurgery and interventional neuroradiology in adults.

Research Proceedings Arterial catheter sampling for plasma noradrenaline assay

Individual benefit:

There is no benefit for the patient

Collective benefit:

Intraoperative hemodynamic optimization with the use of norepinephrine (as noradrenaline tartrate) to maintain blood pressure under general anaesthesia in neurosurgery and interventional neuroradiology in adults. Continued intravenous administration of norepinephrine should meet hemodynamic goals within a narrow time frame. Depending on the intensity of hypotension the dosage is variable. It is adjusted in real time while it is excessive or insufficient at times. Therefore, the development of modeling should predict the kinetic and hemodynamic effects based on dosage and individual.

Risks and minimal constraints added by the research No added risk This clinical research work is "non-interventional" on adult patients who benefit from a neurosurgical or neuroradiological intervention and whose blood pressure monitoring justifies the installation of a blood pressure catheter. The use of blood pressure monitoring and recording monitors and blood samples do not require any additional invasive procedures on patients since it uses the vascular accesses already in place.

The first sample (T0) is taken before the start of the infusion, thus determining the endogenous concentration (C0).

After a norepinephrine bolus, the second sample (T1) is taken at least 15 minutes after the start of the steady flow infusion or 10 minutes after the last flow change to measure the plateau concentration (C1) These fixed timeframes were calculated by taking into account an incompressible timeframe linked to the estimated dead catheter volume of 2 minutes plus the 5 half lives of norepinephrine estimated at 3-4 minutes.

A third sample (T2) is taken 10 minutes after a flow change or before the end of the infusion (end of the procedure).

To study the kinetics of the norepinephrine bolus, a rapid kinetics of 5 samples in TO, T30, T60, T120, T5 minutes is carried out in order to obtain the peak and speed of decrease in norepinephrine blood concentration for 5 patients.

Number of selected subjects Selection of patients up to 30 analysable patients Number of Centre : 1 Research Agenda inclusion period: 18 months duration of participation (treatment + follow-up): duration of the surgical intervention or interventional neuroradiology procedure: 1 day total duration: 18 months Number of planned inclusions by centre and month : 2 Number of subjects required : 30

Statistics

Descriptives: analysis by means of the two-step compartmental approach, which consists in estimating the pharmacokinetic parameters of each individual, then averaging them (obtaining the average pharmacokinetic parameters) and evaluating their distribution for the population studied.

Selection and incorporation of all significant covariates into the basic model by Ascending-descending strategy: the pre-selected covariates are tested one by one on the basic model. Those that meet the criteria described above are selected and introduced at the same time in the basic model. A descending construction is then carried out: the covariates are removed one by one. If the objective function does not increase by more than 6.63 points and the interindividual variability of the parameter of interest is not increased, the covariate is considered to be insignificant. This process is renewed until all covariates in the model are significant.

Validation of the model: Bayesian estimation: it allows once the final model has been validated, the estimation of pharmacokinetic or pharmacodynamic parameters for each individual by taking into account a priori the known information of fixed and random effects, population parameters, residual variability, the value of covariates of the different subjects and n observations of x subjects.

Study Type Observational
Study Design Observational Model: Other
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Not Provided
Sampling Method Probability Sample
Study Population The study involves major patients who have benefited from intraoperative hemodynamic optimization with norepinephrine (as noradrenaline tartrate) for maintaining blood pressure under general anaesthesia in neurosurgery and interventional neuroradiology in adults.
Condition
  • Neurosurgery
  • Intervention
Intervention Other: Pharmacokinetic
Analysis of blood samples
Study Groups/Cohorts Pharmacokinetic
Establish a pharmacokinetic relationship between plasma concentration and the effect of norepinephrine in patients under concentration-target intravenous anesthesia by identifying significant covariates during general anesthesia.
Intervention: Other: Pharmacokinetic
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Recruiting
Estimated Enrollment
 (submitted: March 2, 2018)
30
Original Estimated Enrollment Same as current
Estimated Study Completion Date June 27, 2021
Estimated Primary Completion Date June 27, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria

Inclusion Criteria:

  • 1. Adult patient > 18 years of age with neurosurgery or neurological interventional radiology for whom invasive monitoring of blood pressure is indicated.
  • 2. Patient with persistent low blood pressure during the general anesthesia procedure (Fall > 30% of preoperative MAP registered after patient installation and/or MAP < 55 mmHg) and achieves the depth of anesthesia objective (BIS 40-50).

Exclusion Criteria:

  • 1. A patient on a continuous infusion of norepinephrine or other catecholamine initiated in another department or facility or whose start was not recorded or whose dosage changes were unknown.
  • 2. All causes of hypotension related to the patient's intervention or illness.
Sex/Gender
Sexes Eligible for Study: All
Ages 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts
Contact: Vallée Fabrice, MD +331 49 95 83 74 fabrice.vallee@gmail.com
Contact: Dr Joaquim MATEO Joaquim, MD +33 1 49 95 83 74 joaquim.mateo@aphp.fr
Listed Location Countries France
Removed Location Countries  
 
Administrative Information
NCT Number NCT03454204
Other Study ID Numbers K170902J
2017-A02671-52 ( Other Identifier: IDRCB )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement Not Provided
Responsible Party Assistance Publique - Hôpitaux de Paris
Study Sponsor Assistance Publique - Hôpitaux de Paris
Collaborators Not Provided
Investigators
Principal Investigator: Vallée Fabrice, MD Assistance Publique - Hôpitaux de Paris
PRS Account Assistance Publique - Hôpitaux de Paris
Verification Date August 2020