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

September 13, 2023 updated by: Assistance Publique - Hôpitaux de Paris

Pharmacokinetic and Pharmacodynamic Modelling of Norepinephrine in Patients Under Target Controlled Infusions (TCI) for Anaesthesia : Plasma Concentration and "Site Effect"

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Observational

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
26

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

Study Locations

  • France
      • Paris, France, 75010
        • Service Anesthésie-Réanimation - Hôpital Lariboisière

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

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.

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Other
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort

Group / Cohort

A group or subgroup of participants in an observational study that is assessed for biomedical or health outcomes.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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.
Other: Pharmacokinetic
Analysis of blood samples

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
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)
1 day

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Assistance Publique - Hôpitaux de Paris

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Vallée Fabrice, MD, Assistance Publique - Hopitaux de Paris

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
June 27, 2018

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
June 27, 2023

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
June 27, 2023

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
February 26, 2018

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 2, 2018

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
March 5, 2018

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
September 14, 2023

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
September 13, 2023

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
September 1, 2023

More Information

Terms related to this study

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • K170902J
  • 2017-A02671-52 (Other Identifier: IDRCB)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

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.

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