Dexmedetomidine Pharmacokinetics-pharmacodynamics in Mechanically Ventilated Children With Single-organ Respiratory Failure

Study Overview
=================
Brief Summary
-----------------
Currently, dexmedetomidine is approved by the United States Food and Drug Administration (FDA) for short-term analgosedation (<24h) in mechanically-ventilated critical care adult patients and sedation of non-intubated adult patients prior to and/or during surgical and other procedures. Trials are underway to investigate its pharmacokinetics, clinical efficacy and safety in long-term use. Clinical experience with dexmedetomidine in the paediatric population is limited. Moreover, during childhood many developmental changes take place with consequences on drug exposure and drug response. Finally, critical illness itself can affect drug pharmacokinetics and -dynamics. Therefore, we cannot simply extrapolate adult data for use in children but we are in need of data on pharmacokinetics and pharmacodynamics in every paediatric subpopulation.

Conditions
-----------------
Respiratory Failure

Intervention / Treatment
-----------------
* Drug: dexmedetomidine
* Procedure: Vital signs
* Procedure: blood sampling


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: patients (m/f) admitted to the paediatric intensive care unit expected to require at least 24h of mechanical ventilation patient age : 1 month-15 years patients with single-organ respiratory failure Exclusion Criteria: patients with neurologic conditions that prohibit an evaluation of adequate analgosedation no arterial catheter in place at inclusion patients who have received another investigational drug within 30 days patients on continuous infusion with neuromuscular blockers patients with a life expectancy <72h patients with a known allergy to lorazepam, midazolam and/or morphine heart block pre-existing bradycardia hemodynamically unstable patients (Wernovsky index > 16 points) after full fluid replacement with crystalloid patients with significant renal insufficiency (creatinine plasma level 1 month-5 year : > 1 mg/dl ; 5-10 years : >1.2 mg/dl; > 10 years : > 1.5 mg/dl) patients with significant hepatic insufficiency (aspartate aminase >950 UI/L and prothrombin time < 60 or INR >1.4) previous treatment with α2-adrenoreceptor agonist clonidine within 14 days

Ages Eligible for Study
-----------------
Minimum Age: 1 Month
Maximum Age: 15 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: dexmedetomidine|dexmedetomidine will be given max 48h. In case analgosedation is still needed after stop of the dexmedetomidine infusion, the treatment is switched to conventional analgosedation regimens. Additional drugs are given to every inadequately sedated patient (assessed by regular Comfort scoring). In case of oversedation or adverse drug events (hypotension, bradycardia), a downtitration (or stop) of the dexmedetomidine infusion is needed.|
|Procedure: Vital signs|systolic and diastolic blood pressure, heart rate, respiratory rate,oxygen saturation, temperature are assessed baseline and at least per hour reassessed after starting the dexmedetomidine.|
|Procedure: blood sampling|Blood sampling for pharmacokinetic modelling is limited to a maximum of 1,8 ml/kg (in line with the EMEA guidelines on maximum blood sampling in children). Pharmacokinetic parameters and influence of covariates on these parameters will be assessed by a population pharmacokinetic approach.|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| pharmacokinetic parameters of dexmedetomidine infusion in mechanically ventilated children with single-organ respiratory failure |  | 48 hours | 
| covariates contributing to a variability in exposure and response to dexmedetomidine |  | 48 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| preliminary knowledge on the level of sedation provided by dexmedetomidine |  | 48 hours | 
| preliminary knowledge of safety issues | systolic and diastolic blood pressure, heart rate, respiratory rate, oxygen saturation, temperature are assessed baseline and at least per hour reassessed after starting the dexmedetomidine infusion | 48 hours | 
| knowledge of the contribution of the CYP2A6 and UDP-glucuronosyltransferase genotype (covariate) to the variability in exposure and response to dexmedetomidine |  | 48 hours | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Patients with single-organ failure in need of mechanical ventilation