Fentanyl and Clonidine for Analgesia During Hypothermia in Term Asphyxiated Infants

Study Overview
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Brief Summary
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A prospective pharmacokinetic (PK), pharmacodynamic (PD) and pharmacogenetic (PG) observation study, including the PK/PD/PG relationship, in fentanyl and clonidine administered for analgesia and sedation to term newborn asphyxiated infants receiving hypothermic treatment in the NICU.

Detailed Description
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All patients that are admitted to the study neonatal intensive care units (NICUs) for hypothermic treatment due to perinatal asphyxia are potential study patients, and their parents will be asked for consent. The patient will be treated according to clinical guidelines and will be included in the study if in need for fentanyl and clonidine according to clinical judgment (HIE and pain scores) and as decided by the responsible clinical doctor. The dosing and administration of the drugs will be implemented according to an algorithm based on pain scoring results. Apart from extra blood sampling, the bedside monitoring, investigations (electroencephalography (EEG), echocardiography (ECG), ultrasound of the brain and magnetic resonance imaging, (MRI)) and follow-up (neurologic examination) are the same as for all infants receiving hypothermia according to national and international guidelines. A brief standardised pain stimulation will be performed as part of the pain and stress assessment. In total 50 infants will be included.

Official Title
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Fentanyl and Clonidine for Analgesia During Hypothermia in Term Asphyxiated Infants - a Prospective Pharmacokinetic/Pharmacodynamic/Pharmacogenetic Observational Study. Cohort 1 in The SANNI Project.

Conditions
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Asphyxia Neonatorum

Intervention / Treatment
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* Drug: Fentanyl
* Drug: Fentanyl and clonidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Term infants (≥ gw 36+0) who, according to national guidelines (6), will receive hypothermic treatment following perinatal asphyxia, and are in need for analgesic or sedative medication according to clinical judgment based on Thomsons score and ALPS-Neo. Existing arterial or venous cannulas/catheters for repeated non-traumatic blood sampling Informed and written parental consent. Exclusion Criteria: Atrioventricular (AV)- block I-III or heart rate < 70 . Serious coronary heart disease with need for postnatal surgery Mean arterial blood pressure <35 mmHg despite adequate treatment.

Ages Eligible for Study
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Minimum Age: 36 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Fentanyl<br>All infants in need of analgesia according to an algorithm based on pain assessment results will receive fentanyl as the first analgesic drug. | Drug: Fentanyl<br>* The dosing and administration of fentanyl will serve as the first drug intervention in infants in need of analgesia according to an algorithm based on pain scoring results.<br>|
| Fentanyl and Clonidine<br>Infants in need of further analgesia according to an algorithm based on pain assessment results will receive fentanyl and clonidine as the analgesic drugs. | Drug: Fentanyl and clonidine<br>* In infants in need of further analgesia clonidine will be administered as an add on drug according to an algorithm based on pain scoring results.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK) of fentanyl and clonidine | Analysed with NONMEM (Non-linear Mixed Effect Modelling) populationbased PK statistics | Repeated blood samples over a total of 4 - 7 days] | 
| Neurophysiologic response; by single cortical events and their dynamics in relation to PK | Analyse of single cortical events and their dynamics based on burst detection and measuring features of individual bursts as well as their mass statistical behaviour over time. | From admission to the department until 4- 72 h after reaching normothermia.] | 
| Neurophysiologic response; longer term brain function in relation to PK | Assessment of longer term brain function using measures of long range correlation and brain activity cycling. | From admission to the department until 4- 72 h after reaching normothermia | 
| Neurophysiologic response; global brain network function in relation to PK | Assessment of global brain network function will be based on Activation Synchrony Index. | From admission to the department until 4- 72 h after reaching normothermia | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in/association between physiological parameters (heart rate, blood pressure, peripheral oxygen saturation and NIRS (near-infrared reflectance spectroscopy near-infrared spectroscopy) parameters) in relation to PK parameters |  | From admission to the department until 4- 72 h after reaching normothermia. | 
| Change in pain responses as measured by pain assessment score for continuous pain/stress (ALPS-Neo and Comfort Neo) in relation to PK |  | From admission to the department until 4- 72 h after reaching normothermia. | 
| Procedural pain response at a short standardized pain stimulation; as assessed with change in galvanic skin response, change in serum-cortisol and scored by a procedural pain assessment scale (PIPP-R) in relation to PK. |  | Once during stable treatment with hypothermia and 6 hours of unchanged medication | 
| Pharmacogenetic profile in relation to PK and PD results; how PK/PD phenotypes depend on pharmacogenetic (PG) profiles. |  | One blood sample during study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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fentanyl, Term infants, Analgesia, clonidine, pharmacokinetics, sedation, pharmacodynamics, neurophysiology, pharmacogenetics, asphyxia, hypothermia