Pharmacologic Impact on Sedation Assessments

Study Overview
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Brief Summary
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PISA is an ancillary study to the NIH funded clinical RESTORE Trial (U01 HL086622). This study will provide data that may allow for improved dosing recommendations in this critically ill population of children.

Detailed Description
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PISA is an ancillary study to the NIH funded clinical RESTORE Trial (U01 HL086622). This project will use sophisticated modeling and simulation techniques to evaluate the impact of genetics and other variables such as degree of illness, age, weight and organ dysfunction on the pharmacokinetics and pharmacodynamics of morphine and midazolam in children who are mechanically ventilated for respiratory failure, and require sedation. This proposed work will allow the design of a pharmacologic model that can be used to individualize therapy in children requiring mechanical ventilation with the goal of optimizing sedation while minimizing the duration of mechanical ventilation. This study will provide data that may allow for improved dosing recommendations in this critically ill population of children.

Official Title
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Pharmacologic Impact on Sedation Assessment

Conditions
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Pediatric Acute Lung Injury

Intervention / Treatment
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* Other: Pharmacokinetic Sampling and pharmacogenetic analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria:• Enrolled in RESTORE clinical trial Be greater than or equal to 7 kg Receiving morphine and/or midazolam continuous infusions Give Informed Consent/Assent Exclusion Criteria: Intubated and mechanically ventilated for immediate post-operative care and stabilization Cyanotic heart disease with unrepaired or palliated right to left intracardiac shunt History of single ventricle at any stage of repair Congenital diaphragmatic hernia or paralysis Primary pulmonary hypertension Critical airway (e.g., post laryngotracheal construction) or anatomical obstruction of the lower airway (e.g., mediastinal mass) Ventilator dependent (including noninvasive) on Pediatric Intensive Care Unit (PICU) admission (chronic assisted ventilation) Neuromuscular respiratory failure Spinal cord injury above the lumbar region Pain managed by patient controlled analgesia (PCA) or epidural catheter Family/medical team has decided not to provide full support (patient treatment considered futile) Enrolled in any other sedation clinical trial concurrently or within the last 30 days Known allergy to any of the study medications.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 17 Years

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 |
| --- | --- |
| Sedated, Intubated, Morphine<br>Subjects will receive morphine/midazolam as part of clinical care. Pharmacokinetic and pharmacogenetic sampling and pharmacodynamic monitoring will occur as indicated. Pharmacokinetic samples will be assayed in the laboratory of the Division of Clinical Pharmacology and Therapeutics. Pharmacogenetic samples will be assayed in the laboratory of the Center for Applied Genomics at CHOP. | Other: Pharmacokinetic Sampling and pharmacogenetic analysis<br>* Pharmacogenetic and pharmacokinetic samples will be obtained from a peripheral catheter, central catheter, or venipuncture coordinated with scheduled phlebotomies. Pharmacokinetic and pharmacogenetic analyses will be performed. Pharmacodynamic data will be collected.<br>* Other names: pharmacogenetic Sampling;|
| Sedated, Intubated, Midazolam<br>Subjects will receive morphine/midazolam as part of clinical care. Pharmacokinetic and pharmacogenetic sampling and pharmacodynamic monitoring will occur as indicated. Pharmacokinetic samples will be assayed in the laboratory of the Division of Clinical Pharmacology and Therapeutics. Pharmacogenetic samples will be assayed in the laboratory of the Center for Applied Genomics at CHOP. | Other: Pharmacokinetic Sampling and pharmacogenetic analysis<br>* Pharmacogenetic and pharmacokinetic samples will be obtained from a peripheral catheter, central catheter, or venipuncture coordinated with scheduled phlebotomies. Pharmacokinetic and pharmacogenetic analyses will be performed. Pharmacodynamic data will be collected.<br>* Other names: pharmacogenetic Sampling;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| In children who are mechanically ventilated, to quantitatively define the heritable factors that underlie the variability in 1) midazolam and 2) morphine exposure and response. | This is a pharmacokinetic, pharmacogenetic and pharmacodynamic study examining heritable (specific polymorphisms) on drug exposure, metabolite formation and pharmacodynamic response. | 36-48 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| In children who are mechanically ventilated, to quantitatively define the non-heritable factors that underlie the variability in 1) midazolam and 2) morphine exposure and response. | Polymorphisms in drug metabolizing systems. | 36-48 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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lung injury, sedated, intubated, mechanically ventilated, pediatric