Hypothermia's Impact on Pharmacology

Completed

• Conditions: Cardiac Arrest; Hypothermia

• Registration Number: NCT01560338
• Lead Sponsor: Children's Hospital of Philadelphia

Brief Summary

The purpose of the study will help us understand the complex interaction between hypothermia (cooling) and pharmacogenetics (how specific genes effect how drugs are handled), and their impact on how routinely given sedation drug are broken down and used by the body when given to children after cardiac arrest (when heart stops pumping blood) and are critically ill.

Detailed Description

Background:

Therapeutic hypothermia is used in the pediatric intensive care unit, and is being studied in the setting of pediatric cardiac arrest. Following cardiac arrest, multiple organ dysfunction syndrome, especially renal and hepatic dysfunction, is common and affects the metabolism and excretion of drugs. In addition, very little is known about the impact of hypothermia on a child's ability to metabolize medications. Dose adjustments may be required in the setting of hypothermia to avoid under-dosing and over-dosing of medications. Improper dosing and drug accumulation of sedatives and opiates can worsen existing neurologic, circulatory and respiratory failure. The measurement of the actual drug and metabolite concentrations in the body (pharmacokinetics) provides information on how a child metabolizes medications. In addition, variability in these concentrations after the administration of equal doses to different children may result from genetically driven differences in drug metabolizing systems (pharmacogenetics). Finally, these genetic differences may respond differently to hypothermia. Our overarching hypothesis is that morphine and midazolam disposition will be affected by temperature management even when accounting for potentially confounding quantifiable factors of organ dysfunction and genetic differences.

Objectives:

The objectives of this study, Hypothermia's Impact on Pharmacology 2, are

1. To estimate the impact of hypothermia on the variability in morphine and midazolam pharmacokinetics in children after cardiac arrest and

2. To estimate the impact of genetic factors on the variability in morphine and midazolam pharmacokinetics, specifically in the setting of hypothermia.

Sophisticated modeling and simulation techniques will be utilized to examine the highly dynamic changes in physiology associated with critical illness, drug disposition, pharmacogenetics and temperature modulation. The models created using this approach will be implemented to optimize the prospective treatment of these critically ill children.

Study Design:

Prospective pharmacokinetic study

Study Timeline

• Study Start: 2012-03
• Study First Submitted: 2012-03-20
• Study First Submitted QC: 2012-03-21
• Study First Posted: 2012-03-22
• Primary Completion: 2018-01
• Study Completion: 2018-01-28
• Status Verified: 2021-03
• Last Update Submitted: 2021-03-01
• Last Update Posted: 2021-03-02

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 41

Inclusion Criteria

• Be greater than or equal to three (3) kg
• Receiving or have received morphine and/or midazolam as part of clinical care
• Receiving hypothermia after any cardiac arrest
• Provide Informed Consent

Exclusion Criteria

• Receiving renal replacement therapy [example Continuous Veno-Venous Hemofiltration (CVVH), Continuous Veno-Venous Hemodialysis (CVVHD), and Continuous Veno-Venous Hemodiafiltration (CVVHDF)]
• Receiving plasmapheresis

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Physiologic manifestations of cardiac arrest and Multiple Organ Dysfunction Syndrome (MODS) in relation to morphine and midazolam	2.5 years	The objective of this aim is to identify the physiologic manifestations of cardiac arrest and MODS that underlie the variability in morphine and midazolam pharmacokinetics.

Secondary Outcome Measures

Name	Time	Method
Impact of genetic factors	2.5 years	The objective of this aim is to estimate the impact of genetic factors that underlie the variability in morphine and midazolam pharmacokinetics (PK), specifically in the setting of pediatric cardiac arrest. In this aim we will investigate the effect of genotype on pharmacokinetic parameters for morphine and midazolam.

Trial Locations

Locations (9)

Pennsylvania State University Hersey Medical Center; 🇺🇸 Hershey, Pennsylvania, United States

Univeristy of Michigan; 🇺🇸 Ann Arbor, Michigan, United States

Nationwide Children's Medical Center; 🇺🇸 Columbus, Ohio, United States

University of Alabama at Birmingham; 🇺🇸 Birmingham, Alabama, United States

Children's National Medical Center; 🇺🇸 Washington, District of Columbia, United States

University of Louisville; 🇺🇸 Louisville, Kentucky, United States

University of Pittsburgh; 🇺🇸 Pittsburgh, Pennsylvania, United States

The Children's Hospital of Philadelphia; 🇺🇸 Philadelphia, Pennsylvania, United States

Seattle Children's Hospital; 🇺🇸 Seattle, Washington, United States