Clinical trial NCT01560338: Hypothermia's Impact on Pharmacology
Official title: Impact of Hypothermia on Midazolam and Morphine Pharmacokinetics
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Cardiac Arrest
Hypothermia
Keywords: Pharmacokinetics
Midazolam
Morphine
Cardiac Arrest
Hypothermia
Lead sponsor: Children's Hospital of Philadelphia
Sponsor class: OTHER
First posted: 2012-03-22
Enrollment: 41
Sex: ALL
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The study population is the pediatric population equal to or greater than 3 kg and less than 18 years of age AND have had or currently receiving morphine and/or midazolam AND receive hypothermia after cardiac arrest administered as part of clinical care.

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

Eligibility criteria: 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

Primary outcomes:
measure: Physiologic manifestations of cardiac arrest and Multiple Organ Dysfunction Syndrome (MODS) in relation to morphine and midazolam
timeFrame: 2.5 years
Secondary outcomes:
measure: Impact of genetic factors
timeFrame: 2.5 years
Other outcomes:
measure: Manifestations of hypothermia
timeFrame: 2.5 years
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Louisville
country: United States
facility: University of Louisville
state: Kentucky
city: Ann Arbor
country: United States
facility: Univeristy of Michigan
state: Michigan
city: Columbus
country: United States
facility: Nationwide Children's Medical Center
state: Ohio
city: Hershey
country: United States
facility: Pennsylvania State University Hersey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: The Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
Study officials:
affiliation: Children's Hospital of Philadelphia
name: Athena F Zuppa, MD MSCE
role: PRINCIPAL_INVESTIGATOR
References: