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Hypothermia's Impact on Pharmacology (HIP)

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ClinicalTrials.gov Identifier: NCT01560338
Recruitment Status : Completed
First Posted : March 22, 2012
Last Update Posted : April 11, 2018
Sponsor:
Information provided by (Responsible Party):
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.

Condition or disease
Cardiac Arrest Hypothermia

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 Type : Observational
Actual Enrollment : 41 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Impact of Hypothermia on Midazolam and Morphine Pharmacokinetics
Actual Study Start Date : March 2012
Actual Primary Completion Date : January 2018
Actual Study Completion Date : January 28, 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Midazolam
U.S. FDA Resources

Group/Cohort
Pediatric after Cardiac Arrest
Pediatric patients greater than 3 kg. and less than 18 years suffering cardiac arrest who have been given or currently receiving morphine and/or midazolam and receiving hypothermia.



Primary Outcome Measures :
  1. Physiologic manifestations of cardiac arrest and Multiple Organ Dysfunction Syndrome (MODS) in relation to morphine and midazolam [ Time Frame: 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 :
  1. Impact of genetic factors [ Time Frame: 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.


Other Outcome Measures:
  1. Manifestations of hypothermia [ Time Frame: 2.5 years ]
    The objective of this aim is to identify the manifestations of hypothermia that underlie the variability in morphine and midazolam pharmacokinetics in children after cardiac arrest. In this aim we will investigate the effect of body temperature on PK parameters for morphine and midazolam.


Biospecimen Retention:   Samples With DNA
Whole blood


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Ages Eligible for Study:   up to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01560338


Locations
United States, Alabama
University of Alabama at Birmingham
Birmingham, Alabama, United States, 35294
United States, District of Columbia
Children's National Medical Center
Washington, District of Columbia, United States, 20010
United States, Kentucky
University of Louisville
Louisville, Kentucky, United States, 40202
United States, Michigan
Univeristy of Michigan
Ann Arbor, Michigan, United States, 48109
United States, Ohio
Nationwide Children's Medical Center
Columbus, Ohio, United States, 43205
United States, Pennsylvania
Pennsylvania State University Hersey Medical Center
Hershey, Pennsylvania, United States, 19104
The Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
University of Pittsburgh
Pittsburgh, Pennsylvania, United States, 15224
United States, Washington
Seattle Children's Hospital
Seattle, Washington, United States, 98105
Sponsors and Collaborators
Children's Hospital of Philadelphia
Investigators
Principal Investigator: Athena F Zuppa, MD MSCE Children's Hospital of Philadelphia

Responsible Party: Children's Hospital of Philadelphia
ClinicalTrials.gov Identifier: NCT01560338     History of Changes
Other Study ID Numbers: 12-009214
RO1HL11274501A1 ( Other Identifier: NIHLBI )
First Posted: March 22, 2012    Key Record Dates
Last Update Posted: April 11, 2018
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by Children's Hospital of Philadelphia:
Pharmacokinetics
Midazolam
Morphine
Cardiac Arrest
Hypothermia

Additional relevant MeSH terms:
Heart Arrest
Hypothermia
Heart Diseases
Cardiovascular Diseases
Body Temperature Changes
Signs and Symptoms
Morphine
Midazolam
Analgesics, Opioid
Narcotics
Central Nervous System Depressants
Physiological Effects of Drugs
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Adjuvants, Anesthesia
Hypnotics and Sedatives
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action