Hypothermia's Impact on Pharmacology (HIP)

Impact of Hypothermia on Midazolam and Morphine Pharmacokinetics

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.

Study Overview

• Status: Completed
• Conditions: 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
• Enrollment (Actual): 41

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Univeristy of Michigan
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Medical Center
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 19104
      • Pennsylvania State University Hersey Medical Center
    • Philadelphia, Pennsylvania, United States, 19104
      • The Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15224
      • University of Pittsburgh
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• 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.

Description

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 Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Physiologic manifestations of cardiac arrest and Multiple Organ Dysfunction Syndrome (MODS) in relation to morphine and midazolam	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.	2.5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Impact of genetic factors	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.	2.5 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Manifestations of hypothermia	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.	2.5 years

Collaborators and Investigators

• Sponsor: Children's Hospital of Philadelphia
• Investigators: Principal Investigator: Athena F Zuppa, MD MSCE, Children's Hospital of Philadelphia

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2012
• Primary Completion (Actual): January 1, 2018
• Study Completion (Actual): January 28, 2018

Study Registration Dates

• First Submitted: March 20, 2012
• First Submitted That Met QC Criteria: March 21, 2012
• First Posted (Estimate): March 22, 2012

Study Record Updates

• Last Update Posted (Actual): March 2, 2021
• Last Update Submitted That Met QC Criteria: March 1, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Morphine; Hypothermia; Midazolam; Cardiac Arrest
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Body Temperature Changes; Heart Arrest; Hypothermia
• Other Study ID Numbers: 12-009214; RO1HL11274501A1 (Other Identifier: NIHLBI)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED