Therapeutic Hypothermia to Improve Survival After Cardiac Arrest in Pediatric Patients-THAPCA-IH [In Hospital] Trial (THAPCA-IH)

Therapeutic Hypothermia After Pediatric Cardiac Arrest (In Hospital)

Cardiac arrest is a sudden, unexpected loss of heart function. Therapeutic hypothermia, in which the body's temperature is lowered and maintained several degrees below normal for a period of time, has been used to successfully treat adults who have experienced cardiac arrest. This study will evaluate the efficacy of therapeutic hypothermia at increasing survival rates and reducing the risk of brain injury in infants and children who experience a cardiac arrest while in the hospital.

Study Overview

• Status: Completed
• Conditions: Cardiac Arrest
• Intervention / Treatment: Procedure: Therapeutic Hypothermia; Procedure: Therapeutic Normothermia

Detailed Description

Cardiac arrest occurs when the heart suddenly stops beating and blood flow to the body is halted. It can occur while people are in the hospital because of a medical condition or while people are out of the hospital as a result of an accident or other cause. Cardiac arrest is a serious event that is associated with high rates of death and long-term disability. When a person experiences cardiac arrest,insufficient amount of blood flow and oxygen can result in brain injury.

Therapeutic hypothermia is a therapy that involves a controlled lowering of the body temperature and then maintenance of this lower temperature for a period of time. Therapeutic hypothermia has been successfully used in adults who experience cardiac arrest to improve survival rates and health outcomes, and it has also been studied in newborn infants who have suffered from perinatal asphyxia. The purpose of this study is to evaluate the efficacy of therapeutic hypothermia at improving survival rates and reducing brain injury in infants and children who experience cardiac arrest while in the hospital.

Study researchers will conduct this study in collaboration with the following two pediatric clinical research networks: the Pediatric Emergency Care Applied Research Network (PECARN), funded by the Emergency Medical Services for Children (EMSC) program, and the National Institute of Child Health and Human Development (NICHD) Collaborative Pediatric Critical Care Research Network (CPCCRN).

The study will enroll infants and children who have suffered a cardiac arrest while in the hospital. Randomization must occur within 6 hours of return of spontaneous circulation. Participants will be randomly assigned to receive either therapeutic hypothermia or therapeutic normothermia. Participants receiving therapeutic hypothermia will have their body temperature reduced to between 32° and 34° Celsius (C) and will remain at this temperature for 2 days. Their body temperature will then be slowly increased to the normal temperature of 36° to 37.5° C, which will be maintained until 5 days after the cardiac arrest. Participants receiving therapeutic normothermia will have their normal temperature maintained between 36° and 37.5° C for 5 days after the cardiac arrest. Special temperature control blankets will be placed to maintain their body temperature in the assigned range. After 5 days, each participant's temperature will be managed by their medical care team.

While participants are in the hospital, they will undergo frequent blood and urine collections, chest x-rays, and temperature measurements; parents of participants will complete questionnaires. When participants are ready to leave the hospital, study researchers will perform a physical and functional assessment. Twenty-eight days after the cardiac arrest, researchers will contact parents of participants to gather information on the participants' health and medical condition. At Months 3 and 12, a child development expert will contact parents to gather medical information. At Month 12, participants will attend a study visit for a neurologic examination and testing with a psychologist trained in rehabilitation.

• Study Type: Interventional
• Enrollment (Actual): 329
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • The Hospital For Sick Children
• United Kingdom
  • Birmingham, United Kingdom, B4 6NH
    • Birmingham Children's Hospital
  • Bristol, United Kingdom, BS2 8BJ
    • Bristol Royal Hospital for Children
  • Hampton, United Kingdom, SO16 6YD
    • University of Hampton
  • Liverpool, United Kingdom, L12 2AP
    • Alder Hey Children's Hospital
  • London, United Kingdom, SE1 7EH
    • Evalina Children's at Guys's and St. Thomas' Hospital
  • London, United Kingdom, WC1N 3JH
    • Great Ormand Street Hospital
  • Manchester, United Kingdom, M13 9WL
    • Royal Manchester Children's Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • The Children's Hospital of Alabama
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Children's Hospital
  • California
    • Loma Linda, California, United States, 92354
      • Loma Linda University Children'S Hospital
    • Los Angeles, California, United States, 90095
      • University of California, Los Angeles
    • Los Angeles, California, United States, 90028
      • Children's Hospital of Los Angeles
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
    • San Francisco, California, United States, 94143
      • University of California San Francisco
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • Georgia
    • Atlanta, Georgia, United States, 30306
      • Children's Hospital of Atlanta/Emory University
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Children's Hospital
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Kosair Children's Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan, Mott Children's Hospital
    • Detroit, Michigan, United States, 48201
      • Children's Hospital of Michigan
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University in St. Louis
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke Children's Hospital
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital in Columbus
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Children's Hospital
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philidelphia
    • Pittsburgh, Pennsylvania, United States, 15224
      • University of Pittsburgh
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • LeBonheur Children's Hospital - University of Tennessee at Memphis
  • Texas
    • Dallas, Texas, United States, 75235
      • Children's Medical Center Dallas
    • San Antonio, Texas, United States, 78229
      • University of Texas Health Sciences Center of San Antonio
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • Primary Children's Medical Center
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 days to 18 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patient suffered cardiac arrest requiring chest compressions for at least 2 minutes (120 seconds) with ROSC/ROC; AND
• Age greater than 48 hours (with a corrected gestational age of at least 38 weeks) and less than 18 years; AND
• Patient requires continuous mechanical ventilation; AND
• The cardiac arrest was unplanned (i.e., not part of cardiac surgical procedure)

Exclusion Criteria:

• The parent or legal guardian does not speak English or Spanish (the only two languages in which VABS II is standardized)
• Randomization is impossible within six hours of ROSC; OR
• Patient is on extracorporeal membrane oxygenation (ECMO) when arrest occurs; OR
• Continuous infusion of epinephrine or norepinephrine at very high doses (≥2 ug/kg/minute) received immediately prior to randomization; OR Glasgow Coma Scale motor response of five (localizing pain or for infants less than two years, withdraws to touch) or six (obeys commands, or for infants, normal spontaneous movement) prior to randomization; OR
• History of a prior cardiac arrest with chest compressions for at least two minutes during the current hospitalization but outside the 6 hour window for randomization; OR
• Pre-existing terminal illness with life expectancy < 12 months; OR
• Lack of commitment to aggressive intensive care therapies including do not resuscitate orders and other limitations to care; OR
• Cardiac arrest was associated with severe brain, thoracic, or abdominal trauma; OR
• Active and refractory severe bleeding prior to randomization; OR
• Near drowning in ice water with patient core temperature ≤32 °C on presentation; OR
• Patient is pregnant; OR
• Patient participation in a concurrent interventional trial whose protocol, in the judgment of the THAPCA investigators, prevents effective application of one or both THAPCA therapeutic treatment arms, or otherwise significantly interferes with carrying out the THAPCA protocol; OR

• Patient is newborn with acute birth asphyxia; OR

  _ Patient cared for in a neonatal intensive care unit (NICU) after arrest (ie, would not be admitted to PICU); OR

• Patient has sickle cell anemia; OR
• Patient known to have pre-existing cryoglobulinemia; OR
• Central nervous system tumor with ongoing chemotherapy or radiation therapy; OR
• Chronic hypothermia secondary to hypovolemic, pituitary, or related condition for which body temperature is consistently below 37 °C ; OR progressive degenerative encephalopathy; OR
• Any condition in which direct skin surface cooling would be contraindicated, such as large burns, decubitus ulcers, cellulitis, or other conditions with disrupted skin integrity (NOTE: patients with open chest CPR should be included but placement of cooling mattresses will be modified as needed); OR
• Previous enrollment in the THAPCA Trials.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Therapeutic Hypothermia; Participants will receive therapeutic hypothermia after experiencing cardiac arrest.	Procedure: Therapeutic Hypothermia; Participants who are assigned to receive therapeutic hypothermia will be cooled to a target temperature of 33º C plus or minus 1º C (32° to 34º C). This temperature will be maintained for 48 hours (2 days) and then participants will be warmed to a target temperature of 36.75º C plus or minus 0.75º C (36° to 37.5º C). This temperature will be maintained until 120 hours (5 days) after the cardiac arrest.
ACTIVE_COMPARATOR: Therapeutic Normothermia; Participants will receive therapeutic normothermia after experiencing cardiac arrest.	Procedure: Therapeutic Normothermia; Participants who are assigned to receive therapeutic normothermia will have their temperature maintained at 36.75º C plus or minus 0.75º C (36° to 37.5º C) for 120 hours (5 days) after the cardiac arrest.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival With Good Neurobehavioral Outcome	Survival at one-year anniversary of cardiac arrest, with a standardized VABS-II score of 70 or greater per evaluation performed at any time from 30 days prior to until 183 days after the one-year anniversary of cardiac arrest. Higher values of VABS-II represent a better outcome.	Survival was assessed at one-year anniversary of cardiac arrest; among survivors at this one-year anniversary, the VABS-II valid assessment window ranged from 30 days prior to until 183 days after the one-year anniversary date.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival	Survival at one year after cardiac arrest	Measured at one-year anniversary of cardiac arrest.
Change in Neurobehavioral Function From Pre-cardiac Arrest to 12 Months Post-cardiac Arrest	Change in VABS-II score from baseline to one year, with death at 1 year treated as worst possible outcome, and lowest possible VABS-II score at one year (regardless of baseline VABS-II score) treated as the second worst possible outcome. Since higher levels of VABS-II represent a better outcome, a larger decline (large negative magnitude of change) in VABS-II score from baseline to one year represents a worse outcome.	Survival was assessed at one-year anniversary of cardiac arrest; among survivors at this one-year anniversary, the VABS-II valid assessment window ranged from 30 days prior to until 183 days after the one-year anniversary date.
Neuropsychological Scores (for Participants Who Survive)	Functioning, as assessed by the Mullen Early Learning Composite (for children age < 5 years 9 months) or by the 2-subset version of the Wechsler Abbreviated Scale of Intelligence (WASI). As these two function measures are scaled in the same fashion, the two age groups are combined.	Measured at Month 12

Other Outcome Measures

Outcome Measure	Time Frame
Neurological Abnormality Scores (for Participants Who Survive)	Measured at Month 12

Collaborators and Investigators

• Sponsor: University of Michigan
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Michael Dean, MD, University of Utah

Publications and helpful links

General Publications

• Moler FW, Meert K, Donaldson AE, Nadkarni V, Brilli RJ, Dalton HJ, Clark RS, Shaffner DH, Schleien CL, Statler K, Tieves KS, Hackbarth R, Pretzlaff R, van der Jagt EW, Levy F, Hernan L, Silverstein FS, Dean JM; Pediatric Emergency Care Applied Research Network. In-hospital versus out-of-hospital pediatric cardiac arrest: a multicenter cohort study. Crit Care Med. 2009 Jul;37(7):2259-67. doi: 10.1097/CCM.0b013e3181a00a6a.
• Meert KL, Donaldson A, Nadkarni V, Tieves KS, Schleien CL, Brilli RJ, Clark RS, Shaffner DH, Levy F, Statler K, Dalton HJ, van der Jagt EW, Hackbarth R, Pretzlaff R, Hernan L, Dean JM, Moler FW; Pediatric Emergency Care Applied Research Network. Multicenter cohort study of in-hospital pediatric cardiac arrest. Pediatr Crit Care Med. 2009 Sep;10(5):544-53. doi: 10.1097/PCC.0b013e3181a7045c.
• Moler FW, Donaldson AE, Meert K, Brilli RJ, Nadkarni V, Shaffner DH, Schleien CL, Clark RS, Dalton HJ, Statler K, Tieves KS, Hackbarth R, Pretzlaff R, van der Jagt EW, Pineda J, Hernan L, Dean JM; Pediatric Emergency Care Applied Research Network. Multicenter cohort study of out-of-hospital pediatric cardiac arrest. Crit Care Med. 2011 Jan;39(1):141-9. doi: 10.1097/CCM.0b013e3181fa3c17.
• Moler FW, Silverstein FS, Holubkov R, Slomine BS, Christensen JR, Nadkarni VM, Meert KL, Browning B, Pemberton VL, Page K, Gildea MR, Scholefield BR, Shankaran S, Hutchison JS, Berger JT, Ofori-Amanfo G, Newth CJ, Topjian A, Bennett KS, Koch JD, Pham N, Chanani NK, Pineda JA, Harrison R, Dalton HJ, Alten J, Schleien CL, Goodman DM, Zimmerman JJ, Bhalala US, Schwarz AJ, Porter MB, Shah S, Fink EL, McQuillen P, Wu T, Skellett S, Thomas NJ, Nowak JE, Baines PB, Pappachan J, Mathur M, Lloyd E, van der Jagt EW, Dobyns EL, Meyer MT, Sanders RC Jr, Clark AE, Dean JM; THAPCA Trial Investigators. Therapeutic Hypothermia after In-Hospital Cardiac Arrest in Children. N Engl J Med. 2017 Jan 26;376(4):318-329. doi: 10.1056/NEJMoa1610493. Epub 2017 Jan 24.
• Slomine BS, Silverstein FS, Page K, Holubkov R, Christensen JR, Dean JM, Moler FW; Therapeutic Hypothermia after Pediatric Cardiac Arrest (THAPCA) Trial Investigators. Relationships between three and twelve month outcomes in children enrolled in the therapeutic hypothermia after pediatric cardiac arrest trials. Resuscitation. 2019 Jun;139:329-336. doi: 10.1016/j.resuscitation.2019.03.020. Epub 2019 Mar 26.
• Ichord R, Silverstein FS, Slomine BS, Telford R, Christensen J, Holubkov R, Dean JM, Moler FW; THAPCA Trial Group. Neurologic outcomes in pediatric cardiac arrest survivors enrolled in the THAPCA trials. Neurology. 2018 Jul 10;91(2):e123-e131. doi: 10.1212/WNL.0000000000005773. Epub 2018 Jun 8.
• Slomine BS, Silverstein FS, Christensen JR, Holubkov R, Telford R, Dean JM, Moler FW; Therapeutic Hypothermia after Paediatric Cardiac Arrest (THAPCA) Trial Investigators. Neurobehavioural outcomes in children after In-Hospital cardiac arrest. Resuscitation. 2018 Mar;124:80-89. doi: 10.1016/j.resuscitation.2018.01.002. Epub 2018 Jan 3.
• Holubkov R, Clark AE, Moler FW, Slomine BS, Christensen JR, Silverstein FS, Meert KL, Pollack MM, Dean JM. Efficacy outcome selection in the therapeutic hypothermia after pediatric cardiac arrest trials. Pediatr Crit Care Med. 2015 Jan;16(1):1-10. doi: 10.1097/PCC.0000000000000272.
• Moler FW, Silverstein FS, Meert KL, Clark AE, Holubkov R, Browning B, Slomine BS, Christensen JR, Dean JM. Rationale, timeline, study design, and protocol overview of the therapeutic hypothermia after pediatric cardiac arrest trials. Pediatr Crit Care Med. 2013 Sep;14(7):e304-15. doi: 10.1097/PCC.0b013e31828a863a.
• Pemberton VL, Browning B, Webster A, Dean JM, Moler FW. Therapeutic hypothermia after pediatric cardiac arrest trials: the vanguard phase experience and implications for other trials. Pediatr Crit Care Med. 2013 Jan;14(1):19-26. doi: 10.1097/PCC.0b013e31825b860b.

Helpful Links

• IH THAPCA Abstract

Study record dates

Study Major Dates

• Study Start: September 1, 2009
• Primary Completion (ACTUAL): February 1, 2016
• Study Completion (ACTUAL): February 1, 2016

Study Registration Dates

• First Submitted: April 10, 2009
• First Submitted That Met QC Criteria: April 10, 2009
• First Posted (ESTIMATE): April 13, 2009

Study Record Updates

• Last Update Posted (ACTUAL): June 15, 2018
• Last Update Submitted That Met QC Criteria: May 15, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Keywords: Cardiac Arrest; hypoxic-ischemic encephalopathy; Cardiopulmonary Arrest; Pediatric Cardiac Arrest; VABS; POPC/PCPC; Vineland Adaptive Behavior Scale
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Body Temperature Changes; Heart Arrest; Hypothermia
• Other Study ID Numbers: 620 (GCRC); U01HL094345 (NIH)