Clinical trial NCT00878644: Therapeutic Hypothermia to Improve Survival After Cardiac Arrest in Pediatric Patients-THAPCA-OH [Out of Hospital] Trial
Official title: Therapeutic Hypothermia After Pediatric Cardiac Arrest (Out of Hospital)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cardiac Arrest
Keywords: Cardiac Arrest
Cardiopulmonary Arrest
Pediatric Cardiac Arrest
VABS
Vineland Adaptive Behavior Survey
POPC/PCPC
hypoxic-ichemic encephalopathy
Lead sponsor: University of Michigan
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2009-04-09
Enrollment: 295
Sex: ALL
Minimum age (years): 48
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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 out of the hospital.

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 causes. 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. The treatment may result in reduced brain injury. 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 out of 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 out of 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 to 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 to 37.5° C for 5 days after the cardiac arrest. Special temperature control blankets will be placed to maintain 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Survival With Good Neurobehavioral Outcome
timeFrame: 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 outcomes:
measure: Survival
timeFrame: Measured at one-year anniversary of cardiac arrest.
measure: Change in Neurobehavioral Function From Pre-cardiac Arrest to 12 Months Post-cardiac Arrest
timeFrame: 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.
measure: Neuropsychological Scores (for Participants That Survive)
timeFrame: Measured at Month 12
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: The Children's Hospital of Alabama
state: Alabama
city: Phoenix
country: United States
facility: Phoenix Children's Hospital
state: Arizona
city: Tucson
country: United States
facility: University of Arizona at Tucson
state: Arizona
city: Loma Linda
country: United States
facility: Loma Linda University Children's Hospital
state: California
city: Los Angeles
country: United States
facility: Children's Hospital of Los Angeles
state: California
city: Los Angeles
country: United States
facility: University of California Los Angeles
state: California
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Denver
country: United States
facility: Children's Hospital of Denver/University of Colorado
state: Colorado
city: Washington, D.C.
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Atlanta
country: United States
facility: Children's Hospital of Atlanta/Emory University
state: Georgia
city: Chicago
country: United States
facility: Children's Memorial Hospital
state: Illinois
city: Louisville
country: United States
facility: Kosair Children's Hospital
state: Kentucky
city: Baltimore
country: United States
facility: Johns Hopkins Children's Center
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan, Mott Children's Hospital
state: Michigan
city: Detroit
country: United States
facility: Children's Hospital of Michigan
state: Michigan
city: Minneapolis
country: United States
facility: Children's Hospital and Clinics of Minnesota
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University in St. Louis
state: Missouri
city: New York
country: United States
facility: Children's Hospital of New York - Columbia University Medical Center
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Durham
country: United States
facility: Duke Children's Hospital
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital
state: Ohio
city: Cleveland
country: United States
facility: Rainbow Babies and Children
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital in Columbus
state: Ohio
city: Hershey
country: United States
facility: Penn State Children's Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Children's Hospital of Philidelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Memphis
country: United States
facility: LeBonheur Children's Hospital - University of Tennessee at Memphis
state: Tennessee
city: Dallas
country: United States
facility: Children's Medical Center Dallas
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Sciences Center of San Antonio
state: Texas
city: Salt Lake City
country: United States
facility: Primary Children's Medical Center
state: Utah
city: Seattle
country: United States
facility: Seatlle Children's Hospital
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin/Children's Hospital of Wisconsin
state: Wisconsin
city: Toronto
country: Canada
facility: The Hospital for Sick Children
state: Ontario
Study officials:
affiliation: University of Michigan
name: Frank W Moler, MD, MS
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Utah
name: Michael Dean, MD, MBA
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: Moler FW, Silverstein FS, Holubkov R, Slomine BS, Christensen JR, Nadkarni VM, Meert KL, Clark AE, Browning B, Pemberton VL, Page K, Shankaran S, Hutchison JS, Newth CJ, Bennett KS, Berger JT, Topjian A, Pineda JA, Koch JD, Schleien CL, Dalton HJ, Ofori-Amanfo G, Goodman DM, Fink EL, McQuillen P, Zimmerman JJ, Thomas NJ, van der Jagt EW, Porter MB, Meyer MT, Harrison R, Pham N, Schwarz AJ, Nowak JE, Alten J, Wheeler DS, Bhalala US, Lidsky K, Lloyd E, Mathur M, Shah S, Wu T, Theodorou AA, Sanders RC Jr, Dean JM; THAPCA Trial Investigators. Therapeutic hypothermia after out-of-hospital cardiac arrest in children. N Engl J Med. 2015 May 14;372(20):1898-908. doi: 10.1056/NEJMoa1411480. Epub 2015 Apr 25.
citation: 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.
citation: Moler FW, Silverstein FS, Nadkarni VM, Meert KL, Shah SH, Slomine B, Christensen J, Holubkov R, Page K, Dean JM; THAPCA Trial Investigators. Pediatric out-of-hospital cardiac arrest: Time to goal target temperature and outcomes. Resuscitation. 2019 Feb;135:88-97. doi: 10.1016/j.resuscitation.2018.12.012. Epub 2018 Dec 17.
citation: 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.
citation: Meert K, Telford R, Holubkov R, Slomine BS, Christensen JR, Dean JM, Moler FW; Therapeutic Hypothermia after Paediatric Cardiac Arrest (THAPCA) Trial Investigators. Exploring the safety and efficacy of targeted temperature management amongst infants with out-of-hospital cardiac arrest due to apparent life threatening events. Resuscitation. 2016 Dec;109:40-48. doi: 10.1016/j.resuscitation.2016.09.026. Epub 2016 Oct 11.
citation: Slomine BS, Silverstein FS, Christensen JR, Holubkov R, Page K, Dean JM, Moler FW; THAPCA Trial Group. Neurobehavioral Outcomes in Children After Out-of-Hospital Cardiac Arrest. Pediatrics. 2016 Apr;137(4):e20153412. doi: 10.1542/peds.2015-3412. Epub 2016 Mar 3.
citation: 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.
citation: 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.
citation: 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.