No Benefit, More Complications with Hypothermia after Traumatic Brain Injury

MedicalResearch.com Interview with:

Jamie Cooper AO BMBS MD FRACP FCICM FAHMS Professor of Intensive Care Medicine Monash University Deputy Director & Head of Research,  Intensive Care & Hyperbaric Medicine The Alfred, Melbourne

Prof. Cooper

Jamie Cooper AO
BMBS MD FRACP FCICM FAHMS
Professor of Intensive Care Medicine
Monash University
Deputy Director & Head of Research,
Intensive Care & Hyperbaric Medicine
The Alfred, Melbourne

MedicalResearch.com: What is the background for this study?

Response: 50-60 million people each year suffer a traumatic brain injury (TBI) . When the injury is severe only one half are able to live independently afterwards.

Cooling the brain (hypothermia) is often used in intensive care units for decades to  decrease inflammation and brain swelling and hopefully to improve outcomes, but clinical staff have had uncertainty whether benefits outweigh complications.

We conducted the largest randomised trial of hypothermia in TBI, in 500 patients, in 6 countries, called POLAR. We started cooling by ambulance staff, to give hypothermia the best chance to benefit patients. We continued for 3-7 days in hospital ind ICU. We measured functional outcomes at 6 months.

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Hypothermia for 48 or 24 Hours After Out-of-Hospital Cardiac Arrest?

MedicalResearch.com Interview with:

Hans Kirkegaard, MD, PhD, DMSci, DEAA, DLS Research Center for Emergency Medicine and Department of Anesthesiology and Intensive Care Medicine Aarhus University Hospital and Aarhus University Aarhus, Denmark 

Dr. Kirkegaard

Hans Kirkegaard, MD, PhD, DMSci, DEAA, DLS
Research Center for Emergency Medicine and
Department of Anesthesiology and Intensive Care Medicine
Aarhus University Hospital and Aarhus University
Aarhus, Denmark 

MedicalResearch.com: What is the background for this study?

Response: In 2002, two landmark studies demonstrated that mild therapeutic hypothermia (now known as targeted temperature management, TTM) for 12 or 24 hours improves neurological outcome in adult comatose patients suffering from out of hospital cardiac arrest. Accordingly, international guidelines now recommend TTM for at least 24 hours in this patient group.

However, there are no studies, only case reports that explore the effect of prolonged cooling. We therefore wanted to set up a trial that could fill out this knowledge gap, we hypothesized that doubling the hypothermia dose to 48 hour would improve neurological outcome without increasing the risk of adverse events considerably.

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Refined Hypothermia Parameters for Infants With Encephalopathy

Seetha Shankaran MD Director, Neonatal-Perinatal Medicne Children's Hospital of Michigan and Hutzel Women's Hospital Detroit, MIMedicalResearch.com Interview with:
Seetha Shankaran MD

Director, Neonatal-Perinatal Medicne
Children’s Hospital of Michigan and Hutzel Women’s Hospital
Detroit, MI

Medical Research: What is the background for this study? What are the main findings?

Dr. Shankaran: The background for this study is that term newborn infants born following lack of blood flow and oxygen to the brain are at high risk for death or disability, including motor and developmental handicaps. Hypothermia (lowering the core body temperature to 33-34°C for 72 hours has been shown to decrease the rate of death or disability to 44 to 55%. Hypothermia is currently the only proven therapy to reduce these devastating outcomes. The hypothermia therapy provided to term newborns was based on laboratory experiments that demonstrated that in animal models subjected to hypoxia and ischemia, cooling reduced brain injury. In the NICHD Neonatal Research Network (a group of academic centers across the US), in 2005 we reported the first trial of whole-body cooling to 33.5°C for 72 hours and noted a reduction in death or disability in infancy.  When the infants in the study where followed to childhood, we noted that this reduction in death or disability continued to childhood.

Recent laboratory experiments have demonstrated that brain injury continues for days or weeks after the hypoxic-ischemic injury. Other laboratory experiments noted that cooling for a greater depth than 33-34°C (as long as the temperature does not decrease much lower) can reduce brain injury further. Based on this information, in the NICHD Neonatal Research Network we designed a study, among term infants with moderate or severe encephalopathy to compare longer cooling and deeper cooling to see if death or disability can be reduced. Term infants with moderate or severe encephalopathy were randomly assigned at <6 hours of age to 4 groups of therapy; 33.5°C for 72 hours, 32.0°C for 72 hours, 33.5°C for 120 hours and 32.0°C for 120 hours. The  goal was to compare death or disability rates between the 2 durations of cooling (72 hours vs. 120 hours) and 2 depths of cooling (33.5 C vs. 32.0°C) and was designed to recruit 726 infants. A independent data safety and monitoring committee was appointed by the director of NICHD to monitor safety events after the first 50 infants were enrolled and then following the enrollment of every 25 infants. The safety events monitored included mortality in the neonatal intensive care unit (NICU), cardiac arrhythmia, persistent acidosis and major vessel bleeding or thrombosis. The study was started in October 2010.

Medical Research: What is the background for this study? What are the main findings?

Dr. Shankaran: In November 2013 the study was closed by the data safety and monitoring committee after 8 reviews of study data, following recruitment of 364 neonates because of emerging safety concerns as well as futility analyses. The NICU death rates were 7% (7 of 95) for the 33.5°C for 72 hour group, 14% (13 of 90) for the 32.0°C for 72hr group, 16% (15 of 96) in the 33.5°C for 120 hour group and 17% for the 32.0°C for 120 hour group. The adjusted risk ratio (95% CI) for death for the 120 hour vs. the 72 hour was not significantly different 1.37 (0.92-2.04) nor was it significantly different for the 32.0°C group compared to the 33.5°C group 1.24 (0.69-2.25).  The safety outcomes were similar between the 120 vs. 72 hour groups and the 32.0°C vs. the 33.5°C groups, except that major bleeding occurred among 1% in the 120 group vs. 3% in the 72 hours group, RR 0.25 (0.07-0.91). Futility analyses noted that the probability of detecting benefit of longer cooling, deeper cooling or both for death in the NICU was <2%. The follow -up of infants enrolled into the study for 18 months is on-going.

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