A “Metamorphosis” in Our Approach to Treatment Is Not Likely to Result From a Meta-Analysis of the Use of Therapeutic Hypothermia in Severe Traumatic Brain Injury*

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In this issue of Critical Care Medicine, Crompton et al (1) present a meta-analysis of the effect of therapeutic hypothermia on outcomes after traumatic brain injury (TBI) in both adults and children. Examining the findings of 42 studies evaluating the effect of the use of therapeutic hypothermia versus standard care in more than 3,100 adults and using the same approach in eight studies of over 450 children, they concluded that the use of therapeutic hypothermia was associated with an 18% reduction in mortality and 35% improvement in neurologic outcome in adults. The studies suggested an optimal management strategy of 72 hours of cooling after injury, to a minimum of 33 °C, followed by spontaneous “natural” rewarming. In contrast, a 66% increase in mortality rate and a marginal deterioration of neurologic outcome was seen with the use of therapeutic hypothermia versus standard care in children after severe TBI. Overall, the authors suggest that therapeutic hypothermia is likely a beneficial treatment following TBI in adults but cannot be recommended in children.
To date, the greatest benefit of therapeutic hypothermia in critical care medicine has been achieved in the treatment of perinatal asphyxia in term newborns, where numerous high-quality studies have consistently demonstrated beneficial effects on mortality, short- and long-term neurologic outcome, and structural injury on imaging (reviewed in two). After cardiac arrest in adults, a carefully conducted multicenter study initially suggested benefit from conventional levels of therapeutic hypothermia (3), whereas more recent studies have suggested that equal benefit might be produced by rigorous clamping of temperature in the patients at 36 °C, a strategy often referred to as “targeted temperature management” (TTM) (4). Whether this approach simply prevents fever or represents a level of ultra-mild therapeutic hypothermia remains to be defined, and is a current area of investigation (5, 6). In children, the recent high-quality multicenter therapeutic hypothermia after cardiac arrest trial, although negative for the primary outcome, produced strong trends toward improvements in neurologic outcome and mortality despite being fairly underpowered (7). Some have suggested that it in fact supports the use of mild hypothermia (8). Related to all of these studies, in both adults and children with cardiac arrest, state-of-the-art standard of care has in general moved to either the rigorous prevention of fever or the application of mild therapeutic hypothermia (33–34 °C) generally for a period of 24–48 hours after the insult—or possibly longer if TTM is used.
Despite all of the promise and success of therapeutic hypothermia across the age spectrum in the setting of global ischemic insults such as asphyxia and cardiac arrest and despite suggestion of benefit in a number of single-center studies in TBI, a substantial number of the highest-quality multicenter studies in both adults and children have failed to demonstrate benefit—and if anything have suggested the possibility of detrimental effects. And paradoxically, the most compelling rigorous multicenter studies carried out to date have suggested consistently negative and/or detrimental effects in children (9–13).
Many issues make drawing conclusion from a meta-analysis of studies of therapeutic hypothermia challenging including factors such as the marked heterogeneity in the approaches to cooling, target temperature selected, timing of initiation and duration of cooling, rewarming strategy, inclusion and exclusion criteria for subjects in the studies, and temperature management strategy in the control subjects, not to mention the well-known intercenter differences in background care that is provided (1). Ongoing comparative effectiveness approaches may help us with the latter problem and aid in defining a more consistent optimal approach to standard care (14).

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