Therapeutic hypothermia and Type II errors: Do not throw out the baby with the ice water

After initial enthusiasm for mild therapeutic hypothermia (TH) treatment after brain injuries, including global cerebral ischemia after cardiac arrest, subsequent trials suggested similar benefit using only targeted temperature management (TTM), with fewer side effects. Globally, effective treatment of brain ischemia with TH has declined. Recent data suggest, however, that TH to 33°C may be superior to TTM. We review the background and rationale underlying TH and TTM. We present previously published data from our own laboratory that confirms TH to 33°C provides superior brain cytoprotection, compared to 35°C or 37°C, over a range of delays to treatment and several durations of TH. We illustrate that the treatment effect size of either or 35 is superior to 37, but the effect size difference between 33 and 35, although significant, is small. We estimate that to demonstrate the superiority of TTM over TH, a clinical trial would need between 3,000 and 9,000 patients depending on the desired treatment effect size. Our review and our own data suggest that TH to 33°C is superior to TTM to 36°C, but an extremely large clinical trial would be needed to demonstrate the difference.