Impact of mild endovascular hypothermia initiation and duration on perihemorrhagic edema evolution after intracerebral hemorrhage

Intracerebral hemorrhage (ICH) is a devastating disease with poor outcome. Hematoma volume, secondary hematoma expansion, presence of intraventricular hemorrhage, age, and Glasgow Coma Scale on admission are known as established prognostic predictors. According to recent publications, perihemorrhagic edema (PHE) as a marker of secondary brain injury may also play a role as an important prognostic factor. Specific therapeutic strategies aiming at improvement of clinical outcome are still in the focus of clinical research. As one promising approach, mild therapeutic hypothermia (TH) could be shown to effectively reduce peak PHE volume in the experimental setting and in ICH patients with lower rates of long-term mortality. However, no sufficient data exist about the optimal time to initiate and withdraw TH after ICH. It is suggested that early initiation of TH may improve many aspects of cellular failure induced by the neuroexcitatory cascade, which is provoked after any neuronal injury. Animal studies examined that question mainly in ischemic stroke models and suggested a strong, time-dependent neuroprotective effect of TH with substantial benefits if TH is initiated early after or at onset of ischemia. In ICH animal models, conflicting results have been published dependent on the ICH model used. However, in studies using the collagenase model, delayed application of TH did not affect brain edema. In ICH patients, no data or recommendations about the optimal timing exist. Background and Purpose—Intracerebral hemorrhage (ICH) causes high morbidity and mortality. Recently, perihemorrhagic edema (PHE) has been suggested as an important prognostic factor. Therapeutic hypothermia may be a promising therapeutic option to treat PHE. However, no data exist about the optimal timing and duration of therapeutic hypothermia in ICH. We examined the impact of therapeutic hypothermia timing and duration on PHE evolution. Methods—In this retrospective, single-center, case–control study, we identified patients with ICH treated with mild endovascular hypothermia (target temperature 35°C) from our institutional database. Patients were grouped according to hypothermia initiation (early: days 1–2 and late: days 4–5 after admission) and hypothermia duration (short: 4–8 days and long: 9–15 days). Patients with ICH matched for ICH volume, age, ICH localization, and intraventricular hemorrhage were identified as controls. Relative PHE, temperature, and intracranial pressure course were analyzed. Clinical outcome on day 90 was assessed using the modified Rankin scale (0–3=favorable and 4–6=poor). Results—Thirty-three patients with ICH treated with hypothermia and 37 control patients were included. Early hypothermia initiation led to relative PHE decrease between admission and day 3, whereas median relative PHE increased in control patients (−0.05 [interquartile range, −0.4 to 0.07] and 0.07 [interquartile range, −0.07 to 0.26], respectively; P=0.007) and patients with late hypothermia initiation (0.22 [interquartile range 0.12–0.27]; P=0.037). After day 3, relative PHE increased in all groups without difference. Outcome was not different between patients treated with hypothermia and controls. Conclusions—Early hypothermia initiation after ICH onset seems to have an important impact on PHE evolution, whereas our data suggest only limited impact later than day 3 after onset. (Stroke. 2016;47:2249-2255. DOI: 10.1161/ STROKEAHA.116.013486.)