Hypothermia Reduces Perihemorrhagic Edema After Intracerebral Hemorrhage: But Does It Influence Functional Outcome and Mortality?

Introduction

Intracerebral hemorrhage (ICH) is associated with high morbidity and mortality (Hemphill et al., 2009). The size of hematoma (Broderick et al., 1993) and the perihematomal edema (PHE) (Zazulia et al., 1999; Fernandes et al., 2000; Kollmar et al., 2010) are major factors contributing to poor outcome. However, there is no proven therapy for spontaneous ICH and PHE (Morgenstern et al., 2010). Experimentally, therapeutic hypothermia (TH) leads to neuroprotection after ICH and reduces edema formation (MacLellan et al., 2006; Kawanishi et al., 2008). We have recently investigated this promising therapeutic approach in patients with large life-threatening ICH defined by a size of above 25 mL (Kollmar et al., 2010). These patients were treated by mild TH of 35°C for 10 days (Kollmar et al., 2010). All patients (n=12) treated by mild hypothermia survived until day 90, whereas 28% (n=7) of the matched control patients (n=25) from a local hemorrhage data bank died. Evolution of hematoma volume and PHE were measured using cranial CT. PHE remained stable in the hypothermia patients, whereas it significantly increased in the control group. Data from the control group are in accordance to a recent MRI study, in which PHE volume increases most rapidly within the first 2 days after symptom onset (Venkatasubramanian et al., 2011). In this study edema volume growth was correlated with a decline in neurological status at 48 hours, but not with 3-month functional outcome (Venkatasubramanian et al., 2011). However, we consider that the early phase after symptom onset of ICH is the most critical one and requires effective PHE treatment, because PHE contributes to further brain damage including mass effects and crisis of intracranial pressure. If patients survive this critical period, they might have a good chance to recover. Since TH prevents PHE growth, we investigated the long-term outcome of the patients of our pilot study (Kollmar et al., 2010).

Methods

As described previously (Kollmar et al., 2010), 12 patients who suffered large supratentorial ICH (58±29 mL) with a median ICH score (1) of 3.5 (range 2–4) were treated with endovascular hypothermia at 35°C for a period of 10 days after the bleeding event. All patients survived day 90 and were assessed by the modified Rankin Scale (mRS) (Kollmar et al., 2010). Patients and relatives were contacted 12 months after ICH and a second follow-up survey for mRS was done via telephone.

Results

At the early time point of 90 days after ICH, functional outcome was not favorable in the majority of survivors treated with hypothermia. Six patients were severely disabled (mRS 4), and four patients were in a vegetative state (mRS 5). Only two out of 12 patients were able to walk without assistance (mRS 3). The survey after 12 months showed improvement of functional status in five patients with now totally six patients (50%) being able to walk without assistance. Two patients (16.7%), initially scored 4 and 5 on the mRS, respectively, had died at that time (Fig. 1).

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FIG. 1.

Modified Rankin scale 3 and 12 months after large intracerebral hemorrhage in patients treated with mild hypothermia.

Discussion

Those results are encouraging, because not only short-term (3 months), but also long-term mortality seems to be relatively low in our patients, as compared to available data on ICH (Sacco et al., 2009), despite of the large mean hematoma size in our study. As in large ICH, PHE formation may lead to a considerable additional mass effect, eventually causing herniation (Ropper 1986; Zazulia et al., 1999) hypothermia may have the potential to lower mortality by reducing edema growth.

Another, may be even more important and encouraging finding, is that survival led to functional recovery and regaining of the ability to walk without assistance in a large proportion of our patients (50%) in the long-term follow-up, despite of the relatively high median ICH score value at the time of the bleeding event. In light of the recent debate on hemicraniectomy in malignant middle cerebral artery infarction (Mitchell et al., 2009), the question if lower mortality after large ICH is reached at the cost of survival with a severe deficit also needs to be addressed.

Our preliminary results certainly do not allow any recommendation for the clinical routine, but rather show that this treatment option remains an attractive topic for further clinical research and the effects of hypothermia on mortality and functional outcome in ICH patients need to be investigated in a larger study. Currently, a German-Austrian randomized controlled trial to assess safety, feasibility and efficacy of mild hypothermia after ICH is under way (Kollmar et al., 2011).

Author Disclosure Statement

No competing financial interests exist.