Examining potential side effects of therapeutic hypothermia in experimental intracerebral hemorrhage

Abstract

Studies treating intracerebral hemorrhage (ICH) with therapeutic hypothermia (TH) have shown inconsistent benefits. We hypothesized that TH's anti-inflammatory effects may be responsible as inflammatory cells are essential for removing degrading erythrocytes. Here, we subjected rats to a collagenase-induced striatal ICH followed by whole-body TH (∼33℃ for 11-72 h) or normothermia. We used X-ray fluorescence imaging to spatially quantify total and peri-hematoma iron three days post-injury. At three and seven days, we measured non-heme iron levels. Finally, hematoma volume was quantified on one, three, and seven days. In the injured hemisphere, total iron levels were elevated ( p < 0.001) with iron increasing in the peri-hematoma region ( p = 0.007). Non-heme iron increased from three to seven days (p < 0.001). TH had no effect on any measure of iron ( p ≥ 0.479). At one and three days, TH did not affect hematoma volume ( p ≥ 0.264); however, at seven days there was a four-fold increase in hematoma volume in 40% of treated animals ( p = 0.032). Thus, even when TH does not interfere with initial increases in total and non-heme iron or its containment, TH can cause re-bleeding post-treatment. This serious complication could partly account for the intermittent protection previously observed. This also raises serious concerns for clinical usage of TH for ICH.

Tracking elemental changes in an ischemic stroke model with X-ray fluorescence imaging

“…At present there are few studies employing XFI methods to study changes in ischemic or hemorrhagic stroke [9][10][11][15][16][17][18][19][20][21][22] . This paucity highlights the specialized nature of the team required to perform these types of studies.…”

Hematoma clearance as a therapeutic target in intracerebral hemorrhage: From macro to micro

“…13,14 Deferoxamine is currently in a phase-II clinical trial. 15 Additional adjunct efforts to mitigate secondary brain injury due to ICH have included hypothermia, though effects have been mixed, and preclinical data suggest the rate of late rebleeding may be higher, 16,17 with two clinical trials ongoing currently. 18,19 While immune modulation with potential downregulation of hematoma clearance is a theoretical negative effect of induced hypothermia, augmentation of hematoma clearance through other methods may negate this effect, allowing competing potentially beneficial effects of hypothermia, such as reduced inflammation and excitotoxicity, to predominate.…”

Targeting focal ischemic and hemorrhagic stroke neuroprotection: Current prospects for local hypothermia

“…The pressor response could also explain the mixed LH treatment efficacy following ICH, with several studies failing to find benefit. The disparity in TH treatment efficacy between ischemia and ICH could be in part explained by observations of ICH re‐bleeding associated with both acute systemic TH and LH treatment (John et al, 2015; MacLellan et al, 2004; Wowk et al, 2017). Coupled with the mild coagulopathy that TH causes, the increase in blood pressure and heart rate associated with the pressor response could aggravate re‐bleeding, especially in the acute post‐ICH period (MacLellan et al, 2004; Wowk et al, 2017).…”