Delayed Onset of Prolonged Hypothermia Improves Outcome after Intracerebral Hemorrhage in Rats

Abstract

Prolonged hypothermia reduces ischemic brain injury, but its efficacy after intracerebral hemorrhagic (ICH) stroke is unresolved. Rats were implanted with core temperature telemetry probes and subsequently subjected to an ICH, which was produced by infusing bacterial collagenase into the striatum. Animals were kept normothermic (NORMO), or were made mildly hypothermic (33-35 degrees C) for over 2 days starting 1 hour (HYP-1), 6 hours (HYP-6), or 12 hours (HYP-12) after collagenase infusion. Others were cooled for 7 hours beginning 1 hour after infusion (BRIEF). Skilled reaching, walking, and spontaneous forelimb use were assessed. Normothermic ICH rats sustained, on average, a 36.9-mm3 loss of tissue at 1 month. Only the HYP-12 group had a significantly smaller lesion (25.5 mm3). Some functional improvements were found with this and other hypothermia treatments. Cerebral edema was observed in NORMO rats, and was not lessened significantly by hypothermia (HYP-12). Blood pressure measurements, as determined by telemetry, in BRIEF rats showed that hypothermia increased blood pressure. This BRIEF treatment also resulted in significantly more bleeding at 12 hours after ICH (79.2 microL) versus NORMO-treated rats (58.4 microL) as determined by a spectrophotometric hemoglobin assay. Accordingly, these findings suggest that early hypothermia may fail to lessen lesion size owing to complications, such as elevated blood pressure, whereas much-delayed hypothermia is beneficial after ICH. Future experiments should assess whether counteracting the side effects of early hypothermia enhances protection.

A Simple Method to Induce Focal Brain Hypothermia in Rats

“…Our local cooling method avoided these complications. Importantly, side effects may impact efficacy, as found recently in an ICH model in rats (MacLellan et al, 2004). Accordingly, we predict that, at least in some situations, local cooling would be superior to systemic hypothermia, given an equivalent brain target temperature.…”

“…Such deep levels may only be feasible if either external heating was provided to the rest of the body or if a combination of local deep hypothermia and mild systemic cooling was acceptable, as done recently in neonatal pigs (Tooley et al, 2003). Nonetheless, we have shown that prolonged mild hypothermia, in the therapeutic range for global (Colbourne and Corbett, 1995;Hickey et al, 2000) and focal ischemia Maier et al, 1998;Yanamoto et al, 1996) and ICH (MacLellan et al, 2004), can be safely achieved without systemic problems. Another limitation is that we did not assess this technique in either the gerbil or mouse, which are common stroke models.…”

A Rat Model of Intracerebral Hemorrhage Permitting Hematoma Aspiration plus Intralesional Injection

“…Hematoma volume was quantified at 24 h using a spectrophotometric assay [5,10,17]. in brief, hemispheric brain tissue minus the olfactory bulbs and cerebellum was acquired following transcardial perfusion.…”

Delayed recovery and exaggerated infarct size by post-lesion stress in a rat model of focal cerebral stroke

“…The brains were then dried in an oven (VWR Scientific Products, Batavia, IL) at 100 °C for 24 h. The dry weights of each hemisphere were measured. Edema levels were determined using the wet/dry method (Ito et al, 1980;MacLellan et al, 2004) and the following formula: Brain water content (%)=[(Wet weight−Dry weight)/wet weight]×100.…”