Safety Assessments of Therapeutic Hypothermia for Intracerebral Hemorrhage

  • Author / Creator
    Prokop, Brittany
  • Therapeutic hypothermia (TH) is a common intervention used in a variety of injury profiles. However, when applied to intracerebral hemorrhage (ICH), TH can worsen outcome. Previous research from our lab has shown that TH can aggravate intracranial bleeding both during cooling induction and rewarming phases. Here, I evaluate aspects of the safety of using TH in ICH.
    First, I tested if intra-arterial chilled infusate (ICI), one method of local cooling, is safe to use when active bleeding is present. The experimental group, anesthetized male adult rats, received an infusion of heparinized room temperature saline over 20 minutes into the internal carotid artery at the external carotid bifurcation. Brain temperature change from this infusion was determined using implanted temperature probes in naïve animals. There was an average drop of ~0.1 °C, with a maximum drop of 0.5 °C in the ipsilateral hemisphere, when correcting for contralateral temperature change. Then, the infusion was given following the initiation of collagenase-induced ICH, during a time of active bleeding. Hematoma volume was assessed 24 hours after collagenase injection using a hemoglobin-detecting spectrophotometric assay. There was no difference between ICI and control groups for hematoma volume (p = 0.64). Brain water content (edema) was measured in the ipsilateral and contralateral cortices and striata, as well as the cerebellum, using wet/dry weights. Elemental concentrations were measured using inductively coupled plasma mass spectrometry, and activity and core temperature were monitored using telemetry probes. There was no difference between the ICI and control groups in edema (p = 0.81) or elemental concentrations (p > 0.1) in any region of interest. There was also no difference between the experimental and control group for temperature (p = 0.56), or activity (p = 0.61). These results suggest ICI is safe when implemented in collagenase-induced ICH.
    Clotting factors are inhibited by TH, and this effect may underlie TH-induced bleeding. Also, coagulopathy in late stages of ICH injury could aggravate ongoing bleeding. Therefore, I hypothesized next that late-onset coagulopathy would increase hematoma size. Warfarin (0.4 mg/kg loading dose, 0.25 mg/kg/day maintenance for the following 5 days) was orally administered to naïve rats. Tail bleed time was used to assess anticoagulation 6 hours after the last warfarin dose (day 6). Tail bleed time showed warfarin successfully produced a state of anticoagulation between drug treated and placebo group animals (p = 0.02). A spectrophotometric assay determined that there was no difference (p = 0.28) in the concentration of hemoglobin within the brains of each of the warfarin treated and placebo naïve animal groups. This meant that the warfarin doses successfully induced anticoagulation, without causing spontaneous bleeding. Following this validation, the warfarin dosing regimen was administered to rats, with the loading dose starting 24-hours after collagenase-induced ICH. Tail bleed time between warfarin and placebo treated groups, measured 6 hours following the last dose (day 6), showed warfarin successfully induced longer bleed times (p = 0.008). Additionally, the diameters of blood blots collected during the tail bleed test were measured every 5 minutes. These showed that the warfarin treated group also bled at a faster rate than the placebo group (p = 0.03). Hematoma volume, as determined using a hemoglobin spectrophotometric assay, was not different between the warfarin and placebo treated groups (p = 0.39). These findings suggest that anticoagulation, an isolated factor of TH, does not cause late or re-bleeding in collagenase-induced ICH.
    Prolonged cooling, even if it does not worsen bleeding through coagulopathy, may still negatively affect outcome through other means. Depending on the depth and duration, TH has the potential to broadly affect brain plasticity, especially given the spatial, temporal, and mechanistic overlap with the injury processes that cooling is used to treat. I review experimental and clinical evidence to evaluate whether application of prolonged TH has any adverse or positive effects on post-stroke plasticity. The available data suggest that mild TH does not appear to have any deleterious effect on neuroplasticity; however, there is a need for additional high‐quality preclinical and clinical work in this area.

  • Subjects / Keywords
  • Graduation date
    Spring 2021
  • Type of Item
  • Degree
    Master of Science
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.