The Complex Relationship Between Cooling Parameters and Neuroprotection in a Model of Selective Hypothermia

Thomas K Mattingly; Andrew McDavid; Amparo Wolf; Glen Lieber; Ronald Solar; Donald Lee; Stephen P Lownie

doi:10.3389/fneur.2022.874701

The Complex Relationship Between Cooling Parameters and Neuroprotection in a Model of Selective Hypothermia

Front Neurol. 2022 Apr 25:13:874701. doi: 10.3389/fneur.2022.874701. eCollection 2022.

Authors

Thomas K Mattingly¹, Andrew McDavid², Amparo Wolf³, Glen Lieber⁴, Ronald Solar⁴, Donald Lee⁵, Stephen P Lownie⁶

Affiliations

¹ Department of Neurosurgery, University of Rochester, Rochester, NY, United States.
² Department of Biostatistics and Computational Biology, University of Rochester, Rochester, NY, United States.
³ Department of Neurosurgery, Health Sciences North, Sudbury, ON, Canada.
⁴ ThermopeutiX, Inc., San Diego, CA, United States.
⁵ Department of Medical Imaging, London Health Science Centre, London, ON, Canada.
⁶ Division of Neurosurgery, Halifax Infirmary, Halifax, NS, Canada.

Abstract

Background: Hypothermia remains the best studied neuroprotectant. Despite extensive positive large and small animal data, side effects continue to limit human applications. Selective hypothermia is an efficient way of applying neuroprotection to the brain without the systemic complications of global hypothermia. However, optimal depth and duration of therapeutic hypothermia are still unknown. We analyzed a large animal cohort study of selective hypothermia for statistical relationships between depth or duration of hypothermia and the final stroke volume.

Methods: A cohort of 30 swine stroke subjects provided the dataset for normothermic and selective hypothermic animals. Hypothermic parameters including duration, temperature nadir, and an Area Under the Curve measurement for 34 and 30°C were correlated with the final infarct volumes measured by MRI and histology.

Results: Between group comparisons continue to demonstrate a reduction in infarct volume with selective hypothermia. Histologically-derived infarct volumes were 1.2 mm³ smaller in hypothermia-treated pigs (P = 0.04) and showed a similar, but non-significant reduction in MRI (P = 0.15). However, within the selective hypothermia group, more intense cooling, as measured through increased AUC 34 and decreased temperature nadir was associated with larger infarct proportions by MRI [Pearson's r = 0.48 (p = 0.05) and r = -0.59 (p = 0.01), respectively]. Reevaluation of the entire cohort with quadratic regression demonstrated a U-shaped pattern, wherein the average infarct proportion was minimized at 515 degree-minutes (AUC34) of cooling, and increased thereafter. In a single case of direct brain tissue oxygen monitoring during selective hypothermia, brain tissue oxygen strongly correlated with brain temperature reduction over the course of selective hypothermia to 23°C.

Conclusions: In a large animal model of selective hypothermia applied to focal ischemia, there is a non-monotone relationship between duration and depth of hypothermia and stroke volume reduction. This suggests a limit to depth or duration of selective hypothermia for optimal neuroprotection. Further research is required to delineate more precise depth and duration limits for selective hypothermia.

Keywords: ischemia; ischemia/reperfusion injury; model; stroke; therapeutic hypothermia (TH).