Ultra-Short Duration Hypothermia Prevents Intracranial Pressure Elevation Following Ischaemic Stroke in Rats

Abstract

There is a transient increase in intracranial pressure (ICP) 18–24 h after ischaemic stroke in rats, which is prevented by short-duration hypothermia using rapid cooling methods. Clinical trials of long-duration hypothermia have been limited by feasibility and associated complications, which may be avoided by short-duration cooling. Animal studies have cooled faster than is achievable in patients. We aimed to determine whether gradual cooling at a rate of 2°C/h to 33°C or 1°C/h to 34.5°C, with a 30 min duration at target temperatures, prevented ICP elevation and reduced infarct volume in rats. Transient middle cerebral artery occlusion was performed, followed by gradual cooling to target temperature. Hypothermia to 33°C prevented significant ICP elevation (hypothermia ΔICP = 1.56 ± 2.26 mmHg vs normothermia ΔICP = 8.93 ± 4.82 mmHg; p = 0.02) and reduced infarct volume (hypothermia = 46.4 ± 12.3 mm3 vs normothermia = 85.0 ± 17.5 mm3; p = 0.01). Hypothermia to 34.5°C did not significantly prevent ICP elevation or reduce infarct volume. We showed that gradual cooling to 33°C, at cooling rates achievable in patients, had the same ICP preventative effect as traditional rapid cooling methods. This suggests that this paradigm could be translated to prevent delayed ICP rise in stroke patients.

Short-duration hypothermia completed prior to reperfusion prevents intracranial pressure elevation following ischaemic stroke in rats

“…This study demonstrates the previously reported consistency of ICP and infarct data in response to hypothermia treatment 19 . However, there are a number of limitations that must be noted.…”

“…The results from the present study indicate that hypothermia may be suitable as a potential early treatment strategy following a stroke, prior to reperfusion therapy. Here, animals in the rewarmed pre-reperfusion group reached target temperature 30 min following occlusion and were only maintained at target for 1 h, yet we saw significant ICP rise prevention and infarct volume reduction as were previously reported when animals are cooled during the reperfusion period 4 , 19 . This provides evidence that early administration of short-duration hypothermia may be beneficial to stroke patients, independent of whether it straddles the reperfusion interval, in those receiving reperfusion therapies.…”

Decreased Intracranial Pressure Elevation and Cerebrospinal Fluid Outflow Resistance: A Potential Mechanism of Hypothermia Cerebroprotection Following Experimental Stroke

“…We opted for the gradual cooling hypothermia paradigm as opposed to the traditional rapid cooling techniques that are common in pre-clinical literature. This choice was based on previous findings that show that clinically relevant cooling rates prevent ICP elevation and reduce infarct volume [ 14 ]. Using this paradigm allows us to make greater assumptions about the clinical translatability of hypothermia and its mechanisms that prevent ICP elevation post-stroke.…”

“…No external cooling was necessary as anaesthesia prevented normal regulation of core body temperature. For recovery and rewarming, core body temperature was increased to 35 °C prior to recovery from anaesthesia, and animals were placed in a cage half over a warming pad (Passwell, Glen Osmond, Australia) to allow for self-thermoregulation, per our established technique [ 14 ]. Animals in the normothermia group were kept at 37 °C for the duration of this period.…”

“…We have previously demonstrated that ultra-short duration hypothermia, using clinically relevant cooling rates, prevents ICP elevation and reduces infarct volume 24 h post-stroke in rats [ 14 ]. If the main driver of ICP elevation post-stroke is due to an increase in CSF outflow resistance, it is plausible that hypothermia would decrease CSF outflow resistance and lead to reduced ICP elevation post-stroke in hypothermia animals compared to normothermia controls.…”