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

Will your stroke doctors and hospital be competent enough to get research going in humans that definitely answers the question? Previous hypothermia research showed no definitive evidence in clinical studies.

 

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

Daniel Omileke^1,2, Debbie Pepperall^1,2, Steven W. Bothwell^1,2, Nikolce Mackovski^1,2, Sara Azarpeykan^1,2, Daniel J. Beard^1,2, Kirsten Coupland^1,2, Adjanie Patabendige^1,2 and Neil J. Spratt^1,2,3*

• ¹The School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia
• ²Hunter Medical Research Institute, New Lambton, NSW, Australia
• ³Department of Neurology, John Hunter Hospital, Hunter New England Local Health District, New Lambton, NSW, Australia

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.

Introduction

Stroke is the second leading cause of death worldwide and the number one cause of permanent disability in adults (1, 2). A good collateral flow network is associated with better neurological outcome after stroke (3, 4). The collateral circulation provides residual perfusion to the “at-risk” penumbral tissue and slows down the progression of the infarct core.

Dramatic elevations in intracranial pressure (ICP) occur after experimental ischaemic stroke in animals - in young and aged rats, as well as rats of different strains (5–7). Our preliminary data indicates a significant ICP rise also occurs in stroke patients at 24 h (8). This ICP rise is a potential mechanism for collateral failure associated with delayed infarct expansion, worsening stroke outcome in patients (9, 10). We have previously shown that an increase in ICP causes a dramatic decrease in collateral blood flow and may therefore be responsible for collateral failure (9). Experimental studies have shown that ICP elevation occurs even after small strokes (5, 6, 11, 12) which may explain why it has gone unnoticed in patients with minor stroke, as ICP is normally only measured in large hemispheric stroke, due to the invasive nature of the procedure (13). Short-duration therapeutic hypothermia is a potent, easily implemented strategy that we have recently shown to have robust efficacy in preventing ICP elevation 24 h after stroke in rats (5–7). Multiple previous studies have shown that hypothermia also reduces infarct volume and improves functional outcome after experimental stroke (14), although at the time of these studies the effect on ICP was unknown, and the presumed mechanism of neuroprotection was by modification of a wide range of cell death mechanisms (14, 15). The effects of hypothermia on ICP elevation therefore suggests that direct effects on tissue perfusion via collateral vessels may be an important mechanism of hypothermic cytoprotection. Several early-phase clinical stroke trials using hypothermia as a treatment measure have shown feasibility. However, there is a significant mismatch in cooling duration used in clinical studies, from that shown to be effective in many experimental studies (16). Clinical trials of hypothermia have an average cooling duration of 24 h, with many maintaining hypothermia for up to 72 h (15). In contrast, the vast majority of experimental studies have cooled for 1–6 h (14). Additionally, rodent studies typically achieve target temperature within 10–20 min (14), a rate that cannot be achieved when cooling a human. The necessity of long-duration hypothermia to achieve therapeutic outcome in stroke is questionable. Current protocols resulted from very early clinical studies in patients with extremely large, “malignant” middle cerebral artery (MCA) infarcts, in whom rebound ICP elevation during rewarming was extremely problematic, and on occasion fatal (17). However, these durations are logistically extremely challenging, and increase the risk of complications such as pneumonia (18). Moreover, our experimental data suggests short-duration cooling may prevent rebound ICP elevation, thus obviating the need for very prolonged rewarming. The mismatch between protocols shown to be effective in experimental studies, and those tested in clinical trials, needs to be addressed if there is any hope of translating therapeutic hypothermia for stroke treatment.

We hypothesized that a clinically achievable gradual cooling protocol may require even less time at target temperature than current methods to prevent ICP elevation post-stroke. A milder target temperature for a short duration is easier to achieve and would potentially increase feasibility. We previously showed that hypothermia to 35°C did not lead to a significant increase in ICP 24 h after stroke. However, a slight ICP rise was seen, suggesting that 35°C may be close to the threshold for hypothermia ICP rise prevention (6).

We aimed to determine the benefits of ultra-short duration hypothermia at target temperature on both ICP elevation and infarct volume reduction post-stroke. For this, two hypothermia target temperatures (33 and 34.5°C) were investigated to identify the most feasible hypothermia regimen that still effectively prevented ICP elevation. The “ultra-short” duration refers to the 30 min at target temperatures, which is far shorter than previous studies of short duration cooling (14). We chose 34.5°C, slightly lower than the mildest effective target of 35°C from our previous work, to allow for our use of a gradual paradigm with less time at target temperature than in the previous study. ICP was measured epidurally using a fiber-optic catheter system. Epidural measurements were preferred in this study due to the increased risk of brain damage associated with other methods of ICP monitoring (19). Any damage to the brain has the potential to alter ICP, and therefore influence the primary outcome of this study. Moreover, previous studies have found that epidural ICP recordings correlate well with intraventricular recordings (20, 21), which are the “gold standard” of ICP measurements in humans (19). Additionally, the use of a fiber-optic probe provides high fidelity ICP signals when inserted and sealed in the epidural space (19, 22).

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