Intracranial Pressure Elevation after Ischemic Stroke in Rats: Cerebral Edema is Not the Only Cause, and Short-Duration Mild Hypothermia is a Highly Effective Preventive Therapy

Abstract

In both the human and animal literature, it has largely been assumed that edema is the primary cause of intracranial pressure (ICP) elevation after stroke and that more edema equates to higher ICP. We recently demonstrated a dramatic ICP elevation 24 hours after small ischemic strokes in rats, with minimal edema. This ICP elevation was completely prevented by short-duration moderate hypothermia soon after stroke. Here, our aims were to determine the importance of edema in ICP elevation after stroke and whether mild hypothermia could prevent the ICP rise. Experimental stroke was performed in rats. ICP was monitored and shortduration mild (35°C) or moderate (32.5°C) hypothermia, or normothermia (37°C) was induced after stroke onset. Edema was measured in three studies, using wet-dry weight calculations, T 2 -weighted magnetic resonance imaging, or histology. ICP increased 24 hours after stroke onset in all normothermic animals. Short-duration mild or moderate hypothermia prevented this rise. No correlation was seen between ΔICP and edema or infarct volumes. Calculated rates of edema growth were orders of magnitude less than normal cerebrospinal fluid production rates. These data challenge current concepts and suggest that factors other than cerebral edema are the primary cause of the ICP elevation 24 hours after stroke onset.

Intracranial Pressure and Collateral Blood Flow

“…In this article, we will discuss recent observations from our experimental stroke model, indicating a dramatic increase in intracranial pressure (ICP) occurring around 24 hours after onset of even small stroke. 5,6 We have also shown a significant linear reduction of collateral blood flow in response to progressive ICP elevation. 7 We believe that a similar transient ICP elevation occurring during the first 1 to 2 days post stroke is a likely mechanism to explain delayed infarct expansion in patients with minor stroke.…”

“…7 ICP was raised in a stepwise manner to 30 mm Hg, replicating the median rise seen 24 hours post stroke in our models. 5,6 There was a linear reduction in collateral flow with increasing ICP, to a mean 55% reduction in leptomeningeal collateral blood flow at 30 mm Hg (Figure 2). 7 Such a reduction to the already tenuous penumbral perfusion would be expected to have major effects on penumbral survival.…”

“…Kotwica et al 48 produced variable sized ischemic strokes and found that both small and large strokes had an ICP peak at 24 hours; however, the larger strokes went onto have a second peak at 3 days. Recently, our laboratory have demonstrated 24-hour ICP elevation, occurring in 3 different rat strains (Wistar, 5,6 Long Evans, 5 and Sprague-Dawley ) and 2 different stroke models (proximal intraluminal MCA occlusion 5,6 and small cortical photothrombotic stroke 49 ; in both young 5,6 and aged animals (L.A. Murtha, PhD, unpublished data, 2015). Interestingly, the early (24 hours) ICP elevation is not caused by edema.…”

“…The lack of a link to edema volume was a consistent finding in several series of experiments using histology, wet-dry weight, or in vivo magnetic resonance imaging to measure edema. 6 This then raises the question of why ICP should rise? Using the Monroe-Kellie principles as a conceptual framework, we suggest that either blood volume or CSF volume increases are the likely cause.…”

Ischemic penumbra as a trigger for intracranial pressure rise – A potential cause for collateral failure and infarct progression?

“…Hence, we do not know whether a transient ICP increase occurs in patients with minor stroke as we see in rats. 1,2 However, recent acute stroke imaging studies indicate that the neurological deterioration in patients with delayed infarct expansion most commonly occurs at a very similar time interval. 5 Moreover, deterioration is rarely accompanied by worsening or recurrence of the arterial occlusion as was previously supposed.…”