High Intracranial Pressure Induced Injury in the Healthy Rat Brain

Abstract

Objective We recently showed that increased intracranial pressure (ICP) to 50 mmHg in the healthy rat brain results in microvascular shunt (MVS) flow characterized by tissue hypoxia, edema and increased blood brain barrier permeability. We now determined whether increased ICP results in neuronal injury by Fluoro-Jade stain (FJS) and whether changes in cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRO2) suggest nonnutritive MVS flow. Design Intracranial pressure was elevated by a reservoir of artificial cerebrospinal fluid (CSF) connected to the cisterna magna. Arterial blood gases, cerebral arterial-venous oxygen content difference (CAVDO2) and cerebral blood flow (CBF) by magnetic resonance imaging (MRI) were measured. FJS neurons were counted in histological sections of the right and left dorsal and lateral corticies and hippocampus. Setting University laboratory Subjects Male Sprague Dawley rats. Interventions Arterial pressure support if needed by i.v. dopamine infusion and base deficit corrected by sodium bicarbonate. Measurements and Main Results FJS neurons increased 2.5 and 5.5 fold at ICP of 30 and 50 mmHg; CPP of 57 ± 4 (mean ± SEM) and 47 ± 6 mmHg, respectively, (P<0.001); highest in the right and left cortices. Voxel frequency histograms of CBF showed a pattern consistent with MVS flow by dispersion to higher CBF at high ICP and decreased CMRO2. Conclusions High ICP likely caused neuronal injury due to a transition from normal capillary flow to nonnutritive MVS flow resulting in tissue hypoxia, edema and manifest by a reduction in CMRO2.

Characterization of Retinal Ganglion Cell and Optic Nerve Phenotypes Caused by Sustained Intracranial Pressure Elevation in Mice

“…Together, these phenotypes are highly similar to the key findings of elevated ICP in humans (papilledema, ischemia, RGC thinning, functional deficit, optic nerve injury), and strongly suggest that this model can be used to study human diseases of elevated intracranial pressure such as IIH and SANS 12 – 14 . As inducible models of ICP elevation are otherwise lacking, this system is a major improvement over the few other current models of ICP elevation, which either lack the ability to refine ICP to desired parameters of level and duration or are acute in nature 16 – 18 , 20 .…”

“…Within this context, neuronal ischemia secondary to mechanical trauma and alterations to axoplasmic flow and optic nerve head vasculature is thought to be a key component 12 , 15 . To better understand these processes, there has been considerable interest in identifying animal models to assist in the study of IIH, papilledema, and elevated ICP 16 – 27 . Unfortunately, many of the existing disease models either do not allow for sustained ICP elevation in living animals, do not allow for customizable ICP elevation to levels at the discretion of the investigators, or cannot be performed in genetically tractable organisms such as mice.…”

Meaning of Intracranial Pressure-to-Blood Pressure Fisher-Transformed Pearson Correlation–Derived Optimal Cerebral Perfusion Pressure: Testing Empiric Utility in a Mechanistic Model

“…Other limitations of the model are that CBF is derived without accounting for changes in cerebral metabolism, the effects of medications or CSF diversion on cerebrovascular dynamics, and the consequence of surgical interventions (e.g., craniotomy, hematoma evacuation). Neither does the model account for brain heterogeneity in CA and microvascular nonnutritive phenomena such as shunt flow ( 29 ). That said, there are four advantages of our in silico testing: 1) “ground truth” CA is known and model parameters can be set to desired values; 2) changes in BP and ICP can be controlled and examined; 3) confounding factors can be controlled or eliminated; and 4) measurement errors can be removed as noise level can be controlled.…”

Induced Dynamic Intracranial Pressure and Cerebrovascular Reactivity Assessment of Cerebrovascular Autoregulation After Traumatic Brain Injury with High Intracranial Pressure in Rats

“…To test that, several animal studies used increased ICP to decrease CPP instead of decreasing arterial pressure and reported loss of autoregulation at ~30 mmHg [2-5]. The reason for an “apparently” better preserved autoregulation at a lower CPP was unclear until we showed that in a normal rat brain high ICP-induced a transition of capillary blood flow to high velocity, non-nutritive microvascular shunt (MVS) flow that was associated with brain hypoxia, edema and blood brain barrier (BBB) damage [6-7]. This transition was correlated with loss of CBF autoregulation undetected by static autoregulatory curves but identified by induced dynamic ICP (iPRx) and cerebrovascular (iCVRx) reactivity [8].…”