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Mechanisms of acute brain injury following aneurismal subarachnoid hemorrhage: the role of acute microcirculatory failure. An experimental study in mice.

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posted on 2019-11-22, 18:26 authored by Khalid Abubaker

Background: Aneurismal subarachnoid hemorrhage is the most devastating type of stroke, with two thirds of the affected individuals either die or remain with moderate to severe disability. The majority of patients die during the first few days after subarachnoid hemorrhage (SAH) (Macpherson, Lewsey et al. 2011). This mortality is most likely attributed to a severe, cerebral perfusion pressureindependent reduction of cerebral blood flow (CBF). The mechanisms of this CBF decrease are largely unknown and may be related to disturbances at the - level of the cerebral microcircuiation. This project is an attempt to study the pathophysiological mechanisms by which subarachnoid hemorrhage leads to cerebral perfusion pressure- independent cerebral ischemia. We examined the most widely accepted theory that oxyhemoglobin induced nitric oxide depletion plays a key role in the etiology of cerebral ischemia and brain injury after subarachnoid hemorrhage. In order to achieve this, we investigated any role intravascularfree hemoglobin might play in causing nitrogen oxide depletion by measuring plasma hemoglobin levels after experimental subarachnoid hemorrhage and comparing it with normal animals. We then studied cerebral microcircuiation at 1-3 hours after experimental subarachnoid hemorrhage to check for any ischemic changes at this stage after experimental and, also, to test the correlation between perivascular blood, which served as an index for perivascular hemoglobin, and these ischemic changes.

Methods: Subarachnoid hemorrhage was induced in C57/BL6 mice using Circle of Willis endovascular perforation technique (Feiler, Friedrich et al. 2010). Intravital fluorescence microscopy was used to study cerebral microcirculation 1-3 hours after experimental subarachnoid hemorrhage. Plasma hemoglobin-was measured using the spectrophotometric scanning method of Blakney and Dinwoodie.

Results: Animals had normal physiological parameters throughout the experimental period. Post-hemorrhagic intracranial pressure (ICP) rose to 91 +/- 29mmHg, indicating a comparable severity of SAH in all animals. 56% of observed cerebral vessels were affected by microvasospasm and microthrombosis. These changes were mainly seen in capillaries and small arterioles. 39% of all vasospasms were detected in vessels with 10-20 pm caliber, 28% of vasospasms occurred in vessels with 20-30 µm caliber and 10% in blood vessels with 30-40 µm diameter. 59% of microthrombi were seen blood vessels37% of them occur in vessels with 10-20 µm calibers. 93% of all microvasospasm are associated with blood in the perivascular space compared to only 7% of vasospasm occurring in the absence of perivascular blood. 79% of microthrombi were observed in vessels coated with perivascular blood, compared to 21% of microthrombi detected in the absence of perivascular blood. Plasma hemoglobin levels at 3 & 24 hours after experimental subarachnoid hemorrhage were similar to levels of plasma hemoglobin in control animals. 72 hours after SAH, the levels are higher in SAH animals but the difference is not statistically significant.

Conclusions: As early as 1 hour after subarachnoid hemorrhage there are widespread microvasospasms and microthrombosis affecting cerebral microcirculation. These changes are severe enough and extensive enough to cause early post hemorrhagic cerebral ischemia and to serve as an explanation for early mortality following SAH. Extra- rather than intra-vascular hemoglobin is most likely responsible for cerebral microvasospasm and microthrombosis after experimental subarachnoid hemorrhage.


First Supervisor

Professor Nikolaus Plesnila

Second Supervisor

Professor Ciaran Bolger


A thesis submitted to the Royal College of Surgeons in Ireland for the degree of Doctor of Medicine from the National University of Ireland in 2012.

Published Citation

Abubaker K. Mechanisms of acute brain injury following aneurismal subarachnoid hemorrhage: the role of acute microcirculatory failure. An experimental study in mice. [MD Thesis]. Dublin: Royal College of Surgeons in Ireland; 2012.

Degree Name

Doctor of Medicine (MD)

Date of award


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