CO₂ Has no Therapeutic Effect on Early Micro Vasospasm after Experimental Subarachnoid Hemorrhage

Abstract

In addition to delayed vasospasm also early brain injury, which occurs during the first few days after subarachnoid hemorrhage (SAH) when large cerebral arteries are still fully functional, plays an important role for the outcome after SAH. In the current study, we investigated the hypothesis that carbon dioxide (CO 2 ), a strong cerebral vasodilator, has a therapeutic potential against early posthemorrhagic microvasospasm. C57BL/6 mice (n ¼ 36) and Sprague-Dawley rats (n ¼ 23) were subjected to sham surgery or SAH by filament perforation. The pial microcirculation in the mice was visualized 3 and 24 hours after SAH using intravital fluorescence microscopy. Partial pressure of CO 2 (PaCO 2 ) was modulated by hyper-or hypoventilation or by inhalation of 10% CO 2 . In rats, CO 2 -mediated changes in cerebral blood flow (CBF) were measured at the same time points using laser Doppler fluxmetry. Increased PaCO 2 caused vasodilatation in sham-operated animals. Following SAH, however, cerebral arterioles were nonreactive to CO 2 . This lack of microvascular CO 2 reactivity was accompanied by a complete loss of CO 2 -induced hyperemia. Our data show that CO 2 is not able to dilate spastic microvessels and to increase CBF early after SAH. Future therapeutic approaches will therefore need to address mechanisms beyond CO 2 . Keywords: CO 2 reactivity; intravital microscopy; mice; microcirculation; microvasospasm; subarachnoid hemorrhage INTRODUCTION Subarachnoid hemorrhage (SAH) underlies 6% to 10% of all stroke events yet accounts for 22% to 25% of cerebrovascular-related deaths. Journal of Cerebral Blood1 Only B10% of patients who experience SAH recover completely, and B70% of initially comatose patients die within the first 6 months of the SAH.2 In addition to the severity of the disease also the lack of causal therapeutic options is responsible for this less than optimal situation.The pathophysiology of SAH can be divided into two distinct phases: (1) delayed brain injury associated with delayed macrovasospasm, which occurs later than 5 days after SAH 3-5 and (2) early brain injury (EBI) that occurs within the first few days after SAH when large cerebral vessels are still fully functional. Nevertheless, EBI is associated with acute cerebral hypoperfusion.

High-normal PaCO2 values might be associated with worse outcome in patients with subarachnoid hemorrhage – a retrospective cohort study

“…In an experimental study, hypercapnia led to dilatation of small vessels in sham-operated animals. In animals with experimental SAH, however, higher P a CO 2 levels had no effect on vessel [29]. In our study we could not show a significant association of the proportion of P a CO 2 values > 40 mmHg with DCI.…”

Inversion of neurovascular coupling after subarachnoid hemorrhage in vivo

“…Severe endothelium-dependent dysfunction in vivo was identified for the first time by direct observation of pial vessels 3 and 24 h after SAH using conventional epi-fluorescence microscopy. 10,26,27 However, due to the limited penetration depth of the technology used in these studies, the investigation was limited to vessels on the brain surface. This limitation was overcome using two-photon microscopy, to provide the first in vivo measurements of parenchymal arteriolar functionality 3 h after SAH.…”

Acute changes in neurovascular reactivity after subarachnoid hemorrhage in vivo

“…The few published in vivo studies investigating the cerebral microcirculation after SAH used conventional epifluorescence microscopy and were due to the limited penetration depth of this technology limited to pial vessels. [36][37][38] These vessels were of specific interest in the context of SAH since these are the only cerebral microvessels coming in direct contact with extravasated blood after subarachnoid bleeding. Indeed, pial vessels were shown to constrict after SAH in experimental animals models and in SAH patients thereby suggesting that spasms of cerebral microvessels are one of the main reasons for the cerebral ischemia observed after SAH.…”