Predicting Delayed Cerebral Ischemia Using Micro- and Macrovascular Parameters in Subarachnoid Hemorrhage Patients

BACKGROUND DCI following aSAH affects 30% of all aSAH-patients and is the leading cause of morbidity, mortality, prolonged hospitalization and neuropsychological disturbances in aSAH patients. DCI is defined as the occurrence of new focal deficits (like hemiparesis, apraxia, aphasia or neglect) and/or a decrease in Glasgow Coma Scale score of two or more points lasting for at least one hour and is suggested after exclusion of other causes like electrolyte disturbances, infection or hydrocephalus. The exact underlying mechanisms causing DCI are not fully understood and are thought to be multifactorial. It has become clear that vasospasms eg. narrowing of the cerebral arteries, are not the sole cause of DCI. Recent studies on DCI following aSAH also suggest a multifactorial etiology of DCI involving many microvascular abnormalities including microthrombosis, neuroinflammation and neurovascular uncoupling. The glycocalyx, a gel-like carbohydrate-rich layer lining the luminal side of the endothelium could be involved in the pathophysiology of DCI. It is involved in regulation of inflammation, in regulation of thrombogenesis and in vasomotor responses through nitric oxide release. This makes the glycocalyx a likely actor contributing to DCI.

AIM The aim of this study is twofold. In the first phase, we aim to assess the feasibility of measuring glycocalyx parameters in aSAH patients during a period of two weeks after ictus, the period during which DCI is most likely to develop. Glycocalyx integrity can be studied and quantified using two techniques: by in vivo visualization of glycocalyx width using SDF imaging or measurements of glycocalyx breakdown products in plasma.

The first technique will consist of sublingual and conjunctival glycocalyx measurements using SDF imaging, which indirectly measures the glycocalyx thickness by evaluating the red blood cell column (RBCC) width variations. Other parameters like microvascular density, blood flow, and red blood cell velocity are recorded simultaneously. SDF imaging is a minimally invasive technique previously used and validated by our group for numerous studies on microvascular changes in epilepsy. This imaging technique is painless and can be performed directly on the patient by placing a camera on any easily accessible vascular bed of interest. For obvious reasons, we are unable to visualize the cerebral microcirculation during hospital admission. Instead, only sublingual and conjunctival measurements will allow us to visualize the microcirculation at two different sites, which are differently connected to the cerebral vasculature. The conjunctiva is mostly vascularized by the ophthalmic artery, a branch of the internal carotid artery, whereas the tongue is vascularized by branches of the external carotid artery. Thus, it is possible that the glycocalyx changes following ictus are more pronounced in the vascular territory of the ophthalmic artery than in the sublingual circulation. These different locations could yield different results with regards to the glycocalyx integrity, which we seek to objectify.

The second technique consists of measurements of glycocalyx degradation markers in plasma. Using two techniques will allow a multimodal approach to assess glycocalyx integrity. Other markers of extra-cellular matrix/glycocalyx breakdown, inflammatory cytokines and glucose will be measured to correlate glycocalyx findings with mechanisms that have been shown to contribute to DCI and glycocalyx breakdown. Inflammatory cytokines will be measured both in plasma and cerebrospinal fluid (CSF) (in patients with an external ventricular drain (EVD)).

TCD is a widely used, non-invasive bedside method for the assessment of cerebral hemodynamics, offering information on possible changes due to DCI. This encompasses detecting CVS in the large basal arteries but also distal vascular changes like an increased resistance of the small vessels or altered characteristics of the vessel wall properties. Therefore, TCD is a useful tool to better understand vascular changes following an aSAH leading to DCI, even in patients without vasospasms of large intracranial arteries. Thus, this feasibility study finally seeks to determine the characteristics of the Doppler signal waveforms in aSAH patients and in DCI patients more specifically.