Urinary F₂-Isoprostane Concentration as a Poor Prognostic Factor After Subarachnoid Hemorrhage.

Background

The role of isoprostanes in cerebral vasospasm (CVS) following aneurysmal subarachnoid hemorrhage (aSAH) is controversial. Recent studies have suggested that the level of isoprostanes in cerebrospinal fluid could play a role in outcomes of patients with aSAH. We measured concentration of urinary F₂-isoprostanes (F₂-IsoPs), which is simple and noninvasive.

Methods

A prospective analysis was performed of clinical data and urine samples of 20 patients with aSAH who underwent microsurgical clipping of the aneurysmal neck between May 2016 and January 2017. The role of F₂-IsoPs as a CVS biomarker was analyzed with regard to clinical conditions of patients. Outcome was assessed at discharge and 1-month and 4-month follow-up using the Glasgow Outcome Scale and modified Rankin Scale.

Results

The concentration of urinary F₂-IsoPs was significantly greater in patients with aSAH than in healthy control subjects (P < 0.001). Additionally, increased F₂-IsoP levels on day 3 after aSAH were associated with development of CVS (P = 0.015) and worse neurologic performance after 1 month (P = 0.042) and 4 months (P = 0.027). The prognostic value of urinary F₂-IsoPs on day 3 in terms of CVS was found to be high (area under the curve 0.864, 95% confidence interval 0.691–1.000).

Conclusions

Urinary F₂-IsoPs may be used as a noninvasive prognostic biochemical marker in patients with aSAH. F₂-IsoP levels in urine may have significant implications in pathogenesis of CVS.

Introduction

Stroke is the second leading cause of death and a leading cause of disability in adults. Subarachnoid hemorrhage (SAH) is most commonly caused by a rupture of a cerebral aneurysm. Aneurysmal subarachnoid hemorrhage (aSAH) accounts for <5% of all strokes.¹ It usually affects people approximately 50 years old, who until the occurrence of SAH were completely healthy and professionally active. Patient outcomes are poor with mortality rates of 45% and significant morbidity among survivors.² A major contributor to death and disability in survivors of aSAH is cerebral vasospasm (CVS).³ The most dangerous as well as the least understood complication of aSAH is cerebrovascular spasm leading to delayed cerebral ischemia.4, 5 CVS is complex; it can be diagnosed angiographically and clinically. The narrowing of cerebral arteries visible on angiography occurs in 50%–70% of patients (radiographic vasospasm) and can lead to neurologic deterioration (delayed cerebral ischemia) secondary to focal ischemia in up to 50% of patients surviving SAH (clinical vasospasm).6, 7, 8, 9

Vasospasm almost never occurs before 3 days after SAH, and the peak incidence has been observed between 5 and 7 days after aneurysm rupture. Typically, the risk period lasts 3–14 days. Vasospasm has been associated with blood in the subarachnoid space.10, 11 Nonetheless, studies of pathophysiology of CVS have reported ambiguous results. It is unclear whether the vasoconstrictive action is directly mediated by hemoglobin or hemoglobin-associated compounds. Extravasated blood, specifically, hemoglobin, is known to cause the release of reactive oxygen species (ROS), which take part in the peroxidation of membrane lipids of endothelial cells and the proliferation of smooth muscle cells, leading to CVS.12, 13 ROS, such as superoxide and hydroxyl radicals, are involved in the pathogenesis of various diseases, including ischemia/reperfusion injury, via damaging lipids, proteins, and nucleic acids.¹⁴ Recently, F₂-isoprostanes (F₂-IsoPs) have been demonstrated to be the most specific markers of lipid peroxidation in vivo. F₂-IsoPs are compounds similar to prostaglandins, generated via nonenzymatic, free radical peroxidation of polyunsaturated fatty acids, in particular, arachidonic acid.¹⁵ They are considered oxidative stress markers, as their concentration directly reflects the free radical content. The most extensively analyzed isoprostane, 8-iso-prostaglandin F_2α, has been shown to cause vasoconstriction, platelet aggregation, and induction of DNA synthesis in smooth muscle cells.16, 17 According to an animal study, isoprostanes could cause CVS.¹⁸

In aSAH, both a sudden generalized ischemic event (owing to increased intracranial pressure and decreased cerebral perfusion pressure) and vasospasm may lead to ischemia/reperfusion brain injury. Nevertheless, the connection between ROS and aSAH has not been investigated extensively thus far. There are few studies to date devoted to the pathophysiology of CVS. Most studies have focused on a comparison of the effectiveness of drugs and outcomes. Only oral nimodipine has a level Ia indication for treatment of CVS, whereas intra-arterial and intravenous administration of nimodipine is associated with a beneficial effect on cerebral blood flow if cerebral perfusion pressure is maintained.3, 19 We hypothesized that ROS production after aSAH resulting in increased levels of F_2-IsoPs may serve as a prognostic factor. Therefore, in this pilot study, we collected patient urine samples daily between the second and fifth day after aSAH and quantified the concentration of F₂-isoprostanes. Subsequently, the patients were followed for 4 months to assess the potential clinical value of this marker.