Introduction: Neutrophil-mediated inflammation in the acute phase of intracerebral hemorrhage (ICH) worsens outcome in pre-clinical studies. Intercellular adhesion molecule-1 (ICAM-1), an inducible ligand for integrins and cell-cell adhesion molecules, is critical for neutrophil extravasation. We aimed to determine whether serum levels of ICAM-1 are associated with worse outcomes after ICH. Methods: We conducted a post-hoc analysis of the randomized controlled FAST (Factor-VII-for-Acute-Hemorrhagic-Stroke-Treatment) trial. The study exposure was serum level of ICAM-1, ascertained at admission. The co-primary outcomes were mortality, and death or major disability (modified Rankin Score 4-6) at 90 days. Secondary radiological outcomes were baseline ICH volume, perihematomal edema volume (PHE), and hematoma expansion at 24 hours (ICH volume increase of ≥33% or 6mL). Multivariable linear and logistic regression analyses, adjusted for age, sex, baseline ICH volume, ICH location, and trial treatment arm, were used to test for associations between ICAM-1 and outcomes. Results: Of 841 patients, we included 507 (60%) with complete data (mean age 64 years, 37% women). Hematoma expansion occurred in 169 (34%), while 242 (48%) had a poor outcome. In multivariable analyses, ICAM-1 was associated with mortality (OR, 1.02; 95% confidence interval, CI, 1.01-1.05; p=0.02) and poor outcome (OR, 1.02; CI, 1.01-1.04; p=0.04). In multivariable analyses of radiological outcomes, ICAM-1 was associated with hematoma expansion (OR, 1.03, CI, 1.01-1.07) and baseline PHE (beta, 0.02; SE, 0.001, p=0.01), but was not associated with baseline ICH volume. Conclusions: In this post-hoc analysis of the FAST trial in patients with ICH, admission serum levels of ICAM-1 were associated with hematoma expansion, PHE, and poor outcome. These findings highlight the need to further explore the role of early inflammatory biomarkers in prognostication and as potential therapeutic targets.

BACKGROUND: Neutrophil-mediated inflammation in the acute phase of intracerebral hemorrhage (ICH) worsens outcome in preclinical studies. sICAM-1 (soluble intercellular adhesion molecule-1), an inducible ligand for integrins and cell-cell adhesion molecules, is critical for neutrophil extravasation. We aimed to determine whether serum levels of sICAM-1 are associated with worse outcomes after ICH. METHODS: We conducted a post hoc secondary analysis of an observational cohort using data from the FAST trial (Factor-VII for Acute Hemorrhagic Stroke Treatment). The study exposure was the admission serum level of sICAM-1. The coprimary outcomes were mortality and poor outcome (modified Rankin Scale score 4–6) at 90 days. Secondary radiological outcomes were hematoma expansion at 24 hours and perihematomal edema expansion at 72 hours. We used multiple linear and logistic regression analyses to test for associations between sICAM-1 and outcomes, after adjustment for demographics, ICH severity characteristics, change in the systolic blood pressure in the first 24 hours, treatment randomization arm, and the time from symptom onset to study drug administration. RESULTS: Of 841 patients, we included 507 (60%) with complete data. Hematoma expansion occurred in 169 (33%), while 242 (48%) had a poor outcome. In multivariable analyses, sICAM-1 was associated with mortality (odds ratio, 1.53 per SD increase [95% CI, 1.15–2.03]) and poor outcome (odds ratio, 1.34 per SD increase [CI, 1.06–1.69]). In multivariable analyses of secondary outcomes, sICAM-1 was associated with hematoma expansion (odds ratio, 1.35 per SD increase [CI, 1.11–1.66]), but was not associated with log-transformed perihematomal edema expansion at 72 hours. In additional analyses stratified by treatment assignment, similar results were noted in the recombinant activated factor-VII arm, but not in the placebo arm. CONCLUSIONS: Admission serum levels of sICAM-1 were associated with mortality, poor outcome, and hematoma expansion. Given the possibility of a biological interaction between recombinant activated factor-VII and sICAM-1, these findings highlight the need to further explore the role of sICAM-1 as a potential marker of poor ICH outcomes.

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