C-Reactive Protein Predicts Hematoma Growth in Intracerebral Hemorrhage Mario Di Napoli, MD; Adrian R. Parry-Jones, PhD, MRCP; Craig J. Smith, MD, MRCP; Stephen J. Hopkins, PhD; Mark Slevin, PhD, FRCPath; Luca Masotti, MD; Veronica Campi, PhD; Puneetpal Singh, PhD; Francesca Papa, MD; Aurel Popa-Wagner, MD, PhD; Valerica Tudorica, MD; Daniel Agustin Godoy, MD Background and Purpose—Early hematoma growth (EHG) occurs in about one third of patients with spontaneous intracerebral hemorrhage. The main aim of this study was to investigate the potential of plasma C-reactive protein (CRP) for predicting EHG after acute spontaneous intracerebral hemorrhage. Methods—Plasma CRP was measured within 6 hours of onset (median, 120 minutes) in 399 patients with primary or vitamin K antagonist–associated spontaneous intracerebral hemorrhage and without recent infection. Computed tomography brain scans were performed at baseline and repeated within 24 hours (median, 22 hours). The primary outcome was EHG, defined as absolute growth >12.5 cm3 or relative growth >33%. Secondary outcomes included early neurological worsening (ENW) using the Glasgow Coma Scale and 30-day mortality. Multivariable regression analyses were used to evaluate associations of CRP concentration and outcomes. Kaplan–Meier analysis was used for survival. Results—EHG occurred in 25.8%, ENW in 19.3%, and mortality was 31.8% at 30 days. Thirty-day mortality was significantly higher in patients with ENW (hazard ratio, 3.21; 95% confidence interval, 2.00–5.17; P12.5 cm3 or relative growth >33% from initial to follow-up CT.2,13,14 Other definitions of hematoma expansion (absolute ICH growth, relative ICH growth, and categorized sICH volume) were explored as secondary analyses given the lack of a widely accepted definition of clinically significant hematoma expansion. Secondary outcomes included ENW and 30-day mortality. ENW was defined as ≥3 point decrease in the GCS score for noncomatose patients (GCS>8), or ≥2 point decrease for comatose patients (GCS≤8), or the presence of a new focal neurological deficit, or worsening of previous deficit, assessed using a standardized neurological examination, or the appearance of clinical signs of brain herniation.15 Functional outcome was recorded using the Glasgow Outcome Scale, categorized as good (Glasgow Outcome Scale, 4–5) or poor (Glasgow Outcome Scale, 2–3). To establish a cut-off for normal and elevated CRP, centiles and the corresponding rates of EHG and ENW were compared using receiveroperating characteristic curves. To determine whether hematoma volume affects performance of CRP, we compared c statistics adjusted for baseline sICH volume (categorized a priori as 60 cm3). We calculated sensitivity (S), specificity (T), positive likelihood ratio (+LR) and negative likelihood ratio (−LR), and positive predictive value (+PV) and negative predictive value (−PV). To quantify change in the probability of having EHG or ENW based on CRP, we calculated the gain in clinical certainty.16 Calibration was determined by the calibration slope and intercept. The cohort was randomly divided into derivation and validation cohorts in a 3:1 ratio. The optimal CRP cut-off was determined using Youden method in the derivation set and tested in the validation set. For inter-rater reliability of imaging parameters, intraclass correlation coefficients and ANOVA were used, whereas equivalence of the ABC/2 method and computer-assisted technique was tested with Bland–Altman plots.17 We used Fisher exact test

for comparisons of dichotomous or categorical variables, and t test or Wilcoxon rank-sum test for continuous variables. For Pearson correlation coefficients, we logarithmically transformed positively skewed CRP data to obtain a normal distribution. We performed univariate analyses to explore the association between CRP and outcomes. A logistic regression model was designed to describe adjusted estimates of the association of CRP with outcome, and CRP was treated as a forced variable. Variables that showed a significant (P