Intracerebral hemorrhage (ICH) is a devastating condition with limited treatment options (1). Primary neurological injury results from direct physical tissue damage caused by the formation of the hematoma and subsequent expansion (2, 3). Secondary injury results from a cascade of cellular and molecular processes, initiated by both brain tissue injury and the presence of blood in the brain parenchyma. Secondary injury contributes to perihematomal edema (PHE) formation and mass effect. The inflammatory response is a major component of this and the modulation of inflammation may represent an important therapeutic strategy in ICH (4).

Computed tomography (CT) of the brain in patients with ICH at baseline typically shows low Hounsfield units (HU) in the perihematomal brain, also seen as high signal on T₂-weighted magnetic resonance (MR) imaging, which is thought to be caused by PHE. Recent studies using large ICH cohorts have found growth of PHE in the first 24–72 h to be associated with poor outcome (5–7) but few studies have focused on PHE at baseline (<24 h from onset). Baseline PHE is likely to be driven by hydrostatic pressure associated with an expanding hematoma and the coagulation of extravasated whole blood, with the production of coagulum and serum accumulating in the perihematomal brain parenchyma (8). Subsequent growth (beyond 24 h) is thought to be mediated by vasogenic edema resulting from inflammation induced blood–brain barrier disruption (9). Features of systemic inflammation such as elevated C-reactive Protein (CRP) (10–13), fever (14, 15), and peripheral leukocytosis (16, 17) are often observed in ICH patients and are associated with worse clinical outcomes. CRP is an acute phase reactant induced by interleukin-6 (10), which reflects both systemic and local inflammation (18). However, given different proposed mechanisms of baseline PHE, it remains unclear what role systemic inflammation plays in baseline PHE, as the systemic inflammatory response to ICH takes hours to evolve (18). Baseline systemic inflammation is likely to be more reflective of pre-morbid health and may influence outcome from ICH through different mechanisms.

Our aim was to determine the associations between baseline CRP, as a surrogate marker for inflammation, and baseline EED, first in a unifactorial analysis in the variables true form and then after transforming key variables and adjusting for appropriate confounding variables. In a further step, we tested for an independent association of these measures with 30-day mortality.

In our large, multicenter ICH cohort we did not find an independent association between baseline CRP and baseline edema (measured by EED). Baseline edema (measured by PHE volume) in turn was not associated with 30-day mortality. None of the sensitivity analyses showed a significant association either.

Elevated CRP is commonly observed after ICH with median baseline CRP levels on admission of between 7 and 18 mg/L (10–12, 27, 28). Our median CRP was lower, at 2.5 mg/L. This could be due to earlier admission (shorter ictus to presentation time) and therefore earlier testing. It could as well be due to smaller ICH volumes although some studies have also reported smaller median ICH volumes compared to our cohort (22, 29–32). Natural history data of CRP kinetics beyond the first 24 h after ICH is limited. A previous group examined CRP kinetics in a cohort of 223 ICH patients and noted a median baseline CRP of 7.9 mg/L at a median of 93 min from ictus, which increased to 46 and 88.3 mg/L at 24 and 72 h, respectively (11), with an initial growth trajectory similar to that expected for PHE (5). In our cohort, higher baseline CRP was significantly associated with higher baseline EED in the unifactorial analysis but only showed a trend when adjusting for confounders (p < 0.001 and p = 0.055, respectively). The reduction in the association may be partly accounted for CRP and EED being independently associated with ICH volume. EED at later time points is hypothesized to reflect the intensity of the perihematomal inflammation relatively independently from the effect of baseline hematoma (25). CRP has been found in the perihematomal region from human subjects reflecting a zone of perihematomal inflammation after ICH (11). Although the inflammatory response to ICH in animal models begins within hours of onset, it increases in intensity over the next 48–72 h (33). Our study was restricted to patients within 24 h of symptom onset, thus considerably earlier than the maximal intensity of the inflammatory response. CRP takes up to 6 h to rise significantly after an acute stimulus (34), so measures within a few hours of symptom onset are likely to be more reflective of premorbid background inflammation than of the acute ICH. In our study, median time from onset to CRP measurement was 179 min (85–616 min), thus most measurements were earlier than any ICH-related rise would be expected to occur. The fact that we did not find a significant association most likely is due to the early measurement of CRP in the included cohort.

Higher baseline PHE volume was not independently associated with hazard of mortality within 30 days of ICH event. Absolute PHE volume and growth between 1 and 7 days after ICH ictus have been reported by various groups to be an independent poor prognostic marker after ICH (6, 7, 35–38). Recent studies using EED as an edema metric also demonstrated increasing edema growth at 72 h to be an independent and poor prognostic marker in ICH (5, 26).

We found no independent association between baseline CRP and survival. Several previous studies have investigated the significance of CRP and ICH outcome at different timepoints, with varied findings. In a study of 223 ICH patients admitted within 24 h of onset with daily CRP measurements over the first 72 h, the association between CRP at each time point, 30-day mortality and Glasgow Outcome Score was analyzed (11). In keeping with our findings, CRP on admission [median time from symptom onset to CRP 92 min (48–275 min)] was not associated with outcome. In their study, higher CRP at 24, 48, and 72 h was independently associated with a higher hazard of mortality and poor functional outcome. In a cohort of 961 ICH patients, higher CRP within 24 h of admission was found to be associated with unfavorable 3-month outcome (Glasgow Outcome Score 1–4) after adjusting for confounders (12). However, the exact timing of CRP measurements in relation to onset is not reported. These samples may thus be further from onset and thus less reflective of true baseline CRP. On the other hand, CRP measurement in our cohort could have been at a too early time point to catch the full extent of inflammation as we restricted it to patients within 24 h of symptom onset and the peak of intensity is reached after 48–72 h (33).

There are several limitations to this study. Firstly, our results focused on CRP and edema formation at baseline (<24 h) after ICH, so we do not have data on the evolution of CRP concentrations and edema beyond the first 24 h. Additionally, the exact timing of measurement of CRP was unknown in around a quarter of our study population. Although likelihood for relevant changes over the first few hours is low, evaluation in a further study with exact timing of blood values is needed to confirm this. Besides this, development over time beyond 24 h will also need to be evaluated prospectively in a systematic way with clear time-points of blood values taken as the effect is likely to be larger and show at a later time point. Secondly, although CRP is a sensitive and robust biomarker for systemic inflammation (18), we do not have complete data on CRP nor any data for other markers of systemic inflammatory response such as body temperature and peripheral leukocyte count. This again would be the scope of a prospective study with prespecified laboratory value collection and prespecified time-points. Also, there was a significant amount of missing data in several of the necessary variables including CRP (1,335) leading to the final inclusion of only 1,034 of the total 3,412 patients (30.3%), which probably limits the generalizability of this study. Thirdly, EED is a relatively new PHE metric increasingly being examined in PHE studies (5, 26, 39) after ICH and is a preferred edema metric to examine the perihematomal inflammatory response compared to absolute edema volume (25). The rationale behind this is that EED extends a consistent mean linear distance irrespective of ICH volume. Fourth, functional outcome data were not available in all the included studies on follow-up after ICH. The influence of the above findings on functional outcome should be the subject of future studies. Fifth, the included cohorts mostly only have baseline CT scans available as follow-up CT is not routinely performed in many centers, especially not following a specific time interval, which is normal for a standard clinical cohort. This again could be targeted in a future, prospective study. Lastly, patients recruited to the CROMIS study needed a consent given by themselves or a relative in order to be included into the study leading to exclusion of patients who died early during their hospitalization.

The early systemic inflammatory response, as measured by serum CRP, was not associated with baseline EED in our cohort most likely due to early measurement after symptom onset. This needs to be confirmed in independent, large prospective ICH cohort studies with predetermined inflammatory marker measurements at varying pre-specified time points to better understand the association between systemic inflammation and edema and show an effect if there really is one. Improving our understanding of the drivers of edema, how these change over time and the role of systemic inflammation will further inform future treatment approaches to improve outcomes after ICH.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

The studies involving humans were approved by different ethical committees as multiple cohorts included. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

OS: Conceptualization, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing. IH: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Validation, Visualization, Writing – original draft, Writing – review & editing. TW: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing. CH: Formal analysis, Methodology, Validation, Visualization, Writing – original draft, Writing – review & editing. DWi: Conceptualization, Data curation, Formal analysis, Investigation, Writing – original draft, Writing – review & editing. DSh: Data curation, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing. DSt: Data curation, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing. JP: Data curation, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing. TT: Data curation, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing. AV: Data curation, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing. GS: Data curation, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing. SD: Data curation, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing. DWe: Data curation, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing. AM: Data curation, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing. SA: Data curation, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing. AP-J: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing.