Highlights
- Perihematomal edema (PHE) growth within the first 24 and 72 hours of intracerebral hemorrhage (ICH) onset is independently associated with a higher risk of death or dependence at 90 days.
- Every 1 mL increase in absolute PHE volume at 24 hours correlates with a 4% increase in the odds of a poor functional outcome (mRS 3–6).
- The association remains statistically significant even after adjusting for major prognostic factors, including baseline ICH volume, age, and intraventricular extension.
- PHE represents a critical window for therapeutic intervention aimed at mitigating secondary brain injury.
Background
Spontaneous intracerebral hemorrhage (ICH) remains one of the most devastating forms of stroke, characterized by high mortality rates and profound long-term disability. While the primary injury—the mechanical disruption of brain tissue by the hematoma—occurs almost instantaneously, secondary brain injury (SBI) evolves over hours and days. Perihematomal edema (PHE) is the radiological hallmark of this secondary process.
PHE results from a complex cascade involving blood-brain barrier (BBB) disruption, the release of inflammatory mediators, and the neurotoxic effects of blood degradation products such as thrombin and heme. Despite its biological significance, the independent contribution of PHE to functional outcomes has been a subject of debate. Historically, critics argued that PHE might simply be a surrogate for hematoma volume. However, the emergence of high-resolution computed tomography (CT) and sophisticated volumetric analysis has allowed researchers to isolate the effects of PHE growth from the initial bleeding event. This review synthesizes the findings of the largest individual participant data (IPD) meta-analysis to date on this topic.
Key Content
Pathophysiological Progression of PHE
The development of PHE typically follows a triphasic temporal pattern. The initial phase (0–6 hours) involves the retraction of the clot and the expression of serum into the interstitial space. The second phase (up to 48 hours) is driven by the activation of the coagulation cascade and the inflammatory response. The third phase (several days to weeks) involves the breakdown of red blood cells and the release of hemoglobin-derived iron, which induces oxidative stress and profound cytotoxic edema. The meta-analysis by Samarasekera et al. specifically targeted the early and subacute windows (24 and 72 hours), which are most relevant for acute neurocritical care interventions.
Methodological Framework of the IPD Meta-Analysis
The study utilized a two-stage individual participant data meta-analysis, a gold-standard approach that provides higher statistical power and more granular control over confounders than aggregate data meta-analyses. The inclusion criteria were rigorous: participants required a diagnostic CT within 72 hours, a repeat CT within 14 days, and no surgical intervention or experimental therapies that would artificially alter PHE trajectories. From nearly 13,000 screened records, data from 12 studies (including the VISTA-ICH databank) were harmonized, resulting in a robust cohort of 1,523 participants.
Quantifying the Impact: The 24-Hour and 72-Hour Windows
The primary outcome was death or dependence, defined by a modified Rankin Scale (mRS) score of 3–6 at 90 days. The results provided clear evidence of the detrimental impact of PHE growth:
- The 24-Hour Window: In 1,347 participants, PHE growth at 24±12 hours was strongly associated with poor outcomes. Both unadjusted and adjusted models (controlling for age, sex, baseline ICH volume, and intraventricular extension) showed an Odds Ratio (aOR) of 1.04 per mL increase (95% CI, 1.01–1.06; P<0.01).
- The 72-Hour Window: In 495 participants, the trend continued. Even at this later stage, the growth of PHE remained an independent predictor of death or dependence (aOR 1.02 per 1 mL increase; 95% CI, 1.01–1.04; P<0.01).
These findings suggest that for every additional 10 mL of edema that develops within the first day, a patient’s risk of a poor outcome increases by approximately 40% to 50%.
Differentiation from Primary Hematoma Volume
One of the most significant contributions of this IPD meta-analysis is the confirmation that PHE is not merely a passenger of the hematoma volume. By adjusting for the initial hematoma size and the presence of intraventricular hemorrhage (IVH), the researchers demonstrated that the biological process of edema formation contributes its own unique pathological weight to the clinical trajectory of the patient.
Expert Commentary
The clinical community has long sought a modifiable target for ICH treatment beyond blood pressure control and surgical evacuation (which has shown mixed results in trials like STICH II and MISTIE III). PHE represents an attractive pharmacological target because it is a dynamic, evolving process.
Mechanistic Insights: The independent association found in this meta-analysis reinforces the theory that PHE contributes to local tissue hypoxia, increased intracranial pressure, and metabolic failure in the “peri-infarct” tissue surrounding the clot. If we can inhibit the pathways leading to PHE—such as the sulfonylurea receptor 1 (SUR1)-regulated NCCa-ATP channel or the inflammatory interleukin-1 (IL-1) pathway—we may be able to preserve functional brain tissue.
Clinical Applicability: For the clinician, these findings emphasize the importance of serial imaging. A patient whose hematoma remains stable but whose PHE expands rapidly between 24 and 72 hours is at high risk for clinical deterioration and may require more aggressive osmotic therapy or intensive monitoring. However, the small effect size (2-4% per mL) suggests that therapies must be highly effective at limiting large volumes of edema to change the global mRS outcome.
Controversies and Limitations: While the association is clear, the “causality” remains complex. Is PHE the cause of the poor outcome, or is it a more sensitive biomarker of a more aggressive underlying neuroinflammatory state? Furthermore, this meta-analysis excluded patients who underwent surgery. In the era of minimally invasive surgery for ICH, understanding how clot evacuation affects PHE dynamics is the next logical step for research.
Conclusion
PHE growth is a definitive, independent driver of functional outcomes following intracerebral hemorrhage. The evidence from this individual participant data meta-analysis provides a high level of certainty that early edema expansion (within 24 to 72 hours) significantly increases the risk of death and long-term dependence. These findings establish PHE as a validated surrogate marker for secondary brain injury and a primary candidate for therapeutic targeting in future clinical trials. Ongoing research should focus on identifying the specific patient phenotypes most susceptible to rapid PHE growth and evaluating novel anti-inflammatory and anti-edema agents in this critical early window.
References
- Samarasekera N, Tuck S, Wang X, et al. Perihematomal Edema and Functional Outcome After Intracerebral Hemorrhage: A Meta-Analysis of Individual Participant Data. Stroke. 2026-03-04. PMID: 41778313.
- Hostettler IC, et al. Characteristics and Outcomes of Edema and Hematoma Volumes in Intracerebral Hemorrhage. Stroke. 2019. PMID: 31109245.
- Staykov D, et al. Natural course of perihemorrhagic edema after intracerebral hemorrhage. Stroke. 2011. PMID: 21737798.