Table 1:

Summary of the challenges in PHE assessment and recommendations for future investigations of PHE

Challenges in PHE Assessments	Recommendations for Using PHE in Clinical Research
CT vs. MRI - PHE is easier to delineate on MRI compared to CT. However, MRI is not routinely performed during the hyperacute phase and is more expensive	ICH Size and Location - Further investigations are needed to elucidate the impact of ICH volume and location on PHE progression and its relationship to outcomes - Consider limiting enrollment into studies using PHE as a primary endpoint to moderate-sized ICHs since these patients are more likely to exhibit critical growth of PHE PHE Parameters - Absolute PHE may be a better predictor of outcome than rPHE, particularly in patients with small ICHs - The rate of PHE growth and EED are promising parameters and require further investigations Timing - Interventions aimed at targeting PHE should be initiated within hours of ICH onset and maintained for 3-7 days - Follow-up of PHE progression/resolution a few weeks after treatment is advised to capture the full effect on the intervention on the known natural history of PHE progression
Measurement of PHE Delineation: - Manual delineation is labor intensive and has variable reproducibility - Fully-automated delineation is limited by potential inaccuracies related to spatial normalization of the brain - A semi-automated threshold-based methods may address the limitations above Parameters: - There are no consistent or uniform parameters in use. Various parameters and definitions for PHE have been used in various studies. These include: absolute PHE, relative PHE, rate of PHE growth (volume/time or % change/time), EED, rate of change in EED (volume/time or % change/time) Timing: - The timing of PHE assessments has been inconsistent. PHE progresses fast during the first few days and reaches its peak by 2-3 weeks - Variable times have been reported in the literature varying from 24h to 72h or longer after ICH
Relationship between PHE and Outcome - Variability in timing of PHE and/or outcome assessments and parameters used makes it difficult to fully ascertain the relationship between PHE and long-term functional outcomes after ICH	Study Design - To accurately determine the impact of PHE on outcomes, future studies should:   - Be prospective   - Have pre-specified methods, parameters, and endpoints   - Have adequate sample size calculations and statistical power