The DIST-INFLAME is a sub-study of the DIST in 200 patients.

Background

ICH is the most devastating type of stroke, accounting for half (49%) of 6.5 million annual stroke deaths worldwide and more than half (58%) of disability adjusted life years lost to stroke. Treatment is currently limited to stroke unit care (NNT 18) and blood pressure lowering in the acute phase (NNT 28). In a recent systematic review and meta-analysis, we demonstrated that, despite neutral results in four high quality randomized clinical trials (RCTs) comparing various surgical approaches to medical management, surgery might be beneficial, in particular with minimally invasive approaches and when performed early after symptom onset. In the Dutch Intracerebral Hemorrhage Surgery Trial (DIST) we will assess whether early (within 8 hours of symptom onset) minimally invasive surgery in addition to medical management, improves functional outcome after supratentorial spontaneous ICH. Damage after ICH not only results from the physical disruption of the brain’s cellular architecture and mass effect compressing surrounding tissue. In response to the intraparenchymal blood, the immune system is activated to remove blood and damaged tissue but harms adjacent viable brain parenchyma, resulting in secondary brain injury (SBI). Within hours after ICH onset, activated microglia produce matrix metalloproteinases, degrading the blood brain barrier (BBB) and increasing permeability of the cerebral vasculature allowing an influx of circulating immune cells. In addition, the secondary injury results in perihematomal edema (PHE), which in turn increases the harmful mass effect. PHE rapidly progresses between day 1 and 3, peaking at day 7-10, and has been related to clinical outcome. The rate of iodinated contrast extravasation during CT perfusion (permeability-surface area product; CTP PS) has been suggested as marker of BBB permeability and is easy to perform in the acute setting, as there is ample experience with CTP acquisition and analysis in acute ischemic stroke. It is unclear whether early minimally invasive surgery can diminish SBI after ICH. Early identification of patients at risk of SBI may identify those who may benefit most from anti-inflammatory treatment after ICH.

Aim

1. To determine the effect of early minimally invasive surgery for spontaneous ICH on the inflammatory cascade after ICH, measured by blood and imaging biomarkers
2. To determine whether CTP PS on admission, is indicative of the severity of secondary brain injury after ICH.

Methods

DIST-INFLAME will be a sub-study of the DIST in 200 patients (100 randomized to surgery, 100 to medical management). CTP will be added to the standard CT/CTA at baseline, and a research non-contrast CT will be performed on day 6 (+/- 1) to measure extent and extension of perihematomal edema. Venous blood samples will be taken for immune profiling within 8 hours of symptom onset, and on days 3 and day 6 (+/- 1) post-onset.
Analyses will 1) determine whether patients treated with minimally invasive surgery develop less (perihematomal) edema on non-contrast CT at day 6 (+/- 1) than controls, and whether CTP PS (100mL/min) around the ICH at baseline modifies this effect; 2) compare immune profiles over time in venous blood between surgically treated patients and controls. Based on data from a previous non-randomized study (Mould et al. 2013, doi: 10.1161/STROKEAHA.111.000411), the sample size of 200 patients is sufficient, including the analysis of the modifying effect of CTP PS.

Expected results

1. Obtain information on whether or not minimally invasive surgery affects secondary brain injury. This information is instrumental to determine whether or not anti-inflammatory treatment could be an adjunct therapy to minimally invasive surgery after ICH or not.
2. Define whether CTP PS might be used as an early biomarker of SBI. Identification of an early marker of SBI allows investigation of differential effects of anti-inflammatory treatment in those with prominent and minimal SBI.