Intracerebral hemorrhage is a major public-health problem worldwide [
25]. Larger ICHs are typically associated with high mortality and morbidity, leaving survivors with severe neurological disability. Many questions remain unanswered regarding the clinical management of ICH, although the medical and surgical clinical trials completed in the past 10 years have refined our understanding of the goals of ICH management [
25]. Recently published studies have demonstrated that minimally invasive procedures can successfully evacuate intracerebral hematomas and improve the outcome of patients [
2,
4,
5,
7‐
11]. Minimally invasive stereotactic puncture and thrombolysis therapy have emerged as a promising management strategy for ICH patients [
4,
6]. However, the pathophysiological time window for minimally invasive surgery remains to be elucidated. We are unable to determine this time window in humans. Large animal models of ICH might provide an important tool for physicians to observe the effect of minimally invasive surgery on the perihematomal changes. Previously published studies have demonstrated that the perihematomal pathophysiological changes are associated with a range of substances such as inflammatory mediators, thrombin, hemoglobin breakdown products, oxidative stress, complement, and matrix metalloproteinases [
19,
20,
26]. Matrix metalloproteinases (MMPs) have been implicated in BBB disruption and ICH pathogenesis [
27‐
30]. Several studies have demonstrated that MMP-9 plays an important role in BBB disruption after stroke [
27,
28,
31]. Therefore, administering MMP-9 antagonist to reduce its effect might be beneficial for protecting BBB from disruption [
19,
32]. However, MMP inhibition in spontaneous ICH has solely been made under experimental conditions, and the basic research has yet to yield significant advancements for clinical practice. So, reducing the production of perihematomal MMP-9 by surgical procedures for hematoma evacuation might be a better option. Standard open craniotomy for clearance of intracerebral hematoma often causes damage to the uninjured brain tissue overlying the hematoma. Minimally invasive surgery combines the benefits of surgical clot removal with limited tissue damage and shorter surgery duration [
33]. In the present study, we prepared a rabbit model of ICH to observe the impact of performing the minimally invasive procedure at different stages on perihematomal MMP-9 and its correlation with BBB permeability. The results showed that perihematomal MMP-9 significantly decreased after surgery within different time windows for the evacuation of intracerebral hematoma as compared with the MC group. The quantity of perihematomal MMP-9 was different among the MI subgroups. It was lowest in the 6 h group, and increased gradually as the time window prolonged, reaching the highest level in the 48 h group. The decrease of MMP-9 level in the 6 h and 12 h subgroups was more significant compared to that of the other subgroups, suggesting that the MI procedures for evacuating intracerebral hematoma in early stages could significantly reduce the perihematomal MMP-9 content. The Evans blue content also deceased at each time point as compared with the MC subgroups, suggesting that the permeability of BBB were decreased corresponding to the decreased MMP-9.
Regarding the neurological function, the MI group displayed a significant decreased neurological deficit score two weeks after ICH model preparation compared with the MC group. The 6–12 hour MI subgroup displayed a favorable outcome [
22,
34,
35], suggesting that the MI surgery performed in early stages after ICH could effectively improve the neurofunctional outcome.
Earlier therapeutic time window (0–6 h) would be helpful in reducing the perihematomal secondary brain damages and improving neurological functions. But in clinical practice, the 6–24 h window is usually the earliest surgical procedures can be performed. The interval between the onset of ICH and the ICH evacuation is prolonged by patient presentation to the hospital, diagnostic work-up, procedures for randomization, arrangements for stereotactic navigation, and so on. So we selected 6 h as one of the time points to observe the outcome of neurofunction and the perihematomal changes.
The effects of performing the minimally invasive surgery in super-early stage (0-6 h) on the outcome of treatment were not observed in the current study. This would be a limitation of the present study. A further experimental study would be required for observing the effect of performing the minimally invasive surgery in 3–6 h after ICH to evacuate the hematoma on the outcome of neurofunction, and the perihematomal pathophysiological changes.