Dataset Information

CSF inflammatory response after intraventricular hemorrhage.

ABSTRACT:

Objective

To investigate the temporal pattern and relevant associations of CSF inflammatory measures after intraventricular hemorrhage (IVH).

Methods

We analyzed prospectively collected CSF cell counts and protein and glucose levels from participants in the Clot Lysis Evaluation of Accelerated Resolution of IVH phase III (CLEAR III) trial. Corrected leukocyte count and cell index were calculated to adjust for CSF leukocytes attributable to circulating blood. Data were chronologically plotted. CSF inflammatory measures (daily, mean, median, maximum, and cases with highest quartile response) were correlated with initial IVH volume, IVH clearance rate, thrombolytic treatment, bacterial infection, and adjudicated clinical outcome at 30 and 180 days.

Results

A total of 11,376 data points of CSF results from 464 trial participants were analyzed. Measures of CSF inflammatory response evolved during the resolution of IVH. This was significantly more pronounced with initial IVH volume exceeding 20 mL. Intraventricular alteplase was associated with a significantly augmented inflammatory response compared to saline, even after correcting for initial IVH volume. There was an association but nonpredictive correlation of CSF inflammation measures with culture-positive CSF bacterial infection. None of the CSF inflammatory measures, including cases with upper quartile inflammatory response, was associated with a significant detrimental effect on 30 or 180 days functional outcome or mortality after multivariate adjustment for measures of disease severity.

Conclusions

Aseptic CSF inflammation after IVH is primarily dependent on the volume of initial bleed. Thrombolysis intensifies the inflammatory response, with no apparent detrimental effect on clinical outcome.

Clinicaltrialsgov identifier

NCT00784134.

SUBMITTER: Fam MD

PROVIDER: S-EPMC5634667 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundIntracerebral hemorrhage (ICH) results in a cascade of inflammatory cell activation with recruitment of peripheral leukocytes to the brain parenchyma and surrounding the hematoma. We hypothesized that in patients with ICH and intraventricular hemorrhage (IVH), a robust cerebrospinal fluid (CSF) inflammatory response occurs with leukocyte subtypes being affected by alteplase treatment and contributing to outcomes.MethodsSerum and CSF cell counts from patients in the phase 3 Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage (CLEAR III) trial were analyzed. CSF leukocytes were corrected for the presence of red blood cells. Trends in cell counts were plotted chronologically. Associations were evaluated between serum and CSF leukocyte subtypes and adjudicated functional outcome (modified Rankin Scale; mRS) at 30 and 180 days and bacterial infection according to treatment with intraventricular alteplase versus saline.ResultsA total of 279 and 292 patients had ≥3 differential cell counts from serum and CSF, respectively. CSF leukocyte subtypes evolved during IVH resolution with a significantly augmented inflammatory response for all subtypes in alteplase- compared to saline-treated patients. CSF leukocyte subtypes were not associated with detrimental effect on functional outcomes in the full cohort, but all were associated with poor 30-day outcome in saline-treated patients with IVH volume ≥20 mL. Higher serum lymphocytes were associated with good functional outcomes (mRS 0-3) in the entire cohort and saline-treated but not alteplase-treated group. Conversely, increased serum neutrophil-to-lymphocyte ratio (NLR) in the entire cohort and saline group was associated with worse functional outcomes. Higher median serum lymphocytes were associated with the absence of infection at 7 days.ConclusionsAseptic CSF inflammation after IVH involves all leukocyte subtypes. Serum lymphocytes may be associated with better outcomes by mitigating infection. Alteplase augments the inflammatory response without affecting outcomes.

Project description:Germinal matrix-intraventricular hemorrhage (GM-IVH) is the most frequent intracranial hemorrhage in the preterm infant (PT). Long-term GM-IVH-associated sequelae include cerebral palsy, sensory and motor impairment, learning disabilities, or neuropsychiatric disorders. The societal and health burden associated with GM-IVH is worsened by the fact that there is no successful treatment to limit or reduce brain damage and neurodevelopment disabilities. Caffeine (Caf) is a methylxanthine that binds to adenosine receptors, regularly used to treat the apnea of prematurity. While previous studies support the beneficial effects at the brain level of Caf in PT, there are no studies that specifically focus on the role of Caf in GM-IVH. Therefore, to further understand the role of Caf in GM-IVH, we have analyzed two doses of Caf (10 and 20 mg/kg) in a murine model of the disease. We have analyzed the short (P14) and long (P70) effects of the treatment on brain atrophy and neuron wellbeing, including density, curvature, and phospho-tau/total tau ratio. We have analyzed proliferation and neurogenesis, as well as microglia and hemorrhage burdens. We have also assessed the long-term effects of Caf treatment at cognitive level. To induce GM-IVH, we have administered intraventricular collagenase to P7 CD1 mice and have analyzed these animals in the short (P14) and long (P70) term. Caf showed a general neuroprotective effect in our model of GM-IVH of the PT. In our study, Caf administration diminishes brain atrophy and ventricle enlargement. Likewise, Caf limits neuronal damage, including neurite curvature and tau phosphorylation. It also contributes to maintaining neurogenesis in the subventricular zone, a neurogenic niche that is severely affected after GM-IVH. Furthermore, Caf ameliorates small vessel bleeding and inflammation in both the cortex and the subventricular zone. Observed mitigation of brain pathological features commonly associated with GM-IVH also results in a significant improvement of learning and memory abilities in the long term. Altogether, our data support the promising effects of Caf to reduce central nervous system complications associated with GM-IVH.

Project description:ImportanceIntraventricular thrombolysis reduces intraventricular hemorrhage (IVH) volume in patients with spontaneous intracerebral hemorrhage (ICH), but it is unclear if a similar association with parenchymal ICH volume exists.ObjectiveTo evaluate the association between intraventricular alteplase use and ICH volume as well as the association between a change in parenchymal ICH volume and long-term functional outcomes.Design, setting, and participantsThis cohort study was a post hoc exploratory analysis of data from the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage phase 3 randomized clinical trial with blinded outcome assessments. Between September 1, 2009, and January 31, 2015, patients with ICH and IVH were randomized to receive either intraventricular alteplase or normal saline via an external ventricular drain. Participants with primary IVH were excluded. Data analyses were performed between January 1 and June 30, 2021.ExposureRandomization to receive intraventricular alteplase.Main outcomes and measuresThe primary outcome was the change in parenchymal ICH volume between the hematoma stability and end-of-treatment computed tomography scans. Secondary outcomes were a modified Rankin Scale score higher than 3 and mortality, both of which were assessed at 6 months. The association between alteplase and change in parenchymal ICH volume was assessed using multiple linear regression, whereas the associations between change in parenchymal ICH volume and 6-month outcomes were assessed using multiple logistic regression. Prespecified subgroup analyses were performed for baseline IVH volume, admission ICH volume, and ICH location.ResultsA total of 454 patients (254 men [55.9%]; mean [SD] age, 59 [11] years) were included in the study. Of these patients, 230 (50.7%) were randomized to receive alteplase and 224 (49.3%) to receive normal saline. The alteplase group had a greater mean (SD) reduction in parenchymal ICH volume compared with the saline group (1.8 [0.2] mL vs 0.4 [0.1] mL; P < .001). In the primary analysis, alteplase use was associated with a change in the parenchymal ICH volume in the unadjusted analysis per 1-mL change (β, 1.37; 95% CI, 0.92-1.81; P < .001) and in multivariable linear regression analysis that was adjusted for demographic characteristics, stability ICH and IVH volumes, ICH location, and time to first dose of study drug per 1-mL change (β, 1.20; 95% CI, 0.79-1.62; P < .001). In the secondary analyses, no association was found between change in parenchymal ICH volume and poor outcome (odds ratio [OR], 0.97; 95% CI 0.87-1.10; P = .64) or mortality (OR, 0.97; 95% CI 0.99-1.08; P = .59). Similar results were observed in the subgroup analyses.Conclusions and relevanceThis study found that intraventricular alteplase use in patients with a large IVH was associated with a small reduction in parenchymal ICH volume, but this association did not translate into improved functional outcomes or mortality. Intraventricular thrombolysis should be examined in patients with moderate to large ICH with IVH, especially in a thalamic location.