Design of a prospective, dose-escalation study evaluating the Safety of Pioglitazone for Hematoma Resolution in Intracerebral Hemorrhage (SHRINC).

RATIONALE : Preclinical work demonstrates that the transcription factor peroxisome proliferator-activated receptor gamma plays an important role in augmenting phagocytosis while modulating oxidative stress and inflammation. We propose that targeted stimulation of phagocytosis to promote efficient removal of the hematoma without harming surrounding brain cells may be a therapeutic option for intracerebral hemorrhage. AIMS : The primary objective is to assess the safety of the peroxisome proliferator-activated receptor gamma agonist, pioglitazone, in increasing doses for three-days followed by a maintenance dose, when administered to patients with spontaneous intracerebral hemorrhage within 24 h of symptom onset compared with standard care. We will determine the maximum tolerated dose of pioglitazone. STUDY DESIGN : This is a prospective, randomized, blinded, placebo-controlled, dose-escalation safety trial in which patients with spontaneous intracerebral hemorrhage are randomly allocated to placebo or treatment. The Continual Reassessment Method for dose finding is used to determine the maximum tolerated dose of pioglitazone. Hematoma and edema resolution is evaluated with serial magnetic resonance imaging (MRI) at specified time points. Functional outcome will be evaluated at three- and six-months. OUTCOMES : The primary safety outcome is mortality at discharge. Secondary safety outcomes include mortality at three-months and six-months, symptomatic cerebral edema, clinically significant congestive heart failure, edema, hypoglycemia, anemia, and hepatotoxicity. Radiographic outcomes will explore the time frame for resolution of 25%, 50%, and 75% of the hematoma. Clinical outcomes are measured by the National Institutes of Health Stroke Scale (NIHSS), the Barthel Index, modified Rankin Scale, Stroke Impact Scale-16, and EuroQol at three- and six-months.

Nitric oxide facilitates delivery and mediates improved outcome of autologous bone marrow mononuclear cells in a rodent stroke model.

BACKGROUND: Bone marrow mononuclear cells (MNC) represent an investigational treatment for stroke. The objective of this study was to determine the relevance of vasoactive mediators, generated in response to MNC injection, as factors regulating cerebral perfusion (CP), the biodistribution of MNC, and outcome in stroke. METHODS: Long Evans rats underwent transient middle cerebral artery occlusion. MNC were extracted from the bone marrow at 22 hrs and injected via the internal carotid artery or the femoral vein 2 hours later. CP was measured with MRI or continuous laser Doppler flowmetry. Serum samples were collected to measure vasoactive mediators. Animals were treated with the Nitric Oxide (NO) inhibitor, L-NAME, to establish the relevance of NO-signaling to the effect of MNC. Lesion size, MNC biodistribution, and neurological deficits were assessed. RESULTS: CP transiently increased in the peri-infarct region within 30 min after injecting MNC compared to saline or fibroblast control. This CP increase corresponded temporarily to serum NO elevation and was abolished by L-NAME. Pre-treatment with L-NAME reduced brain penetration of MNC and prevented MNC from reducing infarct lesion size and neurological deficits. CONCLUSIONS: NO generation in response to MNC may represent a mechanism underlying how MNC enter the brain, reduce lesion size, and improve outcome in ischemic stroke.

Inflammatory response to intraventricular hemorrhage: time course, magnitude and effect of t-PA.

BACKGROUND: In 45% of cases of intracerebral hemorrhage (ICH) the hematoma extends into the ventricles (IVH). Intraventricular inflammation may be one mechanism by which IVH exerts deleterious effects. Tissue plasminogen activator instillation into the ventricles (IVT) has been studied for the treatment of IVH; however, its effect on IVH-induced inflammation is unknown. The purpose of this work was to describe the inflammatory response in the CSF following IVH and compare it in patients treated or not treated with IVT. METHODS: Consecutive patients diagnosed with IVH and treated with ventriculostomy were selected from our prospective stroke registry from November 2004 to July 2007. CSF protein, glucose, and WBC (corrected for RBC number) from samples collected up to 19 days after IVH were captured. Patients with evidence of CSF infection were excluded. RESULTS: 29 patients were identified: 18 in the IVT group and 11 in the non-IVT group. The two groups were comparable in terms of stroke severity and IVH volume. A brisk cellular inflammatory reaction developed around day 2, lasted 5 days and then subsided. IVT seemed to attenuate this response. There were no differences in clinical outcomes between groups. CONCLUSIONS: IVH induces intrathecal inflammatory response that peaks at day 5. IVT appears to modify this inflammation. Further work is needed to study the relationship between the intraventricular inflammatory response and patient outcome.

Increased blood-brain barrier permeability on perfusion CT might predict malignant middle cerebral artery infarction.

BACKGROUND AND PURPOSE: Perfusion CT has been used to assess the extent of blood-brain barrier breakdown. The purpose of this study was to determine the predictive value of blood-brain barrier permeability measured using perfusion CT for development of malignant middle cerebral artery infarction requiring hemicraniectomy (HC). METHODS: We retrospectively identified patients from our stroke registry who had middle cerebral artery infarction and were evaluated with admission perfusion CT. Blood-brain barrier permeability and cerebral blood volume maps were generated and infarct volumes calculated. Clinical and radiographic characteristics were compared between those who underwent HC versus those who did not undergo HC. RESULTS: One hundred twenty-two patients (12 HC, 110 no HC) were identified. Twelve patients who underwent HC had developed edema, midline shift, or infarct expansion. Infarct permeability area, infarct cerebral blood volume area, and infarct volumes were significantly different (P < 0.018, P < 0.0211, P < 0.0001, P < 0.0014) between HC and no HC groups. Age (P = 0.03) and admission National Institutes of Health Stroke Scale (P = 0.0029) were found to be independent predictors for HC. Using logistic regression modeling, there was an association between increased infarct permeability area and HC. The OR for HC based on a 5-, 10-, 15-, or 20-cm² increase in infarct permeability area were 1.179, 1.390, 1.638, or 1.932, respectively (95% CI, 1.035 to 1.343, 1.071 to 1.804, 1.108 to 2.423, 1.146 to 3.255, respectively). CONCLUSIONS: Increased infarct permeability area is associated with an increased likelihood for undergoing HC. Because early HC for malignant middle cerebral artery infarction has been associated with better outcomes, the infarct permeability area on admission perfusion CT might be a useful tool to predict malignant middle cerebral artery infarction and need for HC.

Single shot T1rho magnetic resonance imaging of metabolically generated water in vivo.

The use of Oxygen-17 MRI provides great promise for the clinically-useful quantification of metabolism. To bring techniques based on 17O closer to clinical application, we demonstrate imaging of metabolically generated H2 17O in pigs after 17O2 delivery with increased temporal resolution T1rho-weighted imaging and precision delivery of 17O2 gas. The kinetics of the appearance of H2 17O in pig brains are displayed with one to two minutes of 17O2 delivery, the shortest delivery times reported in the literature. It is also shown that H2 17O concentrations can be quantified with single shot T1rho imaging based on a balanced steady state free precession readout, and that with this strategy pausing to reduce T1 saturation increases sensitivity to H2 17O over acquisition in the steady state. Several additional considerations with this sequence, which can be generalized to any pre-encoding cluster, such as energy deposition are considered.