Simon Nagel

Hyperbaric Oxygen Reduces Blood–Brain Barrier Damage and Edema After Transient Focal Cerebral Ischemia

Background and Purpose— Hyperbaric oxygen (HBO) has been shown to protect the brain parenchyma against transient focal cerebral ischemia, but its effects on the ischemic microcirculation are largely unknown. We examined the potential of HBO to reduce postischemic blood–brain barrier (BBB) damage and edema. Methods— Wistar rats and C57/BL6 mice underwent occlusion of the middle cerebral artery (MCAO) for 2 hours. Forty minutes after filament introduction, animals breathed either 100% O2 at 3.0 atmospheres absolute (ata; HBO group) or at 1.0 ata (control) for 1 hour in an HBO chamber. In rats, MRI was performed 15 minutes after MCAO and after 15 minutes and 3, 6, 24, and 72 hours of reperfusion. In mice, BBB permeability for sodium fluorescein was measured after 24-hour reperfusion. Results— Increased BBB permeability on postcontrast T1-weighted (T1w) images had a biphasic pattern. HBO reduced volumes and intensity of enhancement. Mean abnormal enhancing volumes were 71±10 mm3 (control) versus 47±10 mm3 (HBO) at 15 minutes; 111±21 mm3 versus 69±17 mm3 3 hours; 147±44 mm3 versus 83±21 mm3 6 hours; 150±37 mm3 versus 89±14 mm3 24 hours; and 322±52 mm3 versus 215±21 mm3 72 hours (all P<0.05). Interhemispheric quotients of mean gray values on T1w were at 1.73±0.11 versus 1.57±0.07 15 minutes; 1.74±0.07 versus 1.60±0.06 at 3 hours; 1.77±0.07 versus 1.62±0.06 at 6 hours; 1.79±0.10 versus 1.60±0.05 at 24 hours; and 1.81±0.10 versus 1.62±0.07 at 72 hours (all P<0.05). HBO-treated mice had significantly lower postischemic BBB permeability than mice treated with either normobaric hyperoxia or room air. Vasogenic edema assessed on T2w images and histologic sections was significantly lower in HBO-treated rats. Conclusions— Intraischemic HBO therapy reduces early and delayed postischemic BBB damage and edema after focal ischemia in rats and mice.

Effect of Conscious Sedation vs General Anesthesia on Early Neurological Improvement Among Patients With Ischemic Stroke Undergoing Endovascular Thrombectomy: A Randomized Clinical Trial

Importance Optimal management of sedation and airway during thrombectomy for acute ischemic stroke is controversial due to lack of evidence from randomized trials. Objective To assess whether conscious sedation is superior to general anesthesia for early neurological improvement among patients receiving stroke thrombectomy. Design, Setting, and Participants SIESTA (Sedation vs Intubation for Endovascular Stroke Treatment), a single-center, randomized, parallel-group, open-label treatment trial with blinded outcome evaluation conducted at Heidelberg University Hospital in Germany (April 2014-February 2016) included 150 patients with acute ischemic stroke in the anterior circulation, higher National Institutes of Health Stroke Scale (NIHSS) score (>10), and isolated/combined occlusion at any level of the internal carotid or middle cerebral artery. Intervention Patients were randomly assigned to an intubated general anesthesia group (n = 73) or a nonintubated conscious sedation group (n = 77) during stroke thrombectomy. Main Outcomes and Measures Primary outcome was early neurological improvement on the NIHSS after 24 hours (0-42 [none to most severe neurological deficits; a 4-point difference considered clinically relevant]). Secondary outcomes were functional outcome by modified Rankin Scale (mRS) after 3 months (0-6 [symptom free to dead]), mortality, and peri-interventional parameters of feasibility and safety. Results Among 150 patients (60 women [40%]; mean age, 71.5 years; median NIHSS score, 17), primary outcome was not significantly different between the general anesthesia group (mean NIHSS score, 16.8 at admission vs 13.6 after 24 hours; difference, -3.2 points [95% CI, -5.6 to -0.8]) vs the conscious sedation group (mean NIHSS score, 17.2 at admission vs 13.6 after 24 hour; difference, -3.6 points [95% CI, -5.5 to -1.7]); mean difference between groups, -0.4 (95% CI, -3.4 to 2.7; P = .82). Of 47 prespecified secondary outcomes analyzed, 41 showed no significant differences. In the general anesthesia vs the conscious sedation group, substantial patient movement was less frequent (0% vs 9.1%; difference, 9.1%; P = .008), but postinterventional complications were more frequent for hypothermia (32.9% vs 9.1%; P < .001), delayed extubation (49.3% vs 6.5%; P < .001), and pneumonia (13.7% vs 3.9%; P = .03). More patients were functionally independent (unadjusted mRS score, 0 to 2 after 3 months [37.0% in the general anesthesia group vs 18.2% in the conscious sedation group P = .01]). There were no differences in mortality at 3 months (24.7% in both groups). Conclusions and Relevance Among patients with acute ischemic stroke in the anterior circulation undergoing thrombectomy, conscious sedation vs general anesthesia did not result in greater improvement in neurological status at 24 hours. The study findings do not support an advantage for the use of conscious sedation. Trial Registration clinicaltrials.gov Identifier: NCT02126085.

Minocycline and hypothermia for reperfusion injury after focal cerebral ischemia in the rat—Effects on BBB breakdown and MMP expression in the acute and subacute phase

Reperfusion injury is a complication of recanalization therapies after focal cerebral ischemia. The disruption of the blood-brain barrier (BBB) caused by up-regulated metalloproteinases (MMPs) can lead to edema and hemorrhage. Middle cerebral artery occlusion (MCAO=90 min) and reperfusion (R=24 h vs. 5 days) was induced in male Wistar rats. Rats were randomized in four groups: (1) control (C), (2) twice daily minocycline (30 mg/kg bodyweight) every day (M), (3) hypothermia (33 degrees C) for 4 h starting 60 min after occlusion (H), (4) combination of groups 2 and 3 (MH). Serial MRI was performed regarding infarct evolution and BBB disruption, MMP-2 and MMP-9 were assessed by zymography of serum and ischemic brain tissue, and a functional neuroscore was done at 24 h and 5 days. M and H reduced both infarct sizes, volume and signal intensity of BBB breakdown and improved neuroscore at all points in time to the same extent. This was most likely due to inhibition of MMP-2 and MMP-9. The presence of MMP-9 at 24 h or MMP-2 at 5 days in brain tissue correlated with BBB breakdown whereas serum MMP-2- and -9 showed no relationship with BBB breakdown. The combination MH had a small but not significantly additional effect over the single treatments. Minocycline seems to be as neuroprotective as hypothermia in the acute and subacute phase after cerebral ischemia. One essential mechanism is the inhibition of MMPs. The combination therapy is only slightly superior. The net effect of MMPs inhibition up to 5 days after focal cerebral ischemia is still beneficial.

Therapy of Acute Basilar Artery Occlusion Intraarterial Thrombolysis Alone vs Bridging Therapy

Background and Purpose— While intravenous recombinant tissue plasminogen activator (rt-PA) has been approved for acute stroke therapy within 3 hours, the optimum management of basilar artery occlusion (BAO) is still a matter of debate. We compared intraarterial thrombolysis with the combined bridging approach of intravenous abciximab and intraarterial thrombolysis with rt-PA (bridging therapy) in an observational, longitudinal, monocenter study. Methods— Between 1998 and 2006, information for 106 patients with acute BAO were prospectively entered into a local database. Patients eligible for treatment received either intraarterial thrombolysis with rt-PA alone (intraarterial thrombolysis) or were treated with intravenous abciximab and intraarterial rt-PA (bridging therapy). Outcome parameters were recanalization of the basilar artery according to Trial in Myocardial Infarction criteria, survival, and reduction of severe disability and death at 3 months. Logistic regression was used to identify independent predictors for recanalization, survival, and clinical outcome. Results— Of a total of 106 patients with confirmed BAO, 87 patients underwent subsequent angiography. Among those, 75 patients were identified who received the full treatment protocol. Patients in the bridging group had a better recanalization rate (83.7% vs 62.5%; P=0.03), a higher survival rate (58.1% vs 25%; P=0.01), and a better chance for an outcome with no or only mild to moderate disability (modified Rankin Scale score, 0-3; 34.9% vs 12.5%; P=0.02). Symptomatic intracerebral hemorrhage rates were comparable in both groups (14% in the bridging group vs 18.8%; P=0.41). Independent predictors for recanalization were age (OR, 0.95; 95% CI, 0.91-0.99), atrial fibrillation (OR, 6.53; 95% CI, 1.14-37.49), and bridging therapy (OR, 3.37; 95% CI, 1.02 to 11.18). Independent prognostic factors for outcome were Glasgow coma scale score at presentation (OR, 1.24; 95% CI, 1.03-1.45) and the combination of bridging therapy with successful recanalization (OR, 3.744; 95% CI, 1.04-13.43). Conclusion— Bridging therapy for acute BAO with intravenous abciximab and intraarterial rt-PA appears to be safe and yields higher recanalization and improved survival rates, as well as an overall improved chance for a better outcome.

Therapeutic manipulation of the HIF hydroxylases.

The hypoxia-inducible factor (HIF) family of transcription factors is responsible for coordinating the cellular response to low oxygen levels in animals. By regulating the expression of a large array of target genes during hypoxia, these proteins also direct adaptive changes in the hematopoietic, cardiovascular, and respiratory systems. They also play roles in pathological processes, including tumorogenesis. In recent years, several oxygenases have been identified as key molecular oxygen sensors within the HIF system. The HIF hydroxylases regulate the stability and transcriptional activity of the HIF-alpha subunit by catalyzing hydroxylation of specific proline and asparaginyl residues, respectively. They require oxygen and 2-oxoglutarate (2OG) as co-substrates, and depend upon non-heme ferrous iron (Fe(II)) as a cofactor. This article summarizes current understanding of the biochemistry of the HIF hydroxylases, identifies targets for their pharmacological manipulation, and discusses their potential in the therapeutic manipulation of the HIF system.

Intracerebral Hemorrhage With Severe Ventricular Involvement Lumbar Drainage for Communicating Hydrocephalus

Background and Purpose— The objective was to analyze the feasibility of a lumbar drainage (LD) for a communicating malresorptive hydrocephalus in patients with supratentorial hemorrhage (intracerebral hemorrhage) accompanied by severe ventricular involvement (intraventricular hemorrhage) who required an external ventricular drain (EVD). Methods— In this retrospective study, 16 patients received an EVD and concurrent LD and were compared with 39 historical patients treated with EVD alone. The duration of required EVD and need for permanent ventriculoperitoneal-shunt were analyzed. Results— LD was inserted after 12 (4 to 18) days. In LD-treated patients, the LD was capable to replace repeated EVD exchanges, resulting in a shorter EVD-duration (12 versus 16 days) compared with patients treated with EVD alone. The overall duration of extracorporal cerebrospinal fluid drainage was longer (16 days EVD versus 21 days EVD+LD) and the frequency of ventriculoperitoneal-shunt lower (18.75% versus 33%; P<0.03) in LD-treated patients. Conclusion— Our data suggest that LD is safe and feasible for treatment of nonpersistent communicating hydrocephalus after intracerebral hemorrhage. After adequate treatment of the occlusive hydrocephalus using an EVD in the acute phase, LD discloses an alternative for further extracorporal cerebrospinal fluid drainage.

Topographically graded postischemic presence of metalloproteinases is inhibited by hypothermia.

To test the hypothesis that presence of metalloproteases (MMPs), their inhibitors (TIMPs) and their substrate laminin-5 differs between the ischemic core and the surrounding tissue, we examined the impact of middle cerebral artery occlusion/reperfusion (MCA:O/R) on these molecules in different regions of the infarct. We also investigated the influence of hypothermia on the progression of the ischemic lesion and MMP activity. Brain sections from 64 Wistar rats subjected to MCA:O/R were examined by means of cytohistochemistry and zymography. The artery was occluded for 2 h followed by 3, 5, 8 and 12 h of reperfusion. Well characterized antibodies against laminin-5, MMPs and TIMP-2 were used. A total of 32 rats were treated with hypothermia. The presence of each antigen was related to the following regions of interest: ischemic core with BBB breakdown (I(c)), surrounding ischemic tissue without BBB breakdown (I(r)), and the contralateral non-ischemic region (N). Regions of interest were defined by MRI. The I(c) increased over time at the cost of the I(r). BBB breakdown occurred early in the ischemic core and increased over time. Hypothermia reduced the BBB breakdown at all time points. A graded decreased presence of laminin-5 was observed with 16.5+/-3.7(N)>10+/-2.8(I(r))>4+/-1.4(I(c)) immunopositive microvessels/mm(2) at 3 h of reperfusion. MMP-9 showed a reverse pattern with 0 (N)<4+/-0.8(I(r))<10+/-1.5(I(c)) immunopositive microvessels/mm(2). Hypothermia decreased the MMP activity measured by zymography. Laminin-5 and MMP presence relate directly to the degree of postischemic injury. Hypothermia reduces the conversion from the I(r) to ischemic core and the degree of BBB as well as MMP abundance.

Molecular magnetic resonance imaging of acute vascular cell adhesion molecule-1 expression in a mouse model of cerebral ischemia

The pathogenesis of stroke is multifactorial, and inflammation is thought to have a critical function in lesion progression at early time points. Detection of inflammatory processes associated with cerebral ischemia would be greatly beneficial in both designing individual therapeutic strategies and monitoring outcome. We have recently developed a new approach to imaging components of the inflammatory response, namely endovascular adhesion molecule expression on the brain endothelium. In this study, we show specific imaging of vascular cell adhesion molecule (VCAM)-1 expression in a mouse model of middle cerebral artery occlusion (MCAO), and a reduction in this inflammatory response, associated with improved behavioral outcome, as a result of preconditioning. The spatial extent of VCAM-1 expression is considerably greater than the detectable lesion using diffusion-weighted imaging (25% versus 3% total brain volume), which is generally taken to reflect the core of the lesion at early time points. Thus, VCAM-1 imaging seems to reveal both core and penumbral regions, and our data implicate VCAM-1 upregulation and associated inflammatory processes in the progression of penumbral tissue to infarction. Our findings indicate that such molecular magnetic resonance imaging (MRI) approaches could be important clinical tools for patient evaluation, acute monitoring of therapy, and design of specific treatment strategies.

Mechanical thrombectomy with stent retrievers in acute basilar artery occlusion.

BACKGROUND AND PURPOSE: Basilar artery occlusion remains one of the most devastating subtypes of ischemic stroke. The prognosis is poor if early recanalization is not achieved. The purpose of this study was to evaluate the safety and technical feasibility of self-expanding retrievable stents in the endovascular treatment of acute basilar artery occlusion. MATERIALS AND METHODS: Twenty-four patients with acute basilar artery occlusion were treated with Solitaire FR or Revive SE devices between December 2009 and May 2012. Additional treatment included intravenous and/or intra-arterial thrombolysis (21/24) and percutaneous transluminal angioplasty/permanent stent placement (7/24). Recanalization was assessed by means of the TICI score. Clinical outcome was determined at discharge (NIHSS), and at 3 months (mRS). RESULTS: Median NIHSS score on admission was 24; median duration of symptoms was 254 minutes. Successful recanalization (TICI 2b +3) by thrombectomy only was achieved in 18 patients (75%). Intracranial stent deployment after thrombectomy caused by underlying atherosclerotic stenosis was performed in 7 patients. If these patients with intracranial stent placement are included, successful recanalization was achieved in 21 of 24 patients (87.5%). NIHSS improvement ≥10 points was reached in 54% of patients (n = 13/24). Mortality during the first 3 months was 29% (7/24). After 3 months, 8 patients (33%) had a favorable clinical outcome (mRS 0–2). CONCLUSIONS: In our series, application of self-expanding retrievable stents in acute basilar artery occlusion resulted in a high recanalization rate without procedural complications and good clinical outcome in one-third of patients.

MMP-2 and MMP-9 levels in peripheral blood after subarachnoid hemorrhage.

MMPs play an important role in ischemic and hemorrhagic stroke. We analyzed replicate serum samples from 20 normal healthy individuals to assess reproducibility of MMP determinations, and found that MMP-2 and MMP-9 determinations were quite consistent. We then studied the serum levels of MMP-2 and MMP-9 in patients suffering from subarachnoid hemorrhage (SAH), another stroke subtype. Serum MMP-2 and MMP-9 levels from SAH patients were measured sequentially using gelatine zymography in 11 patients after acute SAH. The occurrence of intracerebral aneurysms and vasospasms and the initial Hunt and Hess score were analysed in relation to MMP-levels. MMP-2 levels are significantly decreased while MMP-9 levels are increased in SAH patients relative to controls. MMP-2 levels remain depressed out to day 12 post SAH, but MMP-9 levels may recover by day 12.