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Oxygen therapy reduces secondary hemorrhage after thrombolysis in thromboembolic cerebral ischemia.

ABSTRACT: Hyperbaric oxygen (HBO) and normobaric hyperoxia (NBO) protect the brain parenchyma and the cerebral microcirculation against ischemia. We studied their effect on secondary hemorrhage after thrombolysis in two thromboembolic middle cerebral artery occlusion (MCAO) (tMCAO) models. Beginning 60 minutes after tMCAO with either thrombin-induced thromboemboli (TT) or calcium-induced thromboemboli (CT), spontaneously hypertensive rats (n=96) breathed either air, 100% O(2) (NBO), or 100% O(2) at 3 bar (HBO) for 1 hour. Immediately thereafter, recombinant tissue plasminogen activator (rt-PA, 9 mg/kg) was injected. Although significant reperfusion was observed after thrombolysis in TT-tMCAO, vascular occlusion persisted in CT-tMCAO. In TT-tMCAO, NBO and HBO significantly reduced diffusion-weighted imaging-magnetic resonance imaging (MRI) lesion volume and postischemic blood-brain barrier (BBB) permeability on postcontrast T1-weighted images. NBO and, significantly more potently, HBO reduced macroscopic hemorrhage on T2* MRI and on corresponding postmortem cryosections. Oxygen therapy lowered hemoglobin content and attenuated activation of matrix metalloproteinases in the ischemic hemisphere. In contrast, NBO and HBO failed to reduce infarct size in CT but both decreased BBB damage and microscopic hemorrhagic transformation. Only HBO reduced hemoglobin extravasation in the ischemic hemisphere. In conclusion, NBO and HBO decrease infarct size after thromboembolic ischemia only if recanalization is successful. As NBO and HBO also reduce postthrombolytic intracerebral hemorrhage, combining the two with thrombolysis seems promising.

SUBMITTER: Sun L

PROVIDER: S-EPMC2949252 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Oxygen therapy reduces secondary hemorrhage after thrombolysis in thromboembolic cerebral ischemia.

Sun Li L Zhou Wei W Mueller Christian C Sommer Clemens C Heiland Sabine S Bauer Alexander T AT Marti Hugo H HH Veltkamp Roland R

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20100428 9

Hyperbaric oxygen (HBO) and normobaric hyperoxia (NBO) protect the brain parenchyma and the cerebral microcirculation against ischemia. We studied their effect on secondary hemorrhage after thrombolysis in two thromboembolic middle cerebral artery occlusion (MCAO) (tMCAO) models. Beginning 60 minutes after tMCAO with either thrombin-induced thromboemboli (TT) or calcium-induced thromboemboli (CT), spontaneously hypertensive rats (n=96) breathed either air, 100% O(2) (NBO), or 100% O(2) at 3 bar ...[more]

PMID: 20424638

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Project description:BackgroundExacerbated blood-brain barrier (BBB) damage is related with tissue plasminogen activator (tPA)-induced brain hemorrhage after stroke. Platelets have long been recognized as the cellular orchestrators of primary haemostasis. Recent studies have demonstrated further that platelets are required for supporting intact mature blood vessels and play a crucial role in maintaining vascular integrity during inflammation. Therefore, we sought to investigate whether platelets could reduce tPA-induced deterioration of cerebrovascular integrity and lead to less hemorrhagic transformation.MethodsMice were subjected to models of collagenase-induced intracerebral hemorrhage (ICH) and transient middle cerebral artery (MCA) occlusion. After 2 h of MCA occlusion, tPA (10 mg/kg) was administered as an intravenous bolus injection of 1 mg/kg followed by a 9 mg/kg infusion for 30 min. Immediately after tPA treatment, mice were transfused with platelets. Hemorrhagic volume, infarct size, neurological deficit, tight junction and basal membrane damages, endothelial cell apoptosis, and extravascular accumulation of circulating dextran and IgG, and Evans blue were quantified at 24 h.ResultsPlatelet transfusion resulted in a significant decrease in hematoma volume after ICH. In mice after ischemia, tPA administration increased brain hemorrhage transformation and this was reversed by resting but not activated platelets. Consistent with this, we observed that tPA-induced brain hemorrhage was dramatically exacerbated in thrombocytopenic mice. Transfusion of resting platelets ameliorated tPA-induced loss of cerebrovascular integrity and reduced extravascular accumulation of circulating serum proteins and Evans blue, associated with improved neurological functions after ischemia. No changes were found for infarct volume. Inhibition of platelet receptor glycoprotein VI (GPVI) blunted the ability of platelets to attenuate tPA-induced BBB disruption and hemorrhage after ischemia.ConclusionOur findings demonstrate the importance of platelets in safeguarding BBB integrity and suggest that transfusion of resting platelets may be useful to improve the safety of tPA thrombolysis in ischemic stroke.

Project description:OBJECTIVES:Impaired oxygen delivery due to reduced cerebral blood flow is the hallmark of delayed cerebral ischemia following subarachnoid hemorrhage. Since anemia reduces arterial oxygen content, it further threatens oxygen delivery increasing the risk of cerebral infarction. Thus, subarachnoid hemorrhage may constitute an important exception to current restrictive transfusion practices, wherein raising hemoglobin could reduce the risk of ischemia in a critically hypoperfused organ. In this physiologic proof-of-principle study, we determined whether transfusion could augment cerebral oxygen delivery, particularly in vulnerable brain regions, across a broad range of hemoglobin values. DESIGN:Prospective study measuring cerebral blood flow and oxygen extraction fraction using O-PET. Vulnerable brain regions were defined as those with baseline oxygen delivery less than 4.5?mL/100?g/min. SETTING:PET facility located within the Neurology/Neurosurgery ICU. PATIENTS:Fifty-two patients at risk for delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage with hemoglobin 7-13?g/dL. INTERVENTIONS:Transfusion of one unit of RBCs over 1 hour. MEASUREMENTS AND MAIN RESULTS:Baseline hemoglobin was 9.7?g/dL (range, 6.9-12.9), and cerebral blood flow was 43?±?11?mL/100?g/min. After transfusion, hemoglobin rose from 9.6?±?1.4 to 10.8?±?1.4?g/dL (12%; p < 0.001) and oxygen delivery from 5.0 (interquartile range, 4.4-6.6) to 5.5?mL/100?g/min (interquartile range, 4.8-7.0) (10%; p = 0.001); the response was comparable across the range of hemoglobin values. In vulnerable brain regions, transfusion resulted in a greater (16%) rise in oxygen delivery associated with reduction in oxygen extraction fraction, independent of Hgb level (p = 0.002 vs normal regions). CONCLUSIONS:This study demonstrates that RBC transfusion improves cerebral oxygen delivery globally and particularly to vulnerable regions in subarachnoid hemorrhage patients at risk for delayed cerebral ischemia across a wide range of hemoglobin values and suggests that restrictive transfusion practices may not be appropriate in this population. Large prospective trials are necessary to determine if these physiologic benefits translate into clinical improvement and outweigh the risk of transfusion.

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Oxygen therapy reduces secondary hemorrhage after thrombolysis in thromboembolic cerebral ischemia.

Publications

Oxygen therapy reduces secondary hemorrhage after thrombolysis in thromboembolic cerebral ischemia.

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