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Neuroprotection and the Ischemic Cascade
- Robert A. Felberg, W. Scott Burgin, James C. Grotta
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- Journal:
- CNS Spectrums / Volume 5 / Issue 3 / March 2000
- Published online by Cambridge University Press:
- 07 November 2014, pp. 52-58
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Brain ischemia is a process of delayed neuronal cell death, not an instantaneous event. The concept of neuroprotection is based on this principle. Diminished cerebral blood flow initiates a series of events (the “ischemic cascade”) that lead to cell destruction. This ischemic cascade is akin to a spreading epidemic starting from a hypothesized core of ischemia and radiating outward. If intervention occurs early, the process may be halted.
Interventions have been directed toward salvaging the ischemic penumbra. Hypothermia decreases the size of the ischemic insult in both anecdotal clinical and laboratory reports. In addition, a wide variety of agents have been shown to reduce infant volume in animal models. Pharmacologic interventions that involve thrombolysis, calcium channel blockade, and cell membrane receptor antagonism have been studied and have been found to be beneficial in animal cortical stroke models. Human trials of neuroprotective therapies have been disappointing. Other than thrombolytics, no agents, have shown an unequivocal benefit. The future of neuroprotection will require a logical extension of what has been learned in the laboratory and previous human trials. A sensible approach to the use of multiple-agent cocktails used in combination with thrombolytics is likely to offer the highest chance for benefit.
The Argatroban and tPA Stroke Study
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- By Andrew D. Barreto, Department of Neurology, Stroke Division, The University of Houston-Texas, Houston, TX, USA, James C. Grotta, Department of Neurology, Stroke Division, The University of Houston-Texas, Houston, TX, USA
- Edited by Jeffrey L. Cummings
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- Book:
- Progress in Neurotherapeutics and Neuropsychopharmacology
- Published online:
- 13 May 2010
- Print publication:
- 06 March 2008, pp 35-48
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Summary
ABSTRACT
Background: The benefit of intravenous recombinant tissue plasminogen activator (rtPA) in acute ischemic stroke is related to clot lysis and arterial recanalization. Argatroban is a direct thrombin inhibitor that safely augments the benefit of rtPA in animal stroke models. However, human data on this combination are limited. Design: We report an update of the Argatroban tPA Stroke Study, an ongoing prospective, open-label, dose escalation, safety, and activity study of argatroban and rtPA in patients with ischemic stroke. The primary outcome was incidence of intracerebral hemorrhage; secondary outcome, complete recanalization at 2h. After standard dose intravenous rtPA administration, a 100-μg/kg bolus of argatroban followed by infusion of 1 μg/kg per min for 48 h was adjusted to a target partial thromboplastin time of 1.75 times baseline. Results: Twenty patients with middle cerebral artery occlusions (including 13 men) have been enrolled, with a mean ± SD age of 61 ± 13 years. Baseline median National Institute of Health Stroke Scale score was 12.5 (range, 3–25). The mean ± SD time from symptom onset to argatroban bolus administration was 177 ± 56 min. Symptomatic intracerebral hemorrhage occurred in 2 patients, including 1 with parenchymal hemorrhage type 2. Asymptomatic bleeding occurred in 2 patients and there was 1 death. Recanalization was complete in 7 patients and partial in another 7, and reocclusion occurred in 4 within 2h of rtPA bolus administration.
The Argatroban and tPA Stroke Study
- Andrew D. Barreto, James C. Grotta
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- Journal:
- Progress in Neurotherapeutics and Neuropsychopharmacology / Volume 3 / Issue 1 / January 2008
- Published online by Cambridge University Press:
- 27 November 2007, pp. 35-47
- Print publication:
- January 2008
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ABSTRACT
Background: The benefit of intravenous recombinant tissue plasminogen activator (rtPA) in acute ischemic stroke is related to clot lysis and arterial recanalization. Argatroban is a direct thrombin inhibitor that safely augments the benefit of rtPA in animal stroke models. However, human data on this combination are limited. Design: We report an update of the Argatroban tPA Stroke Study, an ongoing prospective, open-label, dose escalation, safety, and activity study of argatroban and rtPA in patients with ischemic stroke. The primary outcome was incidence of intracerebral hemorrhage; secondary outcome, complete recanalization at 2 h. After standard dose intravenous rtPA administration, a 100-μg/kg bolus of argatroban followed by infusion of 1 μg/kg per min for 48 h was adjusted to a target partial thromboplastin time of 1.75 times baseline. Results: Twenty patients with middle cerebral artery occlusions (including 13 men) have been enrolled, with a mean ± SD age of 61 ± 13 years. Baseline median National Institute of Health Stroke Scale score was 12.5 (range, 3–25). The mean ± SD time from symptom onset to argatroban bolus administration was 177 ± 56 min. Symptomatic intracerebral hemorrhage occurred in 2 patients, including 1 with parenchymal hemorrhage type 2. Asymptomatic bleeding occurred in 2 patients and there was 1 death. Recanalization was complete in 7 patients and partial in another 7, and reocclusion occurred in 4 within 2 h of rtPA bolus administration. Conclusion: The combination of low-dose argatroban and intravenous rtPA may be safe, and produce faster and more complete recanalization, but a larger cohort of patients is required to confirm this pilot study.
81 - The treatment of acute ischemic stroke
- from PART X - CEREBROVASCULAR DISORDERS
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- By Robert A. Felberg, Department of Neurology, University of Texas – Houston Medical Center, Houston, TX, USA, James C. Grotta, Department of Neurology, University of Texas – Houston Medical Center, Houston, TX, USA
- Edited by Arthur K. Asbury, University of Pennsylvania School of Medicine, Guy M. McKhann, The Johns Hopkins University School of Medicine, W. Ian McDonald, University College London, Peter J. Goadsby, University College London, Justin C. McArthur, The Johns Hopkins University School of Medicine
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- Book:
- Diseases of the Nervous System
- Published online:
- 05 August 2016
- Print publication:
- 11 November 2002, pp 1361-1370
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Summary
Historically, the treatment of stroke has been viewed with nihilism. With the approval of intravenous tissue plasminogen activator (i.v.-rTPA) (Nat. Inst. Neurol. Disorders, 1995), the past attitudes of helplessness in the face of stroke are changing. Despite the efficacy of thrombolytic therapy, less than 3% of all ischemic stroke patients are actually treated with i.v.-rTPA. The major reason for this lack of treatment appears to be the short time window. Both human and animal studies suggest that the time window for therapy will remain at approximately 3–6 hours even with the development of successful neuroprotection (Fig. 81.1). For this reason, time is a critically important factor in the treatment of acute stroke.
The approach to acute stroke can be separated into five overlapping concepts. The first and, thus far, most successful is restoring flow through the occluded vessel. The second is altering the ischemic cascade. Third is maximizing collateral flow. Fourth is the prevention of complications and the final concept is the use of a multidisciplinary team and designated Stroke Units to maximize patient care. Recovery and its augmentation is a sixth concept that is beyond the scope of this chapter.
Restoration of flow
The normal perfusion to brain grey matter is 60–70 ml for every 100 grams of brain tissue every minute. When perfusion decreases to less than 25 ml/100 mg/min, the neuron is no longer able to maintain aerobic respiration. If perfusion is not restored, the ischemic tissue will reach a point of no return where cell death is inevitable. This process is very time dependent, with irreversibility occurring after 5–6 hours. However, if flow is restored, then the brain tissue can potentially be spared and neurological function preserved (Figs. 81.2 and 81.3) (Jones et al., 1981). This concept has led to the use of pharmacological and mechanical attempts to disrupt the occluding thrombus. To date, this remains the most efficacious treatment of acute stroke and represents the only Food and Drug Administration approved therapy.
Intravenous thrombolysis
There have been multiple recent trials of intravenous thrombolytics in the setting of acute ischemic stroke. Streptokinase was examined in three major trials enrolling 1192 patients (MAST-I, 1995; Donnan et al., 1996; Multicenter Acute Stroke Trial, 1996).