Brain vulnerability and viability after ischaemia

NATURE REVIEWS | Neuroscience, 21.07.2021

Stefano G. Daniele1,2,3, Georg Trummer4, Konstantin A. Hossmann5, Zvonimir Vrselja1,2, Christoph Benk4, Kevin T. Gobeske6, Domagoj Damjanovic4, David Andrijevic 1,2, Jan- Steffen Pooth 4, David Dellal7, Friedhelm Beyersdorf 4 ✉ and Nenad Sestan1,2,8,9,10,11,12


The susceptibility of the brain to ischaemic injury dramatically limits its viability following interruptions in blood flow. However, data from studies of dissociated cells, tissue specimens, isolated organs and whole bodies have brought into question the temporal limits within which the brain is capable of tolerating prolonged circulatory arrest. This Review assesses cell type- specific mechanisms of global cerebral ischaemia, and examines the circumstances in which the brain exhibits heightened resilience to injury. We suggest strategies for expanding such discoveries to fuel translational research into novel cytoprotective therapies, and describe emerging technologies and experimental concepts. By doing so, we propose a new multimodal framework to investigate brain resuscitation following extended periods of circulatory arrest.

Owing to its high metabolic demand and limited energy reserves1, the brain is highly susceptible to ischaemic  injury. The most common clinical manifestation of cerebral ischaemia is stroke, which results from interruptions in focal blood flow, and affects approximately 800,000 people per year in the United States 2. A more extreme insult known as global cerebral ischaemia occurs when blood flow to the brain stops entirely, such as in the case of cardiac arrest (CA), affecting nearly 350,000 people per year in the United States2. The potential for positive outcomes with stroke treatments has steadily increased over the past decades, but brain resuscitation after CA remains a largely unsolved clinical problem.

To guide treatment options for global ischemia during CA, a three- phase, time- sensitive model was proposed in the early 2000s3. This model consists of electrical (0–4 min after CA), circulatory (4–10 min) and metabolic (more than 10 min) phases, which reflect the temporal progression of ischemic injury and resuscitation physiology. Most cases of out- of- hospital CA (OHCA) present in the metabolic phase, for which current treatment options are limited. Indeed, OHCA outcomes remain disappointingly poor, with  pproximately 10% of patients surviving to hospital discharge2. Furthermore, even if cardiac function is restored, more than half of surviving patients display persistent brain damage and reduced quality of life2,4. Therefore, the vulnerability of the brain to ischaemia is a major limiting factor for successful resuscitation with positive neurological outcomes. Much of our current understanding of cerebral ischaemic injury comes from the use of experimental…



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