Differential pathophysiologic phenotypes of hypoxic ischemic brain injury: considerations for post-cardiac arrest trials
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Differential pathophysiologic phenotypes of hypoxic ischemic brain injury: considerations for post‑cardiac arrest trials Ryan L. Hoiland1,2, Chiara Robba3, David K. Menon4 and Mypinder S. Sekhon5* © 2020 Springer-Verlag GmbH Germany, part of Springer Nature
Dear Editor, Hypoxic ischemic brain injury (HIBI) following cardiac arrest is characterized by primary ischemic injury during circulatory arrest and secondary injury following return of spontaneous circulation (ROSC). Mechanisms accounting for secondary injury include altered calcium homeostasis, neuroinflammation and mitochondrial injury related to inadequate post-resuscitation cerebral blood flow (CBF) and delivery of oxygen (CDO2). Counter to guideline recommendations which advocate to maintain a mean arterial pressure (MAP) of 65–75 mmHg, research efforts are now directed towards investigating the efficacy of higher MAP targets [1] to optimize CDO2 post-ROSC. Jakkula et al. published the results of the COMACARE trial (n = 120) in Intensive Care Medicine [2] of low-normal MAP (65–75 mmHg) versus high MAP (80– 100 mmHg) [2]. No significant differences in the primary or secondary outcomes were detected [2]. Subsequently, Ameloot et al. published a randomized trial corroborating COMACARE wherein no differences of ischemic burden (quantified by magnetic resonance imaging) or clinical neurological outcomes were detected [3] in HIBI patients assigned to ‘low’ or ‘high’ MAP groups. Importantly, the efficacy of MAP augmentation is contingent upon normal oxygen diffusion from the cerebral microvasculature into parenchymal tissue and normal cellular oxygen utilization. While increasing MAP and CDO2 may supply more oxygen to the brain, this strategy only *Correspondence: [email protected] 5 Division of Critical Care Medicine, Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada Full author information is available at the end of the article
addresses one component of the oxygen cascade and does not address the inherent complexities of oxygen diffusion and utilization or the aforementioned pathophysiologic mechanisms underpinning secondary injury. Our research group recently demonstrated that despite invasive neuromonitoring guided goal-oriented management, HIBI patients experience a significant burden of brain hypoxia [4]. We also have shown that a unique ‘diffusion limited’ (DL) pathophysiologic phenotype in a sub-set of HIBI may explain such persistent brain hypoxia [5]. In this instance, despite optimizing convective C DO2, impairments in oxygen diffusion were evidenced by an inability to improve brain tissue oxygenation (PbtO2) [5]. Pathophysiologic mechanisms responsible for DL include mitochondrial dysfunction, blood brain barrier breakdown with resultant perivascular edema or irreversible cell loss. The other sub-set of HIBI patients exhibited intact oxygen diffusion, whereby increases in P btO2 were ‘perfusion dependent’ (PD) [5]. We have included patient examples demonstrating DL
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