Less than 50% of cardiac arrest (CA) survivors exhibit good neurologic outcome, emphasizing the need for new neuroprotective strategies in addition to meticulous management of temperature. Our research performed with a canine model of CA and resuscitation (ROSC) demonstrated neuroprotection with oximetry-guided normoxic resuscitation compared to the previously standard practice of hyperoxic resuscitation. These results contributed to a major change in AHA/ACLS guidelines for CA/ROSC; i.e., minimize ventilatory O2, maintaining hemoglobin oxygen saturation >94%. While these procedures can be safely used in-hospital for CA/ROSC, the risk of hypoxia associated with rapidly lowering inspired O2 makes this paradigm dangerous in pre-hospital resuscitation. In light of these limitations, our primary aim is to determine the level of O2 inspired during the firt 2 hr of critical care in a hospital setting that optimizes neurologic outcome following pre-hospita resuscitation. We hypothesize that in contrast to the benefit of normoxia during early resuscitation, maintenance of moderate hyperoxemia at the period following the initial reperfusion-induced free radical surge, and prior to the onset of inflammation, will improve clinical outcome. Our related, albeit independent secondary aim is to test the hypothesis that inflammation, oxidative stress, and brain mitochondrial dysfunction contribute substantially to post-ischemic brain injury. Comparisons will be made of neurologic, histologic and biochemical outcomes following normoxic, mildly hyperoxic, and severely hyperoxic ventilation and in the absence or presence of sulforaphane-induced expression of cytoprotective genes whose products protect against these injury mechanisms. Methods of approach include use of our highly clinically relevant canine model of CA/ROSC for short-term outcomes, and a rat CA and resuscitation model for long-term outcomes. Additional comparisons between males and females will enhance potential for clinical translation and detect any sexually dimorphic mechanisms of brain injury and responses to different O2 levels or sulforaphane treatment. Translational outcome measures include advanced histopathology and neurobehavioral tests. Mechanistic outcomes include measurements of mitochondrial bioenergetics, cerebral metabolism of 13C-labeled glucose, proton NMR of energy metabolite levels, inflammatory microglial activation, and markers of oxidative stress. Relevance: Results from our studies will provide fresh new insight into the levels of inspired O2 used in a hospital setting that result in best neurologic outcome after out-of-hospital CA/ROSC. These experiments will also determine if treatment with sulforaphane after resuscitation further improves neurologic function, based on stimulated expression of cytoprotective gene products that inhibit oxidative stress, inflammation, and mitochondrial dysfunction. Either approach toward neuroprotection could be safely translated to clinical trials, eventually improving the quality of life experienced by the hundreds of thousands who survive CA each year.

Public Health Relevance

The proposed research will provide insight into the level of oxygen that should be used during in- hospital critical care after out-of-hospital cardiac arrest. Our plan also represents a unique attempt to identify molecular mechanisms of brain injury following cardiac arrest that are resistant to inhibition by optimal critical care. We will also determine if a safe, naturally occurring compound can mitigate these injury mechanisms and improve neurologic outcome. Translation of the knowledge generated by this project to clinical studies could increase the quality of life for the hundreds of thousands who survive cardiac arrest each year.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS091099-02
Application #
9146416
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Koenig, James I
Project Start
2015-09-30
Project End
2020-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Jaber, Sausan M; Bordt, Evan A; Bhatt, Niraj M et al. (2018) Sex differences in the mitochondrial bioenergetics of astrocytes but not microglia at a physiologically relevant brain oxygen tension. Neurochem Int 117:82-90
Andreyev, Alexander; Tamrakar, Pratistha; Rosenthal, Robert E et al. (2018) Calcium uptake and cytochrome c release from normal and ischemic brain mitochondria. Neurochem Int 117:15-22