# Resuscitating the Brain and Heart Following Cardiac Arrest: Targeting Oxygen Toxicity

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2024 · $796,322

## Abstract

ABSTRACT
Oxygen is administered to unconscious, mechanically ventilated patients following successful cardiopulmonary
resuscitation (CPR) from sudden cardiac arrest to ensure adequate oxygenation and to avoid potential worsening
tissue hypoxia. The liberal use of oxygen is near universal because it is regarded as benign and to be of potential
benefit. This dogma is being challenged by growing evidence that oxygen contributes to multi-organ injury and
decreased neurologically intact survival. Understanding the role of oxygen toxicity on post-CA outcomes
represents a major knowledge gap and barrier to improving outcomes. Antioxidants have not been found to be
beneficial and the patterns of injury and mechanism underlying its effects are poorly understood. This project
attempts to address these barriers by testing the effects of restricting oxygen availability through the
administration of hypoxia with a fractional inspired oxygen (FiO2) of 10% between the first- and 7-hours following
CA. We term this therapy oxygen restriction therapy (O2RT). Paradoxically, O2RT increased oxygen
consumption, lowered biomarkers of glycolysis, decreased cellular injury and improved physiological recovery
of the heart and brain resulting in improved survival. In contrast, hyperoxia (FiO2 30%) or room air (FiO2 21%)
had the opposite effects. Both hyperoxia and normoxia following CA stabilized the hypoxia inducible factor 1a
(HIF1a) while O2RT lowered HIF1a. This finding is relevant because HIF1a regulates changes glycolysis and
inflammation. Our findings of HIF1a stabilization suggest potential worsening of tissue hypoxia by hyperoxia or
alternatively aberrant HIF1a stabilization resulting in aerobic glycolysis and inflammation that occurs in
pathologies like cancer. Aim1 further investigates the effects of O2RT vs. hyperoxia on post-CA injury during a
critical 6-hour window of injury. Aim 2 tests the influence of O2RT and hyperoxia on changing patterns of
breathing, blood flow, and metabolism in the heart and brain and Aim 3 interrogates the role of HIF1a in the
brain and heart using cell specific knock out mice. Success of this research will establish the role of oxygen in
mediating post-CA secondary injury while identifying a critical window of injury that can be targeted for
therapeutic benefit and identifying HIF1a as a new therapeutic target for limiting oxygen toxicity.

## Key facts

- **NIH application ID:** 10883379
- **Project number:** 1R01HL169679-01A1
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Alfredo J Garcia
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $796,322
- **Award type:** 1
- **Project period:** 2024-04-02 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10883379

## Citation

> US National Institutes of Health, RePORTER application 10883379, Resuscitating the Brain and Heart Following Cardiac Arrest: Targeting Oxygen Toxicity (1R01HL169679-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10883379. Licensed CC0.

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