Harvard Catalyst Profiles

The Shaefi Lab, housed within the Department of Anesthesia, Critical Care and Pain Medicine at Beth Israel Deaconess Medical Center, focuses on translational and clinical areas of research that investigate the most appropriate perioperative administration and titration of oxygen. The use of oxygen is ubiquitous in clinical practice representing the most widely prescribed drug in the modern in-hospital setting. It is estimated that 15% patient admitted to the hospital and 95% of patients entering an intensive care unit or undergoing surgery receive supplemental oxygen. Overall 50 million people or one sixth of the United States population receives oxygen in these settings every year. Traditionally, anesthesiologists, critical care physicians and other clinicians have almost universally administered oxygen at higher than required levels in order to avoid potentially injurious levels of hypoxemia in their patients. There is mounting evidence that this stance of liberal administration and relative lack of titration of oxygen may not be as benign as first thought. Further, the clinical weight of evidence persuasively supports the finding that high levels of administered oxygen (hyperoxia) without endpoint titration confer more risk than benefit. Compelling preclinical evidence exists for the protective and regenerative aspects of low levels of oxygen (hypoxia) in specific settings. Significant efforts in the Shaefi lab are geared towards an understanding of the mechanisms of this protective hypoxia, especially in the setting of inflammation and sepsis through the use of preclinical models. Further work examining the beneficial role of hypoxia with human subjects in the clinical sphere are ongoing within the Shaefi lab. Admittedly, the concept of titrating hypoxic admixtures in acutely ill patients is fought with challenges. It would be ideal to impart the protective effects of hypoxic cellular exposure while avoiding the unforgiving repercussions of administering hypoxic admissions. Therefore, much of the work within the lab focuses on interventions to up regulate protective hypoxic properties under normoxic conditions, termed pseudo-hypoxia. Both small and large animal preclinical models are focused on developing this very palatable option for treatment, feasibility, safety and efficacy before moving this into human clinical interventional trials. There are various cytoprotective mechanisms activated during cellular stress. Heme Oxygenase-1 is one such mechanism, and is highly upregulated in periods of tissue hypoxia and sepsis. This stress response gene, regulated in part by hypoxia inducible factor, can metabolize heme to its metabolites biliverdin, iron and carbon monoxide. Although some of the mechanisms are unclear, the anti-inflammatory, antimicrobial and overall salutary effects of carbon monoxide have been well characterized in preclinical models. The translational aspect of investigations in the Shaefi lab aim to further delineate aspects of the mechanisms underlying the benefit observed with the administration of low dose exogenous carbon monoxide. Once these effects have been more fully elucidated in preclinical models, stepwise clinical observational and interventional studies will be performed in healthy subjects, patients undergoing major cardiac and noncardiac surgery as well as our vulnerable critically ill patient population