Preoperative Stress Conditioning in Humans: Is Oxygen the Drug of Choice?

Complications following invasive medical and surgical procedures are common and costly. No clinical protocols exist to actively condition patients prior to these high risk interventions. Effective preconditioning algorithms have been repeatedly demonstrated in animal models for more than a quarter century, where brief exposures to hyperthermia (heat shock), ischemia (ischemic preconditioning) or hypoxia have been employed. Heat shock pretreatment confers protection against experimental acute ischemia-reperfusion, endotoxin challenge and other stressors. The resulting state of protection is short lived (hours) and is associated with new gene expression, typical of a cell stress response (CSR). We aim to use the CSR to actively precondition patients before surgery, a process termed stress conditioning (SC). SC is a procedure in which tissues are briefly exposed to a conditioning stressor and recovered to permit the development of a transient state of resistance to ischemia-reperfusion injury. Successful SC of humans prior to surgery may reduce postoperative complications related to periods of hypotension, hypoxia, or ischemia. Stressors such as heat shock, acute ischemia, endotoxin, heavy metals or hypoxia can induce this protected state but are themselves harmful and of limited clinical utility. The identification of a stressor that could induce the CSR in a non-harmful manner seemed unlikely, until high dose oxygen was considered. Human microvascular endothelial cells (HMEC-1) exposed to high dose oxygen at 2.4 ATA × 60-90 min developed increased resistance to an oxidant challenge in vitro (peroxide). The molecular changes described here, together with our understanding of the CSR and SC phenomena, suggest high dose oxygen may be the drug of choice for clinical preconditioning protocols and should be systematically tested in clinical trials. Oxygen dosing includes the following ranges: room air exposure is 0.21 ATA, clinical oxygen therapy 0.3-1.0 ATA (normobaric hyperoxia) and hyperbaric oxygen is 1.5-3.0 ATA (ATA-atmosphere absolute).