Toriyama et al. studied the effect of CO₂ bathing in 83 limbs with critical ischemia and achieved limb salvage in 83% without surgery. They concluded that peripheral vasodilation from CO₂ bathing resulted from an increased parasympathetic and decreased sympathetic activity. Application of transdermal CO₂ produces a remote vasodilation that may be mediated through release of a circulating humoral agent. 

Recently, studies have documented that episodes of brief, non-damaging ischemia occurring in a tissue can induce systemic protection against ischemia-reperfusion injury in a remote organ. This phenomenon, termed remote ischemic conditioning, has been demonstrated to confer protection against ischemic events in the myocardium, brain, and kidney. Although shown to be effective in various clinical and preclinical models, the mechanism(s) of remote protection have not been clearly identified. Both neural and humoral mechanisms have been proposed to contribute to the protection against ischemic damage afforded by remote ischemic conditioning. Basalay et al. have shown that when remote ischemic conditioning is applied before induction of myocardial ischemia, sensory nerves and recruitment of a parasympathetic neural pathway are involved in reduction of infarct size.

Recently, Michelsen and colleagues have demonstrated that dialysate of human plasma from subjects who underwent either ischemic preconditioning or exercise preconditioning reduced infarct size in rabbit hearts, indicating that release of a humoral factor, contributes to the cardioprotective effects of ischemic and exercise preconditioning; however, these circulating substance(s) remain to be identified.

Future investigations will need to monitor heart rate, heart rate variability, and sympathetic nerve activity in order to more fully assess the role of the autonomic nervous system in mediating the sustained increases in SPP and systolic blood pressure reported in this initial study and focus on assessment of plasma samples during and following skin delivery CO₂ application. The D’OXYVA device is safe and can be administered at home.