Hydrocortisone, Ascorbic Acid and Thiamine (HAT Therapy) for the Treatment of Sepsis. Focus on Ascorbic Acid

Abstract

Sepsis is a devastating disease that carries an enormous toll in terms of human suffering and lives lost. Over 100 novel pharmacologic agents that targeted specific molecules or pathways have failed to improve the outcome of sepsis. Preliminary data suggests that the combination of Hydrocortisone, Ascorbic Acid and Thiamine (HAT therapy) may reduce organ failure and mortality in patients with sepsis and septic shock. HAT therapy is based on the concept that a combination of readily available, safe and cheap agents, which target multiple components of the host's response to an infectious agent, will synergistically restore the dysregulated immune response and thereby prevent organ failure and death. This paper reviews the rationale for HAT therapy with a focus on vitamin C.

Keywords: ascorbic acid; hydrocortisone; sepsis; septic shock; thiamine; vitamin C.

Figure 1

Multiple and overlapping effects of hydrocortisone, vitamin C, and thiamine in the setting of bacterial sepsis. Vitamin C and thiamine scavenge free radicals from superoxide (O₂⁻) and inhibit activation of xanthine oxidase and NADPH oxidase. Vitamin C protects the mitochondria from oxidative stress caused by increased leakage of electrons from the dysfunctional electron transport chain and recovers tetrahydrobiopterin (BH4) from dihydrobiopterin (BH2), restoring endothelial nitric oxide synthase (eNOS) activity and increasing eNO bioavailability. Vitamin C inhibits inducible NOS (iNOS) activation, preventing profuse iNO production and peroxynitrite (ONOO⁻) generation. Vitamin C scavenges ONOO⁻, preventing loosening of the tight junctions of the endothelium. Vitamin C and hydrocortisone decrease the activation of nuclear factor κB (NF-κB), thereby decreasing the release of proinflammatory mediators. They restore endothelial tight junctions and increase adrenergic receptor function. Thiamine increases the activity of pyruvate dehydrogenase and alpha ketoglutarate dehydrogenase. These actions act in concert to restore cellular adenosine tri-phosphate (ATP) levels. ↑—increased levels/activity; ↓—decreased levels/activity. Figure adapted from Spoelstra-de Man et al. [19].

Figure 2

Treatment with Hydrocortisone, vitamin C and Thiamine attenuates both the pro- and anti-inflammatory response in patients with sepsis. HAT-hydrocortisone, ascorbic acid and thiamine; SIRS—Systemic Inflammatory Response Syndrome; CARS—Compensatory Anti-inflammatory Response Syndrome.