Ascorbate-dependent vasopressor synthesis: a rationale for vitamin C administration in severe sepsis and septic shock?

Abstract

Severe systemic inflammatory response to infection results in severe sepsis and septic shock, which are the leading causes of death in critically ill patients. Septic shock is characterised by refractory hypotension and is typically managed by fluid resuscitation and administration of catecholamine vasopressors such as norepinephrine. Vasopressin can also be administered to raise mean arterial pressure or decrease the norepinephrine dose. Endogenous norepinephrine and vasopressin are synthesised by the copper-containing enzymes dopamine β-hydroxylase and peptidylglycine α-amidating monooxygenase, respectively. Both of these enzymes require ascorbate as a cofactor for optimal activity. Patients with severe sepsis present with hypovitaminosis C, and pre-clinical and clinical studies have indicated that administration of high-dose ascorbate decreases the levels of pro-inflammatory biomarkers, attenuates organ dysfunction and improves haemodynamic parameters. It is conceivable that administration of ascorbate to septic patients with hypovitaminosis C could improve endogenous vasopressor synthesis and thus ameliorate the requirement for exogenously administered vasopressors. Ascorbate-dependent vasopressor synthesis represents a currently underexplored biochemical mechanism by which ascorbate could act as an adjuvant therapy for severe sepsis and septic shock.

Fig. 1

Effect of ascorbate administration on (a) systolic blood pressure and (b) mean arterial pressure in patients with severe sepsis. Patients were administered placebo (circle, 5 % dextrose and water, n = 6) or ascorbate (inverted triangle, 200 mg/kg/24 h, n = 7). The ascorbate dosage was divided into four equal doses and administered over 30 min every 6 h for 96 h in 50 ml of 5 % dextrose and water [12]. Systolic blood pressure and mean arterial pressure were measured at the bedside using an arterial line (radial artery)

Fig. 2

Ascorbate-dependent synthesis of the catecholamine vasopressors dopamine, norepinephrine and epinephrine. Ascorbate acts as a cofactor for the metallo-enzyme dopamine hydroxylase, and also recycles the enzyme cofactor tetrahydrobiopterin. AA ascorbic acid, DHA dehydroascorbic acid, BH ₄ tetrahydrobiopterin, BH ₂ dihydrobiopterin

Fig. 3

Ascorbate-dependent synthesis of mature carboxy-terminal amidated vasopressin. Ascorbate is a cofactor for the metallo-enzyme peptidylglycine α-amidating monooxygenase (PAM). AA ascorbic acid, DHA dehydroascorbic acid