Ascorbate-dependent Vasopressor Synthesis

A Rationale for Vitamin C Administration in Severe Sepsis and Septic Shock?

Anitra C. Carr; Geoffrey M. Shaw; Alpha A. Fowler; Ramesh Natarajan

Disclosures

Crit Care. 2015;19(418) 

In This Article

Abstract and Introduction

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.

Introduction

Sepsis is a potentially life-threatening systemic inflammatory response to infection which can result in multisystem organ dysfunction (severe sepsis) and refractory hypotension (septic shock).[1] Sepsis is a complex, heterogeneous condition that can be caused by any infectious organism, with Gram-positive infections often predominating.[2] A majority of septic patients have a pulmonary source of infection, such as pneumonia, which results in acute respiratory distress syndrome.[1] Dysfunction of cardiovascular, hepatic, renal and central nervous systems can also occur in severe sepsis.[3] The incidence of severe sepsis is increasing, due to an increasingly aging population,[4] and is currently the leading cause of death in critically ill patients, with mortality rates of 30–50 %.[5] The Surviving Sepsis Campaign has recommended a number of strategies for the management of severe sepsis and septic shock, including fluid resuscitation, infection control, and respiratory and central nervous system support[6] and, despite an increase in incidence, mortality rates appear to be declining.[7]

Septic shock is characterised by severe alterations in the cardiovascular system, including ineffective tissue oxygenation, inappropriate peripheral vasodilation, myocardial dysfunction and altered blood flow distribution, resulting in hypotension refractory to intravenous fluid administration.[1,8] Septic shock is typically managed through the administration of catecholamine vasopressors (dopamine, norepinephrine or epinephrine), with norepinephrine being the preferred vasoconstrictor.[9] Vasopressin is also recommended in the Surviving Sepsis Campaign guidelines to raise mean arterial pressure to target or to decrease the norepinephrine dose.[6] The Vasopressin and Septic Shock Trial (VASST) indicated that vasopressin provided equivalent mortality rates to norepinephrine in patients already receiving vasopressors.[10] Exogenous vasopressor administration to patients with severe sepsis and septic shock, however, can result in adverse side effects such as decreased cardiac output and cardiac arrest, mesenteric ischaemia, skin necrosis, digital ischaemia and hyponatraemia.[11]

Recent pre-clinical and clinical studies have indicated a potential role for ascorbate in ameliorating the pathophysiology of sepsis.[12–14] Numerous studies of septic animals administered high-dose ascorbate have shown improved microvascular changes and survival (reviewed in[14]). A number of mechanisms have been proposed for ascorbate's observed activities in sepsis, but these have primarily focused on its antioxidant and anti-inflammatory functions, including its effects on signal transduction pathways in vascular cells (reviewed in[13]). In contrast, very little attention has been paid to ascorbate's enzyme cofactor activities, particularly its role in the synthesis of vasopressors.[15] In this review we present the hypothesis that adjuvant ascorbate could support endogenous vasopressor synthesis in severe sepsis and septic shock through acting as an essential cofactor for the metallo-enzymes involved in the biosynthesis of vasoactive catecholamines and vasopressin.

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