title: 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.
authors.affiliation: Department of Pathology, University of Otago, Christchurch, PO Box 4345, Christchurch, 8140, New Zealand. anitra.carr@otago.ac.nz.
authors.forename: Anitra C
authors.initials: AC
authors.lastname: Carr
authors.affiliation: Department of Intensive Care Medicine, Christchurch Hospital, Private Bag 4710, Christchurch, 8011, New Zealand. geoff.shaw@cdhb.health.nz.
authors.forename: Geoffrey M
authors.initials: GM
authors.lastname: Shaw
authors.affiliation: Division of Pulmonary Disease and Critical Care Medicine, Department of Internal Medicine, School of Medicine, Virginia Commonwealth University, Box 980050, Richmond, VA, 23298, USA. alpha.fowler@vcuhealth.org.
authors.forename: Alpha A
authors.initials: AA
authors.lastname: Fowler
authors.affiliation: Division of Pulmonary Disease and Critical Care Medicine, Department of Internal Medicine, School of Medicine, Virginia Commonwealth University, Box 980050, Richmond, VA, 23298, USA. ramesh.natarajan@vcuhealth.org.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Natarajan
mesh_terms: D001127:Arginine Vasopressin / Q000627:therapeutic use*; D001205:Ascorbic Acid / Q000008:administration & dosage / Q000627:therapeutic use*; D006439:Hemodynamics; D006801:Humans; D009638:Norepinephrine / Q000096:biosynthesis* / Q000627:therapeutic use; D018805:Sepsis / Q000188:drug therapy*; D012772:Shock, Septic / Q000188:drug therapy*; D014662:Vasoconstrictor Agents / Q000627:therapeutic use; D014667:Vasopressins / Q000096:biosynthesis* / Q000627:therapeutic use
chemical_list: D014662:Vasoconstrictor Agents; D014667:Vasopressins; D001127:Arginine Vasopressin; D001205:Ascorbic Acid; D009638:Norepinephrine