Acute respiratory distress syndrome (ARDS) is a common sepsis-associated organ injury and results in significant mortality^1-4; for instance, the LUNG SAFE study reported 34% to 45% mortality.⁵ Despite advances in understanding mechanisms that lead to ARDS,⁶ disease-modifying strategies have not improved outcomes.^7-12 Previous research found that vitamin C attenuates systemic inflammation, corrects sepsis-induced coagulopathy, and attenuates vascular injury.^13-15 The CITRIS-ALI randomized trial examined whether high-dose vitamin C would reduce organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and ARDS.

Parenterally administered ascorbic acid modulates sepsis-induced inflammation and coagulation in experimental animal models. The objective of this randomized, double-blind, placebo-controlled, phase I trial was to determine the safety of intravenously infused ascorbic acid in patients with severe sepsis.

Background— The most important determinant of longevity in pulmonary arterial hypertension is right ventricular (RV) function, but in contrast to experimental work elucidating the pathobiology of left ventricular failure, there is a paucity of data on the cellular and molecular mechanisms of RV failure. Methods and Results— A mechanical animal model of chronic progressive RV pressure overload (pulmonary artery banding, not associated with structural alterations of the lung circulation) was compared with an established model of angioproliferative pulmonary hypertension associated with fatal RV failure. Isolated RV pressure overload induced RV hypertrophy without failure, whereas in the context of angioproliferative pulmonary hypertension, RV failure developed that was associated with myocardial apoptosis, fibrosis, a decreased RV capillary density, and a decreased vascular endothelial growth factor mRNA and protein expression despite increased nuclear stabilization of hypoxia-induced factor-1α. Induction of myocardial nuclear factor E2-related factor 2 and heme-oxygenase 1 with a dietary supplement (Protandim) prevented fibrosis and capillary loss and preserved RV function despite continuing pressure overload. Conclusion— These data brought into question the commonly held concept that RV failure associated with pulmonary hypertension is due strictly to the increased RV afterload.

Rationale: Most patients with pulmonary arterial hypertension (PAH) die from right heart failure. β-Adrenergic receptor blockade reduces mortality by about 30% in patients with left-sided systolic heart failure, but is not used in PAH. Objectives: To assess the effect of the adrenergic receptor blocker carvedilol on the pulmonary circulation and right heart in experimental pulmonary hypertension in rats. Methods: Angioproliferative pulmonary hypertension was induced in rats by combined exposure to the vascular endothelial growth factor–receptor antagonist SU5416 and hypoxia. Carvedilol treatment was started after establishment of pulmonary hypertension and right heart dysfunction. Measurements and Main Results: Compared with vehicle-treated animals, treatment with carvedilol resulted in increased exercise endurance; improved right ventricular (RV) function (increased tricuspid annular plane systolic excursion and decreased RV dilatation); and an increased cardiac output. The morphology of the pulmonary vessels and the RV afterload were not affected by carvedilol. Carvedilol treatment was associated with enhancement of RV fetal gene reactivation, increased protein kinase G (PKG) activity, and a reduction in capillary rarefaction and fibrosis. Metoprolol had similar but less pronounced effects in the SU5416 and hypoxia model. Cardioprotective effects were noted of both carvedilol and metoprolol in the monocrotaline model. In the case of carvedilol, but not metoprolol, part of these effects resulted from a prevention of monocrotaline-induced lung remodeling. Conclusions: Adrenergic receptor blockade reverses RV remodeling and improves RV function in experimental pulmonary hypertension. β-Adrenergic receptor blockers are not recommended in humans with PAH before their safety and efficacy are assessed in well-designed clinical trials.

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.