Evaluating Vitamin C in Septic Shock: A Randomized Controlled Trial of Vitamin C Monotherapy.

OBJECTIVES: To determine whether IV vitamin C therapy reduces 28-day mortality in patients with septic shock. DESIGN: Multicenter, double-blinded, randomized controlled trial. SETTING: One academic medical ICU and four community ICUs. PATIENTS: Of 167 adult patients within 24 hours of vasopressor initiation for septic shock, 126 consented to participation, and 124 received study drug and were included in analysis. INTERVENTIONS: IV vitamin C (10 mg/mL in normal saline) administered as a 1,000-mg bolus over 30 minutes followed by continuous infusion of 250 mg/hr for 96 hours or placebo of equal volumes of normal saline. MEASUREMENTS AND MAIN RESULTS: Of 124 subjects receiving study drug and included in analysis, 60 received vitamin C and 64 placebo. The primary outcome of all-cause 28-day mortality (vitamin C, 26.7%; placebo, 40.6%; p = 0.10) was lower in the vitamin C arm but did not reach statistical significance. Initiation of renal replacement therapy was higher in the vitamin C arm (vitamin C, 16.7%; placebo, 3.3%; p = 0.015), as was volume of fluid administration within 6 hours of study drug initiation (vitamin C, 1.07 L; placebo, 0.76 L; p = 0.03). There were no statistically significant differences in other secondary outcomes. In post hoc subgroup analysis, there was a decrease in 28-day mortality in the vitamin C arm among patients requiring positive-pressure ventilation at the time of enrollment (vitamin C, 36.3%; placebo, 60.0%; p = 0.05). This trial is registered at clinicaltrials.gov under identifier NCT03338569. CONCLUSIONS: Vitamin C monotherapy failed to significantly reduce mortality in septic shock patients as hypothesized. Our findings do not support its routine clinical use for this purpose.

Understanding persistent bacterial lung infections: clinical implications informed by the biology of the microbiota and biofilms.

The infections found in chronic obstructive pulmonary disease, cystic fibrosis, and bronchiectasis share a number of clinical similarities, the most striking of which is bacterial persistence despite the use of antibiotics. These infections have been clinically described using culture-based methods usually performed on sputum samples, and treatment has been directed towards the bacteria found in this manner. Unfortunately the clinical response to antibiotics is frequently not predictable based on these cultures, and the role of these cultured organisms in disease progression has been debated. The past 20 years have seen a revolution in the techniques used to describe bacterial populations and their growth patterns. These techniques have revealed these persistent lung infections are vastly more complicated than described by traditional, and still widely relied upon, sputum cultures. A better understanding of the initiation and evolution of these infections, and better clinical tools to describe them, will dramatically alter the way patients are cared for. While clinical tests to more accurately describe these infections are not yet available, the better appreciation of these infections afforded by current science should enlighten practitioners as to the care of their patients with these diseases.

Hypoxia: an unusual cause with specific treatment.

Hypoxia is a well-recognized consequence of venous admixture resulting from right to left intracardiac shunting. Right to left shunting is usually associated with high pulmonary artery pressure or alteration in the direction of blood flow due to an anatomical abnormality of the thorax. Surgical or percutaneous closure remains controversial; however it is performed frequently for patients presenting with clinical sequela presumed to be resulting from paradoxical embolization secondary to right to left shunting. We report two patients with hypoxia and dyspnea due to right to left shunting through a patent foramen ovale (PFO) and venous admixture in the absence of elevated pulmonary artery pressures or other predisposing conditions like pneumonectomy or diaphragmatic weakness. Percutaneous closures of the PFOs with the self-centering Amplatzer device resulted in resolution of hypoxia and symptoms related to it.

Malondialdehyde-acetaldehyde (MAA) adducted proteins bind to scavenger receptor A in airway epithelial cells.

Co-exposure to cigarette smoke and ethanol generates malondialdehyde and acetaldehyde, which can subsequently lead to the formation of aldehyde-adducted proteins. We have previously shown that exposure of bronchial epithelial cells to malondialdehyde-acetaldehyde (MAA) adducted protein increases protein kinase C (PKC) activity and proinflammatory cytokine release. A specific ligand to scavenger receptor A (SRA), fucoidan, blocks this effect. We hypothesized that MAA-adducted protein binds to bronchial epithelial cells via SRA. Human bronchial epithelial cells (BEAS-2B) were exposed to MAA-adducted protein (either bovine serum albumin [BSA-MAA] or surfactant protein D [SPD-MAA]) and SRA examined using confocal microscopy, fluorescent activated cell sorting (FACS), and immunoprecipitation. Differentiated mouse tracheal epithelial cells (MTEC) cultured by air-liquid interface were assayed for MAA-stimulated PKC activity and keratinocyte-derived chemokine (KC) release. Specific cell surface membrane dye co-localized with upregulated SRA after exposure to MAA for 3-7 min and subsided by 20 min. Likewise, MAA-adducted protein co-localized to SRA from 3 to 7 min with a subsequent internalization of MAA by 10 min. These results were confirmed using FACS analysis and revealed a reduced mean fluorescence of SRA after 3 min. Furthermore, increased amounts of MAA-adducted protein could be detected by Western blot in immunoprecipitated SRA samples after 3 min treatment with MAA. MAA stimulated PKCε-mediated KC release in wild type, but not SRA knockout mice. These data demonstrate that aldehyde-adducted proteins in the lungs rapidly bind to SRA and internalize this receptor prior to the MAA-adducted protein stimulation of PKC-dependent inflammatory cytokine release in airway epithelium.