Vitamin D to Prevent Lung Injury Following Esophagectomy—A Randomized, Placebo-Controlled Trial

Objectives: Observational studies suggest an association between vitamin D deficiency and adverse outcomes of critical illness and identify it as a potential risk factor for the development of lung injury. To determine whether preoperative administration of oral high-dose cholecalciferol ameliorates early acute lung injury postoperatively in adults undergoing elective esophagectomy. Design: A double-blind, randomized, placebo-controlled trial. Setting: Three large U.K. university hospitals. Patients: Seventy-nine adult patients undergoing elective esophagectomy were randomized. Interventions: A single oral preoperative (3–14 d) dose of 7.5 mg (300,000 IU; 15 mL) cholecalciferol or matched placebo. Measurements and Main Results: Primary outcome was change in extravascular lung water index at the end of esophagectomy. Secondary outcomes included PaO2:FIO2 ratio, development of lung injury, ventilator and organ-failure free days, 28 and 90 day survival, safety of cholecalciferol supplementation, plasma vitamin D status (25(OH)D, 1,25(OH)2D, and vitamin D-binding protein), pulmonary vascular permeability index, and extravascular lung water index day 1 postoperatively. An exploratory study measured biomarkers of alveolar-capillary inflammation and injury. Forty patients were randomized to cholecalciferol and 39 to placebo. There was no significant change in extravascular lung water index at the end of the operation between treatment groups (placebo median 1.0 [interquartile range, 0.4–1.8] vs cholecalciferol median 0.4 mL/kg [interquartile range, 0.4–1.2 mL/kg]; p = 0.059). Median pulmonary vascular permeability index values were significantly lower in the cholecalciferol treatment group (placebo 0.4 [interquartile range, 0–0.7] vs cholecalciferol 0.1 [interquartile range, –0.15 to –0.35]; p = 0.027). Cholecalciferol treatment effectively increased 25(OH)D concentrations, but surgery resulted in a decrease in 25(OH)D concentrations at day 3 in both arms. There was no difference in clinical outcomes. Conclusions: High-dose preoperative treatment with oral cholecalciferol was effective at increasing 25(OH)D concentrations and reduced changes in postoperative pulmonary vascular permeability index, but not extravascular lung water index. This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Drs. Parekh and Dancer are joint first authors. Clinical trial registered with the International Standard Randomized Controlled Trial Registry (ISRCTN27673620) and European Union database of Randomized Controlled Trials (EudraCT 2012-000332-25). Drs. Parekh, Fraser, Gao, Martineau, Perkins, and Thickett designed the study. Drs. Cooper, Tan, and Tucker provided expert advice and aided recruitment. Drs. Parekh, Dancer, Howells, and Mahida recruited patients. Drs. Parekh, Dancer, Scott, D'Souza, and Tang undertook biomarker assays and analyzed the data. Drs. Parekh, Dancer, and Thickett wrote the first draft of the article. All authors contributed to revising the draft critically for important intellectual content and have agreed to the final submitted version. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/29S62lw). Dr. Parekh was funded by the Medical Research Council (MRC) (MR/J011266/1); Drs. Dancer and Thickett by the MRC (G1100196/1) trust; and Dr. Scott by the MRC (MR/L002736/1). Drs. Gao and Perkins are National Institute for Health Research Senior Investigators. Drs. Parekh, Dancer, Mahida, Tang, and Thickett research support for article research from Research Councils UK. Drs. Dancer, Tang, and Thickett's institutions received funding from the MRC. Dr. Howells institution received funding from GlaxoSmithKline. Dr. Perkins disclosed off-label product use of vitamin D. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: d.parekh@bham.ac.uk Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

https://ift.tt/2MFHUQe