Vitamin D for Acute Respiratory Distress Syndrome: Sunshine or Shade?

2071 5September20186September2018 In this issue of Critical Care Medicine, Parekh et al (1) report their results of attenuating acute lung injury (ALI) in postesophagectomy patients by correcting vitamin D deficiency (VDD). After esophagectomy under single-lung ventilation, the severity of ALI was measured by extravascular lung water index (EVLWI) and pulmonary vascular permeability index (PVPI) using Pulse Contour Continuous Cardiac Output transpulmonary thermodilution in this randomized control trial with correction of perioperative VDD. In the treatment arm, the authors prospectively supplemented vitamin D in a randomized group of esophagectomy patients 3–14 days prior to their operation. Their primary outcome measure of efficacy was the EVLWI, whereas secondary outcome measures included plasma vitamin D levels and PVPI. Plasma biomarkers were also compared. Power analysis allotted 34 patients to both arms to detect a significant effect based on the results of their preliminary study. Sixty-eight patients were ultimately enrolled after exclusions for data analysis (35 placebo, 33 vitamin D). Primary outcomes were not significantly different between groups. Secondary outcomes only demonstrated significant differences in PVPI changes from baseline, not absolute numbers, increasing in the placebo arm but not in the vitamin D arm. The treatment group did show significant increases in posttreatment vitamin D levels which persisted through postoperative day 3, but there were no differences between the treatment group patients. There were no differences in clinical outcomes such as Pao 2 /Fio 2 ratios or acute respiratory distress syndrome (ARDS) rates, ventilator-free days or organ failure free days nor survival. Finally, a post hoc analysis correlated the changes in EVLWI and PVPI with vitamin D levels and suggested that a minimum threshold of greater than 50 nmol/L would prevent increases in either variable regardless of study arm. Primary and secondary ARDS culminates in the violation of the alveolar-capillary membrane and flooding of alveoli and lung tissue with edema (2). The ensuing inflammation results in shunting and decreased compliance causing hypoxemia and the propensity for volutrauma exacerbated by mechanical ventilation. The latest Berlin criteria now classify ALI into mild, moderate, or severe ARDS (3). Although more studies have been published on EVLWI and PVPI, the Berlin criteria do not include these variables (4, 5). Pulmonary thermodilution requires a central venous and arterial catheter with serial injections of cold saline and dye. The Stewart-Hamilton and Newman principles use their distribution within the pulmonary vasculature and parenchyma to estimate the intrathoracic thermal volume (ITTV) and intrathoracic blood volume (ITBV), respectively to estimate the EVLWI (ITTV–ITBV) (6). The measurement and calculations can be labor intensive, yet early studies in ARDS have linked decreased EVLWI or PVPI with severity and survival (7, 8). Thermodilution can also differentiate ARDS from hydrostatic edema in other conditions like congestive heart failure (4). It has also been suggested that single-lung ventilation may adversely affect the interpretation of EVLWI by thermodilution (6). In addition to calcium homeostasis, vitamin D also plays a role in immunomodulation, inflammation, and infection control. VDD has been implicated in critical illness, infections, respiratory and renal failure, sepsis, and mortality (9). Parekh et al (1) have previously reviewed the role of VDD in ALI and tested their hypothesis in a preliminary study of VDD correction to prevent ARDS in clinical and murine models with encouraging results that informed the current study (10, 11). On the other hand, Barnett et al (12) did not demonstrate a relationship between VDD and ALI but did see higher 1-year mortality in severe trauma patients with lower admission vitamin D levels. The occurrence rate of ARDS in the study by Parekh et al (1) was possibly lower than expected from their preliminary study in a similar patient population, raising the likelihood of a type II statistical error. A power calculation estimates the sample size needed to insure that the results of the study by Parekh et al (1) reflect the true effect of the intervention and its clinical magnitude. The calculation requires an estimate of the occurrence rate of the disease (ARDS) researchers are treating with their intervention (vitamin D). Accepting a false null hypothesis defines a type II error, that is, no difference in treatment versus control arms, possibly because the study by Parekh et al (1) was underpowered to detect the true difference from a lower than expected occurrence rate of disease (13). An independent statistical analysis performed of the study by Parekh et al (1) results suggests this possibility. The authors clearly set ambitious goals for their study; the ability of vitamin D repletion to affect pathognomonic changes of EVLWI and PVPI in addition to improve outcomes in ARDS. The body of literature on EVLWI and PVPI in ARDS *See also p. e1128.