A nebulised antitumour necrosis factor receptor-1 domain antibody in patients at risk of postoperative lung injury: A randomised, placebo-controlled pilot study.

BACKGROUND: Tumour necrosis factor receptor 1 (TNFR1) signalling mediates the cell death and inflammatory effects of TNF-α. OBJECTIVE: The current clinical trial investigated the effects of a nebulised TNFR1 antagonist (GSK2862277) on signs of lung injury in patients undergoing oesophagectomy. DESIGN: Randomised double-blind (sponsor unblind), placebo-controlled, parallel group study. SETTING: Eight secondary care centres, the United Kingdom between April 2015 and June 2017. PATIENTS: Thirty-three patients undergoing elective transthoracic oesophagectomy. INTERVENTIONS: Patients randomly received a single nebulised dose (26 mg) of GSK2862277 (n = 17) or placebo (n = 16), given 1 to 5 h before surgery; 14 and 16, respectively competed the study. MAIN OUTCOME MEASUREMENTS: Physiological and biochemical markers of lung injury, pharmacokinetic and safety endpoints were measured. The primary endpoint was the change from baseline in pulmonary vascular permeability index (PVPI) at completion of surgery, measured using single-indicator transpulmonary thermodilution. Adjusted point estimates and 95% credible intervals (analogous to conventional confidence intervals) were constructed for each treatment using Bayesian statistical models. RESULTS: The mean change (with 95% credible intervals) from baseline in PVPI on completion of surgery was 0.00 (-0.23, 0.39) in the placebo and 0.00 (-0.24, 0.37) in the GSK2862277 treatment groups. There were no significant treatment-related differences in PaO2/FiO2 or Sequential Organ Failure Assessment score. Levels of free soluble TNFR1, Macrophage Inflammatory Protein-1 alpha and total protein were significantly reduced in the bronchoalveolar lavage fluid of patients treated with GSK2862277 (posterior probability of decrease with GSK2862277 vs. placebo:≥0.977; equivalent to P < 0.05). The frequency of adverse events and serious adverse events were distributed evenly across the two treatment arms. CONCLUSION: Pre-operative treatment with a single 26 mg inhaled dose of GSK2862277 did not result in significantly lower postoperative alveolar capillary leak or extra vascular lung water. Unexpectedly small increases in transpulmonary thermodilution-measured PVPI and extra vascular lung water index at completion of surgery suggest less postoperative lung injury than historically reported, which may have also compromised a clear assessment of efficacy in this trial. GSK2862277 was well tolerated, resulted in expected lung exposure and reduced biomarkers of lung permeability and inflammation. TRIAL REGISTRATION: clinicaltrials.gov: NCT02221037.

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.

The increasing need for biomarkers in intensive care unit-acquired weakness--are microRNAs the solution?

There is an increasing focus on intensive care unit-acquired weakness, its underlying mechanisms and therapeutic options. In this article we offer a commentary on the paper by Bloch and colleagues entitled 'MiR-181a: a potential biomarker of acute muscle wasting following cardiac surgery'. There is a need for biomarkers for intensive care unit-acquired weakness, not only in clinical practice but also in order to streamline future therapeutic trials. MicroRNAs are attractive biomarkers, and may have an important role in this disease. We highlight the significance of the authors' finding of miR-181a, a novel plasma biomarker for the development of acute muscle wasting in post-operative cardiac surgery patients and discuss future research that is needed in this field following on from the study findings.

Dysregulated alveolar function and complications in smokers following oesophagectomy.

Acute respiratory distress syndrome (ARDS) has a significant impact on post-operative morbidity and mortality following oesophagectomy. Smoking is a risk factor for the development of ARDS, although the mechanism is unclear. We examined the effect of smoking on alveolar and systemic inflammation, in addition to alveolar-capillary permeability, leading to ARDS in patients undergoing oesophagectomy. We compared clinical, biomarker and PiCCO system data between current smokers (n=14) and ex-smokers (n=36) enrolled into a translational substudy of the BALTI-P (Beta Agonist Lung Injury Trial Prevention) trial. Current smokers compared with ex-smokers had significantly higher numbers of circulating neutrophils, elevated bronchoalveolar lavage (BAL) interleukin (IL)-1 receptor antagonist (IL-1ra), soluble tumour necrosis factor receptor-1 and pre-operative plasma soluble intercellular adhesion molecule-1, and lower BAL vascular endothelial growth factor and post-operative plasma IL-17 (p<0.05). On post-operative day 1, current smokers had higher extravascular lung water index (9.80 versus 7.90; p=0.026) and pulmonary vascular permeability index (2.09 versus 1.70; p=0.013). Current smokers were more likely to develop ARDS (57% versus 25%; p=0.031) and had a significantly reduced post-operative median survival (421 versus 771 days; p=0.023). Smoking prior to oesophagectomy is associated with dysregulated inflammation, with higher concentrations of inflammatory mediators and lower concentrations of protective mediators. This translates into a higher post-operative inflammatory alveolar oedema, greater risk of ARDS and poorer long-term survival.

ARDS following oesophagectomy: a comparison of two trials.

INTRODUCTION: The Beta Agonist Lung Injury Trial-Prevention (BALTI-P) translational substudy and Vitamin D to Prevent Acute Lung Injury Following Oesophagectomy (VINDALOO) trials recruited patients undergoing oesophagectomy, 4 years apart. The acute respiratory distress syndrome (ARDS) rates were lower in the VINDALOO trial. We sought to identify changes between these two trials and identify risk factors for ARDS in oesophagectomy. METHODS: There were data available from 61 patients in the BALTI-P substudy and 68 from VINDALOO. Databases were available for both trials; additional data were collected. Multivariate logistic regression was used to analyse risk factors for ARDS and postoperative complications in the cohorts combined. RESULTS: Logistic regression analysis showed active smoking was associated with an increase in ARDS (OR 3.91; 95% CI 1.33 to 11.5) and dihydropyridine use (OR 5.34;95% CI 1.56 to 18.3). Hospital length of stay was longer for those who took dihydropyridines (median 29 days (IQR 17-42) vs 13 days (IQR 10-18), P=0.0007) or were diabetic (median 25 days (IQR 14-39) vs 13 (IQR 10-19), P=0.023) but not for current smokers (median in never/ex-smokers 13 (IQR 10-23) vs current smokers 15 (IQR 11-20), P=0.73). CONCLUSIONS: Smoking cessation trials should be promoted. Dihydropyridine effects perioperatively require further clinical and mechanistic evaluation. Patients undergoing oesophagectomy are a useful model for studying perioperative ARDS.

Optimal Vitamin D Supplementation Levels for Cardiovascular Disease Protection.

First described in relation to musculoskeletal disease, there is accumulating data to suggest that vitamin D may play an important role in cardiovascular disease (CVD). In this review we aim to provide an overview of the role of vitamin D status as both a marker of and potentially causative agent of hypertension, coronary artery disease, heart failure, atrial fibrillation, stroke, and peripheral vascular disease. The role of vitamin D levels as a disease marker for all-cause mortality is also discussed. We review the current knowledge gathered from experimental studies, observational studies, randomised controlled trials, and subsequent systematic reviews in order to suggest the optimal vitamin D level for CVD protection.