Comparison of the efficacy and safety of FP-1201-lyo (intravenously administered recombinant human interferon beta-1a) and placebo in the treatment of patients with moderate or severe acute respiratory distress syndrome: study protocol for a randomized controlled trial.

BACKGROUND: Acute respiratory distress syndrome (ARDS) results in vascular leakage, inflammation and respiratory failure. There are currently no approved pharmacological treatments for ARDS and standard of care involves treatment of the underlying cause, and supportive care. The vascular leakage may be related to reduced concentrations of local adenosine, which is involved in maintaining endothelial barrier function. Interferon (IFN) beta-1a up-regulates the cell surface ecto-5'-nucleotidase cluster of differentiation 73 (CD73), which increases adenosine levels, and IFN beta-1 may, therefore, be a potential treatment for ARDS. In a phase I/II, open-label study in 37 patients with acute lung injury (ALI)/ARDS, recombinant human IFN beta-1a was well tolerated and mortality rates were significantly lower in treated than in control patients. METHODS/DESIGN: In this phase III, double-blind, randomized, parallel-group trial, the efficacy and safety of recombinant human IFN beta-1a (FP-1201-lyo) will be compared with placebo in adult patients with ARDS. Patients will be randomly assigned to receive 10 µg FP-1201-lyo or placebo administered intravenously once daily for 6 days and will be monitored for 28 days or until discharged from the intensive care unit. Follow-up visits will then take place at days 90, 180 and 360. The primary endpoint is a composite endpoint including any cause of death at 28 days and days free of mechanical ventilation within 28 days among survivors. Secondary endpoints include: all-cause mortality at 28, 90, 180 and 360 days; organ failure-free days; length of hospital stay; pharmacodynamic assessment including measurement of myxovirus resistance protein A concentrations; and measures of quality of life, respiratory and neurological function at 180 and 360 days. The estimated sample size to demonstrate a reduction in the primary outcome between groups from 30% to 15% is 300 patients, and the study will be conducted in 70-80 centers in nine countries across Europe. DISCUSSION: There are no effective specific treatments for patients with ARDS and mortality rates remain high. The results from this study will provide evidence regarding the efficacy of a potential new therapeutic agent, FP-1201-lyo, in improving the clinical course and outcome for patients with moderate/severe ARDS. TRIAL REGISTRATION: European Union Clinical Trials Register, no: 2014-005260-15 . Registered on 15 July 2017.

Nutrition Delivery Affects Outcomes in Pediatric Acute Respiratory Distress Syndrome.

BACKGROUND: Malnutrition is prevalent in critically ill children. We aim to describe nutrition received by children with acute respiratory distress syndrome (ARDS) and to determine whether provision of adequate nutrition is associated with improved clinical outcomes. MATERIALS AND METHODS: We studied characteristics and outcomes of 2 groups of patients: (1) those who received adequate calories (defined as ≥80% of predicted resting energy expenditure) and (2) those who received adequate protein (defined as ≥1.5g/kg/d of protein). Outcomes of interest were mortality, ventilator-free days (VFDs), intensive care unit (ICU)-free days, multiorgan dysfunction, and need for extracorporeal membrane oxygenation. Categorical variables were analyzed using the Fisher exact test, and continuous variables were analyzed using the Mann-Whitney U test. Univariate and multivariate logistic regression models were used to identify associated risk factors related to these outcomes of interest. RESULTS: In total, 107 patients with ARDS were identified. There was a reduction in ICU mortality in patients who received adequate calories (34.6% vs 60.5%, P = .025) and adequate protein (14.3% vs 60.2%, P = .002) compared with those that did not. Patients with adequate protein intake also had more VFDs (median [interquartile range], 12 [3.0-19.0] vs 0 [0.0-14.8] days; P = .005). After adjusting for severity of illness, adequate protein remained significantly associated with decreased mortality (adjusted odds ratio [95% confidence interval], 0.09 [0.01-0.94]; P = .044). CONCLUSION: Our study demonstrated that adequate nutrition delivery in children with ARDS was associated with improved clinical outcomes. Protein delivery may have potentially more impact than overall caloric delivery.

Should Immune-Enhancing Formulations Be Used for Patients With Acute Respiratory Distress Syndrome?

The potential for regulating immune function in acute respiratory distress syndrome (ARDS) through enteral-administered anti-inflammatory lipids has generated much interest over the past 20 years. Yet recommendations remain inconclusive regarding the utilization of ω-3 fatty acids in patients with ARDS and acute lung injury (ALI). Studies are limited in number, with differing methods, small sample sizes, and conflicting results, making recommendations difficult to interpret.

The Role of Omega-3 Polyunsaturated Fatty Acids in the Treatment of Patients with Acute Respiratory Distress Syndrome: A Clinical Review.

Acute respiratory distress syndrome (ARDS) is defined as the acute onset of noncardiogenic edema and subsequent gas-exchange impairment due to a severe inflammatory process. Recent report on the prognostic value of eicosanoids in patients with ARDS suggests that modulating the inflammatory response through the use of polyunsaturated fatty acids may be a useful strategy for ARDS treatment. The use of enteral diets enriched with eicosapentaenoic acid (EPA) and gamma-linolenic acid (GLA) has reported promising results, showing an improvement in respiratory variables and haemodynamics. However, the interpretation of the studies is limited by their heterogeneity and methodology and the effect of ω-3 fatty acid-enriched lipid emulsion or enteral diets on patients with ARDS remains unclear. Therefore, the routine use of ω-3 fatty acid-enriched nutrition cannot be recommended and further large, homogeneous, and high-quality clinical trials need to be conducted to clarify the effectiveness of ω-3 polyunsaturated fatty acids.

The Omega-3 Fatty Acid Docosahexaenoic Acid Modulates Inflammatory Mediator Release in Human Alveolar Cells Exposed to Bronchoalveolar Lavage Fluid of ARDS Patients.

BACKGROUND: This study investigated whether the 1 : 2 ω-3/ω-6 ratio may reduce proinflammatory response in human alveolar cells (A549) exposed to an ex vivo inflammatory stimulus (bronchoalveolar lavage fluid (BALF) of acute respiratory distress syndrome (ARDS) patients). Methods. We exposed A549 cells to the BALF collected from 12 ARDS patients. After 18 hours, fatty acids (FA) were added as docosahexaenoic acid (DHA, ω-3) and arachidonic acid (AA, ω-6) in two ratios (1 : 2 or 1 : 7). 24 hours later, in culture supernatants were evaluated cytokines (TNF-α, IL-6, IL-8, and IL-10) and prostaglandins (PGE2 and PGE3) release. The FA percentage content in A549 membrane phospholipids, content of COX-2, level of PPARγ, and NF-κB binding activity were determined. RESULTS: The 1 : 2 DHA/AA ratio reversed the baseline predominance of ω-6 over ω-3 in the cell membranes (P < 0.001). The proinflammatory cytokine release was reduced by the 1 : 2 ratio (P < 0.01 to <0.001) but was increased by the 1 : 7 ratio (P < 0.01). The 1 : 2 ratio reduced COX-2 and PGE2 (P < 0.001) as well as NF-κB translocation into the nucleus (P < 0.01), while it increased activation of PPARγ and IL-10 release (P < 0.001). Conclusion. This study demonstrated that shifting the FA supply from ω-6 to ω-3 decreased proinflammatory mediator release in human alveolar cells exposed to BALF of ARDS patients.

Enteral Immunomodulatory Diet (Omega-3 Fatty Acid, γ-Linolenic Acid and Antioxidant Supplementation) for Acute Lung Injury and Acute Respiratory Distress Syndrome: An Updated Systematic Review and Meta-Analysis.

UNLABELLED: Enteral immunomodulatory nutrition is considered as a promising therapy for the treatment of acute lung injury and acute respiratory distress syndrome (ALI/ARDS). However, there are still some divergences, and it is unclear whether this treatment should be recommended for patients with ALI/ARDS. Therefore, we conducted this systematic review and meta-analysis to assess the efficacy and safety of an enteral immunomodulatory diet on the clinical outcomes of ALI/ARDS patients. METHODS: We retrieved potentially relevant clinical trials though electronic databases. All trials of enteral immunomodulatory diet for ALI/ARDS were included. Analyses of the overall all-cause mortality, 28-day ventilator-free days and 28-day intensive care unit (ICU) free days were conducted. RESULTS: In total six controlled trials were evaluated. The pooled results did not show a significant reduction in the risk of all-cause mortality (M-H RR (the overall Mantel-Haenszel relative risk), 0.81 (95% CI, 0.50-1.31); p = 0.38; 6 trials, n = 717) in ALI/ARDS patients treated with the immunomodulatory diet. This treatment also did not extend the ventilator-free days and ICU-free days. However, patients with high mortality might benefit from this treatment. CONCLUSIONS: The enteral immunomodulatory diet could not reduce the severity of the patients with ALI/ARDS. Whereas, for ALI/ARDS patients with high mortality, this treatment might reduce the all-cause mortality, but its use should be treated with discretion.

Modulation of Dietary Lipid Composition During Acute Respiratory Distress Syndrome: Systematic Review and Meta-Analysis.

BACKGROUND: Pharmaconutrition including omega-3 and competitive analogs of omega-6 fatty acids has been used to modulate the inflammatory response during acute respiratory distress syndrome (ARDS). The clinical benefit of this approach when assessed in prospective randomized clinical trials has been inconsistent. We tried to assess the reasons for the conflicting results, including the possible influence of the composition of the control solution. METHODS: We collected data from studies listed in PubMed, Ovid, the Cochrane Database of Systematic Reviews, Embase, the U.S. National Institute of Health database, and the ARDSnet database up to March 2013. We included all trials that evaluated effects of enteral pharmaconutrition vs a control solution on mortality, ventilator-free days, length of stay (LOS) in the intensive care unit (ICU), and ICU-free days. A sensitivity analysis was carried out to study the influence of the lipid content of the control solution. RESULTS: We found 7 eligible studies (802 patients; 405 randomized to pharmaconutrition). The aggregated results showed no overall effect on mortality (risk ratio [RR] = 0.83 [0.55-1.25], P = .37), but there was a mortality benefit when only studies in which pharmaconutrition was compared to a lipid-rich control solution were considered (RR = 0.57 [0.41-0.78], P < .001). ICU LOS was shorter in patients randomized to pharmaconutrition (RR = 0.5 [0.85-0.16]). CONCLUSION: Use of enteral pharmaconutrition in patients with ARDS was associated with decreased mortality only when the comparator solution contained a greater amount of lipid than is currently recommended. Hence, there is insufficient evidence to support the use of enteral pharmaconutrition in ARDS.

Nutrition therapy for ALI and ARDS.

The importance of nutrition support in critically ill patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) cannot be overstated. ALI and ARDS are characterized by a proinflammatory response associated with hypercatabolism that could lead to significant nutrition deficits. Nutrition support is necessary to prevent cumulative caloric deficits, malnutrition, loss of lean body mass, and deterioration of respiratory muscle strength. Furthermore, early delivery of enteral nutrition has been associated with the modulation of stress and the systemic immune response as well as the attenuation of disease severity.

[Immune-enhancing diet (IED) for acute respiratory distress syndrome].

A 63-year-old man who was involved in a traffic accident was transferred to our hospital. He was unconscious and had a flail chest. On chest X-ray, he had a left hemopneumothorax and multiple rib fractures. After endotracheal intubation, a 16 Fr chest tube was immediately inserted, and drainage was started with negative pressure suction. Intravenous administration of sivelestat sodium hydrate and methylprednisolone was ineffective, but the Pao2/Fio2 ratio improved rapidly after enteral nutrition with an immune-enhancing diet (IED, Oxepa) was started. The patient was extubated on hospital day 34. This case suggests that an IED may be useful for the treatment of acute respiratory distress syndrome.

The pulmonary physician in critical care - part 9: non-ventilatory strategies in ARDS.

Pharmacological approaches to the treatment of ARDS are reviewed. Future treatments should be targeted at elements of the pathological process that produce specific clinical problems.

Use of indirect calorimetry to optimize nutrition support and assess physiologic dead space in the mechanically ventilated ICU patient: a case study approach.

Indirect calorimetry (IC) is an accurate method of estimating a patient's energy expenditure, particularly the complex critically ill patient who benefits most from an individualized regimen of nutritional support. This bedside technique measures variables related to gas exchange and replaces assumptions about physiologic stress. When indirect calorimetry data are augmented by an arterial blood gas analysis of carbon dioxide (PaCO2), the dead space to tidal volume ratio (VD/VT) can be determined for an individual patient. These data can be valuable to the healthcare team when checking reasons for weaning failure. A case study approach to a 69-year-old man with acute respiratory distress syndrome and biliary sepsis will demonstrate the utility of this measurement. Attention to precise nutritional support and optimal gas exchange can influence the outcome of critically ill mechanically ventilated patients. This discussion highlights the potential benefits of indirect calorimetry for critical care nurses.

Adult respiratory distress syndrome in pediatric patients. II. Management.

Adult respiratory distress syndrome, a clinical syndrome of respiratory failure that follows many kinds of insults, often in patients with no previous pulmonary disease, occurs in pediatric patients. This group of disorders has a typical clinical, pathologic, and pathophysiologic course, the hallmark of which is injury to the alveolar-capillary membrane with increased permeability of the pulmonary vasculature and pulmonary edema. Resolution may occur at any stage, but most patients die and many develop chronic lung disease requiring respiratory support for weeks or months. Multiple organ system failure, secondary infection, and irreversible respiratory dysfunction are responsible for the poor outcome. The underlying mechanisms that relate injury to the development of pulmonary disease are unclear. In some cases there may be direct injury to the lung, but in others, such as septic shock, there are mediators that link the initial insult to the subsequent lung injury. The leukocyte may have a central role in this process, although this is uncertain. Therapeutic measures needed to support the patient, especially increased inspired oxygen, are additional factors in the progression of lung disease. Current therapy, as summarized in Table II, is primarily supportive. Efforts to treat ARDS after it is clinically apparent have been disappointing. The pathogenic mechanisms that lead to ARDS are probably well advanced by the time the syndrome is diagnosed on the basis of the usual clinical signs. Therefore an emphasis on understanding the mechanisms of lung injury so that specific markers can be used to predict which patients will develop ARDS, allowing intervention in the early stages of the process, may prove rewarding.