Novel translational approaches to the search for precision therapies for acute respiratory distress syndrome.

In the 50 years since acute respiratory distress syndrome (ARDS) was first described, substantial progress has been made in identifying the risk factors for and the pathogenic contributors to the syndrome and in characterising the protein expression patterns in plasma and bronchoalveolar lavage fluid from patients with ARDS. Despite this effort, however, pharmacological options for ARDS remain scarce. Frequently cited reasons for this absence of specific drug therapies include the heterogeneity of patients with ARDS, the potential for a differential response to drugs, and the possibility that the wrong targets have been studied. Advances in applied biomolecular technology and bioinformatics have enabled breakthroughs for other complex traits, such as cardiovascular disease or asthma, particularly when a precision medicine paradigm, wherein a biomarker or gene expression pattern indicates a patient's likelihood of responding to a treatment, has been pursued. In this Review, we consider the biological and analytical techniques that could facilitate a precision medicine approach for ARDS

Regulation of vascular endothelial growth factor bioactivity in patients with acute lung injury

Background: Reduced bioactive vascular endothelial growth factor (VEGF) has been demonstrated in several inflammatory lung conditions including the acute respiratory distress syndrome (ARDS). sVEGFR-1, a soluble form of VEGF-1 receptor, is a potent natural inhibitor of VEGF. We hypothesised that sVEGFR-1 plays an important role in the regulation of the bioactivity of VEGF within the lung in patients with ARDS. Methods: Forty one patients with ARDS, 12 at risk of developing ARDS, and 16 normal controls were studied. Bioactive VEGF, total VEGF, and sVEGFR-1 were measured by ELISA in plasma and bronchoalveolar lavage (BAL) fluid. Reverse transcriptase polymerase chain reaction for sVEGFR-1 was performed on BAL cells. Results: sVEGFR-1 was detectable in the BAL fluid of 48% (20/41) of patients with early ARDS (1.4– 54.8 ng/ml epithelial lining fluid (ELF)) compared with 8% (1/12) at risk patients (p = 0.017) and none of the normal controls (p = 0.002). By day 4 sVEGFR-1 was detectable in only 2/18 ARDS patients (p = 0.008). Patients with detectable sVEGFR-1 had lower ELF median (IQR) levels of bioactive VEGF than those without detectable sVEGFR-1 (1415.2 (474.9–3192) pg/ml v 4761 (1349–7596.6) pg/ml, median difference 3346 pg/ml (95% CI 305.1 to 14711.9), p = 0.016), but there was no difference in total VEGF levels. BAL cells expressed mRNA for sVEGFR-1 and produced sVEGFR-1 protein which increased following incubation with tumour necrosis factor a. Conclusion: This study shows for the first time the presence of sVEGFR-1 in the BAL fluid of patients with ARDS. This may explain the presence of reduced bioactive VEGF in patients early in the course of ARDS

Cisplatin-Based Chemotherapy for Pulmonary Metastasized Germ Cell Tumors of the Testis - Be Aware of Acute Respiratory Distress Syndrome

Background: Cisplatin-based combination chemotherapy is regarded as standard of care for patients with advanced germ cell tumors. In patients with lung metastases and a high tumor load, an association between induction chemotherapy and the development of a `tumor-associated' acute respiratory distress syndrome (ARDS) has been hypothesized. Case Report: We report the clinical course of a 19-year-old patient who rapidly developed fatal ARDS during the first cycle of chemotherapy using the PEI regimen (cisplatin, etoposide and ifosfamide) for a metastasized (lung, liver, lymph nodes) germ cell tumor of the testis. Conclusion: Further clinical research in order to better define risk factors for developing ARDS in this patient population as well as novel strategies for the prevention and treatment of ARDS in those patients are necessary

Prone Positioning for ARDS. still misunderstood and misused

Acute respiratory distress syndrome (ARDS) is a clinical syndrome characterized by a non-cardiogenic pulmonary edema with bilateral chest X-ray opacities and hypoxemia refractory to oxygen therapy and low level of positive end-expiratory pressure (1). Recently, a large observational study reported an ARDS prevalence of 10.4% of all ICU admissions and of 23.4% of all subjects receiving mechanical ventilation (2). Despite these alarming numbers, according to the most recent literature, ARDS is still under-recognized, undertreated, and associated with a mortality rate that in the most severe forms is close to 50% (2)

Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries

IMPORTANCE: Limited information exists about the epidemiology, recognition, management, and outcomes of patients with the acute respiratory distress syndrome (ARDS). OBJECTIVES: To evaluate intensive care unit (ICU) incidence and outcome of ARDS and to assess clinician recognition, ventilation management, and use of adjuncts-for example prone positioning-in routine clinical practice for patients fulfilling the ARDS Berlin Definition. DESIGN, SETTING, AND PARTICIPANTS:The Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE) was an international, multicenter, prospective cohort study of patients undergoing invasive or noninvasive ventilation, conducted during 4 consecutive weeks in the winter of 2014 in a convenience sample of 459 ICUs from 50 countries across 5 continents. EXPOSURES:Acute respiratory distress syndrome. MAIN OUTCOMES AND MEASURES: The primary outcome was ICU incidence of ARDS. Secondary outcomes included assessment of clinician recognition of ARDS, the application of ventilatory management, the use of adjunctive interventions in routine clinical practice, and clinical outcomes from ARDS. RESULTS: Of 29,144 patients admitted to participating ICUs, 3022 (10.4%) fulfilled ARDS criteria. Of these, 2377 patients developed ARDS in the first 48 hours and whose respiratory failure was managed with invasive mechanical ventilation. The period prevalence of mild ARDS was 30.0% (95% CI, 28.2%-31.9%); of moderate ARDS, 46.6% (95% CI, 44.5%-48.6%); and of severe ARDS, 23.4% (95% CI, 21.7%-25.2%). ARDS represented 0.42 cases per ICU bed over 4 weeks and represented 10.4% (95% CI, 10.0%-10.7%) of ICU admissions and 23.4% of patients requiring mechanical ventilation. Clinical recognition of ARDS ranged from 51.3% (95% CI, 47.5%-55.0%) in mild to 78.5% (95% CI, 74.8%-81.8%) in severe ARDS. Less than two-thirds of patients with ARDS received a tidal volume 8 of mL/kg or less of predicted body weight. Plateau pressure was measured in 40.1% (95% CI, 38.2-42.1), whereas 82.6% (95% CI, 81.0%-84.1%) received a positive end-expository pressure (PEEP) of less than 12 cm H2O. Prone positioning was used in 16.3% (95% CI, 13.7%-19.2%) of patients with severe ARDS. Clinician recognition of ARDS was associated with higher PEEP, greater use of neuromuscular blockade, and prone positioning. Hospital mortality was 34.9% (95% CI, 31.4%-38.5%) for those with mild, 40.3% (95% CI, 37.4%-43.3%) for those with moderate, and 46.1% (95% CI, 41.9%-50.4%) for those with severe ARDS. CONCLUSIONS AND RELEVANCE: Among ICUs in 50 countries, the period prevalence of ARDS was 10.4% of ICU admissions. This syndrome appeared to be underrecognized and undertreated and associated with a high mortality rate. These findings indicate the potential for improvement in the management of patients with ARDS

Newly recognized causes of acute lung injury: transfusion of blood products, severe acute respiratory syndrome, and avian influenza.

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a clinical syndrome that has an ever-growing list of potential causes. The transfusion of blood products is often a life-saving therapy, but it can be associated with the development of ALI/ARDS. Transfusion-related ALI is now the leading cause of transfusion-associated fatalities in the United States. Two infectious causes of ALI/ARDS, severe acute respiratory syndrome and H5N1 influenza, have recently emerged and have the potential for pandemic spread. This article discusses the clinical importance, pathogenesis, diagnosis, management, and prevention of these newly recognized causes of respiratory failure

Prone position: Does it help with acute respiratory distress syndrome (ARDS) requiring extracorporeal membrane oxygenation (ECMO)?

Introduction: Lung protective ventilation therapy with low tidal volume-high PEEP is the standard treatment for the patients with acute respiratory distress syndrome (ARDS). Oscillators are occasionally used for salvage ventilation in cases where poor compliance restricts the use of traditional ventilation with ARDS. In addition to ventilator therapy, prone positioning has been used to improve oxygenation. We presented a challenging case of ARDS, which failed medical management extracorporeal membrane oxygenation (ECMO) support and oscillatory ventilation. Prone positioning was initiated which improved oxygenation, respiratory compliance and posterior atelectasis. Case presentation: A 41-year-old morbid obese female developed ARDS due to influenza pneumonia. The patient remained hypoxic despite optimum medical and ventilator management and required veno-venous extracorporeal membrane oxygenation (VV ECMO). CT scan of the chest showed ARDS with posterior consolidation. Despite ARDSnet ventilation support, antiviral therapy and ECMO support, there was no clinical improvement. High frequency oscillatory ventilation was initiated on ECMO day #13, which resulted in no respiratory improvement over the next 5 days. On ECMO day #18, the patient was placed on a Rotaprone? bed Therapy, utilizing a proning strategy of 16 hours a day. The clinical improvements observed were resolving of the consolidation on CXR, improvements in ventilatory parameters and decreased oxygen requirements. The patient was successfully weaned off ECMO on POD#25 (8 days post prone bed). Conclusions: Prone position improved oxygen saturation and pulmonary compliance in severe ARDS requiring ECMO and it might facilitate early weaning

Serum antioxidants as predictors of the adult respiratory distress syndrome in septic patients

Adult respiratory distress syndrome (ARDS) can develop as a complication of various disorders, including sepsis, but it has not been possible to identify which of the patients at risk will develop this serious disorder. We have investigated the ability of six markers, measured sequentially in blood, to predict development of ARDS in 26 patients with sepsis. At the initial diagnosis of sepsis (6-24 h before the development of ARDS), serum manganese superoxide dismutase concentration and catalase activity were higher in the 6 patients who subsequently developed ARDS than in 20 patients who did not develop ARDS. These changes in antioxidant enzymes predicted the development of ARDS in septic patients with the same sensitivity, specificity, and efficiency as simultaneous assessments of serum lactate dehydrogenase activity and factor VIII concentration. By contrast, serum glutathione peroxidase activity and α1Pi-elastase complex concentration did not differ at the initial diagnosis of sepsis between patients who did and did not subsequently develop ARDS, and were not as effective in predicting the development of ARDS. Measurement of manganese superoxide dismutase and catalase, in addition to the other markers, should facilitate identification of patients at highest risk of ARDS and allow prospective treatment