Simvastatin in the Acute Respiratory Distress Syndrome

Background

Studies in animals and in vitro and phase 2 studies in humans suggest that statins may be beneficial in the treatment of the acute respiratory distress syndrome (ARDS). This study tested the hypothesis that treatment with simvastatin would improve clinical outcomes in patients with ARDS.

Methods

In this multicenter, double-blind clinical trial, we randomly assigned (in a 1:1 ratio) patients with an onset of ARDS within the previous 48 hours to receive enteral simvastatin at a dose of 80 mg or placebo once daily for a maximum of 28 days. The primary outcome was the number of ventilator-free days to day 28. Secondary outcomes included the number of days free of nonpulmonary organ failure to day 28, mortality at 28 days, and safety.

Results

The study recruited 540 patients, with 259 patients assigned to simvastatin and 281 to placebo. The groups were well matched with respect to demographic and baseline physiological variables. There was no significant difference between the study groups in the mean (±SD) number of ventilator-free days (12.6±9.9 with simvastatin and 11.5±10.4 with placebo, P=0.21) or days free of nonpulmonary organ failure (19.4±11.1 and 17.8±11.7, respectively; P=0.11) or in mortality at 28 days (22.0% and 26.8%, respectively; P=0.23). There was no significant difference between the two groups in the incidence of serious adverse events related to the study drug.

Conclusions

Simvastatin therapy, although safe and associated with minimal adverse effects, did not improve clinical outcomes in patients with ARDS. (Funded by the U.K. National Institute for Health Research Efficacy and Mechanism Evaluation Programme and others; HARP-2 Current Controlled Trials number, ISRCTN88244364.)

Aspirin therapy in patients with acute respiratory distress syndrome (ARDS) is associated with reduced intensive care unit mortality: a prospective analysis

INTRODUCTION: Acute respiratory distress syndrome (ARDS) is a common clinical syndrome with high mortality and long-term morbidity. To date there is no effective pharmacological therapy. Aspirin therapy has recently been shown to reduce the risk of developing ARDS, but the effect of aspirin on established ARDS is unknown.

METHODS: In a single large regional medical and surgical ICU between December 2010 and July 2012, all patients with ARDS were prospectively identified and demographic, clinical, and laboratory variables were recorded retrospectively. Aspirin usage, both pre-hospital and during intensive care unit (ICU) stay, was included. The primary outcome was ICU mortality. We used univariate and multivariate logistic regression analyses to assess the impact of these variables on ICU mortality.

RESULTS: In total, 202 patients with ARDS were included; 56 (28%) of these received aspirin either pre-hospital, in the ICU, or both. Using multivariate logistic regression analysis, aspirin therapy, given either before or during hospital stay, was associated with a reduction in ICU mortality (odds ratio (OR) 0.38 (0.15 to 0.96) P = 0.04). Additional factors that predicted ICU mortality for patients with ARDS were vasopressor use (OR 2.09 (1.05 to 4.18) P = 0.04) and APACHE II score (OR 1.07 (1.02 to 1.13) P = 0.01). There was no effect upon ICU length of stay or hospital mortality.

CONCLUSION: Aspirin therapy was associated with a reduced risk of ICU mortality. These data are the first to demonstrate a potential protective role for aspirin in patients with ARDS. Clinical trials to evaluate the role of aspirin as a pharmacological intervention for ARDS are needed.

Unexpected Role for Adaptive αβTh17 Cells in Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) is a devastating disorder characterized by increased alveolar permeability with no effective treatment beyond supportive care. Current mechanisms underlying ARDS focus on alveolar endothelial and epithelial injury caused by products of innate immune cells and platelets. However, the role of adaptive immune cells in ARDS remains largely unknown. In this study, we report that expansion of Ag-specific αβTh17 cells contributes to ARDS by local secretion of IL-17A, which in turn directly increases alveolar epithelial permeability. Mice with a highly restrictive defect in Ag-specific αβTh17 cells were protected from experimental ARDS induced by a single dose of endotracheal LPS. Loss of IL-17 receptor C or Ab blockade of IL-17A was similarly protective, further suggesting that IL-17A released by these cells was responsible for this effect. LPS induced a rapid and specific clonal expansion of αβTh17 cells in the lung, as determined by deep sequencing of the hypervariable CD3RβVJ region of the TCR. Our findings could be relevant to ARDS in humans, because we found significant elevation of IL-17A in bronchoalveolar lavage fluid from patients with ARDS, and rIL-17A directly increased permeability across cultured human alveolar epithelial monolayers. These results reveal a previously unexpected role for adaptive immune responses that increase alveolar permeability in ARDS and suggest that αβTh17 cells and IL-17A could be novel therapeutic targets for this currently untreatable disease.

Mesenchymal stromal cells for treatment of the acute respiratory distress syndrome: The beginning of the story

In spite of decades of research, the acute respiratory distress syndrome (ARDS) continues to have an unacceptably high mortality and morbidity. Mesenchymal stromal cells (MSCs) present a promising candidate for the treatment of this condition and have demonstrated benefit in preclinical models. MSCs, which are a topic of growing interest in many inflammatory disorders, have already progressed to early phase clinical trials in ARDS. While a number of their mechanisms of effect have been elucidated, a better understanding of the complex actions of these cells may pave the way for MSC modifications, which might enable more effective translation into clinical practice.

Innate Lymphoid Cells are the Predominant Source of Interleukin-17A During the Early Pathogenesis of Acute Respiratory Distress Syndrome

Rationale: IL-17A is purported to help drive early pathogenesis in acute respiratory distress syndrome (ARDS) by enhancing neutrophil recruitment. Whilst IL-17A is the archetypal cytokine of T helper (Th)17 cells, it is produced by a number of lymphocytes, the source during ARDS being unknown.

Objectives: To identify the cellular source and the role of IL17A in the early phase of lung injury

Methods: Lung injury was induced in WT (C57BL/6) and IL-17 KO mice with aerosolised LPS (100 µg) or Pseudomonas aeruginosa infection. Detailed phenotyping of the cells expressing RORγt, the transcriptional regulator of IL-17 production, in the mouse lung at 24 hours was carried out by flow cytometry.

Measurement and Main Results: A 100-fold reduction in neutrophil infiltration was observed in the lungs of the IL-17A KO compared to wild type (WT) mice. The majority of RORγt+ cells in the mouse lung were the recently identified type 3 innate lymphoid cells (ILC3). Detailed characterisation revealed these pulmonary ILC3s (pILC3s) to be discrete from those described in the gut. The critical role of these cells was verified by inducing injury in Rag2 KO mice which lack T cells but retain ILCs. No amelioration of pathology was observed in the Rag2 KO mice.

Conclusions: IL-17 is rapidly produced during lung injury and significantly contributes to early immunopathogenesis. This is orchestrated largely by a distinct population of pILC3 cells. Modulation of pILC3s’ activity may potentiate early control of the inflammatory dysregulation seen in ARDS, opening up new therapeutic targets.

Aspirin as a potential treatment in sepsis or acute respiratory distress syndrome

Sepsis is a common condition that is associated with significant morbidity, mortality and health-care cost. Pulmonary and non-pulmonary sepsis are common causes of the acute respiratory distress syndrome (ARDS). The mortality from ARDS remains high despite protective lung ventilation, and currently there are no specific pharmacotherapies to treat sepsis or ARDS. Sepsis and ARDS are characterised by activation of the inflammatory cascade. Although there is much focus on the study of the dysregulated inflammation and its suppression, the associated activation of the haemostatic system has been largely ignored until recently. There has been extensive interest in the role that platelet activation can have in the inflammatory response through induction, aggregation and activation of leucocytes and other platelets. Aspirin can modulate multiple pathogenic mechanisms implicated in the development of multiple organ dysfunction in sepsis and ARDS. This review will discuss the role of the platelet, the mechanisms of action of aspirin in sepsis and ARDS, and aspirin as a potential therapy in treating sepsis and ARDS.

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.

Fluid strategies and outcomes in patients with acute respiratory distress syndrome, systemic inflammatory response syndrome and sepsis: a protocol for a systematic review and meta-analysis

Background
Fluid administration to critically ill patients remains the subject of considerable controversy. While intravenous fluid given for resuscitation may be life-saving, a positive fluid balance over time is associated with worse outcomes in critical illness. The aim of this systematic review is to summarise the existing evidence regarding the relationship between fluid administration or balance and clinically important patient outcomes in critical illness.

Methods
We will search Medline, EMBASE, the Cochrane Central Register of Controlled Trials from 1980 to the present and key conference proceedings from 2009 to the present. We will include studies of critically ill adults and children with acute respiratory distress syndrome (ARDS), sepsis and systemic inflammatory response syndrome (SIRS). We will include randomised controlled trials comparing two or more fluid regimens of different volumes of fluid and observational studies reporting the relationship between volume of fluid administered or fluid balance and outcomes including mortality, lengths of intensive care unit and hospital stay and organ dysfunction. Two independent reviewers will assess articles for eligibility, data extraction and quality appraisal. We will conduct a narrative and/or meta-analysis as appropriate.

Discussion
While fluid management has been extensively studied and discussed in the critical care literature, no systematic review has attempted to summarise the evidence for post-resuscitation fluid strategies in critical illness. Results of the proposed systematic review will inform practice and the design of future clinical trials.

Systematic review registration
PROSPERO CRD42013005608. (http://​www.​crd.​york.​ac.​uk/​PROSPERO/​)

Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome presents as hypoxia and bilateral pulmonary infiltrates on chest imaging in the absence of heart failure sufficient to account for this clinical state. Management is largely supportive, and is focused on protective mechanical ventilation and the avoidance of fluid overload. Patients with severe hypoxaemia can be managed with early short-term use of neuromuscular blockade, prone position ventilation, or extracorporeal membrane oxygenation. The use of inhaled nitric oxide is rarely indicated and both β2 agonists and late corticosteroids should be avoided. Mortality remains at approximately 30%.

Effects of physiotherapy on hemodynamic variables in newborns with Acute Respiratory Distress Syndrome

Background: Acute respiratory distress syndrome (ARDS) is a frequent respiratory disturbance in preterm newborns. Preceding investigations evaluated chronic physiotherapy effects on newborns with different lung diseases; however, no study analyzed acute physiotherapy treatment on premature newborns with ARDS. In this study we aimed to evaluate the acute effects of chest and motor physiotherapy treatment on hemodynamic variables in preterm newborns with ARDS. Methods: We evaluated heart rate (HR), respiratory rate (RR), systolic (SAP), mean (MAP) and diastolic arterial pressure (DAP), temperature and oxygen saturation (SO(2)%) in 44 newborns with ARDS. We compared all variables between six periods in one day: before first physiotherapy treatment vs. after first physiotherapy treatment vs. before second physiotherapy treatment vs. after second physiotherapy treatment vs. before third physiotherapy treatment vs. after third physiotherapy treatment. Variables were measured 2 minutes before and 5 minutes after each physiotherapy session. We applied Anova one way followed by post hoc Bonferroni test. Results: HR (147.5 +/- 9.5 bpm vs. 137.7 +/- 9.3 bpm; p<0.001), RR (45.5 +/- 8.7cpm vs. 41.5 +/- 6.7 cpm; p=0.001), SAP (70.3 +/- 10.4 mmHg vs. 60.1 +/- 7.1 mmHg; p=0.001) and MAP (55.7 +/- 10 mmHg vs. 46 +/- 6.6 mmHg; p=0.001) were significantly reduced after the third physiotherapy treatment compared to before the first session. There were no significant changes regarding temperature, DAP and SO(2) %. Conclusion: Chest and motor physiotherapy acutely improves HR, RR, SAP, MAP and SO(2) % in newborns with ARDS.

Positive end-expiratory pressure in acute respiratory distress syndrome: should the 'open lung strategy' be replaced by a 'protective lung strategy'?

In patients with acute respiratory distress syndrome, positive end-expiratory pressure is associated with alveolar recruitment and lung hyperinflation despite the administration of a low tidal volume. The best positive end-expiratory pressure should correspond to the best compromise between recruitment and distension, a condition that coincides with the best respiratory elastance.

Lung ultrasound in acute respiratory distress syndrome and acute lung injury

Purpose of reviewLung ultrasound at the bedside can provide accurate information on lung status in critically ill patients with acute respiratory distress syndrome.Recent findingsLung ultrasound can replace bedside chest radiography and lung computed tomography for assessment of pleural effusion, pneumothorax, alveolar- interstitial syndrome, lung consolidation, pulmonary abscess and lung recruitment/de-recruitment. It can also accurately determine the type of lung morphology at the bedside (focal or diffuse aeration loss), and therefore it is useful for optimizing positive end-expiratory pressure. The learning curve is brief, so most intensive care physicians will be able to use it after a few weeks of training.SummaryLung ultrasound is noninvasive, easily repeatable and allows assessment of changes in lung aeration induced by the various therapies. It is among the most promising bedside techniques for monitoring patients with acute respiratory distress syndrome.

Early administration of inhaled nitric oxide to children with acute respiratory distress syndrome and its effects on oxygenation and ventilator settings: prospective preliminary report of ten patients

Aim. To establish a protocol for the early introduction of inhaled nitric oxide (iNO) therapy in children with acute respiratory distress syndrome (ARDS) and to assess its acute and sustained effects on oxygenation and ventilator settings.Patients and Methods. Ten children with ARDS, aged 1 to 132 months (median, 11 months), with arterial saturation of oxygen <88% while receiving a fraction of inspired oxygen (FiO(2)) 0.6 and a positive end-expiratory pressure of greater than or equal to 10 cm H2O were included in the study. The acute response to iNO was assessed in a 4-hour dose-response test, and positive response was defined as an increase in the PaO2/FiO(2) ratio of 10 mmHg above baseline values. Conventional therapy was not changed during the test. In the following days, patients who had shown positive response continued to receive the lowest iNO dose. Hemodynamics, PaO2/FiO(2), oxygenation index, gas exchange, and methemoglobin levels were obtained when needed. Inhaled nitric oxide withdrawal followed predetermined rules.Results. At the end of the 4-hour test, all the children showed significant improvement in the PaO2/FiO(2) ratio (63.6%) and the oxygenation index (44.9%) compared with the baseline values. Prolonged treatment was associated with improvement in oxygenation, so that FiO(2) and peak inspiratory pressure could be quickly and significantly reduced., No toxicity from methemoglobin or nitrogen dioxide was observed.Conclusion. Administration of iNO to children is safe. iNO causes rapid and sustained improvement in oxygenation without adverse effects. Ventilator settings can safely be reduced during iNO treatment.