ARDS

Managing Acute Respiratory Distress Syndrome

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Background

Acute respiratory distress syndrome (ARDS) is a form of hypoxemic respiratory failure with high mortality. The mainstays of therapy are supportive and are designed to minimize further lung injury from mechanical ventilation. With the large number of patients with ARDS during the early COVID-19 pandemic, new data supports some revisions to standard care of patients with ARDS. The ATS has now released an update of its 2017 guideline, originally published in association with the European Society of Intensive Care Medicine and the Society of Critical Care Medicine (Am J Respir Crit Care Med 2017; 195:1253. opens in new tab).

Key Points

  • Administration of steroids is recommended, although without specific guidance on choice of steroid, dose, timing, or duration. The document suggests following steroid recommendations for specific causes of ARDS (e.g., COVID-19, community-acquired pneumonia).
  • Neuromuscular blockade (NMB) is recommended in early treatment of patients with severe ARDS (partial pressure of oxygen [PaO2]:fraction of inspired oxygen [FiO2] <100) and courses should be limited to 48 hours or shorter.
  • Venovenous extracorporeal membrane oxygenation (ECMO) now is recommended for select patients with severe ARDS (PaO2:FiO2 <80 or pH <7.25 with PaCO2 ≥60 mm Hg), although with low certainty of evidence.
  • Higher levels of positive end-expiratory pressure (PEEP) are recommended for patients with moderate-to-severe ARDS.
  • Recruitment maneuvers (i.e., short duration holds of higher inspiratory pressure, designed to open atelectatic alveoli) are strongly discouraged.
  • Strong recommendations for both low tidal volume ventilation and prone positioning for moderate-to-severe ARDS remain from the 2017 guideline.

Comment

This guideline addresses use of steroids and neuromuscular blockade, both of which were omitted in the 2017 guideline. Administration of steroids should be considered in all patients with attention to the cause of ARDS and concomitant conditions (e.g., sepsis) to determine dose and duration. More cautious use of NMB makes sense, although it can be helpful in patients with severe ARDS and ventilator dyssynchrony. Venovenous ECMO remains resource-intense and should be considered only after optimization of mechanical ventilation, prone positioning, and neuromuscular blockade administration.

Gut Bacteria May Drive Inflammation in Sepsis, ARDS

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Microbiome disruption in lungs may play key role in diseases.

Bacteria that live in the gut also show up in the lungs of critically ill patients with acute respiratory distress syndrome (ARDS) and in a mouse model of sepsis, suggesting a shared mechanism of pathogenesis for the two deadly diseases.
Bacterial gene sequencing was used to identify the gut bacteria which are not detectable using conventional culture. Greater concentrations of gut bacteria in bronchoalveolar lavage fluid from patients with ARDS were associated with greater inflammation, wrote researcher Robert P. Dickson, MD, of the University of Michigan Medical School, Ann Arbor, and colleagues in the journal Nature Microbiology.

The researchers noted that while the intestinal microbiome has long been recognized as having a key role in both sepsis and ARDS, conventional culture-based studies have failed to demonstrate translocation of bacteria from the gut to the lungs.
In a series of newly reported studies, Dickson and colleagues used bacterial gene sequencing to identify entire communities of bacteria, now a standard method for microbiome studies. The approach allowed the researchers to identify bacteria in the lungs not seen with conventional culture.
It also permitted the researchers to study communities of bacteria rather than individual species, Dickson explained.
“The main new finding is that gut bacteria, which can normally not be found in the lungs, are detectable in the lungs of animals and humans with common diseases of critical illness,” Dickson told MedPage Today. “This disorder of the lung microbiome was associated with how much inflammation we measured in the blood and in the lungs.”
Inflammation plays a key role in both sepsis and ARDS, and the findings raise the possibility that this inflammation may be due, at least in part, to alterations in bacterial communities, he added.

In their initial studies, the researchers used an established mouse model of sepsis — via cecal ligation and puncture (CLP) — to study the microbiota of the gastrointestinal and respiratory tracts by sequencing bacterial 16S ribosomal RNA-encoding genes.
Bacterial communities in the lungs of the mice with sepsis were found to be significantly different from those of untreated (control) mice.
“Lung communities of post-sepsis mice were significantly enriched with numerous bacteria found in the murine gut, including members of the Bacteroidales order Enterococcus species, and Lachnospiraceae sp. The two most abundant taxonomic groups, comprising nearly 40% of community members, were members of the Bacteroidales order, an abundant member of the murine gut microbiome,” the researchers wrote.
Five days post-sepsis, bacterial communities from lungs of post-sepsis mice remained distinct from those of all control mice, but the bacterial communities were indistinguishable from control mice at 2 weeks and 8 weeks following CLP.
In another round of studies, the researchers sequenced bacterial communities from 100 specimens of bronchoalveolar lavage (BAL) fluid collected from 68 patients with ARDS and compared these communities to those of seven healthy volunteers.
The researchers focused on the Bacteroides genus (OTU009), which was classified to the same order as the operational taxonomic units (OTUs) enriched in the post-sepsis lungs of the experimental mice.
This gut-associated Bacteroides OTU was common and abundant in the BAL fluid of patients with ARDS and was not detected in reagent control specimens nor in the BAL fluid of healthy subjects.
“Among patients with ARDS, we observed a significant association between relative abundance of this gut-associated Bacteroides OTU and patients’ concurrent serum TNF-α concentration,” the researchers wrote. “This finding indicates that enrichment of gut bacteria in the lung microbiome is correlated with severity of acute systemic inflammation.”
No association was seen between Bacteroides OTU abundance and alveolar TNF-α concentration, suggesting that gut-lung bacterial translocation correlates with systemic, but not alveolar, inflammation.
The researchers wrote that definitive proof of gut-lung translocation will require additional study, “including techniques such as paired metagenomic comparisons of gut and lung microbiota and the use of labelled ‘tracer’ bacteria in gnotobiotic animals.”
They noted that the confirmation of gut-lung translocation and alteration of the lung microbiome in ARDS and sepsis could lead to novel therapeutic strategies to prevent and treat these deadly disorders, even though this mechanism is likely only one of several that lead to ARDS and sepsis.

Aspirin Therapy Fails to Reduce ARDS

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Initiating aspirin therapy to emergency room patients at risk of lung injury does not influence the chance that these patients will experience acute respiratory distress syndrome(ARDS), researchers reported here.

The development of ARDS occurred within 7 days in 20 of 195 patients (10.3%) assigned to aspirin and in 17 of 195 patients (8.7%) presenting in the emergency room (P=0.53), reported Daryl Kor, MD, of the Mayo Clinic in Rochester, Minn.

n presenting their research at the annual meeting of the American Thoracic Society, additionally, Kor and colleagues reported no statistically significant differences in ventilator-free days, in length of stay in the intensive care unit, in hospital length of stay, in 28-day survival, or in bleeding events. The study was published online in the Journal of American Medical Association simultaneously with its presentation here.
“Among at-risk patients presenting to the emergency department, the use of aspirin compared with placebo did not reduce the risk of ARDS at 7 days,” Kor reported. “The findings of this Phase 2b trial do not support continuation to a larger Phase 3 trial.”
Patients who were included in the trial received a loading dose of aspirin 325 mg, followed by daily 81 mg doses within 24 hours of emergency department presentation and continued to hospital day 7, discharge, or death. The median age of the patients was 57 years, and 48% of the patients included in the study were women. Patients were evaluated on the basis of the Lung Injury Prediction Score — with a score of 4 or greater the threshold for the aspirin therapy.
The researchers suggested that aspirin might make a difference in outcomes “based on the body of existing experimental data demonstrating alterations in platelet function during the development of ARDS. Platelet activation, aggregation, and sequestration, as well as modulation of anti-inflammatory lipid mediators, including leukotrienes, thromboxane, and prostaglandins,have all been implicated as important mediators of ARDS progression and severity. Aspirin directly modifies these mechanistic pathways, making it a plausible preventive and therapeutic measure in this setting.”
But in the clinical trial, treatment with aspirin didn’t improve outcomes.
Ventilator-free days through day 28 were 24.9 among the patients on aspirin; 25.2 among those on placebo (P=0.72).
Intensive care unit length of stay was 5.2 days among patients treated with aspirin; 5.4 days among patients who received placebo (P=0.87).
Hospital length of stay was 8.8 days among the aspirin-treated patients; 9.0 days among those on placebo (P=0.79).
Survival at 28 days was 90% for both cohorts (P=0.92).
One-year estimated survival was 73% among the patients on aspirin and 75% among the placebo patients (P=0.79).
No statistically significant differences were found in measures of safety. Eleven patients or 5.6% of those on aspirin experienced bleeding events compared with 5 patients or 2.6% of patients on placebo (P=0.13).

Kor reported that the trial results were likely shaped by a less than expected rate of ARDS in the population. The rate of 9.5% was far lower than the predicted 18% rate, he reported. “In addition to the lower than expected rate of ARDS, low rates of mechanical ventilation, acute kidney injury, and mortality suggest that the enrolled study population may have had a more modest overall severity of illness than what was anticipated at study onset,” the researchers stated. “As a result, the external validity of our findings in a cohort of critically ill patients with greater severity of illness remains unclear. Still, the results of this trial appear robust and consistent between the clinical and biomarker outcome measures.”
In an editorial that accompanied the study in JAMA, John Reilly, MD, instructor in medicine, and Jason Christie, MD, professor of medicine at the University of Pennsylvania, wrote:
“The attributable mortality associated with ARDS in the setting of critical illness is controversial, but ARDS is associated with increased length of intensive care unit stay, duration of ventilatory support, and poor long-term function and neurocognitive outcomes.
“Preventing ARDS is a worthy goal; however, ARDS is not a patient-centered outcome, nor a validated surrogate outcome for patient-centered outcomes,” they suggested. “Additionally, preventing ARDS does not ensure either improved survival or post-hospitalization quality of life. It is possible that an intervention may decrease ARDS risk but actually increase mortality.
“For example, if aspirin reduced ARDS incidence but resulted in significant bleeding complications or other unforeseen effects, the therapy should be avoided. Alternatively, an immunomodulatory therapy that reduces ARDS risk also may reduce pathogen clearance in patients with sepsis, resulting in overall negative effects.
“Conventional ARDS trials have chosen mortality as a primary outcome. In an ARDS prevention trial with mortality of 9%, as seen in the LIPS-A study, conducting a larger trial with sufficient power to detect mortality effects would be excessively expensive and likely infeasible.
“Ideally, future trials would both aim to prevent ARDS but also focus on mortality, functional status, or hospital costs in a population selected to be at highest risk and most likely to respond to a specific therapy,” they suggested.

The Use of Inhaled Prostaglandins in Patients With ARDS

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OBJECTIVE:  This study aimed to determine whether inhaled prostaglandins are associated with improvement in pulmonary physiology or mortality in patients with ARDS and assess adverse effects.

METHODS:  The following data sources were used: PubMed, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, reference lists, conference proceedings, and ClinicalTrials.gov. Studies selected included randomized controlled trials and nonrandomized studies. For data extraction, two reviewers independently screened titles and abstracts for eligibility. With regard to data synthesis, 25 studies (two RCTs) published over 21 years (1993-2014) were included. The PROSPERO registration number was CRD42014013180.

RESULTS:  One randomized controlled trial showed no difference in the change in mean Pao2 to Fio2 ratio when comparing inhaled alprostadil to placebo: 141.2 (95% CI, 120.8-161.5) to 161.5 (95% CI, 134.6-188.3) vs 163.4 (95% CI, 140.8-186.0) to 186.8 (95% CI, 162.9-210.7), P = .21. Meta-analysis of the remaining studies demonstrated that inhaled prostaglandins were associated with improvement in Pao2 to Fio2 ratio (16 studies; 39.0% higher; 95% CI, 26.7%-51.3%), and Pao2(eight studies; 21.4% higher; 95% CI, 12.2%-30.6%), and a decrease in pulmonary artery pressure (−4.8 mm Hg; 95% CI, −6.8 mm Hg to −2.8 mm Hg). Risk of bias and heterogeneity were high. Meta-regression found no association with publication year (P = .862), baseline oxygenation (P = .106), and ARDS etiology (P = .816) with the treatment effect. Hypotension occurred in 17.4% of patients in observational studies.

CONCLUSIONS:  In ARDS, inhaled prostaglandins improve oxygenation and decrease pulmonary artery pressures and may be associated with harm. Data are limited both in terms of methodologic quality and demonstration of clinical benefit. The use of inhaled prostaglandins in ARDS needs further study.

“Proning” Benefits Patients with Severe ARDS.

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Acute respiratory distress syndrome–associated 28-day mortality was halved in patients who spent most of the day face down.

 

Patients with acute respiratory distress syndrome (ARDS) commonly develop consolidation of the dependent lung regions. For many years, physicians have transitioned severely hypoxemic patients from supine to prone position to improve aeration of these areas and gas exchange. Small studies of “proning” demonstrated improved oxygenation without affecting more important outcomes; meta-analyses suggested proning could lower ARDS-associated mortality (Intensive Care Med 2010; 36:585).

This large French trial involved 466 patients with moderate-to-severe ARDS (ratio of partial pressure of arterial oxygen to fraction of inspired oxygen [PaO2:FiO2] <150, with FiO2 0.6; positive end-expiratory pressure, 5 cm H2O). All patients received low tidal-volume ventilation and were randomized to daily prone positioning or to supine positioning only. Intervention patients were placed in the prone position within 1 hour of randomization and underwent an average of four sessions of proning (mean duration per daily session, 17.3 hours). At randomization, >80% of patients were receiving neuromuscular blockade, and approximately 40% were receiving glucocorticoids. Mortality at 28 days was 16% in the prone group and 33% in the supine group.

Comment: These results give new life to the practice of proning. Although this intervention is not suitable for all patients with acute respiratory distress syndrome (e.g., those with recent sternotomy or facial trauma), proning should be considered early for most patients with severe disease. Almost all patients in this study received neuromuscular blockade, which reinforces earlier administering of short-term paralytics for severe hypoxemia. Patients in this study were proned for prolonged periods. Delivering care safely to patients in this position for most of the day will require additional training of nurses and other providers.

 

Source: Journal Watch General Medicine

Use of Prone Positioning During Ventilatory Support Found Superior in ARDS.

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In patients with acute respiratory distress syndrome (ARDS), use of the prone position during ventilatory support roughly doubled survival at the 1- and 3-month marks, according to a New England Journal of Medicinestudy.

Researchers followed outcomes in nearly 500 patients with severe ARDS who were randomized either to prone positioning for at least 16 consecutive hours a day, or to being left supine. By 28 days, mortality was 16% in the prone group, versus 33% in the supine group; at 90 days, the prone-positioning advantage held: 24% versus 41%.

An editorialist calls the results “compelling,” and the treatment effect “virtually unprecedented in modern medicine.” He cautions, however, that the logistics of turning patients to the prone position from supine requires teamwork to avoid kinking and extubation. The article includes a video showing how this can be accomplished with three people.

Source: NEJM 

Efficacy of ibuprofen and pentoxifylline in the treatment of phosgene-induced acute lung injury.

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Phosgene, a highly reactive former warfare gas, is a deep lung irritant which produces adult respiratory distress syndrome (ARDS)-like symptoms following inhalation. Death caused by phosgene involves a latent, 6-24-h, fulminating non-cardiogenic pulmonary edema. The following dose-ranging study was designed to determine the efficacy of a non-steroidal anti-inflammatory drug, ibuprofen (IBU), and a methylxanthine, pentoxifylline (PTX). These drugs were tested singly and in combination to treat phosgene-induced acute lung injury in rats. Ibuprofen, in concentrations of 15-300 mg kg-1 (i.p.), was administered to rats 30 min before and 1 h after the start of whole-body exposure to phosgene (80 mg m-3 for 20 min). Pentoxifylline, 10-120 mg kg-1 (i.p.), was first administered 15 min prior to phosgene exposure and twice more at 45 and 105 min after the start of exposure. Five hours after phosgene inhalation, rats were euthanized, the lungs were removed and wet weight values were determined gravimetrically. Ibuprofen administered alone significantly decreased lung wet weight to body weight ratios compared with controls (P < or = 0.01) whereas PTX, at all doses tested alone, did not. In addition, the decrease in lung wet weight to body weight ratio observed with IBU+PTX could be attributed entirely to the dose of IBU employed. This is the first study to show that pre- and post-treatment with IBU can significantly reduce lung edema in rats exposed to phosgene.

Source: Journal of applied Toxicology

Respiratory distress syndrome in patients with advanced cancer treated with pentoxifylline: a randomized study.

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Abstract

The inappropriate endogenous secretion of tumour necrosis factor (TNF) could play a role in the pathogenesis of acute respiratory distress syndrome (ARDS), one of the most frequent causes of death in cancer patients. Because of its capacity to inhibit TNF secretion in vitro, pentoxifylline (PTX) could be extremely useful in ARDS therapy. In this study 30 advanced cancer patients with ARDS were randomized to receive either the conventional care or conventional care plus PTX (100 mg i.v. twice a day for 7 days followed by an oral administration of 400 mg three times a day) to evaluate the efficacy of PTX in reducing TNF serum levels and in improving the symptoms of this syndrome. Serum levels of TNF were measured before and after 7 days of therapy. The percentage of patients alive at 7 days was significantly higher in the PTX-treated group than in the controls (12/15 versus 3/15; P < 0.001). The mean survival time was significantly higher in the PTX-treated group than in the controls. A clinical and/or radiological improvement was obtained in 11/15 patients treated with PTX and in only 2/15 patients in the conventional care group (P < 0.01). TNF mean levels significantly decrease in the PTX-treated group. These data confirm in vivo the capacity of PTX to inhibit TNF secretion in patients with ARDS. Moreover PTX therapy may improve the symptoms related to ARDS without particular toxic effects.

Source:Pubmed.

Improved Survival in ARDS With Early Cisatracurium Use

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Neuromuscular Blockers in Early Acute Respiratory Distress Syndrome

Papazian L, Forel JM, Gacouin A, et al; ACURASYS Study Investigators
N Engl J Med. 2010;363:1107-1116

Study Summary

In acute respiratory distress syndrome (ARDS), close attention to lung protective ventilation and prevention of nosocomial complications is key, particularly given a lack of specific therapy to improve survival. Papazian and colleagues sought to determine whether early administration of neuromuscular blocking agents might improve outcomes in patients with severe ARDS. Critically ill patients were identified within 48 hours of severe ARDS developing (partial pressure of arterial oxygen [PaO2]/fraction of inspired oxygen [FiO2] ratio < 150) and were randomly assigned to receive, for 48 hours, either cisatracurium (n = 178 patients) or placebo (n = 162 patients). Mortality at 28 days was 23.7% with cisatracurium and 33.3% with placebo (P = .05); 90-day mortality was 31.6% in the cisatracurium group and 40.7% in the placebo group (P = .08). After adjustment for differences in baseline PaO2/FiO2 ratio, plateau pressure, and illness severity (Simplified Acute Physiology II score), the hazard ratio for death at 90 days in the cisatracurium group compared with the placebo group was 0.68 (95% confidence interval [CI], 0.48 to 0.98; P = .04). The rate of intensive care unit-acquired paresis did not differ between the 2 groups. The investigators concluded that early administration of neuromuscular blocking agents improved 90-day survival and increased the time off the ventilator without increasing muscle weakness in patients with severe ARDS.

Viewpoint

This clinical trial suggests an important clinical outcome benefit of early neuromuscular blockade in the treatment of patients with severe ARDS. This is remarkable in an era when new evidence about pulmonary artery catheterization,[1] tracheostomy,[2] transfusion,[3] and low tidal volume ventilation[4] has led to critical care physicians often doing “less” rather than “more.” Despite this contrast, the real challenge of this study is assessing the veracity of the findings and determining the potential application to our patients with acute lung injury and ARDS.

The first question cannot be answered with absolute certainty. Although this study was conducted in 20 French intensive care units, because the results are somewhat counterintuitive and lack biologic rationale, confirmation of the clinical benefits in another study population is desirable. Further exploration of the mechanism(s) by which cisatracurium neuromuscular blockade improves survival is also important. For the second question, although it has long been appreciated that those with acute lung injury and ARDS rarely die of refractory respiratory failure or hypoxemia, this does occur in a small proportion (approximately 5%) of patients.[5] For this subgroup, which represents those with the most severe and refractory hypoxemia, treatment with neuromuscular blockade could be lifesaving by reducing oxygen consumption and mitigating arterial (and tissue) hypoxia. Are these the patients represented in this study who were enrolled with a PaO2/FiO2 ratio < 150? The available data suggest that this is the case, given that the average PaO2/FiO2 ratio at enrollment was just over 100 with ventilator-delivered positive end-expiratory pressure exceeding 9 cm H2O, and that the beneficial effect of cisatracurium on survival was confined to the two thirds of patients with PaO2/FiO2 ratios < 120. If the benefits observed in this study are reproduced in other studies with similar or more diverse populations, then applying early neuromuscular blockade with cisatracurium could represent the next frontier of therapy in patients with severe ARDS.

source: medscape