Acute Respiratory Distress Syndrome Thompson, B. Taylor; Chambers, Rachel C; Liu, Kathleen D
The New England journal of medicine,
08/2017, Letnik:
377, Številka:
6
Journal Article
Recenzirano
This month marks the 50th anniversary of the first description of the condition now termed the acute respiratory distress syndrome, or ARDS. The authors of this review discuss our current ...understanding of the pathobiology and treatment of ARDS.
The efficacy of drotrecogin alpha (activated) (DrotAA) for sepsis has been controversial. In this trial, there was no significant difference in all-cause mortality at 28 or 90 days between adults ...with sepsis who were treated with DrotAA and those treated with placebo.
Recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), was approved for the treatment of severe sepsis in 2001 on the basis of the Prospective Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study,
1
a phase 3 international, randomized, controlled trial that was stopped early for efficacy after the enrollment of 1690 patients with severe sepsis. Absolute mortality in the intention-to-treat population was reduced by 6.1 percentage points, a relative risk reduction of 19.4%. Subsequent subgroup analysis suggested that the mortality benefit was limited to patients with increased illness severity (i.e., those with more than one . . .
Purpose
Using latent class analysis (LCA), we have consistently identified two distinct subphenotypes in four randomized controlled trial cohorts of ARDS. One subphenotype has hyper-inflammatory ...characteristics and is associated with worse clinical outcomes. Further, within three negative clinical trials, we observed differential treatment response by subphenotype to randomly assigned interventions. The main purpose of this study was to identify ARDS subphenotypes in a contemporary NHLBI Network trial of infection-associated ARDS (SAILS) using LCA and to test for differential treatment response to rosuvastatin therapy in the subphenotypes.
Methods
LCA models were constructed using a combination of biomarker and clinical data at baseline in the SAILS study (
n
= 745). LCA modeling was then repeated using an expanded set of clinical class-defining variables. Subphenotypes were tested for differential treatment response to rosuvastatin.
Results
The two-class LCA model best fit the population. Forty percent of the patients were classified as the “hyper-inflammatory” subphenotype. Including additional clinical variables in the LCA models did not identify new classes. Mortality at day 60 and day 90 was higher in the hyper-inflammatory subphenotype. No differences in outcome were observed between hyper-inflammatory patients randomized to rosuvastatin therapy versus placebo.
Conclusions
LCA using a two-subphenotype model best described the SAILS population. The subphenotypes have features consistent with those previously reported in four other cohorts. Addition of new class-defining variables in the LCA model did not yield additional subphenotypes. No treatment effect was observed with rosuvastatin. These findings further validate the presence of two subphenotypes and demonstrate their utility for patient stratification in ARDS.
This trial revisited research conducted about a decade ago that showed a survival benefit with early neuromuscular blockade in patients with acute respiratory distress syndrome. The new trial did not ...show a benefit with neuromuscular blockade with respect to overall survival or other clinical outcomes.
Both quality improvement and clinical research efforts over the past few decades have focused on consensus definition of sepsis and acute respiratory distress syndrome (ARDS). Although clinical ...definitions based on readily available clinical data have advanced recognition and timely use of broad supportive treatments, they likely hinder the identification of more targeted therapies that manipulate select biological mechanisms underlying critical illness. Sepsis and ARDS are by definition heterogeneous, and patients vary in both their underlying biology and their severity of illness. We have long been able to identify subtypes of sepsis and ARDS that confer different prognoses. The key is that we are now on the verge of identifying subtypes that may confer different response to therapy. In this perspective, inspired by a 2015 American Thoracic Society International Conference Symposium entitled "Lumpers and Splitters: Phenotyping in Critical Illness," we highlight promising approaches to uncovering patient subtypes that may predict treatment responsiveness and not just differences in prognosis. We then discuss how this information can be leveraged to improve the success and translatability of clinical trials by using predictive enrichment and other design strategies. Last, we discuss the challenges and limitations to identifying biomarkers and endotypes and incorporating them into routine clinical practice.
Purpose
Our objective was to revise the definition of acute respiratory distress syndrome (ARDS) using a conceptual model incorporating reliability and validity, and a novel iterative approach with ...formal evaluation of the definition.
Methods
The European Society of Intensive Care Medicine identified three chairs with broad expertise in ARDS who selected the participants and created the agenda. After 2 days of consensus discussions a draft definition was developed, which then underwent empiric evaluation followed by consensus revision.
Results
The Berlin Definition of ARDS maintains a link to prior definitions with diagnostic criteria of timing, chest imaging, origin of edema, and hypoxemia. Patients may have ARDS if the onset is within 1 week of a known clinical insult or new/worsening respiratory symptoms. For the bilateral opacities on chest radiograph criterion, a reference set of chest radiographs has been developed to enhance inter-observer reliability. The pulmonary artery wedge pressure criterion for hydrostatic edema was removed, and illustrative vignettes were created to guide judgments about the primary cause of respiratory failure. If no risk factor for ARDS is apparent, however, objective evaluation (e.g., echocardiography) is required to help rule out hydrostatic edema. A minimum level of positive end-expiratory pressure and mutually exclusive PaO
2
/FiO
2
thresholds were chosen for the different levels of ARDS severity (mild, moderate, severe) to better categorize patients with different outcomes and potential responses to therapy.
Conclusions
This panel addressed some of the limitations of the prior ARDS definition by incorporating current data, physiologic concepts, and clinical trials results to develop the Berlin definition, which should facilitate case recognition and better match treatment options to severity in both research trials and clinical practice.
Two distinct acute respiratory distress syndrome (ARDS) subphenotypes have been identified using data obtained at time of enrolment in clinical trials; it remains unknown if these subphenotypes are ...durable over time.
To determine the stability of ARDS subphenotypes over time.
Secondary analysis of data from two randomised controlled trials in ARDS, the ARMA trial of lung protective ventilation (n=473; patients randomised to low tidal volumes only) and the ALVEOLI trial of low versus high positive end-expiratory pressure (n=549). Latent class analysis (LCA) and latent transition analysis (LTA) were applied to data from day 0 and day 3, independent of clinical outcomes.
In ALVEOLI, LCA indicated strong evidence of two ARDS latent classes at days 0 and 3; in ARMA, evidence of two classes was stronger at day 0 than at day 3. The clinical and biological features of these two classes were similar to those in our prior work and were largely stable over time, though class 2 demonstrated evidence of progressive organ failures by day 3, compared with class 1. In both LCA and LTA models, the majority of patients (>94%) stayed in the same class from day 0 to day 3. Clinical outcomes were statistically significantly worse in class 2 than class 1 and were more strongly associated with day 3 class assignment.
ARDS subphenotypes are largely stable over the first 3 days of enrolment in two ARDS Network trials, suggesting that subphenotype identification may be feasible in the context of clinical trials.
Ventilator-induced Lung Injury Beitler, Jeremy R; Malhotra, Atul; Thompson, B Taylor
Clinics in chest medicine,
12/2016, Letnik:
37, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Prevention of ventilator-induced lung injury (VILI) can attenuate multiorgan failure and improve survival in at-risk patients. Clinically significant VILI occurs from volutrauma, barotrauma, ...atelectrauma, biotrauma, and shear strain. Differences in regional mechanics are important in VILI pathogenesis. Several interventions are available to protect against VILI. However, most patients at risk of lung injury do not develop VILI. VILI occurs most readily in patients with concomitant physiologic insults. VILI prevention strategies must balance risk of lung injury with untoward side effects from the preventive effort, and may be most effective when targeted to subsets of patients at increased risk.
OBJECTIVES:The contribution of bacterial coinfection to critical illness associated with 2009 influenza A virus infection remains uncertain. The objective of this study was to determine whether ...bacterial coinfection increased the morbidity and mortality of 2009 influenza A.
DESIGN:Retrospective and prospective cohort study.
SETTING:Thirty-five adult U.S. intensive care units over the course of 1 yr.
PATIENTS:Six hundred eighty-three critically ill adults with confirmed or probable 2009 influenza A.
INTERVENTIONS:None.
MEASUREMENTS AND MAIN RESULTS:A confirmed or probable case was defined as a positive 2009 influenza A test result or positive test for influenza A that was otherwise not subtyped. Bacterial coinfection was defined as documented bacteremia or any presumed bacterial pneumonia with or without positive respiratory tract culture within 72 hrs of intensive care unit admission. The mean age was 45 ± 16 yrs, mean body mass index was 32.5 ± 11.1 kg/m, and mean Acute Physiology and Chronic Health Examination II score was 21 ± 9, with 76% having at least one comorbidity. Of 207 (30.3%) patients with bacterial coinfection on intensive care unit admission, 154 had positive cultures with Staphylococcus aureus (n = 57) and Streptococcus pneumoniae (n = 19), the most commonly identified pathogens. Bacterial coinfected patients were more likely to present with shock (21% vs. 10%; p = .0001), require mechanical ventilation at the time of intensive care unit admission (63% vs. 52%; p = .005), and have longer duration of intensive care unit care (median, 7 vs. 6 days; p = .05). Hospital mortality was 23%; 31% in bacterial coinfected patients and 21% in patients without coinfection (p = .002). Immunosuppression (relative risk 1.57; 95% confidence interval 1.20 –2.06; p = .0009) and Staphylococcus aureus at admission (relative risk 2.82; 95% confidence interval 1.76–4.51; p < .0001) were independently associated with increased mortality.
CONCLUSIONS:Among intensive care unit patients with 2009 influenza A, bacterial coinfection diagnosed within 72 hrs of admission, especially with Staphylococcus aureus, was associated with significantly higher morbidity and mortality.
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