Existing studies of risk factors for physical impairments in acute lung injury (ALI) survivors were potentially limited by single-center design or relatively small sample size.
To evaluate risk ...factors for three measures of physical impairments commonly experienced by survivors of ALI in the first year after hospitalization.
A prospective, longitudinal study of 6- and 12-month physical outcomes (muscle strength, 6-minute-walk distance, and Short Form SF-36 Physical Function score) for 203 survivors of ALI enrolled from 12 hospitals participating in the ARDS Network randomized trials. Multivariable regression analyses evaluated the independent association of critical illness-related variables and intensive care interventions with impairments in each physical outcome measure, after adjusting for patient demographics, comorbidities, and baseline functional status.
At 6 and 12 months, respectively, mean (± SD) values for strength (presented as proportion of maximum strength score evaluated using manual muscle testing) was 92% (± 8%) and 93% (± 9%), 6-minute-walk distance (as percent-predicted) was 64% (± 22%) and 67% (± 26%), and SF-36 Physical Function score (as percent-predicted) was 61% (± 36%) and 67% (± 37%). After accounting for patient baseline status, there was significant association and statistical interaction of mean daily dose of corticosteroids and intensive care unit length of stay with impairments in physical outcomes.
Patients had substantial impairments, from predicted values, for 6-minute-walk distance and SF-36 Physical Function outcome measures. Minimizing corticosteroid dose and implementing existing evidence-based methods to reduce duration of intensive care unit stay and associated patient immobilization may be important interventions for improving ALI survivors' physical outcomes.
Increased procoagulant activity in the alveolar compartment and uncontrolled inflammation are hallmarks of the acute respiratory distress syndrome (ARDS). Here, we investigated whether the contact ...phase system of coagulation is activated and may regulate inflammatory responses in human lungs. Components of the contact phase system were characterized in bronchoalveolar lavage fluids (BALF) from 54 ARDS patients and 43 controls, and their impact on cytokine/chemokine expression in human precision cut lung slices (PCLS) was assessed by a PCR array. Activation of the contact system, associated with high levels of coagulation factor XIIa (Hageman factor, FXIIa), plasma kallikrein and bradykinin, occurred rapidly in ARDS lungs after the onset of the disease and virtually normalized within one week from time of diagnosis. FXII levels in BALF were higher in ARDS non-survivors than survivors and were positively correlated with tumor necrosis factor (TNF)-α concentration. FXII induced the production and release of interleukin (IL)-8, IL-1β, IL-6, leukemia inhibitory factor (LIF), CXCL5 and TNF-α in human PCLS in a kallikrein-kinin-independent manner. In conclusion, accumulation of FXII in ARDS lungs may contribute to the release of pro-inflammatory mediators and is associated with clinical outcome. FXII inhibition may thus offer a novel and promising therapeutic approach to antagonize overwhelming inflammatory responses in ARDS lungs without interfering with vital haemostasis.
Because experimental studies have shown that intact alveolar epithelial fluid transport function is critical for resolution of pulmonary edema and acute lung injury, we measured net alveolar fluid ...clearance in 79 patients with acute lung injury or the acute respiratory distress syndrome. Pulmonary edema fluid and plasma were sampled serially in the first 4 hours after intubation. Net alveolar fluid clearance was calculated from sequential edema fluid protein measurements. Mean alveolar fluid clearance was 6%/h. Of the patients, 56% had impaired alveolar fluid clearance (< 3%/h), 32% had submaximal clearance (> or = 3%/h, < 14%/h), and 13% had maximal clearance (> or = 14%/h). These findings are contrasted to our recent report of 65 patients with hydrostatic pulmonary edema, in whom mean alveolar fluid clearance was 13%/h; only 25% had impaired clearance whereas 75% had submaximal or maximal clearance (J Appl Physiol 1999;87:1301-1312). Acute lung injury with maximal alveolar fluid clearance were more likely to be female (p = 0.03), and less likely to have sepsis (p = 0.01). Endogenous and exogenous catecholamines did not correlate with alveolar fluid clearance. Patients with maximal alveolar fluid clearance had significantly lower mortality and a shorter duration of mechanical ventilation. In summary, in contrast to hydrostatic pulmonary edema, alveolar fluid clearance in patients with acute lung injury and the acute respiratory distress syndrome is impaired in the majority of patients, and maximal alveolar fluid clearance is associated with better clinical outcomes.
Extracorporeal life support (ECLS) can support gas exchange in patients with the acute respiratory distress syndrome (ARDS). During ECLS, venous blood is drained from a central vein via a cannula, ...pumped through a semipermeable membrane that permits diffusion of oxygen and carbon dioxide, and returned via a cannula to a central vein. Two related forms of ECLS are used. Venovenous extracorporeal membrane oxygenation (ECMO), which uses high blood flow rates to both oxygenate the blood and remove carbon dioxide, may be considered in patients with severe ARDS whose oxygenation or ventilation cannot be maintained adequately with best practice conventional mechanical ventilation and adjunctive therapies, including prone positioning. Extracorporeal carbon dioxide removal (ECCO
2
R) uses lower blood flow rates through smaller cannulae and provides substantial CO
2
elimination (~ 20–70% of total CO
2
production), albeit with marginal improvement in oxygenation. The rationale for using ECCO
2
R in ARDS is to facilitate lung-protective ventilation by allowing a reduction of tidal volume, respiratory rate, plateau pressure, driving pressure and mechanical power delivered by the mechanical ventilator. This narrative review summarizes physiological concepts related to ECLS, as well as the rationale and evidence supporting ECMO and ECCO
2
R for the treatment of ARDS. It also reviews complications, limitations, and the ethical dilemmas that can arise in treating patients with ECLS. Finally, it discusses future key research questions and challenges for this technology.
Despite progress in the supportive care available for critically ill patients, few advances have been made in the search for effective disease-modifying therapeutic options. The fact that many trials ...in critical care medicine have not identified a treatment benefit is probably due, in part, to the underlying heterogeneity of critical care syndromes. Numerous approaches have been proposed to divide populations of critically ill patients into more meaningful subgroups (subphenotypes), some of which might be more useful than others. Subclassification systems driven by clinical features and biomarkers have been proposed for acute respiratory distress syndrome, sepsis, acute kidney injury, and pancreatitis. Identifying the systems that are most useful and biologically meaningful could lead to a better understanding of the pathophysiology of critical care syndromes and the discovery of new treatment targets, and allow recruitment in future therapeutic trials to focus on predicted responders. This Review discusses proposed subphenotypes of critical illness syndromes and highlights the issues that will need to be addressed to translate subphenotypes into clinical practice.
Many lung diseases, such as the acute respiratory distress syndrome (ARDS), display significant regional heterogeneity with patches of severely injured tissue adjacent to apparently healthy tissue. ...Current mouse models that aim to mimic ARDS generally produce diffuse injuries that cannot reproducibly generate ARDS's regional heterogeneity. This deficiency prevents the evaluation of how well therapeutic agents reach the most injured regions and precludes many regenerative medicine studies since it is not possible to know which apparently healing regions suffered severe injury initially. Finally, these diffuse injury models must be relatively mild to allow for survival, as their diffuse nature does not allow for residual healthy lung to keep an animal alive long enough for many drug and regenerative medicine studies. To solve all of these deficiencies in current animal models, we have created a simple and reproducible technique to selectively induce lung injury in specific areas of the lung. Our technique, catheter-in-catheter selective lung injury (CICSLI), involves guiding an inner catheter to a particular area of the lung and delivering an injurious agent mixed with nanoparticles (fluorescently and/or radioactively labeled) that can be used days later to track the location and extent of where the initial injury occurred. Furthermore, we demonstrate that CICSLI can produce a more severe injury than diffuse models, yet has much higher survival since CICSLI intentionally leaves lung regions undamaged. Collectively, these attributes of CICSLI will allow investigators to better study how drugs act within heterogeneous lung pathologies and how regeneration occurs in severely damaged lung tissue, thereby aiding the development of new therapies for ARDS and other heterogenous lung diseases.
Sepsis is the most important predisposing cause inducing acute respiratory distress syndrome (ARDS); however, the mechanism of sepsis leading to the development of ARDS remains to be elucidated. ...Suppression of the mitogen‑activated protein kinase (MAPK) signal by blocking the phosphorylation of Jun N‑terminal kinase (JNK) and p38 in lung tissues could alleviate acute lung injury induced by sepsis. MAPK signaling may have a crucial role in development of the sepsis‑induced acute lung injury. The specific inhibitors of JNK and p38 MAPK, SP600125 and SB203580, were administrated by intragastric injection 4 h before induction of ARDS after cecal ligation and puncture (CLP). Rats were sacrificed at 1, 6 or 24 h after CLP challenge. The histological evaluation, lung water content, and biochemical analysis were performed. The results revealed that the JNK and p38 MAPK inhibitor improved lung permeability, attenuated system inflammation, further alleviated the lung injury induced by sepsis. In conclusion, JNK and p38 MAPK signaling are essential for the development of ARDS following sepsis. Further studies are needed to illuminate the detailed mechanisms of JNK and p38 MAPK signaling in sepsis‑induced ARDS.
In 2015, the Pediatric Acute Lung Injury Consensus Conference (PALICC) provided the first pediatric-specific definitions for acute respiratory distress syndrome (pediatric acute respiratory distress ...syndrome PARDS). These definitions have since been operationalized in cohort and interventional PARDS studies. As substantial data have accrued since 2015, we have an opportunity to assess the construct validity and utility of the initial PALICC definitions. Therefore, the Second PALICC (PALICC-2) brought together multiple PARDS experts and aimed to identify and summarize relevant evidence related to the definition and epidemiology of PARDS and create modifications to the definition of PARDS.
MEDLINE (Ovid), Embase (Elsevier), and CINAHL Complete (EBSCOhost).
We included studies of subjects with PARDS, or at risk for PARDS, excluding studies pertaining primarily to adults except as specified for identifying age-specific cutoffs.
Title/abstract review, full-text review, and data extraction using a standardized data collection form.
The Grading of Recommendations Assessment, Development, and Evaluation approach was used to identify and summarize evidence and develop recommendations. A total of 97 studies were identified for full-text extraction addressing distinct aspects of the PARDS definition, including age, timing, imaging, oxygenation, modes of respiratory support, and specific coexisting conditions. Data were assessed in a Patient/Intervention/Comparator/Outcome format when possible, and formally summarized for effect size, risk, benefit, feasibility of implementation, and equity. A total of 17 consensus-based definition statements were made that update the definition of PARDS, as well as the related diagnoses of "Possible PARDS" and "At-Risk for PARDS." These statements are presented alongside a summary of the relevant epidemiology.
We present updated, data-informed consensus statements on the definition for PARDS and the related diagnoses of "Possible PARDS" and "At-Risk for PARDS."
To longitudinally evaluate the association of post-ICU muscle weakness and associated trajectories of weakness over time with 5-year survival.
Longitudinal prospective cohort study over 5 years of ...follow-up.
Thirteen ICUs in four hospitals in Baltimore, MD.
One hundred fifty-six acute respiratory distress syndrome survivors.
None.
Strength was evaluated with standardized manual muscle testing using the Medical Research Council sum score (range, 0-60; higher is better), with post-ICU weakness defined as sum score less than 48. Muscle strength was assessed at hospital discharge and at 3, 6, 12, 24, 36, and 48 months after acute respiratory distress syndrome. At discharge, 38% of patients had muscle weakness. Every one point increase in sum score at discharge was associated with improved survival (hazard ratio 95% CI, 0.96 0.94-0.98), with similar findings longitudinally (0.95 0.93-0.98). Having weakness at discharge was associated with worse 5-year survival (1.75 1.01-3.03), but the association was attenuated (1.54 0.82-2.89) when evaluated longitudinally over follow-up. Persisting and resolving trajectories of muscle weakness, occurring in 50% of patients during follow-up, were associated with worse survival (3.01 1.12-8.04; and 3.14 1.40-7.03, respectively) compared to a trajectory of maintaining no muscle weakness.
At hospital discharge, greater than one third of acute respiratory distress syndrome survivors had muscle weakness. Greater strength at discharge and throughout follow-up was associated with improved 5-year survival. In patients with post-ICU weakness, both persisting and resolving trajectories were commonly experienced and associated with worse survival during follow-up.
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