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The role of non-invasive respiratory support (high-flow nasal oxygen and noninvasive ventilation) in the management of acute hypoxemic respiratory failure and acute respiratory distress syndrome is debated. The oxygenation improvement coupled with lung and diaphragm protection produced by non-invasive support may help to avoid endotracheal intubation, which prevents the complications of sedation and invasive mechanical ventilation. However, spontaneous breathing in patients with lung injury carries the risk that vigorous inspiratory effort, combined or not with mechanical increases in inspiratory airway pressure, produces high transpulmonary pressure swings and local lung overstretch. This ultimately results in additional lung damage (patient self-inflicted lung injury), so that patients intubated after a trial of noninvasive support are burdened by increased mortality. Reducing inspiratory effort by high-flow nasal oxygen or delivery of sustained positive end-expiratory pressure through the helmet interface may reduce these risks. In this physiology-to-bedside review, we provide an updated overview about the role of noninvasive respiratory support strategies as early treatment of hypoxemic respiratory failure in the intensive care unit. Noninvasive strategies appear safe and effective in mild-to-moderate hypoxemia (PaO2/FiO2 > 150 mmHg), while they can yield delayed intubation with increased mortality in a significant proportion of moderate-to-severe (PaO2/FiO2 ≤ 150 mmHg) cases. High-flow nasal oxygen and helmet noninvasive ventilation represent the most promising techniques for first-line treatment of severe patients. However, no conclusive evidence allows to recommend a single approach over the others in case of moderate-to-severe hypoxemia. During any treatment, strict physiological monitoring remains of paramount importance to promptly detect the need for endotracheal intubation and not delay protective ventilation.

OBJECTIVES We recently found that distinct body temperature trajectories of infected patients correlated with survival. Understanding the relationship between the temperature trajectories and the host immune response to infection could allow us to immunophenotype patients at the bedside using temperature. The objective was to identify whether temperature trajectories have consistent associations with specific cytokine responses in two distinct cohorts of infected patients. DESIGN Prospective observational study. SETTING Large academic medical center between 2013 and 2019. SUBJECTS Two cohorts of infected patients: 1) patients in the ICU with septic shock and 2) hospitalized patients with Staphylococcus aureus bacteremia. INTERVENTIONS Clinical data (including body temperature) and plasma cytokine concentrations were measured. Patients were classified into four temperature trajectory subphenotypes using their temperature measurements in the first 72 hours from the onset of infection. Log-transformed cytokine levels were standardized to the mean and compared with the subphenotypes in both cohorts. MEASUREMENTS AND MAIN RESULTS The cohorts consisted of 120 patients with septic shock (cohort 1) and 88 patients with S. aureus bacteremia (cohort 2). Patients from both cohorts were classified into one of four previously validated temperature subphenotypes: "hyperthermic, slow resolvers" (n = 19 cohort 1; n = 13 cohort 2), "hyperthermic, fast resolvers" (n = 18 C1; n = 24 C2), "normothermic" (n = 54 C1; n = 31 C2), and "hypothermic" (n = 29 C1; n = 20 C2). Both "hyperthermic, slow resolvers" and "hyperthermic, fast resolvers" had high levels of G-CSF, CCL2, and interleukin-10 compared with the "hypothermic" group when controlling for cohort and timing of cytokine measurement (p < 0.05). In contrast to the "hyperthermic, slow resolvers," the "hyperthermic, fast resolvers" showed significant decreases in the levels of several cytokines over a 24-hour period, including interleukin-1RA, interleukin-6, interleukin-8, G-CSF, and M-CSF (p < 0.001). CONCLUSIONS Temperature trajectory subphenotypes are associated with consistent cytokine profiles in two distinct cohorts of infected patients. These subphenotypes could play a role in the bedside identification of cytokine profiles in patients with sepsis.

PURPOSES OF REVIEW: Critically ill patients frequently require mechanical ventilation as part of their care. Administration of analgesia and sedation to ensure patient comfort and facilitate mechanical ventilation must be balanced against the known negative consequences of excessive sedation. The present review focuses on the current evidence for sedation management during mechanical ventilation, including choice of sedatives, sedation strategies, and special considerations for acute respiratory distress syndrome (ARDS). RECENT FINDINGS: The Society of Critical Care Medicine recently published their updated clinical practice guidelines for analgesia, agitation, sedation, delirium, immobility, and sleep in adult patients in the ICU. Deep sedation, especially early in the course of mechanical ventilation, is associated with prolonged time to liberation from mechanical ventilation, longer ICU stays, longer hospital stays, and increased mortality. Dexmedetomidine may prevent ICU delirium when administered nocturnally at low doses; however, it was not shown to improve mortality when used as the primary sedative early in the course of mechanical ventilation, though the majority of patients in the informing study failed to achieve the prescribed light level of sedation. In a follow up to the ACURASYS trial, deep sedation with neuromuscular blockade did not result in improved mortality compared to light sedation in patients with severe ARDS. SUMMARY: Light sedation should be targeted early in the course of mechanical ventilation utilizing daily interruptions of sedation and/or nursing protocol-based algorithms, even in severe ARDS.

Mechanical ventilation practices in patients with acute respiratory distress syndrome (ARDS) have progressed with a growing understanding of the disease pathophysiology. Paramount to the care of affected patients is the delivery of lung-protective mechanical ventilation which prioritizes tidal volume and plateau pressure limitation. Lung protection can probably be further enhanced by scaling target tidal volumes to the specific respiratory mechanics of individual patients. The best procedure for selecting optimal positive end-expiratory pressure (PEEP) in ARDS remains uncertain; several relevant issues must be considered when selecting PEEP, particularly lung recruitability. Noninvasive ventilation must be used with caution in ARDS as excessively high respiratory drive can further exacerbate lung injury; newer modes of delivery offer promising approaches in hypoxemic respiratory failure. Airway pressure release ventilation offers an alternative approach to maximize lung recruitment and oxygenation, but clinical trials have not demonstrated a survival benefit of this mode over conventional ventilation strategies. Rescue therapy with high-frequency oscillatory ventilation is an important option in refractory hypoxemia. Despite a disappointing lack of benefit (and possible harm) in patients with moderate or severe ARDS, possibly due to lung hyperdistention and right ventricular dysfunction, high-frequency oscillation may improve outcome in patients with very severe hypoxemia.

Rationale:Early mobilization and physical rehabilitation improve functional outcomes and are essential to high quality critical care. Despite its importance, it is common for rehabilitation to be deferred in the critically ill due to a variety of barriers, including infection with SARS-CoV-2. We present a single academic center's experience providing physical and occupational therapy to critically ill patients infected with SARS-CoV-2. Methods:All patients with Coronavirus Disease 2019 (COVID-19) associated illness admitted to the intensive care unit (ICU) from March 1st to July 31st, 2020 were identified in this retrospective chart review. Patients who received at least one therapy treatment session were included in the study. Results:Three-hundred and seventy-nine physical and occupational therapy sessions were conducted with 116 patients. The majority (85%) of patients were admitted to the ICU for hypoxemic respiratory failure. The median number of treatment sessions during ICU admission per patient was 2, (IQR: 1-4). The median time from ICU admission to first PT session was 4 days (IQR, 3-5). The median percentage of ICU days with physical and occupational therapy treatment was 33% (IQR, 21-50). The median session length was 25 minutes (IQR, 25-30min). Sitting was achieved in 353 sessions, (93%) standing was achieved in 261 sessions (69%), walking was achieved in 185 sessions (48%), and sitting in the bedside chair 118 times (31%).Patients with respiratory failure completed therapy sessions while receiving mechanical ventilation (21% of sessions), high flow nasal cannula (45% of sessions), non-invasive positive pressure ventilation by helmet and facemask (7% of sessions), and ECMO (12% of sessions). Patients requiring vasoactive medications (4%) and continuous renal replacement therapy (6%) were also treated by physical and occupational therapy. Delirium, determined by confusion assessment method (CAM-ICU), was frequently encountered by the physical and occupational therapy teams and was not an absolute barrier (32%) (Table 1). Discharge destinations included: home (n=57, 61%), acute rehabilitation units (n=16, 17%), long term acute care hospitals (n=9, 10%), sub-acute care centers (n=8, 8%), and skilled nursing facilities (n=4, 4%). No members of the therapy team were diagnosed with SARS-CoV-2 during the study period. Conclusions:This report demonstrates the feasibility of conducting physical and occupational therapy in COVID-19 specific ICUs. Providing therapy services appeared to be safe for patients and members of the therapy team, as adverse events were rare and no therapist was diagnosed with COVID-19.

Rationale:Patients with COVID-19 frequently develop severe respiratory disease and may require invasive mechanical ventilation. A study of primarily white patients intubated for COVID-19 associated respiratory failure found predictors of 28-day mortality to be respiratory system compliance, age, tidal volume, arterial pH and heart rate. Little is known about the outcomes of minority populations with severe COVID-19 pneumonia. Therefore, we present an analysis of the predictors of mortality in a group of primarily African American patients with COVID-19 associated respiratory failure. Methods:All adult patients admitted to the University of Chicago COVID-19 intensive care unit receiving invasive mechanical ventilation between March 1st and June 31st, 2020 were identified. Patients were included in the study if they had at least one recorded measure of plateau airway pressure while receiving volume-controlled ventilation allowing determination of driving pressure and lung compliance. Univariable analysis was conducted comparing survivors with those who died in-hospital followed by construction of a multivariable logistic regression model predicting in-hospital mortality based on significant factors from univariable analysis, excluding colinear variables. Results:Eighty-five patients were included in this retrospective study. Patients were primarily African American (n=73, 86%). Among all study patients, median tidal volume was 6.0 cc/kg ideal body weight (IQR 5.8-6.2), PEEP was 8 cm H2O (IQR 5.0-10), and driving pressure was 14 cm H2O (IQR 11-16). Median respiratory system compliance was 27 ml/cm H2O (IQR 21-34). Salvage therapies for refractory hypoxemia in the cohort included prone positioning (27%), paralysis (27%), inhaled pulmonary vasodilators (19%), and extracorporeal membrane oxygenation (1%). In the multivariable logistic regression model, age (OR 1.077, 95% CI 1.031 to 1.125, p=0.001) and driving pressure (OR 1.174, 95% CI 1.009 to 1.366, p=0.038) were found to be independent predictors of mortality. Conclusions:In a predominantly African American patient population with COVID-19 pneumonia requiring invasive mechanical ventilation, higher driving pressure was predictive of overall mortality. These finding are consistent with the work of Botta et al (2020), who demonstrated reduced lung compliance was predictive of mortality among a largely white group of patients with severe COVID-19 pneumonia. While minority populations infected with COVID-19 have been found worse outcomes, early lung mechanics appear to be comparable to white patients. These findings support that higher driving pressures and low lung compliance are indicative of serious lung injury which may lead to death.

Acute Respiratory Distress Syndrome (ARDS) is one of the most demanding conditions in an Intensive Care Unit (ICU). Management of analgesia and sedation in ARDS is particularly challenging. An expert panel was convened to produce a “state-of-the-art” article to support clinicians in the optimal management of analgesia/sedation in mechanically ventilated adults with ARDS, including those with COVID-19. Current ICU analgesia/sedation guidelines promote analgesia first and minimization of sedation, wakefulness, delirium prevention and early rehabilitation to facilitate ventilator and ICU liberation. However, these strategies cannot always be applied to patients with ARDS who sometimes require deep sedation and/or paralysis. Patients with severe ARDS may be under-represented in analgesia/sedation studies and currently recommended strategies may not be feasible. With lightened sedation, distress-related symptoms (e.g., pain and discomfort, anxiety, dyspnea) and patient-ventilator asynchrony should be systematically assessed and managed through interprofessional collaboration, prioritizing analgesia and anxiolysis. Adaptation of ventilator settings (e.g., use of a pressure-set mode, spontaneous breathing, sensitive inspiratory trigger) should be systematically considered before additional medications are administered. Managing the mechanical ventilator is of paramount importance to avoid the unnecessary use of deep sedation and/or paralysis. Therefore, applying an “ABCDEF-R” bundle (R = Respiratory-drive-control) may be beneficial in ARDS patients. Further studies are needed, especially regarding the use and long-term effects of fast-offset drugs (e.g., remifentanil, volatile anesthetics) and the electrophysiological assessment of analgesia/sedation (e.g., electroencephalogram devices, heart-rate variability, and video pupillometry). This review is particularly relevant during the COVID-19 pandemic given drug shortages and limited ICU-bed capacity.

BackgroundInterleukin-6 (IL-6)-mediated hyperinflammation may contribute to the high mortality of coronavirus disease 2019 (Covid-19). Tocilizumab, an IL-6 receptor blocking monoclonal antibody, has been repurposed for Covid-19, but prospective trials and dose-finding studies in Covid-19 are lacking.MethodsWe conducted a phase 2 trial of low-dose tocilizumab in hospitalized adult patients with Covid-19, radiographic pulmonary infiltrate, fever, and C-reactive protein (CRP) ≥ 40 mg/L who did not require mechanical ventilation. Dose cohorts were determined by a trial Operations Committee, stratified by CRP and epidemiologic risk factors. A range of doses from 40 to 200 mg (low-dose tocilizumab) was evaluated, with allowance for one repeat dose at 24-48 hours. The primary objective was to assess the relationship of dose to fever resolution and CRP response. Outcomes were compared with retrospective controls with Covid-19. Correlative studies evaluating host antibody response were performed in parallel.FindingsA total of 32 patients received low-dose tocilizumab. This cohort had improved fever resolution (75·0% vs. 34·2%, p = 0·001) and CRP decline (86·2% vs. 14·3%, p < 0·001) in the 24-48 hours following drug administration, as compared to the retrospective controls (N=41). The probabilities of fever resolution or CRP decline did not appear to be dose-related (p=0·80 and p=0·10, respectively). Within the 28-day follow-up, 5 (15·6%) patients died. For patients who recovered, median time to clinical recovery was 3 days (IQR, 2-5). Clinically presumed and/or cultured bacterial superinfections were reported in 5 (15·6%) patients. Correlative biological studies demonstrated that tocilizumab-treated patients produced anti-SARS-CoV-2 antibodies comparable to controls.InterpretationLow-dose tocilizumab was associated with rapid improvement in clinical and laboratory measures of hyperinflammation in hospitalized patients with Covid-19. Results of this trial and its correlative biological studies provide rationale for a randomized, controlled trial of low-dose tocilizumab in Covid-19.FundingClinicalTrials.gov number NCT04331795. Study infrastructure was supported by NIH CTSA UL1 TR000430.Research in ContextEvidence before this studyMany patients with novel coronavirus disease 2019 (Covid-19) develop acute lung injury and hypoxic respiratory failure possibly due to a hyperinflammatory state similar to the cytokine release syndrome that occurs as a complication of chimeric antigen receptor T-cell therapy. Interleukin-6 (IL-6) has been implicated in both processes, leading to the hypothesis that patients with Covid-19 may benefit from IL-6 axis-directed therapies such as the IL-6 receptor-blocking monoclonal antibody tocilizumab. No dose-finding studies have been performed for tocilizumab in the setting of Covid-19.Added value of this studyThis prospective phase 2 clinical trial is, to our knowledge, the first to evaluate low-dose tocilizumab in patients with Covid-19 and the first to evaluate the effect of tocilizumab on anti-SARS-CoV-2 antibody response.Implications of all the available evidenceThe COVIDOSE study, together with retrospective and real-world evidence studies demonstrating the efficacy of tocilizumab, suggests that low-dose tocilizumab is a potential treatment for hyperinflammation among patients with Covid-19 and merits randomized, controlled testing in this patient population.

International audience; Mechanical ventilation may have adverse effects on both the lung and the diaphragm. Injury to the lung is mediated by excessive mechanical stress and strain, whereas the diaphragm develops atrophy as a consequence of low respiratory effort and injury in case of excessive effort. The lung and diaphragm-protective mechanical ventilation approach aims to protect both organs simultaneously whenever possible. This review summarizes practical strategies for achieving lung and diaphragm-protective targets at the bedside, focusing on inspiratory and expiratory ventilator settings, monitoring of inspiratory effort or respiratory drive, management of dyssynchrony, and sedation considerations. A number of potential future adjunctive strategies including extracorporeal CO2 removal, partial neuromuscular blockade, and neuromuscular stimulation are also discussed. While clinical trials to confirm the benefit of these approaches are awaited, clinicians should become familiar with assessing and managing patients' respiratory effort, based on existing physiological principles. To protect the lung and the diaphragm, ventilation and sedation might be applied to avoid excessively weak or very strong respiratory efforts and patient-ventilator dysynchrony.

International audience; Mechanical ventilation can cause acute diaphragm atrophy and injury, and this is associated with poor clinical outcomes. Although the importance and impact of lung-protective ventilation is widely appreciated and well established, the concept of diaphragm-protective ventilation has recently emerged as a potential complementary therapeutic strategy. This Perspective, developed from discussions at a meeting of international experts convened by PLUG (the Pleural Pressure Working Group) of the European Society of Intensive Care Medicine, outlines a conceptual framework for an integrated lung- and diaphragm-protective approach to mechanical ventilation on the basis of growing evidence about mechanisms of injury. We propose targets for diaphragm protection based on respiratory effort and patient–ventilator synchrony. The potential for conflict between diaphragm protection and lung protection under certain conditions is discussed; we emphasize that when conflicts arise, lung protection must be prioritized over diaphragm protection. Monitoring respiratory effort is essential to concomitantly protect both the diaphragm and the lung during mechanical ventilation. To implement lung- and diaphragm-protective ventilation, new approaches to monitoring, to setting the ventilator, and to titrating sedation will be required. Adjunctive interventions, including extracorporeal life support techniques, phrenic nerve stimulation, and clinical decision-support systems, may also play an important role in selected patients in the future. Evaluating the clinical impact of this new paradigm will be challenging, owing to the complexity of the intervention. The concept of lung- and diaphragm-protective ventilation presents a new opportunity to potentially improve clinical outcomes for critically ill patients.

The primary goals of mechanical ventilation are to improve gas exchange and relieve respiratory distress while allowing time for the resolution of respiratory failure. Because mechanical ventilation can cause ventilator-induced lung injury, a third goal is to reduce and prevent damage caused by the ventilator. Therefore, personalizing ventilator management based on a patient’s underlying disease process and physiology is imperative. A brief overview of mechanical ventilation is provided, but this chapter focuses on strategies to reduce and prevent lung injury during mechanical ventilation, as well as common causes and fixes of ventilator asynchrony.

Objectives Many survivors of acute respiratory distress syndrome have poor long-term outcomes possibly due to supportive care practices during "invasive" mechanical ventilation. Helmet noninvasive ventilation in acute respiratory distress syndrome may reduce intubation rates; however, it is unknown if avoiding intubation with helmet noninvasive ventilation alters the consequences of surviving acute respiratory distress syndrome. Design Long-term follow-up data from a previously published randomized controlled trial. Patients Adults patients with acute respiratory distress syndrome enrolled in a previously published clinical trial. Setting Adult ICU. Intervention None. Measurements and main results The primary outcome was functional independence at 1 year after hospital discharge defined as independence in activities of daily living and ambulation. At 1 year, patients were surveyed to assess for functional independence, survival, and number of institution-free days, defined as days alive spent living at home. The presence of ICU-acquired weakness and functional independence was also assessed by a blinded therapist on hospital discharge. On hospital discharge, there was a greater prevalence of ICU-acquired weakness (79.5% vs 38.6%; p = 0.0002) and less functional independence (15.4% vs 50%; p = 0.001) in the facemask group. One-year follow-up data were collected for 81 of 83 patients (97.6%). One-year mortality was higher in the facemask group (69.2% vs 43.2%; p = 0.017). At 1 year, patients in the helmet group were more likely to be functionally independent (40.9% vs 15.4%; p = 0.015) and had more institution-free days (median, 268.5 [0-354] vs 0 [0-323]; p = 0.017). Conclusions Poor functional recovery after invasive mechanical ventilation for acute respiratory distress syndrome is common. Helmet noninvasive ventilation may be the first intervention that mitigates the long-term complications that plague survivors of acute respiratory distress syndrome managed with noninvasive ventilation.

Background: The purpose of this guideline is to optimize evaluation and management of patients with obesity hypoventilation syndrome (OHS).Methods: A multidisciplinary panel identified and prioritized five clinical questions. The panel performed systematic reviews of available studies (up to July 2018) and followed the Grading of Recommendations, Assessment, Development, and Evaluation evidence-to-decision framework to develop recommendations. All panel members discussed and approved the recommendations.Recommendations: After considering the overall very low quality of the evidence, the panel made five conditional recommendations. We suggest that: 1) clinicians use a serum bicarbonate level

Purpose of review To summarize the recent evidence regarding the use of noninvasive strategies for de novo acute hypoxemic respiratory failure (AHRF). Recent findings New guidelines for the use of noninvasive ventilation (NIV) in acute respiratory failure have been published. In parallel, high-flow nasal cannula (HFNC) is an emerging noninvasive strategy for AHRF patients. Although some have cautioned against the use of NIV in AHRF, new encouraging data about the use of a helmet interface for NIV in acute respiratory distress syndrome may overcome the limitations of facemask NIV. Summary In the last two decades, the use of NIV and HFNC in patients with AHRF has considerably expanded, changing the paradigm of management of AHRF. Choice of each technique should be based according to centre experience and patient tolerability. However, when using noninvasive strategies for AHRF, it is crucial to predefine specific criteria for intubation and monitor patients closely for early detection of clinical deterioration to avoid delayed intubation.

Background ICU-acquired weakness (ICU-AW) has immediate and long-term consequences for critically ill patients. Strategies for the prevention of weakness include modification of known risk factors, such as hyperglycemia and immobility. Intensive insulin therapy (IIT) has been proposed to prevent critical illness polyneuropathy. However, the effect of insulin and early mobilization on clinically apparent weakness is not well known. Methods This is a secondary analysis of all patients with mechanical ventilation (N = 104) previously enrolled in a randomized controlled trial of early occupational and physical therapy vs conventional therapy, which evaluated the end point of functional independence. Every patient had IIT and blinded muscle strength testing on hospital discharge to determine the incidence of clinically apparent weakness. The effects of insulin dose and early mobilization on the incidence of ICU-AW were assessed. Results On logistic regression analyses, early mobilization and increasing insulin dose prevented the incidence of ICU-AW (OR, 0.18, P = .001; OR, 0.001, P = .011; respectively) independent of known risk factors for weakness. Early mobilization also significantly reduced insulin requirements to achieve similar glycemic goals as compared with control patients (0.07 units/kg/d vs 0.2 units/kg/d, P Conclusions The duel effect of early mobilization in reducing clinically relevant ICU-AW and promoting euglycemia suggests its potential usefulness as an alternative to IIT.

Noninvasive ventilation (NIV) with a face mask is relatively ineffective at preventing endotracheal intubation in patients with acute respiratory distress syndrome (ARDS). Delivery of NIV with a helmet may be a superior strategy for these patients.To determine whether NIV delivered by helmet improves intubation rate among patients with ARDS.Single-center randomized clinical trial of 83 patients with ARDS requiring NIV delivered by face mask for at least 8 hours while in the medical intensive care unit at the University of Chicago between October 3, 2012, through September 21, 2015.Patients were randomly assigned to continue face mask NIV or switch to a helmet for NIV support for a planned enrollment of 206 patients (103 patients per group). The helmet is a transparent hood that covers the entire head of the patient and has a rubber collar neck seal. Early trial termination resulted in 44 patients randomized to the helmet group and 39 to the face mask group.The primary outcome was the proportion of patients who required endotracheal intubation. Secondary outcomes included 28-day invasive ventilator-free days (ie, days alive without mechanical ventilation), duration of ICU and hospital length of stay, and hospital and 90-day mortality.Eighty-three patients (45% women; median age, 59 years; median Acute Physiology and Chronic Health Evaluation [APACHE] II score, 26) were included in the analysis after the trial was stopped early based on predefined criteria for efficacy. The intubation rate was 61.5% (n = 24) for the face mask group and 18.2% (n = 8) for the helmet group (absolute difference, -43.3%; 95% CI, -62.4% to -24.3%; P .001). The number of ventilator-free days was significantly higher in the helmet group (28 vs 12.5, P .001). At 90 days, 15 patients (34.1%) in the helmet group died compared with 22 patients (56.4%) in the face mask group (absolute difference, -22.3%; 95% CI, -43.3 to -1.4; P = .02). Adverse events included 3 interface-related skin ulcers for each group (ie, 7.6% in the face mask group had nose ulcers and 6.8% in the helmet group had neck ulcers).Among patients with ARDS, treatment with helmet NIV resulted in a significant reduction of intubation rates. There was also a statistically significant reduction in 90-day mortality with helmet NIV. Multicenter studies are needed to replicate these findings.clinicaltrials.gov Identifier: NCT01680783.

Traditionally, endotracheal intubation has been used as a treatment for patients with respiratory failure who require mechanical ventilation. Although intubation can be life saving, it is also associated with significant morbidity.1 Immunocompromised patients with acute hypoxemic respiratory failure are at particularly high risk; these patients often require high levels of ventilatory support (ie, positive end-expiratory pressure [PEEP] and fractions of inspired oxygen [Fio2]). Intubated patients usually require sedative medications, analgesic agents, or both and are at risk for many complications seen in the intensive care unit (ICU), such as ventilator-associated pneumonia, ICU-acquired weakness,2 venous thromboembolism,3 delirium, and cognitive dysfunction.4 As such, these patients typically have a high associated mortality, estimated at approximately 50%.5

Background Idiopathic pulmonary fibrosis exhibits differential progression from the time of diagnosis but the molecular basis for varying progression rates is poorly understood. The aim of the present study was to ascertain whether differential miRNA expression might provide one explanation for rapidly versus slowly progressing forms of IPF. Methodology and Principal Findings miRNA and mRNA were isolated from surgical lung biopsies from IPF patients with a clinically documented rapid or slow course of disease over the first year after diagnosis. A quantitative PCR miRNA array containing 88 of the most abundant miRNA in the human genome was used to profile lung biopsies from 9 patients with rapidly progressing IPF, 6 patients with slowly progressing IPF, and 10 normal lung biopsies. Using this approach, 11 miRNA were significantly increased and 36 were significantly decreased in rapid biopsies compared with normal biopsies. Slowly progressive biopsies exhibited 4 significantly increased miRNA and 36 significantly decreased miRNA compared with normal lung. Among the miRNA present in IPF with validated mRNA targets were those with regulatory effects on epithelial-mesenchymal transition (EMT). Five miRNA (miR-302c, miR-423-5p, miR-210, miR-376c, and miR-185) were significantly increased in rapid compared with slow IPF lung biopsies. Additional analyses of rapid biopsies and fibroblasts grown from the same biopsies revealed that the expression of AGO1 and AGO2 (essential components of the miRNA processing RISC complex) were lower compared with either slow or normal lung biopsies and fibroblasts. Conclusion These findings suggest that the development and/or clinical progression of IPF might be the consequence of aberrant miRNA processing.