Clinical Characteristics and Outcomes of COVID-19 Acute Respiratory Distress Syndrome (ARDS) Survivors in Early Pandemic: A Single Healthcare System Retrospective Study.

INTRODUCTION:  Acute respiratory distress syndrome (ARDS) management in the intensive care unit (ICU) has attracted strong interest since the start of the COVID-19 pandemic. Our retrospective study aims to describe the outcomes and predictors of mortality of ARDS associated with COVID-19 within one university-based healthcare system. METHODS:  We identified 165 patients within our healthcare system during the months of April 2020 through July 2020, who were admitted to our medical ICUs and eligible for our study. Baseline patient characteristics, ICU and hospital course information, ICU interventions, ventilator settings, and hospital complications were collected and analyzed using descriptive statistical techniques. RESULTS:  Our cohort had an average age of 64. No significant difference in mortality was identified with male vs. female gender or BMI. Most of the patient cohort was identified as black (68.2%). The overall mortality of our cohort was 38.2%. Hyperlipidemia, coronary artery disease, and chronic obstructive pulmonary disease were all associated with higher mortality. There was a significant difference in mortality between those with higher observed ventilator plateau pressures at 24 hours and higher driving pressures at 24 hours. CONCLUSION:  COVID-19-associated ARDS is associated with significant mortality. Physicians should be aware of pre-existing conditions potentially related to worse outcomes so that they receive an appropriate level of care in a timely manner. Ventilator management should focus on maintaining low intra-thoracic pressure changes. Prospective studies are needed to guide COVID-19-associated ARDS management.

Characteristics, Outcomes, and Trends of Patients With COVID-19-Related Critical Illness at a Learning Health System in the United States.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic continues to surge in the United States and globally. OBJECTIVE: To describe the epidemiology of COVID-19-related critical illness, including trends in outcomes and care delivery. DESIGN: Single-health system, multihospital retrospective cohort study. SETTING: 5 hospitals within the University of Pennsylvania Health System. PATIENTS: Adults with COVID-19-related critical illness who were admitted to an intensive care unit (ICU) with acute respiratory failure or shock during the initial surge of the pandemic. MEASUREMENTS: The primary exposure for outcomes and care delivery trend analyses was longitudinal time during the pandemic. The primary outcome was all-cause 28-day in-hospital mortality. Secondary outcomes were all-cause death at any time, receipt of mechanical ventilation (MV), and readmissions. RESULTS: Among 468 patients with COVID-19-related critical illness, 319 (68.2%) were treated with MV and 121 (25.9%) with vasopressors. Outcomes were notable for an all-cause 28-day in-hospital mortality rate of 29.9%, a median ICU stay of 8 days (interquartile range [IQR], 3 to 17 days), a median hospital stay of 13 days (IQR, 7 to 25 days), and an all-cause 30-day readmission rate (among nonhospice survivors) of 10.8%. Mortality decreased over time, from 43.5% (95% CI, 31.3% to 53.8%) to 19.2% (CI, 11.6% to 26.7%) between the first and last 15-day periods in the core adjusted model, whereas patient acuity and other factors did not change. LIMITATIONS: Single-health system study; use of, or highly dynamic trends in, other clinical interventions were not evaluated, nor were complications. CONCLUSION: Among patients with COVID-19-related critical illness admitted to ICUs of a learning health system in the United States, mortality seemed to decrease over time despite stable patient characteristics. Further studies are necessary to confirm this result and to investigate causal mechanisms. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

Interstitial Lung Disease Associated Acute Respiratory Failure Requiring Invasive Mechanical Ventilation: A Retrospective Analysis.

BACKGROUND: Interstitial Lung Disease [ILD] patients requiring Invasive Mechanical Ventilation [IMV] for Acute Respiratory Failure [ARF] are known to have a poor prognosis. Few studies have investigated determinants of outcomes and the utility of trialing Non-Invasive Positive Pressure Ventilation [NIPPV] prior to IMV to see if there are any effect[s] on mortality or morbidity. METHODS: A retrospective study was designed using patients at four different intensive care units within one health care system. The primary objective was to determine if there are differences in outcomes for in-hospital and one-year mortality between patients who undergo NIPPV prior to IMV and those who receive only IMV. A secondary objective was to identify potential determinants of outcomes. RESULTS: Out of 54 ILD patients with ARF treated with IMV, 20 (37.0%) survived until hospital discharge and 10 (18.5%) were alive at one-year. There was no significant mortality difference between patients trialed on NIPPV prior to IMV and those receiving only IMV. Several key determinants of outcomes were identified with higher mortality, including higher ventilatory support, idiopathic pulmonary fibrosis (IPF) subtype, high dose steroids, use of vasopressors, supraventricular tachycardias (SVTs), and higher body mass index. CONCLUSION: Considering that patients trialed on NIPPV prior to IMV were associated with no mortality disadvantage to patients treated with only IMV, trialing patients on NIPPV may identify responders and avoid complications associated with IMV. Increased ventilator support, need of vasopressors, SVTs, and high dose steroids reflect higher mortality and palliative care involvement should be considered as early as possible if a lung transplant is not an option.

Cerebral fat embolism syndrome in sickle cell disease without evidence of shunt.

Fat embolism syndrome (FES) is a known complication of sickle cell disease (SCD) that occurs secondary to vaso-occlusive crises, bone marrow infarction, and the subsequent release of fat globules into the venous circulation. Although neurologic involvement is common, the pathophysiology of cerebral fat emboli remains controversial. While fat microemboli can enter the arterial circulation through right-to-left shunts, the systemic release of free fatty acids may also cause indirect endothelial damage and disruption of the blood-brain-barrier. We present an unusual case of cerebral fat emboli in SCD that occurred in the absence of acute chest syndrome or right-to-left shunt, favoring a biochemical etiology. Treatment of FES includes supportive care and emergent red cell exchange transfusions.

Dietary curcumin increases antioxidant defenses in lung, ameliorates radiation-induced pulmonary fibrosis, and improves survival in mice.

The effectiveness of lung radiotherapy is limited by radiation tolerance of normal tissues and by the intrinsic radiosensitivity of lung cancer cells. The chemopreventive agent curcumin has known antioxidant and tumor cell radiosensitizing properties. Its usefulness in preventing radiation-induced pneumonopathy has not been tested previously. We evaluated dietary curcumin in radiation-induced pneumonopathy and lung tumor regression in a murine model. Mice were given 1% or 5% (w/w) dietary curcumin or control diet prior to irradiation and for the duration of the experiment. Lungs were evaluated at 3 weeks after irradiation for acute lung injury and inflammation by evaluating bronchoalveolar lavage (BAL) fluid content for proteins, neutrophils and at 4 months for pulmonary fibrosis. In a separate series of experiments, an orthotopic model of lung cancer using intravenously injected Lewis lung carcinoma (LLC) cells was used to exclude possible tumor radioprotection by dietary curcumin. In vitro, curcumin boosted antioxidant defenses by increasing heme oxygenase 1 (HO-1) levels in primary lung endothelial and fibroblast cells and blocked radiation-induced generation of reactive oxygen species (ROS). Dietary curcumin significantly increased HO-1 in lungs as early as after 1 week of feeding, coinciding with a steady-state level of curcumin in plasma. Although both 1% and 5% w/w dietary curcumin exerted physiological changes in lung tissues by significantly decreasing LPS-induced TNF-alpha production in lungs, only 5% dietary curcumin significantly improved survival of mice after irradiation and decreased radiation-induced lung fibrosis. Importantly, dietary curcumin did not protect LLC pulmonary metastases from radiation killing. Thus dietary curcumin ameliorates radiation-induced pulmonary fibrosis and increases mouse survival while not impairing tumor cell killing by radiation.

Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial.

BACKGROUND: Approaches to removal of sedation and mechanical ventilation for critically ill patients vary widely. Our aim was to assess a protocol that paired spontaneous awakening trials (SATs)-ie, daily interruption of sedatives-with spontaneous breathing trials (SBTs). METHODS: In four tertiary-care hospitals, we randomly assigned 336 mechanically ventilated patients in intensive care to management with a daily SAT followed by an SBT (intervention group; n=168) or with sedation per usual care plus a daily SBT (control group; n=168). The primary endpoint was time breathing without assistance. Data were analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00097630. FINDINGS: One patient in the intervention group did not begin their assigned treatment protocol because of withdrawal of consent and thus was excluded from analyses and lost to follow-up. Seven patients in the control group discontinued their assigned protocol, and two of these patients were lost to follow-up. Patients in the intervention group spent more days breathing without assistance during the 28-day study period than did those in the control group (14.7 days vs 11.6 days; mean difference 3.1 days, 95% CI 0.7 to 5.6; p=0.02) and were discharged from intensive care (median time in intensive care 9.1 days vs 12.9 days; p=0.01) and the hospital earlier (median time in the hospital 14.9 days vs 19.2 days; p=0.04). More patients in the intervention group self-extubated than in the control group (16 patients vs six patients; 6.0% difference, 95% CI 0.6% to 11.8%; p=0.03), but the number of patients who required reintubation after self-extubation was similar (five patients vs three patients; 1.2% difference, 95% CI -5.2% to 2.5%; p=0.47), as were total reintubation rates (13.8%vs 12.5%; 1.3% difference, 95% CI -8.6% to 6.1%; p=0.73). At any instant during the year after enrolment, patients in the intervention group were less likely to die than were patients in the control group (HR 0.68, 95% CI 0.50 to 0.92; p=0.01). For every seven patients treated with the intervention, one life was saved (number needed to treat was 7.4, 95% CI 4.2 to 35.5). INTERPRETATION: Our results suggest that a wake up and breathe protocol that pairs daily spontaneous awakening trials (ie, interruption of sedatives) with daily spontaneous breathing trials results in better outcomes for mechanically ventilated patients in intensive care than current standard approaches and should become routine practice.

Systemic polyethylene glycol-modified (PEGylated) superoxide dismutase and catalase mixture attenuates radiation pulmonary fibrosis in the C57/bl6 mouse.

PURPOSE: Since oxidative injury is implicated in radiation-induced tissue damage to the lung, we studied systemically administered polyethylene glycol (PEGylated) antioxidant enzymes (AOEs) as pulmonary radioprotectors in mice. METHODS AND MATERIALS: C57/bl6 Mice received 13.5 Gy single-dose irradiation to the thorax. One cohort also received 100 microg of a 1:1 mixture of PEG-AOEs {PEG-catalase and PEG-superoxide dismutase (SOD)} intravenously, pre-irradiation and subgroups were evaluated at variable time-points for inflammation and fibrosis. Potential for AOE tumor protection was studied by thoracic irradiation of mice with Lewis lung carcinoma. RESULTS: At 48 h post-irradiation, control irradiated mice had marked elevations of tissue p21, Bax and TGF-beta1 in lungs, not seen in irradiated, PEG-AOE-treated mice. TUNEL staining of lung sections was performed at just one time-point (24 h post-irradiation) and revealed a decrease in apoptotic cells with AOE treatment. At four months post-irradiation, these mice had significantly increased pulmonary fibrosis as measured by hydroxyproline content. Mice treated with PEG-AOE prior to irradiation had 4-month hydroxyproline levels that were similar to that of unirradiated controls (p = 0.28). This corresponded to less pulmonary fibrosis as visualized histologically when compared with mice irradiated without AOEs. PEG-AOEs did not prevent post-irradiation pulmonary inflammation or lung cancer response to irradiation. CONCLUSIONS: A mixture of PEG-SOD and PEG-CAT successfully diminished radiation pulmonary fibrosis in mice. There was also a corresponding effect on several early biomarkers of lung injury and decreased apoptosis. There were no significant effects on acute pneumonitis or tumor protection.

KL4-surfactant prevents hyperoxic and LPS-induced lung injury in mice.

KL(4)-surfactant contains the novel KL(4) peptide, sinapultide, which mimics properties of the hydrophobic pulmonary surfactant protein SP-B, in a phospholipid formulation and may be lung protective in experimental acute respiratory distress syndrome/acute lung injury. Our objective was to determine the protective role of airway delivery of KL(4)-surfactant in murine models of hyperoxic and lipopolysaccharide (LPS)-induced lung injury and further explore the mechanisms of protection. For the hyperoxic injury model, mice exposed to 80% O(2) for 6 days received an intranasal bolus of vehicle, beractant, or KL(4)-surfactant on days 3, 4, 5, and 6 of the exposure, and lungs were evaluated on day 7. Mice in the LPS-induced lung injury model received an intratracheal bolus of LPS followed by an intranasal bolus of KL(4)-surfactant or control at 1, 3, and 19 hr post-LPS challenge, and lungs were evaluated after 24 hr. To explore the mechanisms of protection, in vitro assays were performed with human and murine endothelial cell monolayers, and polymorphonuclear leukocyte (PMN) transmigration in the presence or absence of KL(4)-surfactant or lipid controls was evaluated. Based on morphology, histopathology, white blood cell count, percentage of PMNs, and protein concentration in bronchoalveolar lavage fluid, our data showed KL(4)-surfactant, unlike vehicle or beractant, blocked neutrophil influx into alveoli and suppressed lung injury. Furthermore, in vitro assays showed KL(4)-surfactant decreased neutrophil transmigration at the endothelial cell level. KL(4)-surfactant decreased inflammation and lung permeability compared with controls in both mouse models of lung injury. Evidence suggests the anti-inflammatory mechanism of the KL(4)-peptide is through inhibition of PMN transmigration through the endothelium.

Dietary flaxseed supplementation ameliorates inflammation and oxidative tissue damage in experimental models of acute lung injury in mice.

Flaxseed (FS) is a nutritional supplement with high concentrations of (n-3) fatty acids and lignans that have anti-inflammatory and antioxidant properties. The use of FS in the prevention or treatment of acute lung disease is unknown. In this study, we evaluated diets with high FS content in experimental murine models of acute lung injury and inflammation. The kinetics of lignan accumulation in blood, following 10% FS supplementation, was determined using liquid chromatography tandem mass spectrometry. Mice were fed isocaloric control and 10% FS-supplemented diets for at least 3 wk and challenged by hyperoxia (80% oxygen), intratracheal instillation of lipopolysaccharide, or acid aspiration. Bronchoalveolar lavage was evaluated for white blood cells, neutrophils, and proteins after a 24 h postintratracheal challenge of hydrochloric acid or lipopolysaccharide, or after 6 d of hyperoxia. Lung lipid peroxidation was assessed by tissue malondialdehyde concentrations. The plasma concentrations of the FS lignans, enterodiol and enterolactone, were stable after mice had eaten the diets for 2 wk. Following hyperoxia and acid aspiration, bronchoalveolar lavage neutrophils decreased in FS-supplemented mice (P = 0.012 and P = 0.027, respectively), whereas overall alveolar white blood cell influx tended to be lower (P = 0.11). In contrast, neither lung injury nor inflammation was ameliorated by FS following lipopolysaccharide instillation. Lung malondialdehyde levels were lower in hyperoxic mice than in unchallenged mice (P = 0.0001), and decreased with FS treatment following acid aspiration (P = 0.011). Dietary FS decreased lung inflammation and lipid peroxidation, suggesting a protective role against pro-oxidant-induced tissue damage in vivo.

Intrapulmonary IFN-beta gene therapy using an adenoviral vector is highly effective in a murine orthotopic model of bronchogenic adenocarcinoma of the lung.

Given previous work showing that an adenoviral vector expressing IFN-beta (Ad.IFNbeta) was highly effective in eradicating i.p. mesothelioma tumors, the antitumor efficacy of this agent was evaluated in an orthotopic model of bronchogenic adenocarcinoma of the lung. These transgenic mice have a conditionally expressed, oncogenic K-rasG12D allele that can be activated by intratracheal administration of an adenovirus expressing Cre recombinase (Ad.Cre). K-rasG12D mutant mice were given Ad.Cre intranasally to activate the oncogene. Mice were then given 10(9) plaque-forming units of a control vector (Ad.LacZ) or Ad.IFNbeta intranasally 3 and 4 weeks later, a time when lung tumors had been established. Cells derived from K-ras-mutated lung tumors were also grown in the flanks of mice to study mechanisms of therapeutic responses. In two separate experiments, untreated tumor-bearing mice all died by day 57 (median survival, 49 days). Ad.LacZ-treated mice all died by day 71 (median survival, 65 days). In contrast, 90% to 100% of mice treated with Ad.IFNbeta were long-term survivors (>120 days; P < 0.001). In addition, immunity to re-challenge with tumor cells was induced. In vitro and flank tumor studies showed that Ad.IFNbeta induced direct tumor cell killing and that depleting natural killer or CD8+ T cells, but not CD4+ T cells, with antibodies attenuated the effect of Ad.IFNbeta. These studies, showing remarkable antitumor activity in this orthotopic lung cancer model, provide strong preclinical support for a trial of Ad.IFNbeta to treat human non-small cell lung cancer.