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Phenotypes and personalized medicine in the acute respiratory distress syndrome INTENSIVE CARE MEDICINE Matthay, M. A., Arabi, Y. M., Siegel, E. R., Ware, L. B., Bos, L. J., Sinha, P., Beitler, J. R., Wick, K. D., Curley, M. Q., Constantin, J., Levitt, J. E., Calfee, C. S. 2020: 2136?52
Abstract

Although the acute respiratory distress syndrome (ARDS) is well defined by the development of acute hypoxemia, bilateral infiltrates and non-cardiogenic pulmonary edema, ARDS is heterogeneous in terms of clinical risk factors, physiology of lung injury, microbiology, and biology, potentially explaining why pharmacologic therapies have been mostly unsuccessful in treating ARDS. Identifying phenotypes of ARDS and integrating this information into patient selection for clinical trials may increase the chance for efficacy with new treatments. In this review, we focus on classifying ARDS by the associated clinical disorders, physiological data, and radiographic imaging. We consider biologic phenotypes, including plasma protein biomarkers, gene expression, and common causative microbiologic pathogens. We will also discuss the issue of focusing clinical trials on the patient's phase of lung injury, including prevention, administration of therapy during early acute lung injury, and treatment of established ARDS. A more in depth understanding of the interplay of these variables in ARDS should provide more success in designing and conducting clinical trials and achieving the goal of personalized medicine.

View details for DOI 10.1007/s00134-020-06296-9

View details for Web of Science ID 000590531800001

View details for PubMedID 33206201

View details for PubMedCentralID PMC7673253
Cytokine profile in plasma of severe COVID-19 does not differ from ARDS and sepsis. JCI insight Wilson, J. G., Simpson, L. J., Ferreira, A., Rustagi, A., Roque, J. A., Asuni, A., Ranganath, T., Grant, P. M., Subramanian, A. K., Rosenberg-Hasson, Y., Maecker, H., Holmes, S., Levitt, J. E., Blish, C., Rogers, A. J. 2020
Abstract

BACKGROUND: Elevated levels of inflammatory cytokines have been associated with poor outcomes among COVID-19 patients. It is unknown, however, how these levels compare to those observed in critically ill patients with ARDS or sepsis due to other causes.METHODS: We used a luminex assay to determine expression of 76 cytokines from plasma of hospitalized COVID-19 patients and banked plasma samples from ARDS and sepsis patients. Our analysis focused on detecting statistical differences in levels of 6 cytokines associated with cytokine storm (IL-1b, IL-1RA, IL-6, IL-8, IL-18, and TNFalpha) between patients with moderate COVID-19, severe COVID-19, and ARDS or sepsis.RESULTS: 15 hospitalized COVID-19 patients, 9 of whom were critically ill, were compared to critically ill patients with ARDS (n = 12) or sepsis (n = 16). There were no statistically significant differences in baseline levels of IL-1b, IL-1RA, IL-6, IL-8, IL-18, and TNFalpha between patients with COVID-19 and critically ill controls with ARDS or sepsis.CONCLUSIONS: Levels of inflammatory cytokines were not higher in severe COVID-19 patients than in moderate COVID-19 or critically ill patients with ARDS or sepsis in this small cohort. Broad use of immunosuppressive therapies in ARDS has failed in numerous Phase 3 studies; use of these therapies in unselected patients with COVID-19 may be unwarranted.FUNDING: A.J.R.: Stanford ICU Biobank NHLBI K23 HL125663. C.A.B.: Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Diseases #1016687; NIH/NIAID U19AI057229-16 (PI MM Davis); Stanford Maternal Child Health Research Institute; Chan Zuckerberg Biohub.

View details for DOI 10.1172/jci.insight.140289

View details for PubMedID 32706339
Systemic and Inhaled Corticosteroids, with or without Beta Agonists, as Adjuvant Therapy in Community Acquired Pneumonia. Acta medica academica Helgeson, S. A., Levitt, J. E., Festic, E. 2020; 49 (1): 9?20
Abstract

The aim is to provide a narrative review of the role of corticosteroids, with and without inhaled beta agonist, in communityacquired pneumonia. Community and health-care associated pneumonia remain leading causes of morbidity and mortality despite appropriate antibiotic therapy. The pneumonia-associated adverse outcomes are not only related to the infectious organism, but also to a dysfunctional host-immune response resulting in overwhelming inflammation. Use of systemic corticosteroids as adjuvant therapy in pneumonia remains controversial. Multiple randomized clinical trials evaluating corticosteroids in patients with community acquired pneumonia have found discrepant results in terms of benefits and adverse effects. Inhaled delivery of corticosteroids offer the potential advantage of providing therapeutic benefits directly to the lung, with minimal to no adverse systemic effects. CONCLUSION: Although meta-analyses suggest potential benefits in a select group of patients with more severe pneumonia, the ideal timing, dose, route of delivery, duration, and patient selection remain to be established. A smaller body of literature suggests benefit of inhaled corticosteroids, with or without inhaled beta agonists, but future large scale clinical trials are needed to establish clinical benefit with inhaled delivery.

View details for DOI 10.5644/ama2006-124.279

View details for PubMedID 32738113
Characteristics and Outcomes of Individuals With Pre-existing Kidney Disease and COVID-19 Admitted to Intensive Care Units in the United States. American journal of kidney diseases : the official journal of the National Kidney Foundation Flythe, J. E., Assimon, M. M., Tugman, M. J., Chang, E. H., Gupta, S., Shah, J., Sosa, M. A., DeMauro Renaghan, A., Melamed, M. L., Wilson, F. P., Neyra, J. A., Rashidi, A., Boyle, S. M., Anand, S., Christov, M., Thomas, L. F., Edmonston, D., Leaf, D. E. 2020
Abstract

Underlying kidney disease is an emerging risk factor for more severe COVID-19 illness. We examined the clinical courses of critically ill COVID-19 patients with and without pre-existing kidney disease and investigated the association between degree of underlying kidney disease and in-hospital outcomes.Retrospective cohort study SETTINGS & PARTICIPANTS: 4,264 critically ill COVID-19 patients (143 dialysis patients, 521 chronic kidney disease [CKD] patients, and 3,600 patients without CKD) admitted to ICUs at 68 hospitals in the United States.Presence (versus absence) of pre-existing kidney disease OUTCOME(S): In-hospital mortality (primary); respiratory failure, shock, ventricular arrhythmia/ cardiac arrest, thromboembolic event, major bleed, and acute liver injury (secondary) ANALYTICAL APPROACH: We used standardized differences to compare patient characteristics (values >0.10 indicate a meaningful difference between groups) and multivariable adjusted Fine and Gray survival models to examine outcome associations.Dialysis patients had a shorter time from symptom onset to ICU admission compared to other groups (median [quartile 1-quartile 3] days: 4 [2-9] for dialysis patients; 7 [3-10] for CKD patients; 7 [4-10] for patients without pre-existing kidney disease). More dialysis patients (25%) reported altered mental status than those with CKD (20%, standardized difference = 0.12) and no kidney disease (12%, standardized difference = 0.36). Half of dialysis and CKD patients died within 28-days of ICU admission versus 35% of patients without pre-existing kidney disease. Compared to patients without pre-existing kidney disease, dialysis patients had a higher risk of 28-day in-hospital death (adjusted HR 1.41; 95% CI 1.09, 1.81), while patients with CKD had an intermediate risk (adjusted HR 1.25; 95% CI 1.08, 1.44).Potential residual confounding CONCLUSIONS: Findings highlight the high mortality of individuals with underlying kidney disease and severe COVID-19, underscoring the importance of identifying safe and effective COVID-19 therapies for this vulnerable population.

View details for DOI 10.1053/j.ajkd.2020.09.003

View details for PubMedID 32961244
The Association Between Endotracheal Tube Size and Aspiration (During Flexible Endoscopic Evaluation of Swallowing) in Acute Respiratory Failure Survivors. Critical care medicine Krisciunas, G. P., Langmore, S. E., Gomez-Taborda, S., Fink, D., Levitt, J. E., McKeehan, J., McNally, E., Scheel, R., Rubio, A. C., Siner, J. M., Vojnik, R., Warner, H., White, S. D., Moss, M. 2020
Abstract

To determine whether a modifiable risk factor, endotracheal tube size, is associated with the diagnosis of postextubation aspiration in survivors of acute respiratory failure.Prospective cohort study.ICUs at four academic tertiary care medical centers.Two hundred ten patients who were at least 18 years old, admitted to an ICU, and mechanically ventilated with an endotracheal tube for longer than 48 hours were enrolled.Within 72 hours of extubation, all patients received a flexible endoscopic evaluation of swallowing examination that entailed administration of ice, thin liquid, thick liquid, puree, and cracker boluses. Patient demographics, treatment variables, and hospital outcomes were abstracted from the patient's medical records. Endotracheal tube size was independently selected by the patient's treating physicians.For each flexible endoscopic evaluation of swallowing examination, laryngeal pathology was evaluated, and for each bolus, a Penetration Aspiration Scale score was assigned. Aspiration (Penetration Aspiration Scale score ? 6) was further categorized into nonsilent aspiration (Penetration Aspiration Scale score = 6 or 7) and silent aspiration (Penetration Aspiration Scale score = 8). One third of patients (n = 68) aspirated (Penetration Aspiration Scale score ? 6) on at least one bolus, 13.6% (n = 29) exhibited silent aspiration, and 23.8% (n = 50) exhibited nonsilent aspiration. In a multivariable analysis, endotracheal tube size (? 7.5 vs ? 8.0) was significantly associated with patients exhibiting any aspiration (Penetration Aspiration Scale score ? 6) (p = 0.016; odds ratio = 2.17; 95% CI 1.14-4.13) and with risk of developing laryngeal granulation tissue (p = 0.02).Larger endotracheal tube size was associated with increased risk of aspiration and laryngeal granulation tissue. Using smaller endotracheal tubes may reduce the risk of postextubation aspiration.

View details for DOI 10.1097/CCM.0000000000004554

View details for PubMedID 32804785
Development of an accurate bedside swallowing evaluation decision tree algorithm for detecting aspiration in acute respiratory failure survivors. Chest Moss, M., White, S. D., Warner, H., Dvorkin, D., Fink, D., Gomez-Taborda, S., Higgins, C., Krisciunas, G. P., Levitt, J. E., McKeehan, J., McNally, E., Rubio, A., Scheel, R., Siner, J. M., Vojnik, R., Langmore, S. E. 2020
Abstract

The bedside swallowing evaluation (BSE) is an assessment of swallowing function and airway safety during swallowing. After extubation, the BSE is often used to identify the risk of aspiration in acute respiratory failure (ARF) survivors.We conducted a multi-center prospective study of ARF survivors to determine the accuracy of the BSE and to develop a decision tree algorithm to identify aspiration risk.and Methods: Patients extubated after ?48 hours of mechanical ventilation were eligible. Study procedures included the BSE followed by a gold-standard evaluation, the flexible endoscopic evaluation of swallowing (FEES).Overall, 213 patients were included in the final analysis. Median time from extubation to BSE was 25 hours (interquartile range=21-45 hours). FEES was completed 1 hour after the BSE (interquartile range=0.5-2 hours). A total of 33% (70/213, 95%CI=26.6-39.2%) of patients aspirated on at least one FEES bolus consistency test. Thin liquids were the most commonly aspirated consistency; 27% (54/197, 95%CI =21-34%). The BSE detected any aspiration with an accuracy of 52% (95%CI =45-58%), a sensitivity of 83% (95%CI =74-92%), and negative predictive value of 81% (95%CI=72-91%). Using recursive partitioning analyses, a five variable BSE-based decision tree algorithm was developed that improved the detection of aspiration with an accuracy of 81% (95%CI=75-87%), sensitivity of 95% (95%CI =90-98%), and negative predictive value of 97% (95%CI =95-99%).The BSE demonstrates variable accuracy to identify patients at high risk for aspiration. Our decision tree algorithm may enhance the BSE and be used to identify patients at high risk for aspiration yet requires further validation.

View details for DOI 10.1016/j.chest.2020.07.051

View details for PubMedID 32721404
Abnormalities of Aspiration and Swallowing Function in Survivors of Acute Respiratory Failure. Dysphagia Langmore, S. E., Krisciunas, G. P., Warner, H., White, S. D., Dvorkin, D., Fink, D., McNally, E., Scheel, R., Higgins, C., Levitt, J. E., McKeehan, J., Deane, S., Siner, J. M., Vojnik, R., Moss, M. 2020
Abstract

The mechanisms responsible for aspiration are relatively unknown in patients recovering from acute respiratory failure (ARF) who required mechanical ventilation. Though many conditions may contribute to swallowing dysfunction, alterations in laryngeal structure and swallowing function likely play a role in the development of aspiration. At four university-based tertiary medical centers, we conducted a prospective cohort study of ARF patients who required intensive care and mechanical ventilation for at least 48�h. Within 72�h after extubation, a Fiberoptic Flexible Endoscopic Evaluation of Swallowing (FEES) examination was performed. Univariate and multivariable analyses examined the relationship between laryngeal structure and swallowing function abnormalities. Aspiration was the primary outcome, defined as a Penetration- Aspiration Scale (PAS) score of 6 or greater. Two other salient signs of dysphagia-spillage and residue-were secondary outcomes. A total of 213 patients were included in the final analysis. Aspiration was detected in 70 patients (33%) on at least one bolus. The most commonly aspirated consistency was thin liquids (27%). In univariate analyses, several abnormalities in laryngeal anatomy and structural movement were significantly associated with aspiration, spillage, and residue. In a multivariable analysis, the only variables that remained significant with aspiration were pharyngeal weakness (Odds ratio?=?2.57, 95%CI?=?1.16-5.84, p?=?0.019) and upper airway edema (Odds ratio?=?3.24, 95%CI?=?1.44-7.66, p?=?0.004). These results demonstrated that dysphagia in ARF survivors is multifactorial and characterized by both anatomic and physiologic abnormalities. These findings may have important implications for the development of novel interventions to treat dysphagia in ARF survivors.Clinical Trials Registration ClinicalTrials.gov Identifier: NCT02363686, Aspiration in Acute Respiratory Failure Survivors.

View details for DOI 10.1007/s00455-020-10199-8

View details for PubMedID 33156398
Quantitative Assessment of Blood Lactate in Shock: Measure of Hypoxia or Beneficial Energy Source. BioMed research international Levitt, D. G., Levitt, J. E., Levitt, M. D. 2020; 2020: 2608318
Abstract

Blood lactate concentration predicts mortality in critically ill patients and is clinically used in the diagnosis, grading of severity, and monitoring response to therapy of septic shock. This paper summarizes available quantitative data to provide the first comprehensive description and critique of the accepted concepts of the physiology of lactate in health and shock, with particular emphasis on the controversy of whether lactate release is simply a manifestation of tissue hypoxia versus a purposeful transfer ("shuttle") of lactate between tissues. Basic issues discussed include (1) effect of nonproductive lactate-pyruvate exchange that artifactually enhances flux measurements obtained with labeled lactate, (2) heterogeneous tissue oxygen partial pressure (Krogh model) and potential for unrecognized hypoxia that exists in all tissues, and (3) pathophysiology that distinguishes septic from other forms of shock. Our analysis suggests that due to exchange artifacts, the turnover rate of lactate and the lactate clearance are only about 60% of the values of 1.05mmol/min/70kg and 1.5L/min/70kg, respectively, determined from the standard tracer kinetics. Lactate turnover reflects lactate release primarily from muscle, gut, adipose, and erythrocytes and uptake by the liver and kidney, primarily for the purpose of energy production (TCA cycle) while the remainder is used for gluconeogenesis (Cori cycle). The well-studied physiology of exercise-induced hyperlactatemia demonstrates massive release from the contracting muscle accompanied by an increased lactate clearance that may occur in recovering nonexercising muscle as well as the liver. The very limited data on lactate kinetics in shock patients suggests that hyperlactatemia reflects both decreased clearance and increased production, possibly primarily in the gut. Our analysis of available data in health and shock suggests that the conventional concept of tissue hypoxia can account for most blood lactate findings and there is no need to implicate a purposeful production of lactate for export to other organs.

View details for DOI 10.1155/2020/2608318

View details for PubMedID 33150168
Early High-Dose Vitamin D3 for Critically Ill, Vitamin D-Deficient Patients. The New England journal of medicine National Heart, L., Ginde, A. A., Brower, R. G., Caterino, J. M., Finck, L., Banner-Goodspeed, V. M., Grissom, C. K., Hayden, D., Hough, C. L., Hyzy, R. C., Khan, A., Levitt, J. E., Park, P. K., Ringwood, N., Rivers, E. P., Self, W. H., Shapiro, N. I., Thompson, B. T., Yealy, D. M., Talmor, D. 2019
Abstract

BACKGROUND: Vitamin D deficiency is a common, potentially reversible contributor to morbidity and mortality among critically ill patients. The potential benefits of vitamin D supplementation in acute critical illness require further study.METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 3 trial of early vitamin D3 supplementation in critically ill, vitamin D-deficient patients who were at high risk for death. Randomization occurred within 12 hours after the decision to admit the patient to an intensive care unit. Eligible patients received a single enteral dose of 540,000 IU of vitamin D3 or matched placebo. The primary end point was 90-day all-cause, all-location mortality.RESULTS: A total of 1360 patients were found to be vitamin D-deficient during point-of-care screening and underwent randomization. Of these patients, 1078 had baseline vitamin D deficiency (25-hydroxyvitamin D level, <20 ng per milliliter [50 nmol per liter]) confirmed by subsequent testing and were included in the primary analysis population. The mean day 3 level of 25-hydroxyvitamin D was 46.9�23.2 ng per milliliter (117�58 nmol per liter) in the vitamin D group and 11.4�5.6 ng per milliliter (28�14 nmol per liter) in the placebo group (difference, 35.5 ng per milliliter; 95% confidence interval [CI], 31.5 to 39.6). The 90-day mortality was 23.5% in the vitamin D group (125 of 531 patients) and 20.6% in the placebo group (109 of 528 patients) (difference, 2.9 percentage points; 95% CI, -2.1 to 7.9; P=0.26). There were no clinically important differences between the groups with respect to secondary clinical, physiological, or safety end points. The severity of vitamin D deficiency at baseline did not affect the association between the treatment assignment and mortality.CONCLUSIONS: Early administration of high-dose enteral vitamin D3 did not provide an advantage over placebo with respect to 90-day mortality or other, nonfatal outcomes among critically ill, vitamin D-deficient patients. (Funded by the National Heart, Lung, and Blood Institute; VIOLET ClinicalTrials.gov number, NCT03096314.).

View details for DOI 10.1056/NEJMoa1911124

View details for PubMedID 31826336
Relationship Between Laryngeal Sensation, Length of Intubation, and Aspiration in Patients with Acute Respiratory Failure DYSPHAGIA Borders, J. C., Fink, D., Levitt, J. E., McKeehan, J., McNally, E., Rubio, A., Scheel, R., Siner, J. M., Taborda, S., Vojnik, R., Warner, H., White, S., Langmore, S. E., Moss, M., Krisciunas, G. P. 2019; 34 (4): 521?28
View details for DOI 10.1007/s00455-019-09980-1

View details for Web of Science ID 000477579600004
Effect of Titrating Positive End-Expiratory Pressure (PEEP) With an Esophageal Pressure-Guided Strategy vs an Empirical High PEEP-FIO2 Strategy on Death and Days Free From Mechanical Ventilation Among Patients With Acute Respiratory Distress Syndrome A Randomized Clinical Trial Beitler, J. R., Sarge, T., Banner-Goodspeed, V. M., Gong, M. N., Cook, D., Novack, V., Loring, S. H., Talmor, D., Loring, S., Banner-Goodspeed, V., Fish, E., Jinadasa, S., Ritz, R., Previtera, J., Lee, L., Clarke, F., Piraino, T., Levitt, J., Vojnik, R., Park, P., Brierley, K., Haas, C., Weirauch, A., Fan, E., Matte, A., Harris, R., Kone, M., Heard, S., Longtine, K., Lellouche, F., Bouchard, P., Rubinson, L., McGrain, J., Griesdale, D. G., Foster, D., Oeckler, R., Amsbaugh, A., Jimenez, E., Danesh, V., Slutsky, A. S., Hall, J., Hubmayr, R. D., Rubenfeld, G., Schoenfeld, D., EPVent-2 Study Grp AMER MEDICAL ASSOC. 2019: 846?57
Abstract

Adjusting positive end-expiratory pressure (PEEP) to offset pleural pressure might attenuate lung injury and improve patient outcomes in acute respiratory distress syndrome (ARDS).To determine whether PEEP titration guided by esophageal pressure (PES), an estimate of pleural pressure, was more effective than empirical high PEEP-fraction of inspired oxygen (Fio2) in moderate to severe ARDS.Phase 2 randomized clinical trial conducted at 14 hospitals in North America. Two hundred mechanically ventilated patients aged 16 years and older with moderate to severe ARDS (Pao2:Fio2 ?200 mm Hg) were enrolled between October 31, 2012, and September 14, 2017; long-term follow-up was completed July 30, 2018.Participants were randomized to PES-guided PEEP (n?=?102) or empirical high PEEP-Fio2 (n?=?98). All participants received low tidal volumes.The primary outcome was a ranked composite score incorporating death and days free from mechanical ventilation among survivors through day 28. Prespecified secondary outcomes included 28-day mortality, days free from mechanical ventilation among survivors, and need for rescue therapy.Two hundred patients were enrolled (mean [SD] age, 56 [16] years; 46% female) and completed 28-day follow-up. The primary composite end point was not significantly different between treatment groups (probability of more favorable outcome with PES-guided PEEP: 49.6% [95% CI, 41.7% to 57.5%]; P?=?.92). At 28 days, 33 of 102 patients (32.4%) assigned to PES-guided PEEP and 30 of 98 patients (30.6%) assigned to empirical PEEP-Fio2 died (risk difference, 1.7% [95% CI, -11.1% to 14.6%]; P?=?.88). Days free from mechanical ventilation among survivors was not significantly different (median [interquartile range]: 22 [15-24] vs 21 [16.5-24] days; median difference, 0 [95% CI, -1 to 2] days; P?=?.85). Patients assigned to PES-guided PEEP were significantly less likely to receive rescue therapy (4/102 [3.9%] vs 12/98 [12.2%]; risk difference, -8.3% [95% CI, -15.8% to -0.8%]; P?=?.04). None of the 7 other prespecified secondary clinical end points were significantly different. Adverse events included gross barotrauma, which occurred in 6 patients with PES-guided PEEP and 5 patients with empirical PEEP-Fio2.Among patients with moderate to severe ARDS, PES-guided PEEP, compared with empirical high PEEP-Fio2, resulted in no significant difference in death and days free from mechanical ventilation. These findings do not support PES-guided PEEP titration in ARDS.ClinicalTrials.gov Identifier NCT01681225.

View details for DOI 10.1001/jama.2019.0555

View details for Web of Science ID 000460351600015

View details for PubMedID 30776290
Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomised phase 2a safety trial LANCET RESPIRATORY MEDICINE Matthay, M. A., Calfee, C. S., Zhuo, H., Thompson, B., Wilson, J. G., Levitt, J. E., Rogers, A. J., Gotts, J. E., Wiener-Kronish, J. P., Bajwa, E. K., Donahoe, M. P., McVerry, B. J., Ortiz, L. A., Exline, M., Christman, J. W., Abbott, J., Delucchi, K. L., Caballero, L., McMillan, M., McKenna, D. H., Liu, K. D. 2019; 7 (2): 154?62
View details for DOI 10.1016/S2213-2600(18)30418-1

View details for Web of Science ID 000457172000025
Relationship Between Laryngeal Sensation, Length of Intubation, and Aspiration in Patients with Acute Respiratory Failure. Dysphagia Borders, J. C., Fink, D., Levitt, J. E., McKeehan, J., McNally, E., Rubio, A., Scheel, R., Siner, J. M., Taborda, S. G., Vojnik, R., Warner, H., White, S. D., Langmore, S. E., Moss, M., Krisciunas, G. P. 2019
Abstract

Dysphagia is common in hospitalized patients post-extubation and associated with poor outcomes. Laryngeal sensation is critical for airway protection and safe swallowing. However, current understanding of the relationship between laryngeal sensation and aspiration in post-extubation populations is limited. Acute respiratory failure patients requiring intensive care unit admission and mechanical ventilation received a Flexible Endoscopic Evaluation of Swallowing (FEES) within 72h of extubation. Univariate and multivariable analyses were performed to examine the relationship between laryngeal sensation, length of intubation, and aspiration. Secondary outcomes included pharyngolaryngeal secretions, pneumonia, and diet recommendations. One-hundred and three patients met inclusion criteria. Fifty-one patients demonstrated an absent laryngeal adductor reflex (LAR). Altered laryngeal sensation correlated with the presence of secretions (p=0.004). There was a significant interaction between the LAR, aspiration, and duration of mechanical ventilation. Altered laryngeal sensation was significantly associated with aspiration on FEES only in patients with a shorter length of intubation (p=0.008). Patients with altered laryngeal sensation were prescribed significantly more restricted liquid (p=0.03) and solid (p=0.001) diets. No relationship was found between laryngeal sensation and pneumonia. There is a high prevalence of laryngeal sensory deficits in mechanically ventilated patients post-extubation. Altered laryngeal sensation was associated with secretions, aspiration, and modified diet recommendations especially in those patients with a shorter length of mechanical ventilation. These results demonstrate that laryngeal sensory abnormalities impact the development of post-extubation dysphagia.

View details for PubMedID 30694412
Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomised phase 2a safety trial. The Lancet. Respiratory medicine Matthay, M. A., Calfee, C. S., Zhuo, H., Thompson, B. T., Wilson, J. G., Levitt, J. E., Rogers, A. J., Gotts, J. E., Wiener-Kronish, J. P., Bajwa, E. K., Donahoe, M. P., McVerry, B. J., Ortiz, L. A., Exline, M., Christman, J. W., Abbott, J., Delucchi, K. L., Caballero, L., McMillan, M., McKenna, D. H., Liu, K. D. 2018
Abstract

BACKGROUND: Treatment with bone-marrow-derived mesenchymal stromal cells (MSCs) has shown benefits in preclinical models of acute respiratory distress syndrome (ARDS). Safety has not been established for administration of MSCs in critically ill patients with ARDS. We did a phase 2a trial to assess safety after administration of MSCs to patients with moderate to severe ARDS.METHODS: We did a prospective, double-blind, multicentre, randomised trial to assess treatment with one intravenous dose of MSCs compared with placebo. We recruited ventilated patients with moderate to severe ARDS (ratio of partial pressure of oxygen to fractional inspired oxygen <27 kPa and positive end-expiratory pressure [PEEP] ?8 cm H2O) in five university medical centres in the USA. Patients were randomly assigned 2:1 to receive either 10 * 106/kg predicted bodyweight MSCs or placebo, according to a computer-generated schedule with a variable block design and stratified by site. We excluded patients younger than 18 years, those with trauma or moderate to severe liver disease, and those who had received cancer treatment in the previous 2 years. The primary endpoint was safety and all analyses were done by intention to treat. We also measured biomarkers in plasma. MSC viability was tested in a post-hoc analysis. This trial is registered with ClinicalTrials.gov, number NCT02097641.FINDINGS: From March 24, 2014, to Feb 9, 2017 we screened 1038 patients, of whom 60 were eligible for and received treatment. No patient experienced any of the predefined MSC-related haemodynamic or respiratory adverse events. One patient in the MSC group died within 24 h of MSC infusion, but death was judged to be probably unrelated. 28-day mortality did not differ between the groups (30% in the MSC group vs 15% in the placebo group, odds ratio 2�4, 95% CI 0�5-15�1). At baseline, the MSC group had numerically higher mean scores than the placebo group for Acute Physiology and Chronic Health Evaluation III (APACHE III; 104 [SD 31] vs 89 [33]), minute ventilation (11�1 [3�2] vs 9�6 [2�4] L/min), and PEEP (12�4 [3�7] vs 10�8 [2�6] cm H2O). After adjustment for APACHE III score, the hazard ratio for mortality at 28 days was 1�43 (95% CI 0�40-5�12, p=0�58). Viability of MSCs ranged from 36% to 85%.INTERPRETATION: One dose of intravenous MSCs was safe in patients with moderate to severe ARDS. Larger trials are needed to assess efficacy, and the viability of MSCs must be improved.FUNDING: National Heart, Lung, and Blood Institute.

View details for PubMedID 30455077
Effect of Rosuvastatin on Acute Kidney Injury in Sepsis-Associated Acute Respiratory Distress Syndrome. Canadian journal of kidney health and disease Hsu, R. K., Truwit, J. D., Matthay, M. A., Levitt, J. E., Thompson, B. T., Liu, K. D. 2018; 5: 2054358118789158
Abstract

Background: Acute kidney injury (AKI) commonly occurs in patients with sepsis and acute respiratory distress syndrome (ARDS).Objective: To investigate whether statin treatment is protective against AKI in sepsis-associated ARDS.Design: Secondary analysis of data from Statins for Acutely Injured Lungs in Sepsis (SAILS), a randomized controlled trial that tested the impact of rosuvastatin therapy on mortality in patients with sepsis-associated ARDS.Setting: 44 hospitals in the National Heart, Lung, and Blood Institute ARDS Clinical Trials Network.Patients: 644 of 745 participants in SAILS who had available baseline serum creatinine data and who were not on chronic dialysis.Measurements: Our primary outcome was AKI defined using the Kidney Disease Improving Global Outcomes creatinine criteria. Randomization to rosuvastatin vs placebo was the primary predictor. Additional covariates include demographics, ARDS etiology, and severity of illness.Methods: We used multivariable logistic regression to analyze AKI outcomes in 511 individuals without AKI at randomization, and 93 with stage 1 AKI at randomization.Results: Among individuals without AKI at randomization, rosuvastatin treatment did not change the risk of AKI (adjusted odds ratio: 0.99, 95% confidence interval [CI]: 0.67-1.44). Among those with preexisting stage 1 AKI, rosuvastatin treatment was associated with an increased risk of worsening AKI (adjusted odds ratio: 3.06, 95% CI: 1.14-8.22). When serum creatinine was adjusted for cumulative fluid balance among those with preexisting stage 1 AKI, rosuvastatin was no longer associated worsening AKI (adjusted odds ratio: 1.85, 95% CI: 0.70-4.84).Limitations: Sample size, lack of urine output data, and prehospitalization baseline creatinine.Conclusion: Treatment with rosuvastatin in patients with sepsis-associated ARDS did not protect against de novo AKI or worsening of preexisting AKI.

View details for PubMedID 30116543
Randomized Clinical Trial of a Combination of an Inhaled Corticosteroid and Beta Agonist in Patients at Risk of Developing the Acute Respiratory Distress Syndrome CRITICAL CARE MEDICINE Festic, E., Carr, G. E., Cartin-Ceba, R., Hinds, R. F., Banner-Goodspeed, V., Bansal, V., Asuni, A. T., Talmor, D., Rajagopalan, G., Frank, R. D., Gajic, O., Matthay, M. A., Levitt, J. E. 2017; 45 (5): 798-805
Abstract

Effective pharmacologic treatments directly targeting lung injury in patients with the acute respiratory distress syndrome are lacking. Early treatment with inhaled corticosteroids and beta agonists may reduce progression to acute respiratory distress syndrome by reducing lung inflammation and enhancing alveolar fluid clearance.Double-blind, randomized clinical trial (ClinicalTrials.gov: NCT01783821). The primary outcome was longitudinal change in oxygen saturation divided by the FIO2 (S/F) through day 5. We also analyzed categorical change in S/F by greater than 20%. Other outcomes included need for mechanical ventilation and development of acute respiratory distress syndrome.Five academic centers in the United States.Adult patients admitted through the emergency department at risk for acute respiratory distress syndrome.Aerosolized budesonide/formoterol versus placebo bid for up to 5 days.Sixty-one patients were enrolled from September 3, 2013, to June 9, 2015. Median time from presentation to first study drug was less than 9 hours. More patients in the control group had shock at enrollment (14 vs 3 patients). The longitudinal increase in S/F was greater in the treatment group (p = 0.02) and independent of shock (p = 0.04). Categorical change in S/F improved (p = 0.01) but not after adjustment for shock (p = 0.15). More patients in the placebo group developed acute respiratory distress syndrome (7 vs 0) and required mechanical ventilation (53% vs 21%).Early treatment with inhaled budesonide/formoterol in patients at risk for acute respiratory distress syndrome is feasible and improved oxygenation as assessed by S/F. These results support further study to test the efficacy of inhaled corticosteroids and beta agonists for prevention of acute respiratory distress syndrome.

View details for DOI 10.1097/CCM.0000000000002284

View details for Web of Science ID 000399522200007

View details for PubMedID 28240689
Proteomic study of acute respiratory distress syndrome: current knowledge and implications for drug development EXPERT REVIEW OF PROTEOMICS Levitt, J. E., Rogers, A. J. 2016; 13 (5): 457-469
Abstract

The acute respiratory distress syndrome (ARDS) is a common cause of acute respiratory failure, and is associated with substantial mortality and morbidity. Dozens of clinical trials targeting ARDS have failed, with no drug specifically targeting lung injury in widespread clinical use. Thus, the need for drug development in ARDS is great. Targeted proteomic studies in ARDS have identified many key pathways in the disease, including inflammation, epithelial injury, endothelial injury or activation, and disordered coagulation and repair. Recent studies reveal the potential for proteomic changes to identify novel subphenotypes of ARDS patients who may be most likely to respond to therapy and could thus be targeted for enrollment in clinical trials. Nontargeted studies of proteomics in ARDS are just beginning and have the potential to identify novel drug targets and key pathways in the disease. Proteomics will play an important role in phenotyping of patients and developing novel therapies for ARDS in the future.

View details for DOI 10.1586/14789450.2016.1172481

View details for PubMedID 27031735
Increased Resource Use in Lung Transplant Admissions in the Lung Allocation Score Era AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Maxwelll, B. G., Mooney, J. J., Lee, P. H., Levitt, J. E., Chhatwani, L., Nicolls, M. R., Zamora, M. R., Valentine, V., Weill, D., Dhillon, G. S. 2015; 191 (3): 302-308
Abstract

Rationale: In 2005, the lung allocation score (LAS) was implemented to prioritize organ allocation to minimize waiting-list mortality and maximize one-year survival. It resulted in transplantation of older and sicker patients without changing one-year survival. Its effect on resource utilization is unknown. Objective: To determine changes in resource utilization over time in lung transplant admissions Methods: Solid organ transplant recipients were identified within the Nationwide Inpatient Sample (NIS) data from 2000 to 2011. Joinpoint regression methodology was performed to identify a time point of change in mean total hospital charges amongst lung transplant and other solid organ transplant recipients. Two temporal lung transplant recipient cohorts identified by joinpoint regression were compared for baseline characteristics and resource utilization, including total charges for index hospitalization, charges per day, length of stay, discharge disposition, tracheostomy, and need for extracorporeal membrane oxygenation (ECMO). Measurements and Main Results: A significant point of increased total hospital charges occurred for lung transplant recipients in 2005, corresponding to LAS implementation, that was not seen in other solid organ transplant recipients. Total transplant hospital charges increased by 40% in the post-LAS cohort [$569,942 ($53,229) vs. $407,489 ($28,360)] along with an increased median length of stay, daily charges, and discharge disposition other than to home. Post-LAS recipients also had higher post-transplant utilization of ECMO (OR 2.35, 95% CI 1.56, 3.55) and higher incidence of tracheostomy (OR 1.52, 95% CI 1.22, 1.89). Conclusions: LAS implementation is associated with a significant increase in resource utilization during index hospitalization for lung transplant.

View details for DOI 10.1164/rccm.201408-1562OC

View details for Web of Science ID 000348827000014

View details for PubMedID 25517213
Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial. The Lancet. Respiratory medicine Wilson, J. G., Liu, K. D., Zhuo, H., Caballero, L., McMillan, M., Fang, X., Cosgrove, K., Vojnik, R., Calfee, C. S., Lee, J., Rogers, A. J., Levitt, J., Wiener-Kronish, J., Bajwa, E. K., Leavitt, A., McKenna, D., Thompson, B. T., Matthay, M. A. 2015; 3 (1): 24-32
Abstract

No effective pharmacotherapy for acute respiratory distress syndrome (ARDS) exists, and mortality remains high. Preclinical studies support the efficacy of mesenchymal stem (stromal) cells (MSCs) in the treatment of lung injury. We aimed to test the safety of a single dose of allogeneic bone marrow-derived MSCs in patients with moderate-to-severe ARDS.The STem cells for ARDS Treatment (START) trial was a multicentre, open-label, dose-escalation, phase 1 clinical trial. Patients were enrolled in the intensive care units at University of California, San Francisco, CA, USA, Stanford University, Stanford, CA, USA, and Massachusetts General Hospital, Boston, MA, USA, between July 8, 2013, and Jan 13, 2014. Patients were included if they had moderate-to-severe ARDS as defined by the acute onset of the need for positive pressure ventilation by an endotracheal or tracheal tube, a PaO2:FiO2 less than 200 mm Hg with at least 8 cm H2O positive end-expiratory airway pressure (PEEP), and bilateral infiltrates consistent with pulmonary oedema on frontal chest radiograph. The first three patients were treated with low dose MSCs (1 million cells/kg predicted bodyweight [PBW]), the next three patients received intermediate dose MSCs (5 million cells/kg PBW), and the final three patients received high dose MSCs (10 million cells/kg PBW). Primary outcomes included the incidence of prespecified infusion-associated events and serious adverse events. The trial is registered with ClinicalTrials.gov, number NCT01775774.No prespecified infusion-associated events or treatment-related adverse events were reported in any of the nine patients. Serious adverse events were subsequently noted in three patients during the weeks after the infusion: one patient died on study day 9, one patient died on study day 31, and one patient was discovered to have multiple embolic infarcts of the spleen, kidneys, and brain that were age-indeterminate, but thought to have occurred before the MSC infusion based on MRI results. None of these severe adverse events were thought to be MSC-related.A single intravenous infusion of allogeneic, bone marrow-derived human MSCs was well tolerated in nine patients with moderate to severe ARDS. Based on this phase 1 experience, we have proceeded to phase 2 testing of MSCs for moderate to severe ARDS with a primary focus on safety and secondary outcomes including respiratory, systemic, and biological endpoints.The National Heart, Lung, and Blood Institute.

View details for DOI 10.1016/S2213-2600(14)70291-7

View details for PubMedID 25529339
Evolving Epidemiology and Definitions of the Acute Respiratory Distress Syndrome and Early Acute Lung Injury CLINICS IN CHEST MEDICINE Sweatt, A. J., Levitt, J. E. 2014; 35 (4): 609-?
Abstract

This article reviews the evolving definitions and epidemiology of the acute respiratory distress syndrome (ARDS) and highlights current efforts to improve identification of high-risk patients, thus to target prevention and early treatment before progression to ARDS. This information will be important for general practitioners and intensivists interested in improving the care of patients at risk for ARDS, and clinical researchers interested in designing clinical trials targeting the prevention and early treatment of acute lung injury.

View details for DOI 10.1016/j.ccm.2014.08.002

View details for Web of Science ID 000346214200002
Evolving epidemiology and definitions of the acute respiratory distress syndrome and early acute lung injury. Clinics in chest medicine Sweatt, A. J., Levitt, J. E. 2014; 35 (4): 609-624
Abstract

This article reviews the evolving definitions and epidemiology of the acute respiratory distress syndrome (ARDS) and highlights current efforts to improve identification of high-risk patients, thus to target prevention and early treatment before progression to ARDS. This information will be important for general practitioners and intensivists interested in improving the care of patients at risk for ARDS, and clinical researchers interested in designing clinical trials targeting the prevention and early treatment of acute lung injury.

View details for DOI 10.1016/j.ccm.2014.08.002

View details for PubMedID 25453413
Design and implementation of the START (STem cells for ARDS Treatment) trial, a phase 1/2 trial of human mesenchymal stem/stromal cells for the treatment of moderate-severe acute respiratory distress syndrome ANNALS OF INTENSIVE CARE Liu, K. D., Wilson, J. G., Zhuo, H., Caballero, L., McMillan, M. L., Fang, X., Cosgrove, K., Calfee, C. S., Lee, J., Kangelaris, K. N., Gotts, J. E., Rogers, A. J., Levitt, J. E., Wiener-Kronish, J. P., Delucchi, K. L., Leavitt, A. D., McKenna, D. H., Thompson, B. T., Matthay, M. A. 2014; 4
View details for DOI 10.1186/s13613-014-0022-z

View details for Web of Science ID 000345167000001
Designing a better "nest": applicable to preventing hospital exposures to risk factors for acute respiratory distress syndrome or just retrospective study design? Critical care medicine Levitt, J. 2014; 42 (1): 197-198
View details for DOI 10.1097/CCM.0b013e3182a11eab

View details for PubMedID 24346523

View details for PubMedCentralID PMC3869104
Design and implementation of the START (STem cells for ARDS Treatment) trial, a phase 1/2 trial of human mesenchymal stem/stromal cells for the treatment of moderate-severe acute respiratory distress syndrome. Annals of intensive care Liu, K. D., Wilson, J. G., Zhuo, H., Caballero, L., McMillan, M. L., Fang, X., Cosgrove, K., Calfee, C. S., Lee, J., Kangelaris, K. N., Gotts, J. E., Rogers, A. J., Levitt, J. E., Wiener-Kronish, J. P., Delucchi, K. L., Leavitt, A. D., McKenna, D. H., Thompson, B. T., Matthay, M. A. 2014; 4: 22-?
Abstract

Despite advances in supportive care, moderate-severe acute respiratory distress syndrome (ARDS) is associated with high mortality rates, and novel therapies to treat this condition are needed. Compelling pre-clinical data from mouse, rat, sheep and ex vivo perfused human lung models support the use of human mesenchymal stem (stromal) cells (MSCs) as a novel intravenous therapy for the early treatment of ARDS.This article describes the study design and challenges encountered during the implementation and phase 1 component of the START (STem cells for ARDS Treatment) trial, a phase 1/2 trial of bone marrow-derived human MSCs for moderate-severe ARDS. A trial enrolling 69 subjects is planned (9 subjects in phase 1, 60 subjects in phase 2 treated with MSCs or placebo in a 2:1 ratio).This report describes study design features that are unique to a phase 1 trial in critically ill subjects and the specific challenges of implementation of a cell-based therapy trial in the ICU.Experience gained during the design and implementation of the START study will be useful to investigators planning future phase 1 clinical trials based in the ICU, as well as trials of cell-based therapy for other acute illnesses.NCT01775774 and NCT02097641.

View details for DOI 10.1186/s13613-014-0022-z

View details for PubMedID 25593740
Prehospital use of inhaled steroids and incidence of acute lung injury among patients at risk JOURNAL OF CRITICAL CARE Festic, E., Ortiz-Diaz, E., Lee, A., Li, G., Kor, D. J., Adebola, A., Akca, O., Hoth, J., Levitt, J. E., Carter, R., Gajic, O. 2013; 28 (6): 985-991
Abstract

Inhaled corticosteroids (ICSs) attenuated lung injury in animal studies. We investigated the association between prehospital ICS and incidence of acute lung injury (ALI) among patients at risk.In this ancillary analysis of the large multicenter Lung Injury Prediction Study cohort, we developed a propensity score for prehospital ICS use followed by matching, for all patients and for a subgroup of patients with at least 1 risk factor for direct pulmonary injury. The primary outcome was ALI; secondary outcomes included acute respiratory distress syndrome, need for invasive mechanical ventilation, and hospital mortality.Of the 5126 patients, 401 (8%) were using ICS. Acute lung injury developed in 343 (7%). The unadjusted incidence of ALI was 4.7% vs 6.9% (P = .12) among those in ICS compared with non-ICS group. In the "direct" lung injury subgroup, the unadjusted incidence of ALI was 4.1% vs 10.6% (P = 0.006). After propensity matching, the estimated effect for ALI in the whole cohort was 0.69 (95% confidence interval, 0.39-1.2; P = .18), and that in the direct subgroup was 0.56 (95% confidence interval, 0.22-1.46; P = .24).Preadmission use of ICS in a hospitalized population of patients at risk for ALI was not significantly associated with a lower incidence of ALI once controlled by comprehensive propensity-matched analysis.

View details for DOI 10.1016/j.jcrc.2013.08.011

View details for Web of Science ID 000326945100020

View details for PubMedID 24075297

View details for PubMedCentralID PMC4219561
Early acute lung injury: criteria for identifying lung injury prior to the need for positive pressure ventilation*. Critical care medicine Levitt, J. E., Calfee, C. S., Goldstein, B. A., Vojnik, R., Matthay, M. A. 2013; 41 (8): 1929-1937
Abstract

Mortality associated with acute lung injury remains high. Early identification of acute lung injury prior to onset of respiratory failure may provide a therapeutic window to target in future clinical trials. The recently validated Lung Injury Prediction Score identifies patients at risk for acute lung injury but may be limited for routine clinical use. We sought to empirically derive clinical criteria for a pragmatic definition of early acute lung injury to identify patients with lung injury prior to the need for positive pressure ventilation.Prospective observational cohort study.Stanford University Hospital.We prospectively evaluated 256 patients admitted to Stanford University Hospital with bilateral opacities on chest radiograph without isolated left atrial hypertension.None.Of the 256 patients enrolled, 62 patients (25%) progressed to acute lung injury requiring positive pressure ventilation. Clinical variables (through first 72 hr or up to 6 hr prior to acute lung injury) associated with progression to acute lung injury were analyzed by backward regression. Oxygen requirement, maximal respiratory rate, and baseline immune suppression were independent predictors of progression to acute lung injury. A simple three-component early acute lung injury score (1 point for oxygen requirement > 2-6 L/min or 2 points for > 6 L/min; 1 point each for a respiratory rate ? 30 and immune suppression) accurately identified patients who progressed to acute lung injury requiring positive pressure ventilation (area under the receiver-operator characteristic curve, 0.86) and performed similarly to the Lung Injury Prediction Score. An early acute lung injury score greater than or equal to 2 identified patients who progressed to acute lung injury with 89% sensitivity and 75% specificity. Median time of progression from early acute lung injury criteria to acute lung injury requiring positive pressure ventilation was 20 hours.This pragmatic definition of early acute lung injury accurately identified patients who progressed to acute lung injury prior to requiring positive pressure ventilation. Pending further validation, these criteria could be useful for future clinical trials targeting early treatment of acute lung injury.

View details for DOI 10.1097/CCM.0b013e31828a3d99

View details for PubMedID 23782966
Emerging Pharmacological Therapies for Prevention and Early Treatment of Acute Lung Injury SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE Ortiz-Diaz, E., Festic, E., Gajic, O., Levitt, J. E. 2013; 34 (4): 448-458
Abstract

Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) are serious complications of acute illness and injury, associated with an inpatient mortality of up to 40%. Despite considerable basic science and clinical research, therapeutic options for established ALI are limited. Survivors of ARDS are often faced with poor health-related quality of life, depressive-anxiety disorders, cognitive deficits, and financial strain. An attractive approach toward managing ALI lies in its prevention and early treatment. In addition to improving recognition of at-risk patients, it is necessary to identify novel treatments targeting the pathways that may prevent or ameliorate lung injury. The rationale and animal and clinical evidence for aspirin, systemic and inhaled steroids, ?-agonists, renin-angiotensin axis blockers, statins, peroxisome proliferator agonist receptor ligands, curcumin, and inhaled heparin are included in this narrative review. Randomized, controlled trials are currently being designed and implemented to address their efficacy in populations at risk for ALI.

View details for DOI 10.1055/s-0033-1351118

View details for Web of Science ID 000322911200003

View details for PubMedID 23934714
OXYGEN SATURATION TO FRACTION OF INSPIRED OXYGEN RATIO ON ADMISSION IS A PREDICTOR OF ARDS DEVELOPMENT AMONG PATIENTS AT RISK Festic, E., Levitt, J., Kor, D., Gajic, O. LIPPINCOTT WILLIAMS & WILKINS. 2012: U176
View details for Web of Science ID 000312045700599
Pathogenetic and predictive value of biomarkers in patients with ALI and lower severity of illness: results from two clinical trials AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Agrawal, A., Zhuo, H., Brady, S., Levitt, J., Steingrub, J., Siegel, M. D., Soto, G., Peterson, M. W., Chesnutt, M. S., Matthay, M. A., Liu, K. D. 2012; 303 (8): L634-L639
Abstract

Plasma and bronchoalveolar lavage (BAL) biomarkers related to the pathogenesis of acute lung injury (ALI) have previously been associated with poorer clinical outcomes and increased disease severity among patients with ALI. Whether these biomarkers have predictive value in a less severely ill population that excludes septic patients with high APACHE II scores is currently unknown. We tested the association of plasma and BAL biomarkers with physiological markers of ALI severity or clinically relevant outcomes in a secondary analysis of a clinical trial of activated protein C for the treatment of ALI. Plasma plasminogen activator inhibitor-1 (PAI-1) and mini-BAL protein were both significantly associated with increased oxygenation index (P = 0.02 and 0.01, respectively), whereas there was a trend toward an association between IL-6 and oxygenation index (P = 0.057). High plasma IL-6, thrombomodulin, and mini-BAL protein were all significantly associated with fewer ventilator-free days (VFDs) (P = 0.01, 0.01, and 0.05, respectively); no markers were associated with mortality, but we hypothesized that this was due to the small size of our cohort and the low death rate. To confirm these associations in a larger sample, we identified a restricted cohort of patients from the ARDS Network ALVEOLI study with similar baseline characteristics. We retested the associations of the significant biomarkers with markers of severity and clinical outcomes and studied IL-8 as an additional biomarker given its important predictive value in prior studies. In this restricted cohort, IL-6 was significantly associated with oxygenation index (P = 0.02). Both IL-6 and IL-8 were associated with decreased VFDs and increased 28-day mortality. Future studies should be focused on examining larger numbers of patients with less severe ALI to further test the relative predictive value of plasma and mini-BAL biomarkers for clinically relevant outcomes, including VFDs and mortality, and for their prospective utility in risk stratification for future clinical trials.

View details for DOI 10.1152/ajplung.00195.2012

View details for Web of Science ID 000309996300002

View details for PubMedID 22865551

View details for PubMedCentralID PMC3469636
Clinical review: Early treatment of acute lung injury - paradigm shift toward prevention and treatment prior to respiratory failure CRITICAL CARE Levitt, J. E., Matthay, M. A. 2012; 16 (3)
Abstract

ABSTRACT: Acute lung injury (ALI) remains a major cause of morbidity and mortality in critically ill patients. Despite improved understanding of the pathogenesis of ALI, supportive care with a lung protective strategy of mechanical ventilation remains the only treatment with a proven survival advantage. Most clinical trials in ALI have targeted mechanically ventilated patients. Past trials of pharmacologic agents may have failed to demonstrate efficacy in part due to the resultant delay in initiation of therapy until several days after the onset of lung injury. Improved early identification of at-risk patients provides new opportunities for risk factor modification to prevent the development of ALI and novel patient groups to target for early treatment of ALI before progression to the need for mechanical ventilation. This review will discuss current strategies that target prevention of ALI and some of the most promising pharmacologic agents for early treatment of ALI prior to the onset of respiratory failure that requires mechanical ventilation.

View details for DOI 10.1186/cc11144

View details for Web of Science ID 000313197500058

View details for PubMedID 22713281

View details for PubMedCentralID PMC3580596
Clarithromycin for prevention of bronchiolitis obliterans syndrome in lung allograft recipients CLINICAL TRANSPLANTATION Dhillon, G. S., Valentine, V. G., Levitt, J., Patel, P., Gupta, M. R., Duncan, S. R., Seoane, L., Weill, D. 2012; 26 (1): 105-110
Abstract

Bronchiolitis obliterans syndrome (BOS) is the major limitation to long-term survival following lung transplantation and strategies to reduce its incidence have remained elusive. Macrolides may stabilize lung function in patients with established BOS. Their role, however, in prevention of BOS remains unexamined.Survival and BOS-free survival of 102 lung allograft recipients (LARs), transplanted at a single center between July 1995 and December 2001 who routinely received clarithromycin, were compared with two different control groups. The first control group consisted of 44 LARs from the same center who were transplanted from January 2002 onwards and did not receive clarithromycin. The second control group consisted of a contemporaneous cohort of 5089 recipients, transplanted between 1995 and 2001, reported to the United Network for Organ Sharing database.When compared with the first control group, BOS-free survival was reduced in LARs receiving clarithromycin. Univariate (hazard ratio [HR] 3.13, p-value = 0.004) and multivariate (HR 3.49, p-value = 0.04) analyses showed that routine use of clarithromycin was associated with an increased risk of developing BOS. When compared with the second control group, the five-yr survival of clarithromycin group was similar (p-value = 0.24).Routine use of clarithromycin does not delay development of BOS or improve survival.

View details for DOI 10.1111/j.1399-0012.2011.01420.x

View details for PubMedID 21352378
PATIENT-RELATED FACTORS ASSOCIATED WITH HOSPITAL DISCHARGE TO A CARE FACILITY AFTER CRITICAL ILLNESS AMERICAN JOURNAL OF CRITICAL CARE Gehlbach, B. K., Salamanca, V. R., Levitt, J. E., Sachs, G. A., Sweeney, M. K., Pohlman, A. S., Charbeneau, J., Krishnan, J. A., Hall, J. B. 2011; 20 (5): 378-386
Abstract

Many critically ill patients are transferred to other care facilities instead of to home at hospital discharge.To identify patient-related factors associated with hospital discharge to a care facility after critical illness and to estimate the magnitude of risk associated with each factor.Retrospective cohort study of 548 survivors of critical illness in a medical intensive care unit. Multivariable logistic regression was used to identify independent risk factors for discharge to a care facility. Only the first 72 hours of intensive care were analyzed.Approximately one-quarter of the survivors of critical illness were discharged to a care facility instead of to home. This event occurred more commonly in older patients, even after adjustment for severity of illness and comorbid conditions (odds ratio [OR] 1.8 for patients ? 65 years of age vs patients < 65 years; 95% confidence interval [CI], 1.1-3.1; P = .02). The risk was greatest for patients who received mechanical ventilation (OR, 3.4; 95% CI, 2.0-5.8; P < .001) or had hospitalizations characterized by severe cognitive dysfunction (OR, 8.1; 95% CI, 1.3-50.6; P = .02) or poor strength and/or mobility (OR, 31.7; 95% CI, 6.4-157.3; P < .001). The model showed good discrimination (area under the curve, 0.82; 95% CI, 0.77-0.86).The model, which did not include baseline function or social variables, provided good discrimination between patients discharged to a care facility after critical illness and patients discharged to home. These results suggest that future research should focus on the debilitating effects of respiratory failure and on conditions with cognitive and neuromuscular sequelae.

View details for DOI 10.4037/ajcc2011827

View details for Web of Science ID 000294460500006

View details for PubMedID 21885459
The utility of clinical predictors of acute lung injury: towards prevention and earlier recognition. Expert review of respiratory medicine Levitt, J. E., Matthay, M. A. 2010; 4 (6): 785-797
Abstract

Despite significant advances in our understanding of the pathophysiology of acute lung injury, a lung-protective strategy of mechanical ventilation remains the only therapy with a proven survival advantage. Numerous pharmacologic therapies have failed to show benefit in multicenter clinical trials. The paradigm of early, goal-directed therapy of sepsis suggests greater clinical benefit may derive from initiating therapy prior to the onset of respiratory failure that requires mechanical ventilation. Thus, there is heightened interest in more accurate and complete characterization of high-risk patient populations and identification of patients in the early stage of acute lung injury, prior to the need for mechanical ventilation. This article discusses the growing literature on clinical predictors of acute lung injury (including risk factors for specific subgroups) with an emphasis on transfusion-related risk factors and recent research targeting the early identification of high-risk patients and those with early acute lung injury prior to the onset of respiratory failure.

View details for DOI 10.1586/ers.10.78

View details for PubMedID 21128753

View details for PubMedCentralID PMC3044497
Impact of Hepatitis B Core Antibody Positive Donors in Lung and Heart-Lung Transplantation: An Analysis of the United Network for Organ Sharing Database TRANSPLANTATION Dhillon, G. S., Levitt, J., Mallidi, H., Valentine, V. G., Gupta, M. R., Sista, R., Weill, D. 2009; 88 (6): 842-846
Abstract

The availability of suitable lung and heart-lung allografts for transplantation remains poor. Accepting organs from donors with positive serological studies for hepatitis B could potentially expand the donor pool. The aim of this study was to assess the impact of donor hepatitis B core antibody (HBcAb) status on outcomes of lung and heart-lung transplant recipients.Using United Network for Organ Sharing/Organ Procurement and Transplantation Network data, we compared outcomes of 13,233 recipients of HBcAb negative organs with 333 recipients of HBcAb positive donor organs.We found that the unadjusted 1-year survival of recipients of HBcAb positive donor was worse, but there was no difference in survival after adjusting for baseline donor and recipient differences. On multivariate analysis, recipient and donor age, procedure type, era of transplant, baseline medical condition, diagnosis, and donor hepatitis C antibody status impacted 1- and 5-year survival. However, donor HBcAb status did not impact 1- or 5-year survival posttransplant.Lung and heart-lung allografts from HBcAb positive donors may be safely used, which would increase the number of transplants performed without compromising recipient outcomes.

View details for DOI 10.1097/TP.0b013e3181b4e1fd

View details for PubMedID 19920785
Does Itraconazole Improve Quality of Life in Severe Asthma with Fungal Sensitization? AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Khazeni, N., Levitt, J. E. 2009; 180 (2): 191-192
View details for Web of Science ID 000268112500021

View details for PubMedID 19578143
The pathogenetic and prognostic value of biologic markers in acute lung injury. Journal of intensive care medicine Levitt, J. E., Gould, M. K., Ware, L. B., Matthay, M. A. 2009; 24 (3): 151-167
Abstract

Over the past 2 decades, measurement of biomarkers in both the airspaces and plasma early in the course of acute lung injury has provided new insights into the mechanisms of lung injury. In addition, biologic markers of cell-specific injury, acute inflammation, and altered coagulation correlate with mortality from acute lung injury in several single center studies as well as in multicenter clinical trials. To date, biomarkers have been measured largely for research purposes. However, with improved understanding of their role in the pathogenesis of acute lung injury, biomarkers may play an important role in early detection of lung injury, risk stratification for clinical trials, and, ultimately, tailoring specific therapies to individual patients. This article provides a review of biologic markers in acute lung injury, with an emphasis on recent analysis of results from multicenter clinical trials.

View details for DOI 10.1177/0885066609332603

View details for PubMedID 19282296
Identification of Early Acute Lung Injury at Initial Evaluation in an Acute Care Setting Prior to the Onset of Respiratory Failure CHEST Levitt, J. E., Bedi, H., Calfee, C. S., Gould, M. K., Matthay, M. A. 2009; 135 (4): 936-943
Abstract

Despite being a focus of intensive investigation, acute lung injury (ALI) remains a major cause of morbidity and mortality. However, the current consensus definition impedes identification of patients with ALI before they require mechanical ventilation. To establish a definition of early ALI (EALI), we carried out a prospective cohort study to identify clinical predictors of progression to ALI.Potential cases of EALI were identified by daily screening of chest radiographs (CXRs) for all adult emergency department and new medicine service admissions at Stanford University Hospital.Of 1,935 screened patients with abnormal CXRs, we enrolled 100 patients admitted with bilateral opacities present < 7 days and not due exclusively to left atrial hypertension. A total of 33 of these 100 patients progressed to ALI requiring mechanical ventilation during their hospitalization. Progression to ALI was associated with immunosuppression, the modified Rapid Emergency Medicine Score, airspace opacities beyond the bases, systemic inflammatory response syndrome, and the initial oxygen requirement (> 2 L/min). On multivariate analysis, only an initial oxygen requirement > 2 L/min predicted progression to ALI (odds ratio, 8.1; 95% confidence interval, 2.7 to 24.5). A clinical diagnosis of EALI, defined by hospital admission with bilateral opacities on CXR not exclusively due to left atrial hypertension and an initial oxygen requirement of > 2 L/min, was 73% sensitive and 79% specific for progression to ALI.A new clinical definition of EALI may have value in identifying patients with ALI early in their disease course.

View details for DOI 10.1378/chest.08-2346

View details for Web of Science ID 000265113800012

View details for PubMedID 19188549

View details for PubMedCentralID PMC2758305
Randomized clinical trial of activated protein C for the treatment of acute lung injury AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Liu, K. D., Levitt, J., Zhuo, H., Kallet, R. H., Brady, S., Steingrub, J., Tidswell, M., Siegel, M. D., Soto, G., Peterson, M. W., Chesnutt, M. S., Phillips, C., Weinacker, A., Thompson, B. T., Eisner, M. D., Matthay, M. A. 2008; 178 (6): 618-623
Abstract

Microvascular injury, inflammation, and coagulation play critical roles in the pathogenesis of acute lung injury (ALI). Plasma protein C levels are decreased in patients with acute lung injury and are associated with higher mortality and fewer ventilator-free days.To test the efficacy of activated protein C (APC) as a therapy for patients with ALI.Eligible subjects were critically ill patients who met the American/European consensus criteria for ALI. Patients with severe sepsis and an APACHE II score of 25 or more were excluded. Participants were randomized to receive APC (24 microg/kg/h for 96 h) or placebo in a double-blind fashion within 72 hours of the onset of ALI. The primary endpoint was ventilator-free days.APC increased plasma protein C levels (P = 0.002) and decreased pulmonary dead space fraction (P = 0.02). However, there was no statistically significant difference between patients receiving placebo (n = 38) or APC (n = 37) in the number of ventilator-free days (median [25-75% interquartile range]: 19 [0-24] vs. 19 [14-22], respectively; P = 0.78) or in 60-day mortality (5/38 vs. 5/37 patients, respectively; P = 1.0). There were no differences in the number of bleeding events between the two groups.APC did not improve outcomes from ALI. The results of this trial do not support a large clinical trial of APC for ALI in the absence of severe sepsis and high disease severity.

View details for DOI 10.1164/rccm.200803-419OC

View details for Web of Science ID 000259158600011

View details for PubMedID 18565951

View details for PubMedCentralID PMC2542435
Diagnostic utility of B-type natriuretic peptide in critically ill patients with pulmonary edema: a prospective cohort study CRITICAL CARE Levitt, J. E., Vinayak, A. G., Gehlbach, B. K., Pohlman, A., Van Cleve, W., Hall, J. B., Kress, J. P. 2008; 12 (1)
Abstract

Distinguishing pulmonary edema due to acute lung injury (ALI) or the acute respiratory distress syndrome (ARDS) from hydrostatic or cardiogenic edema is challenging in critically ill patients. B-type natriuretic peptide (BNP) can effectively identify congestive heart failure in the emergency room setting but, despite increasing use, its diagnostic utility has not been validated in the intensive care unit (ICU).We performed a prospective, blinded cohort study in the medical and surgical ICUs at the University of Chicago Hospitals. Patients were eligible if they were admitted to the ICU with respiratory distress, bilateral pulmonary edema and a central venous catheter suggesting either high-pressure (cardiogenic) or low-pressure (ALI/ARDS) pulmonary edema. BNP levels were measured within 48 hours of ICU admission and development of pulmonary edema and onward up to three consecutive days. All levels were drawn simultaneously with the measurement of right atrial or pulmonary artery wedge pressure. The etiology of pulmonary edema--cardiogenic or ALI/ARDS--was determined by three intensivists blinded to BNP levels.We enrolled a total of 54 patients (33 with ALI/ARDS and 21 with cardiogenic edema). BNP levels were lower in patients with ALI/ARDS than in those with cardiogenic edema (496 +/- 439 versus 747 +/- 476 pg/ml, P = 0.05). At an accepted cutoff of 100 pg/ml, specificity for the diagnosis of ALI/ARDS was high (95.2%) but sensitivity was poor (27.3%). Cutoffs at higher BNP levels improved sensitivity at considerable cost to specificity. Invasive measures of filling pressures correlated poorly with initial BNP levels and subsequent day BNP values fluctuated unpredictably and without correlation with hemodynamic changes and net fluid balance.BNP levels drawn within 48 hours of admission to the ICU do not reliably distinguish ALI/ARDS from cardiogenic edema, do not correlate with invasive hemodynamic measurements, and do not track predictably with changes in volume status on consecutive daily measurements.

View details for DOI 10.1186/cc6764

View details for Web of Science ID 000254812500043

View details for PubMedID 18194554

View details for PubMedCentralID PMC2374600
Daily sedative interruption in mechanically ventilated patients at risk for coronary artery disease CRITICAL CARE MEDICINE Kress, J. P., Vinayak, A. G., Levitt, J., Schweickert, W. D., Gehlbach, B. K., Zimmerman, F., Pohlman, A. S., Hall, J. B. 2007; 35 (2): 365-371
Abstract

To determine the prevalence of myocardial ischemia in mechanically ventilated patients with coronary risk factors and compare periods of sedative interruption vs. sedative infusion.Prospective, blinded observational study.Medical intensive care unit of tertiary care medical center.Intubated, mechanically ventilated patients with established coronary artery disease risk factors.Continuous three-lead Holter monitors with ST-segment analysis by a blinded cardiologist were used to detect myocardial ischemia. Ischemia was defined as ST-segment elevation or depression of >0.1 mV from baseline.Comparisons between periods of awakening from sedation vs. sedative infusion were made. Vital signs, catecholamine levels, and time with ischemia detected by Holter monitor during the two periods were compared. Heart rate, mean arterial pressure, rate-pressure product, respiratory rate, and catecholamine levels were all significantly higher during sedative interruption. Eighteen of 74 patients (24%) demonstrated ischemic changes. Patients with myocardial ischemia had a longer intensive care unit length of stay (17.4+/-17.5 vs. 9.6+/-6.7 days, p=.04). Despite changes in vital signs and catecholamine levels during sedative interruption, fraction of ischemic time did not differ between the time awake vs. time sedated [median [interquartile range] of 0% [0, 0] compared with 0% [0, 0] while they were sedated [p=.17]). The finding of similar fractions of ischemic time between awake and sedated states persisted with analysis of the subgroup of 18 patients with ischemia.Myocardial ischemia is common in critically ill mechanically ventilated patients with coronary artery disease risk factors. Daily sedative interruption is not associated with an increased occurrence of myocardial ischemia in these patients.

View details for DOI 10.1097/01.CCM.0000254334.46406.B3

View details for Web of Science ID 000243739100004

View details for PubMedID 17205005
Usefulness of the external jugular vein examination in detecting abnormal central venous pressure in critically ill patients ARCHIVES OF INTERNAL MEDICINE Vinayak, A. G., Levitt, J., Gehlbach, B., Pohlman, A. S., Hall, J. B., Kress, J. P. 2006; 166 (19): 2132-2137
Abstract

Central venous pressure (CVP) provides important information for the management of critically ill patients. The external jugular vein (EJV) is easier to visualize than the internal jugular vein and may give a reliable estimate of CVP.To determine the usefulness of the EJV examination in detecting abnormal CVP values, we performed a prospective blinded evaluation comparing it with CVP measured using an indwelling catheter in critically ill patients with central venous catheters. Blinded EJV examinations were performed by clinicians with 3 experience levels (attending physicians, residents and fellows, and interns and fourth-year medical students) to estimate CVP (categorized as low [/=10 cm of water]). The usefulness of the EJV examination in discriminating low vs high CVP was measured using receiver operating characteristic curve analysis.One hundred eighteen observations were recorded among 35 patients. The range of CVP values was 2 to 20 cm of water. The EJV was easier to visualize than the internal jugular vein (mean visual analog scale score, 8 vs 5; P<.001). The reliability for determining low and high CVP was excellent, with areas under the curve of 0.95 (95% confidence interval [CI], 0.88-1.00) and 0.97 (95% CI, 0.92-1.00), respectively, for attending physicians and 0.86 (95% CI, 0.78-0.95) and 0.90 (95% CI, 0.84-0.96), respectively, for all examiners.The EJV examination correlates well with catheter-measured CVP and is a reliable means of identifying low and high CVP values.

View details for Web of Science ID 000241467500010

View details for PubMedID 17060544
Treatment of acute lung injury: Historical perspective and potential future therapies SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE Levitt, J. E., Matthay, M. A. 2006; 27 (4): 426-437
Abstract

The acute respiratory distress syndrome (ARDS) was first described by Ashbaugh and colleagues in 1967. However, despite considerable efforts, early progress in treatment was slowed by lack of consistent definitions and appropriately powered clinical trials. In 1994, the American-European Consensus Conference on ARDS established criteria defining ARDS as well as acute lung injury (ALI). Additionally, the conference established research directives and international coordination of clinical studies. Current incidence of ALI in the United States is estimated at 200,000 cases per year with a mortality rate approaching 40%. Mechanical ventilation, using positive end-expiratory pressure and reduced tidal volumes and inspiratory pressures, along with improved supportive care has increased survival rates. However, to date, pharmacological therapies have failed to improve survival in multicenter clinical trials. This article focuses on clinical treatments for ALI that have been tested in phase II and III clinical trials as well as a discussion of potential future therapies.

View details for DOI 10.1055/s-2006-948296

View details for Web of Science ID 000239897800011

View details for PubMedID 16909376
Poor choice of primary outcome in a clinical trial of pirfenidone in patients with IPF AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LEVITT, J., Gould, M. K. 2005; 172 (9): 1228-1229
View details for Web of Science ID 000232971400019

View details for PubMedID 16249322

Joseph�Levitt, MD, MS

Assistant Professor of Medicine (Pulmonary and Critical Care Medicine) at the Stanford University Medical Center

Medicine - Pulmonary, Allergy & Critical Care Medicine

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