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1. Causes, Consequences, and Treatments of Sleep and Circadian Disruption in the ICU: An Official American Thoracic Society Research Statement

Author

Melissa P. Knauert, Najib T. Ayas, Karen J. Bosma, Xavier Drouot, Mojdeh S. Heavner, Robert L. Owens, Paula L. Watson, M. Elizabeth Wilcox, Brian J. Anderson, Makayla L. Cordoza, John W. Devlin, Rosalind Elliott, Brian K. Gehlbach, Timothy D. Girard, Biren B. Kamdar, Amy S. Korwin, Elizabeth R. Lusczek, Sairam Parthasarathy, Claudia Spies, Jag Sunderram, Irene Telias, Gerald L. Weinhouse, and Phyllis C. Zee

Subjects
circadian rhythm, Pulmonary and Respiratory Medicine, Polysomnography, Respiratory System, Critical Care and Intensive Care Medicine, Medical and Health Sciences, United States, research priority, sleep deficiency, delirium, Medical, Humans, critical illness, Sleep, Societies, Sleep Research
Abstract

Background: Sleep and circadian disruption (SCD) is common and severe in the ICU. On the basis of rigorous evidence in non-ICU populations and emerging evidence in ICU populations, SCD is likely to have a profound negative impact on patient outcomes. Thus, it is urgent that we establish research priorities to advance understanding of ICU SCD. Methods: We convened a multidisciplinary group with relevant expertise to participate in an American Thoracic Society Workshop. Workshop objectives included identifying ICU SCD subtopics of interest, key knowledge gaps, and research priorities. Members attended remote sessions from March to November 2021. Recorded presentations were prepared and viewed by members before Workshop sessions. Workshop discussion focused on key gaps and related research priorities. The priorities listed herein were selected on the basis of rank as established by a series of anonymous surveys. Results: We identified the following research priorities: establish an ICU SCD definition, further develop rigorous and feasible ICU SCD measures, test associations between ICU SCD domains and outcomes, promote the inclusion of mechanistic and patient-centered outcomes within large clinical studies, leverage implementation science strategies to maximize intervention fidelity and sustainability, and collaborate among investigators to harmonize methods and promote multisite investigation. Conclusions: ICU SCD is a complex and compelling potential target for improving ICU outcomes. Given the influence on all other research priorities, further development of rigorous, feasible ICU SCD measurement is a key next step in advancing the field.

Published
2023

2. A Sweet Tutorial to the SUGAR Method of Language Sampling

Author

Stacey L. Pavelko and Robert E. Owens

Subjects
General Medicine
Abstract

Purpose: The purposes of this tutorial are (a) to describe a method of language sample analysis (LSA) referred to as SUGAR (Sampling Utterances and Grammatical Analysis Revised) and (b) to offer step-by-step instructions detailing how to collect, transcribe, analyze, and interpret the results of a SUGAR language sample. Method: The tutorial begins with an overview of current LSA use, including barriers to clinical implementation, followed by an overview of the SUGAR method. Next, the SUGAR method is described in detail, including collecting the sample, transcribing the sample, analyzing the sample, and interpreting the results. To illustrate the method, each section includes an accompanying appendix that provides an example of a sample transcript and the various analyses. Conclusions: SUGAR offers speech-language pathologists one way to conduct LSA that is cost free, valid, and efficient. Clinicians can collect, transcribe, and analyze samples in approximately 21 min. The results of a SUGAR analysis can be used to document the presence of a language impairment, obtain a detailed description of a child's conversational language use, identify intervention targets, and develop intervention goals.

Published
2023

3. The freshman sleep and health (FRoSH) study: Examining sleep and weight gain in incoming college freshmen

Author

Stuti J. Jaiswal, Ashna Aggarwal, Yunyue Zhang, Jeremy Orr, Kratika Mishra, Cathy Y. Lu, Eric Johnson, Nathan E. Wineinger, and Robert L. Owens

Subjects
Public Health, Environmental and Occupational Health
Abstract

Examine how changes in sleep duration, objectively measured by activity trackers, impact weight gain in incoming college freshman.Supplemental data for this article can be accessed online at https://doi.org/10.1080/07448481.2022.2032720.

Published
2023

4. POINT

Author

Bradley A. Edwards, Amy S. Jordan, Christopher N. Schmickl, and Robert L. Owens

Subjects
Pulmonary and Respiratory Medicine, Cardiology and Cardiovascular Medicine, Critical Care and Intensive Care Medicine
Published
2023

5. Neurocheck Frequency

Author

Jamie Nicole, LaBuzetta, Max R, Kazer, Biren B, Kamdar, Robert L, Owens, John H, Evans, Lauren, Stone, and Atul, Malhotra

Subjects
General Medicine
Abstract

Following acute brain injury, patients in the intensive care unit often undergo hourly or every-other-hour exams ("neurochecks") to monitor for neurodeterioration. We assessed health care provider attitudes towards neurocheck frequency and evaluated providers' ideal neurocheck frequency.This was a cross-sectional, online survey distributed in Spring 2021 at a tertiary care academic medical center. Providers from multiple intensive care unit and neuroscience clinical specialties including attending faculty, medical trainees, advanced practice providers, and bedside nurses were invited to participate.Among 177 participants, 61 (34%) and 116 (66%) were self-identified as ordering and performing providers, respectively. The survey response rate was 58% among physicians and 51% among bedside nurses with neurological expertise. The most common medical and non-medical reasons for ordering hourly neurochecks were "a specific diagnosis with anticipated course" and "standard of care", respectively. Compared with ordering providers, performing providers felt guidelines regarding neurocheck frequency (P0.01) and duration (P0.01) should be proscriptive. Conversely, ordering providers felt hourly neurochecks were detrimental to patients with acute brain injury (P=0.02) and believed they would not utilize hourly neurochecks if there was another mode of monitoring available (P=0.03). Performing providers identified multiple patient-related factors impacting the difficulty of and their willingness to perform frequent neurochecks, and only 70% of neurochecks were perceived to be performed as ordered. Both ordering and performing providers preferred every-other-hour neurochecks following acute brain injury.This survey revealed clinically relevant differences in ordering versus performing provider attitudes about frequent neurochecks. Providers preferred every-other-hour rather than hourly neurochecks.

Published
2022

6. Very Low Driving-Pressure Ventilation in Patients With COVID-19 Acute Respiratory Distress Syndrome on Extracorporeal Membrane Oxygenation: A Physiologic Study

Author

Mazen Odish, Travis Pollema, Angela Meier, Mark Hepokoski, Cassia Yi, Roger Spragg, Hemal H. Patel, Laura E. Crotty Alexander, Xiaoying (Shelly) Sun, Sonia Jain, Tatum S. Simonson, Atul Malhotra, and Robert L. Owens

Subjects
Adult, Physical Injury - Accidents and Adverse Effects, Receptor for Advanced Glycation End Products, Clinical Trials and Supportive Activities, Cardiorespiratory Medicine and Haematology, Extracorporeal Membrane Oxygenation, Rare Diseases, Clinical Research, Anesthesiology, Humans, 2.1 Biological and endogenous factors, Prospective Studies, Aetiology, Acute Respiratory Distress Syndrome, Lung, Respiratory Distress Syndrome, screening and diagnosis, Interleukin-6, Respiration, Interleukin-8, COVID-19, biomarkers, ventilator-induced lung injury, 4.1 Discovery and preclinical testing of markers and technologies, Detection, Anesthesiology and Pain Medicine, Artificial, Respiratory, low driving pressure ventilation, Cardiology and Cardiovascular Medicine
Abstract

ObjectivesTo determine in patients with acute respiratory distress syndrome (ARDS) on venovenous extracorporeal membrane oxygenation (VV ECMO) whether reducing driving pressure (ΔP) would decrease plasma biomarkers of inflammation and lung injury (interleukin-6 [IL-6], IL-8, and the soluble receptor for advanced glycation end-products sRAGE).DesignA single-center prospective physiologic study.SettingAt a single university medical center.ParticipantsAdult patients with severe COVID-19 ARDS on VV ECMO.InterventionsParticipants on VV ECMO had the following biomarkers measured: (1) pre-ECMO with low-tidal-volume ventilation (LTVV), (2) post-ECMO with LTVV, (3) during low-driving-pressure ventilation (LDPV), (4) after 2 hours of very low driving-pressure ventilation (V-LDPV, main intervention ΔP=1 cmH2O), and (5) 2 hours after returning to LDPV.Main measurements and resultsTwenty-six participants were enrolled; 21 underwent V-LDPV. There was no significant change in IL-6, IL-8, and sRAGE from LDPV to V-LDPV and from V-LDPV to LDPV. Only participants (9 of 21) with nonspontaneous breaths had significant change (p < 0.001) in their tidal volumes (Vt) (mean ± SD), 1.9 ± 0.5, 0.1 ± 0.2, and 2.0 ± 0.7 mL/kg predicted body weight (PBW). Participants with spontaneous breathing, Vt were unchanged-4.5 ± 3.1, 4.7 ± 3.1, and 5.6 ± 2.9 mL/kg PBW (p=0.481 and p=0.065, respectively). There was no relationship found when accounting for Vt changes and biomarkers.ConclusionsBiomarkers did not significantly change with decreased ΔPs or Vt changes during the first 24 hours post-ECMO. Despite deep sedation, reductions in Vt during V-LDPV were not reliably achieved due to spontaneous breaths. Thus, patients on VV ECMO for ARDS may have higher Vt (ie, transpulmonary pressure) than desired despite low ΔPs or Vt.

Published
2023

7. Pathogenesis of obstructive sleep apnea in people living with HIV

Author

Jeremy E. Orr, Rebecca J. Theilmann, Charles B. Hicks, Chantal Darquenne, Pamela N. DeYoung, Sonia Jain, Maile Y. Karris, Robert L. Owens, Christopher N. Schmickl, Atul Malhotra, and Bradley A. Edwards

Subjects
medicine.medical_specialty, Sleep Apnea, Physiology, Polysomnography, Human immunodeficiency virus (HIV), HIV Infections, medicine.disease_cause, Medical and Health Sciences, Body Mass Index, Pathogenesis, stomatognathic system, Clinical Research, Physiology (medical), Internal medicine, Behavioral and Social Science, Humans, Medicine, Lung, obstructive sleep apnea, Sleep Apnea, Obstructive, Obstructive, business.industry, Prevention, HIV, Biological Sciences, Middle Aged, medicine.disease, nervous system diseases, respiratory tract diseases, Obstructive sleep apnea, Infectious Diseases, fatigue, Sleep Research, Sleep, business, Research Article
Abstract

Obstructive sleep apnea (OSA) is highly prevalent in people living with human immunodeficiency virus (HIV) (PLWH), and it might contribute to frequently reported symptoms and comorbidities. Traditional risk factors for OSA are often absent in PLWH, suggesting that HIV or HIV medications might predispose to OSA. Therefore, we measured the anatomical and nonanatomical traits important for OSA pathogenesis in those with and without HIV. We recruited virally suppressed PLWH who had been previously diagnosed with OSA (PLWH + OSA) adherent to positive airway pressure (PAP) therapy, along with age-, sex-, and body mass index (BMI)-matched OSA controls. All participants underwent a baseline polysomnogram to assess OSA severity and a second overnight research sleep study during which the airway pressure was adjusted slowly or rapidly to measure the OSA traits. Seventeen PLWH + OSA and 17 OSA control participants were studied [median age = 58 (IQR = 54–65) yr, BMI = 30.7 (28.4–31.8) kg/m(2), apnea-hypopnea index = 46 (24–74)/h]. The groups were similar, although PLWH + OSA demonstrated greater sleepiness (despite PAP) and worse sleep efficiency on baseline polysomnography. On physiological testing during sleep, there were no statistically significant differences in OSA traits (including V(eupnea), V(arousal), V(passive), V(active), and loop gain) between PLWH + OSA and OSA controls, using mixed-effects modeling to account for age, sex, and BMI and incorporating each repeated measurement (range = 72–334 measures/trait). Our data suggest that well-treated HIV does not substantially impact the pathogenesis of OSA. Given similar underlying physiology, existing available therapeutic approaches are likely to be adequate to manage OSA in PLWH, which might improve symptoms and comorbidities. NEW & NOTEWORTHY Clinical data suggest an increased risk of obstructive sleep apnea (OSA) in people living with HIV (PLWH), while OSA might account for chronic health issues in this population. We characterized the anatomical and nonanatomical OSA traits in PLWH + OSA compared with OSA controls, using detailed physiological measurements obtained during sleep. Our data suggest against a major impact of HIV on OSA pathogenesis. Available OSA management strategies should be effective to address this potentially important comorbidity in PLWH.

Published
2021

8. Sleep Outcomes From AWAKE-HF: A Randomized Clinical Trial of Sacubitril/Valsartan vs Enalapril in Patients With Heart Failure and Reduced Ejection Fraction

Author

Kade Birkeland, Raj M. Khandwalla, Emmanuel Fombu, Steven R. Steinhubl, Jonas F. Dorn, J. Thomas Heywood, Daniel Grant, and Robert L. Owens

Subjects
medicine.medical_specialty, Central sleep apnea, Tetrazoles, Cheyne–Stokes respiration, Sacubitril, Angiotensin Receptor Antagonists, Enalapril, Internal medicine, medicine, Humans, Wakefulness, Heart Failure, business.industry, Aminobutyrates, Biphenyl Compounds, Stroke Volume, medicine.disease, Obstructive sleep apnea, Drug Combinations, Valsartan, Heart failure, Cardiology, medicine.symptom, Sleep, Cardiology and Cardiovascular Medicine, business, Sacubitril, Valsartan, medicine.drug
Abstract

Background Heart failure and sleep-disordered breathing have been increasingly recognized as co-occurring conditions. Their bidirectional relationship warrants investigation into whether heart failure therapy improves sleep and sleep-disordered breathing. We sought to explore the effect of treatment with sacubitril/valsartan on sleep-related endpoints from the AWAKE-HF study. Methods and Results AWAKE-HF was a randomized, double-blind study conducted in 23 centers in the United States. Study participants with heart failure with reduced rejection fraction and New York Heart Association class II or III symptoms were randomly assigned to receive treatment with either sacubitril/valsartan or enalapril. All endpoints were assessed at baseline and after 8 weeks of treatment. Portable sleep-monitoring equipment was used to measure the apnea-hypopnea index, including obstructive and central events. Total sleep time, wake after sleep onset and sleep efficiency were exploratory measures assessed using wrist actigraphy. The results were as follows 140 patients received treatment in the double-blind phase (sacubitril/valsartan, n = 70; enalapril, n = 70). At baseline, 39% and 40% of patients randomly assigned to receive sacubitril/valsartan or enalapril, respectively, presented with undiagnosed, untreated, moderate-to-severe sleep-disordered breathing (≥ 15 events/h), and nearly all had obstructive sleep apnea. After 8 weeks of treatment, the mean 4% apnea-hypopnea index changed minimally from 16.3/h to 15.2/h in the sacubitril/valsartan group and from 16.8/h to 17.6/h in the enalapril group. Mean total sleep time was long at baseline and decreased only slightly in both treatment groups at week 8 (–14 and –11 minutes for sacubitril/valsartan and enalapril, respectively), with small changes in wake after sleep onset and sleep efficiency in both groups. Conclusions In a cohort of patients with heart failure with reduced rejection fraction who met prescribing guidelines for sacubitril/valsartan, one-third had undiagnosed moderate-to-severe obstructive sleep apnea. The addition of sacubitril/valsartan therapy did not significantly improve sleep-disordered breathing or sleep duration or efficiency. Patients who meet indications for treatment with sacubitril/valsartan should be evaluated for sleep-disordered breathing.

Published
2021

9. Passive longitudinal weight and cardiopulmonary monitoring in the home bed

Author

Nicholas Harrington, Quan M. Bui, Zhe Wei, Brandon Hernandez-Pacheco, Pamela N. DeYoung, Andrew Wassell, Bayan Duwaik, Akshay S. Desai, Deepak L. Bhatt, Parag Agnihotri, Robert L. Owens, Todd P. Coleman, and Kevin R. King

Subjects
Monitoring, Polysomnography, Science, Myocardial Ischemia, Bioengineering, Beds, Cardiovascular, Article, Heart Rate, Clinical Research, Behavioral and Social Science, Humans, Longitudinal Studies, Coronary Artery Bypass, Physiologic, Lung, Monitoring, Physiologic, Heart Failure, Multidisciplinary, Respiration, Body Weight, Diagnostic markers, Circulation, Heart Disease, Good Health and Well Being, Chronic Disease, Medicine, Cardiomyopathies, Sleep, Biomedical engineering, Algorithms
Abstract

Home health monitoring has the potential to improve outpatient management of chronic cardiopulmonary diseases such as heart failure. However, it is often limited by the need for adherence to self-measurement, charging and self-application of wearables, or usage of apps. Here, we describe a non-contact, adherence-independent sensor, that when placed beneath the legs of a patient’s home bed, longitudinally monitors total body weight, detailed respiratory signals, and ballistocardiograms for months, without requiring any active patient participation. Accompanying algorithms separate weight and respiratory signals when the bed is shared by a partner or a pet. Validation studies demonstrate quantitative equivalence to commercial sensors during overnight sleep studies. The feasibility of detecting obstructive and central apneas, cardiopulmonary coupling, and the hemodynamic consequences of non-sustained ventricular tachycardia is also established. Real-world durability is demonstrated by 3 months of in-home monitoring in an example patient with heart failure and ischemic cardiomyopathy as he recovers from coronary artery bypass grafting surgery. BedScales is the first sensor to measure adherence-independent total body weight as well as longitudinal cardiopulmonary physiology. As such, it has the potential to create a multidimensional picture of chronic disease, learn signatures of impending hospitalization, and enable optimization of care in the home.

Published
2021

10. Respiratory Therapists in an ICU Recovery Clinic: Two Institutional Experiences and Review of the Literature

Author

Alison Nestor, Amy L. Bellinghausen, Robert L. Owens, Frank Chu, Joseph Morrell, Brad W. Butcher, and Le Tm Ho

Subjects
Pulmonary and Respiratory Medicine, education.field_of_study, medicine.medical_specialty, ARDS, Mindfulness, business.industry, Population, Psychological intervention, Cognition, General Medicine, Critical Care and Intensive Care Medicine, medicine.disease, Mental health, Multidisciplinary approach, medicine, education, Intensive care medicine, business, Psychosocial
Abstract

Post-intensive care syndrome is an increasingly recognized complication of critical illness, with patients reporting new problems in physical, mental health and/or psychosocial, and cognitive function for months to years after their acute illness. As a way of diagnosing and treating post-intensive care syndrome, many centers around the world have established ICU recovery clinics, which take a multidisciplinary approach to care after the ICU. Dyspnea and pulmonary dysfunction are frequently encountered concerns in the post-ICU population. Despite this, few ICU recovery clinics have described how respiratory therapists (RTs) can contribute to treating these symptoms. We reviewed the literature with regard to the roles of an RT in post-ICU follow-up, described our institutional experiences with having RTs as part of our ICU recovery clinics, and identified additional ways that RTs might contribute to a post-intensive care syndrome diagnosis and treatment. Although RTs can provide invaluable experience and contributions to an ICU recovery clinic, there are few articles in the published literature on the ways in which this can be accomplished. We, therefore, provide analogies to other multidisciplinary clinic models as well as our own experiences. Future studies should focus on examining the impact of respiratory therapy diagnostic testing and interventions in the ICU recovery clinic on both patient and provider outcomes.

Published
2021

11. Optimal NIV Medicare Access Promotion: Patients With COPD

Author

Nicholas S. Hill, Gerard J. Criner, Richard D. Branson, Bartolome R. Celli, Neil R. MacIntyre, Amen Sergew, Peter C. Gay, Robert L. Owens, Lisa F. Wolfe, Joshua O. Benditt, Loutfi S. Aboussouan, John M. Coleman, Dean R. Hess, Timothy I. Morgenthaler, Atul Malhotra, Richard B. Berry, Karin G. Johnson, Marc I. Raphaelson, Babak Mokhlesi, Christine H. Won, Bernardo J. Selim, Barry J. Make, Bernie Y. Sunwoo, Nancy A. Collop, Susheel P. Patil, Alejandro D. Chediak, Eric J. Olson, and Kunwar Praveen Vohra

Subjects
Pulmonary and Respiratory Medicine, Obesity hypoventilation syndrome, medicine.medical_specialty, Central sleep apnea, business.industry, medicine.medical_treatment, Sleep apnea, Critical Care and Intensive Care Medicine, medicine.disease, Sleep medicine, Apnea–hypopnea index, Oxygen therapy, Positive airway pressure, medicine, Continuous positive airway pressure, Cardiology and Cardiovascular Medicine, business, Intensive care medicine
Abstract

This document summarizes suggestions of the central sleep apnea (CSA) Technical Expert Panel working group. This paper shares our vision for bringing the right device to the right patient at the right time. For patients with CSA, current coverage criteria do not align with guideline treatment recommendations. For example, CPAP and oxygen therapy are recommended but not covered for CSA. On the other hand, bilevel positive airway pressure (BPAP) without a backup rate may be a covered therapy for OSA, but it may worsen CSA. Narrow coverage criteria that require near elimination of obstructive breathing events on CPAP or BPAP in the spontaneous mode, even if at poorly tolerated pressure levels, may preclude therapy with BPAP with backup rate or adaptive servoventilation, even when those devices provide demonstrably better therapy. CSA is a dynamic disorder that may require different treatments over time, sometimes switching from one device to another; an example is switching from BPAP with backup rate to an adaptive servoventilation with automatic end-expiratory pressure adjustments, which may not be covered. To address these challenges, we suggest several changes to the coverage determinations, including: (1) a single simplified initial and continuing coverage definition of CSA that aligns with OSA; (2) removal of hypoventilation terminology from coverage criteria for CSA; (3) all effective therapies for CSA should be covered, including oxygen and all PAP devices with or without backup rates or servo-mechanisms; and (4) patients shown to have a suboptimal response to one PAP device should be allowed to add oxygen or change to another PAP device with different capabilities if shown to be effective with testing.

Published
2021

12. Optimal NIV Medicare Access Promotion: Patients With Hypoventilation Syndromes

Author

Babak Mokhlesi, Christine H. Won, Barry J. Make, Bernardo J. Selim, Bernie Y. Sunwoo, Peter C. Gay, Robert L. Owens, Lisa F. Wolfe, Joshua O. Benditt, Loutfi S. Aboussouan, John M. Coleman, Dean R. Hess, Nicholas S. Hill, Gerard J. Criner, Richard D. Branson, Bartolome R. Celli, Neil R. MacIntyre, Amen Sergew, Timothy I. Morgenthaler, Atul Malhotra, Richard B. Berry, Karin G. Johnson, Marc I. Raphaelson, Nancy A. Collop, Susheel P. Patil, Alejandro D. Chediak, Eric J. Olson, and Kunwar Praveen Vohra

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, Promotion (rank), Hypoventilation syndromes, business.industry, media_common.quotation_subject, medicine, Cardiology and Cardiovascular Medicine, Critical Care and Intensive Care Medicine, Intensive care medicine, business, media_common
Published
2021

13. Optimal NIV Medicare Access Promotion: Patients With OSA

Author

Susheel P. Patil, Nancy A. Collop, Alejandro D. Chediak, Eric J. Olson, Kunwar Praveen Vohra, Peter C. Gay, Robert L. Owens, Lisa F. Wolfe, Joshua O. Benditt, Loutfi S. Aboussouan, John M. Coleman, Dean R. Hess, Nicholas S. Hill, Gerard J. Criner, Richard D. Branson, Bartolome R. Celli, Neil R. MacIntyre, Amen Sergew, Timothy I. Morgenthaler, Atul Malhotra, Richard B. Berry, Karin G. Johnson, Marc I. Raphaelson, Babak Mokhlesi, Christine H. Won, Bernardo J. Selim, Barry J. Make, and Bernie Y. Sunwoo

Subjects
Pulmonary and Respiratory Medicine, Cardiology and Cardiovascular Medicine, Critical Care and Intensive Care Medicine
Published
2021

14. Executive Summary

Author

Peter C. Gay, Robert L. Owens, Lisa F. Wolfe, Joshua O. Benditt, Loutfi S. Aboussouan, John M. Coleman, Dean R. Hess, Nicholas S. Hill, Gerard J. Criner, Richard D. Branson, Bartolome R. Celli, Neil R. MacIntyre, Amen Sergew, Timothy I. Morgenthaler, Atul Malhotra, Richard B. Berry, Karin G. Johnson, Marc I. Raphaelson, Babak Mokhlesi, Christine H. Won, Bernardo J. Selim, Barry J. Make, Bernie Y. Sunwoo, Nancy A. Collop, Susheel P. Patil, Alejandro D. Chediak, Eric J. Olson, and Kunwar Praveen Vohra

Subjects
Pulmonary and Respiratory Medicine, Obesity hypoventilation syndrome, medicine.medical_specialty, Executive summary, Central sleep apnea, business.industry, MEDLINE, Critical Care and Intensive Care Medicine, medicine.disease, Sleep medicine, Scientific evidence, Family medicine, Positive airway pressure, medicine, Cardiology and Cardiovascular Medicine, business, Respiratory care
Abstract

The current national coverage determinations (NCDs) for noninvasive ventilation for patients with thoracic restrictive disorders, COPD, and hypoventilation syndromes were formulated in 1998. New original research, updated formal practice guidelines, and current consensus expert opinion have accrued that are in conflict with the existing NCDs. Some inconsistencies in the NCDs have been noted, and the diagnostic and therapeutic technology has also advanced in the last quarter century. Thus, these and related NCDs relevant to bilevel positive airway pressure for the treatment of OSA and central sleep apnea need to be updated to ensure the optimal health of patients with these disorders. To that end, the American College of Chest Physicians organized a multisociety (American Thoracic Society, American Academy of Sleep Medicine, and American Association for Respiratory Care) effort to engage experts in the field to: (1) identify current barriers to optimal care; (2) highlight compelling scientific evidence that would justify changes from current policies incorporating best evidence and practice; and (3) propose suggestions that would form the basis for a revised NCD in each of these 5 areas (thoracic restrictive disorders, COPD, hypoventilation syndromes, OSA, and central sleep apnea). The expert panel met during a 2-day virtual summit in October 2020 and subsequently crafted written documents designed to achieve provision of "the right device to the right patient at the right time." These documents have been endorsed by the participating societies following peer review and publication in CHEST and will be used to inform efforts to revise the current NCDs.

Published
2021

15. Optimal NIV Medicare Access Promotion: Patients With Thoracic Restrictive Disorders

Author

Lisa F. Wolfe, Joshua O. Benditt, Loutfi Aboussouan, Dean R. Hess, John M. Coleman, Peter C. Gay, Robert L. Owens, Loutfi S. Aboussouan, Nicholas S. Hill, Gerard J. Criner, Richard D. Branson, Bartolome R. Celli, Neil R. MacIntyre, Amen Sergew, Timothy I. Morgenthaler, Atul Malhotra, Richard B. Berry, Karin G. Johnson, Marc I. Raphaelson, Babak Mokhlesi, Christine H. Won, Bernardo J. Selim, Barry J. Make, Bernie Y. Sunwoo, Nancy A. Collop, Susheel P. Patil, Alejandro D. Chediak, Eric J. Olson, and Kunwar Praveen Vohra

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, Promotion (rank), business.industry, media_common.quotation_subject, Medicine, Cardiology and Cardiovascular Medicine, Critical Care and Intensive Care Medicine, business, Intensive care medicine, media_common
Published
2021

16. Optimal NIV Medicare Access Promotion: Patients With Central Sleep Apnea

Author

Timothy I. Morgenthaler, Atul Malhotra, Richard B. Berry, Karin G. Johnson, Marc Raphaelson, Peter C. Gay, Robert L. Owens, Lisa F. Wolfe, Joshua O. Benditt, Loutfi S. Aboussouan, John M. Coleman, Dean R. Hess, Nicholas S. Hill, Gerard J. Criner, Richard D. Branson, Bartolome R. Celli, Neil R. MacIntyre, Amen Sergew, Marc I. Raphaelson, Babak Mokhlesi, Christine H. Won, Bernardo J. Selim, Barry J. Make, Bernie Y. Sunwoo, Nancy A. Collop, Susheel P. Patil, Alejandro D. Chediak, Eric J. Olson, and Kunwar Praveen Vohra

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, Promotion (rank), Central sleep apnea, business.industry, media_common.quotation_subject, Emergency medicine, medicine, Cardiology and Cardiovascular Medicine, Critical Care and Intensive Care Medicine, business, medicine.disease, media_common
Published
2021

21. Randomized Clinical Trials or Convenient Controls: TREWS or FALSE?

Author

Shamim Nemati, Supreeth P. Shashikumar, Andre L. Holder, Gabriel Wardi, and Robert L. Owens

Abstract

We read with interest the Adams et al.1 report of the TREWS machine learning (ML)-based sepsis early warning system. The authors conclude that large-scale randomized trials are needed to confirm their observations, but assert that their findings indicate the potential for the TREWS system to identify sepsis patients early and improve patient outcomes, including a significant decrease in mortality. However, this conclusion is based upon a comparison of those whose alert was confirmed vs. not confirmed within 3 hours, rather than random allocation to TREWS vs. no TREWS. Using data from over 650,000 patient encounters across two distinct healthcare systems, we show that the findings of Adams et al. are likely to be severely biased due to the failure to adjust for ‘processes of care’-related confounding factors.

Published
2022

23. Long-Term Domiciliary Noninvasive Ventilation for COPD

Author

Robert L. Owens

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, Respiratory rate, Critical Care and Intensive Care Medicine, Hypoxemia, Hypercapnia, Pulmonary Disease, Chronic Obstructive, 03 medical and health sciences, 0302 clinical medicine, Quality of life, medicine, Humans, Intensive care medicine, COPD, Noninvasive Ventilation, business.industry, Oxygen Inhalation Therapy, General Medicine, medicine.disease, Obstructive sleep apnea, 030228 respiratory system, Quality of Life, Breathing, Noninvasive ventilation, medicine.symptom, business
Abstract

COPD can lead to abnormalities in oxygenation as well as ventilation. Thanks to pioneering work by Dr Thomas Petty, supplemental oxygen therapy has been shown to improve morbidity and mortality for individuals with COPD and severe daytime hypoxemia. However, efforts to augment ventilation have been less uniformly successful. Recent studies employing a so-called high-intensity noninvasive ventilation strategy, which used high inspiratory pressures and backup breathing frequency to reduce arterial carbon dioxide levels, have shown improved quality of life and reduced mortality. Thus, efforts are underway to better identify and treat patients with COPD who might benefit from noninvasive ventilation, though many practical questions remain.

Published
2021

24. Rebuttal From Dr Edwards et al

Author

Bradley A. Edwards, Amy S. Jordan, Christopher N. Schmickl, and Robert L. Owens

Subjects
Pulmonary and Respiratory Medicine, Cardiology and Cardiovascular Medicine, Critical Care and Intensive Care Medicine
Published
2023

25. Recovering from COVID ARDS and post-intensive care syndrome

Author

Amy L Bellinghausen and Robert L Owens

Subjects
Pulmonary and Respiratory Medicine, Intensive Care Units, Respiratory Distress Syndrome, SARS-CoV-2, Critical Illness, COVID-19, Humans, Respiration, Artificial
Published
2022

26. Role of RNA silencing in plant-viroid interactions and in viroid pathogenesis

Author

Francesco Di Serio, Robert A. Owens, Beatriz Navarro, Pedro Serra, Ángel Emilio Martínez de Alba, Sonia Delgado, Alberto Carbonell, and Selma Gago-Zachert

Subjects
Cancer Research, Infectious Diseases, Virology
Abstract

Viroids are small, single-stranded, non-protein coding and circular RNAs able to infect host plants in the absence of any helper virus. They may elicit symptoms in their hosts, but the underlying molecular pathways are only partially known. Here we address the role of post-transcriptional RNA silencing in plant-viroid-interplay, with major emphasis on the involvement of this sequence-specific RNA degradation mechanism in both plant antiviroid defence and viroid pathogenesis. This review is a tribute to the memory of Dr. Ricardo Flores, who largely contributed to elucidate this and other molecular mechanisms involved in plant-viroid interactions.

Published
2022

27. Sleep Deficiency, Sleep Apnea, and Chronic Lung Disease

Author

Bernie Y. Sunwoo and Robert L. Owens

Subjects
Pulmonary and Respiratory Medicine, Adult, Pulmonary Disease, Chronic Obstructive, Sleep Apnea, Obstructive, Sleep Apnea Syndromes, Quality of Life, Humans, Sleep
Abstract

With sleep occupying up to one-third of every adult's life, addressing sleep is essential to overall health. Sleep disturbance and deficiency are common in patients with chronic lung diseases and associated with worse clinical outcomes and poor quality of life. A detailed history incorporating nocturnal respiratory symptoms, symptoms of obstructive sleep apnea (OSA) and restless legs syndrome, symptoms of anxiety and depression, and medications is the first step in identifying and addressing the multiple factors often contributing to sleep deficiency in chronic lung disease. Additional research is needed to better understand the relationship between sleep deficiency and the spectrum of chronic lung diseases.

Published
2022

28. The impact of daytime transoral neuromuscular stimulation on upper airway physiology - A mechanistic clinical investigation

Author

Brandon Nokes, Christopher N. Schmickl, Rebbecca Brena, Nana Naa‐Oye Bosompra, Dillon Gilbertson, Scott A. Sands, Rakesh Bhattacharjee, Dwayne L. Mann, Robert L. Owens, Atul Malhotra, and Jeremy E. Orr

Subjects
Adult, Male, Sleep Apnea, Obstructive, Sleep Apnea, Obstructive, Electromyography, Physiology, Polysomnography, Snoring, Clinical Sciences, Medical Physiology, Neurosciences, flow-limited breathing, Middle Aged, Tongue, genioglossus, Clinical Research, Physiology (medical), upper airway training, Humans, obstructive sleep apneasnoring, Sleep Research, Lung
Abstract

There is a need for alternatives to positive airway pressure for the treatment of obstructive sleep apnea and snoring. Improving upper airway dilator function might alleviate upper airway obstruction. We hypothesized that transoral neuromuscular stimulation would reduce upper airway collapse in concert with improvement in genioglossal muscle function. Subjects with simple snoring and mild OSA (AHI

Published
2022

29. The separation angle of the free surface of a viscous fluid at a straight edge

Author

Robert Gwyn Owens

Subjects
Mechanics of Materials, Mechanical Engineering, Condensed Matter Physics
Abstract

We rework some of the die-swell singularity analysis for Stokes flow, originally by Ramalingam (Ramalingam, 1994 Fiber spinning and rheology of liquid-crystalline polymers, PhD thesis, Massachusetts Institute of Technology) in appendix A of his PhD thesis, in an attempt to demonstrate that for capillary numbers in the range $(0,\infty )$ the curvature may enter into the normal stress balance on the free surface and lead to separation angles exceeding $180^{\circ }$ and infinite curvature at the separation point. The singular coefficients in the asymptotic solution and the free surface shape in a neighbourhood of the separation point cannot be determined by a local analysis of the Michael type (Michael, Mathematika, vol. 5, 1958, pp. 82–84) but must be found from matching with the solution valid away from the die edge. The numerical method that we use in the truncated die-swell domain is a boundary element method incorporating the singular solution near the separation point. Although there is some variation in the extrudate swell ratios at different capillary numbers reported in the numerical literature, our results for capillary numbers $Ca$ from $1$ to $1000$ are within the range of values published in earlier papers. The computed separation angles at different values of $Ca$ agree well with the range of separation angles to be found in experimental and numerical papers. The separation angle appears to converge to a value different from $180^{\circ }$ as $Ca$ increases, leading us to conclude that the case of zero surface tension ( $Ca=\infty$ , with corresponding separation angle of $180^{\circ }$ ), is a singular limit.

Published
2022

30. Outcome of acute hypoxaemic respiratory failure: insights from the LUNG SAFE Study

Author

Pham, Tài, Pesenti, Antonio, Bellani, Giacomo, Rubenfeld, Gordon, Fan, Eddy, Bugedo, Guillermo, Lorente, José Angel, Fernandes, Antero do Vale, Van Haren, Frank, Bruhn, Alejandro, Rios, Fernando, Esteban, Andres, Gattinoni, Luciano, Larsson, Anders, McAuley, Daniel F., Ranieri, Marco, Thompson, B. Taylor, Wrigge, Hermann, Brochard, Laurent J., Laffey, John G, Antonio Pesenti, John G Laffey, Laurent Brochard, Andres Esteban, Luciano Gattinoni, Frank van Haren, Anders Larsson, Daniel F McAuley, Marco Ranieri, Gordon Rubenfeld, B Taylor Thompson, Hermann Wrigge, Arthur S Slutsky, Giacomo Bellani, Tài Pham, Eddy Fan, Fernando Rios, Thierry Sottiaux, Pieter Depuydt, Fredy S Lora, Luciano Cesar Azevedo, Guillermo Bugedo, Haibo Qiu, Marcos Gonzalez, Juan Silesky, Vladimir Cerny, Jonas Nielsen, Manuel Jibaja, Dimitrios Matamis, Jorge Luis Ranero, Pravin Amin, S M Hashemian, Kevin Clarkson, Kiyoyasu Kurahashi, Asisclo Villagomez, Amine Ali Zeggwagh, Leo M Heunks, Jon Henrik Laake, Jose Emmanuel Palo, Antero do Vale Fernandes, Dorel Sandesc, Yaasen Arabi, Vesna Bumbasierevic, Nicolas Nin, Jose A Lorente, Lise Piquilloud, Fekri Abroug, Lia McNamee, Javier Hurtado, Ed Bajwa, Gabriel Démpaire, Hektor Sula, Lordian Nunci, Alma Cani, Alan Zazu, Christian Dellera, Carolina S Insaurralde, Risso V Alejandro, Julio Daldin, Mauricio Vinzio, Ruben O Fernandez, Luis P Cardonnet, Lisandro R Bettini, Mariano Carboni Bisso, Emilio M Osman, Mariano G Setten, Pablo Lovazzano, Javier Alvarez, Veronica Villar, Norberto C Pozo, Nicolas Grubissich, Gustavo A Plotnikow, Daniela N Vasquez, Santiago Ilutovich, Norberto Tiribelli, Ariel Chena, Carlos A Pellegrini, María G Saenz, Elisa Estenssoro, Matias Brizuela, Hernan Gianinetto, Pablo E Gomez, Valeria I Cerrato, Marco G Bezzi, Silvina A Borello, Flavia A Loiacono, Adriana M Fernandez, Serena Knowles, Claire Reynolds, Deborah M Inskip, Jennene J Miller, Jing Kong, Christina Whitehead, Shailesh Bihari, Aylin Seven, Amanda Krstevski, Helen J Rodgers, Rebecca T Millar, Toni E McKenna, Irene M Bailey, Gabrielle C Hanlon, Anders Aneman, Joan M Lynch, Raman Azad, John Neal, Paul W Woods, Brigit L Roberts, Mark R Kol, Helen S Wong, Katharina C Riss, Thomas Staudinger, Xavier Wittebole, Caroline Berghe, Pierre A Bulpa, Alain M Dive, Rik Verstraete, Herve Lebbinck, Joris Vermassen, Philippe Meersseman, Helga Ceunen, Jonas I Rosa, Daniel O Beraldo, Claudio Piras, Adenilton M Rampinelli, Antonio P Nassar Jr, Sergio Mataloun, Marcelo Moock, Marlus M Thompson, Claudio H Gonçalves, Ana Carolina P Antônio, Aline Ascoli, Rodrigo S Biondi, Danielle C Fontenele, Danielle Nobrega, Vanessa M Sales, Ahmad Yazid Bin Hj Abul Wahab, Maizatul Ismail, Suresh Shindhe, John Laffey, Francois Beloncle, Kyle G Davies, Rob Cirone, Venika Manoharan, Mehvish Ismail, Ewan C Goligher, Mandeep Jassal, Erin Nishikawa, Areej Javeed, Gerard Curley, Nuttapol Rittayamai, Matteo Parotto, Niall D Ferguson, Sangeeta Mehta, Jenny Knoll, Antoine Pronovost, Sergio Canestrini, Alejandro R Bruhn, Patricio H Garcia, Felipe A Aliaga, Pamela A Farías, Jacob S Yumha, Claudia A Ortiz, Javier E Salas, Alejandro A Saez, Luis D Vega, Eduardo F Labarca, Felipe T Martinez, Nicolás G Carreño, Pilar Lora, Haitao Liu, Ling Liu, Rui Tang, Xiaoming Luo, Youzhong An, Huiying Zhao, Yan Gao, Zhe Zhai, Zheng L Ye, Wei Wang, Wenwen Li, Qingdong Li, Ruiqiang Zheng, Wenkui Yu, Juanhong Shen, Xinyu Li, Tao Yu, Weihua Lu, Ya Q Wu, Xiao B Huang, Zhenyang He, Yuanhua Lu, Hui Han, Fan Zhang, Renhua Sun, Hua X Wang, Shu H Qin, Bao H Zhu, Jun Zhao, Jian Liu, Bin Li, Jing L Liu, Fa C Zhou, Qiong J Li, Xing Y Zhang, Zhou Li-Xin, Qiang Xin-Hua, Liangyan Jiang, Yuan N Gao, Xian Y Zhao, Yuan Y Li, Xiao L Li, Chunting Wang, Qingchun Yao, Rongguo Yu, Kai Chen, Huanzhang Shao, Bingyu Qin, Qing Q Huang, Wei H Zhu, Ai Y Hang, Ma X Hua, Yimin Li, Yonghao Xu, Yu D Di, Long L Ling, Tie H Qin, Shou H Wang, Junping Qin, Yi Han, Suming Zhou, Monica P Vargas, Juan I Silesky Jimenez, Manuel A González Rojas, Jaime E SolisQuesada, Christian M Ramirez-Alfaro, Jan Máca, Peter Sklienka, Jakob Gjedsted, Aage Christiansen, Boris G Villamagua, Iguel Llano, Philippe Burtin, Gautier Buzancais, Pascal Beuret, Nicolas Pelletier, Satar Mortaza, Alain Mercat, Jonathan Chelly, Sébastien Jochmans, Nicolas Terzi, Cédric Daubin, Guillaume Carteaux, Nicolas de Prost, Jean-Daniel Chiche, Fabrice Daviaud, Muriel Fartoukh, Guillaume Barberet, Jerome Biehler, Jean Dellamonica, Denis Doyen, Jean-Michel Arnal, Anais Briquet, Sami Hraiech, Laurent Papazian, Arnaud Follin, Damien Roux, Jonathan Messika, Evangelos Kalaitzis, Laurence Dangers, Alain Combes, Siu-Ming Au, Gaetan Béduneau, Dorothée Carpentier, Elie H Zogheib, Herve Dupont, Sylvie Ricome, Francesco L Santoli, Sebastien L Besset, Philippe Michel, Bruno Gelée, Pierre-Eric Danin, Bernard Goubaux, Philippe J Crova, Nga T Phan, Frantz Berkelmans, Julio C Badie, Romain Tapponnier, Josette Gally, Samy Khebbeb, Jean-Etienne Herbrecht, Francis Schneider, PierreLouis M Declercq, Jean-Philippe Rigaud, Jacques Duranteau, Anatole Harrois, Russell Chabanne, Julien Marin, Charlene Bigot, Sandrine Thibault, Mohammed Ghazi, Messabi Boukhazna, Salem Ould Zein, Jack R Richecoeur, Daniele M Combaux, Fabien Grelon, Charlene Le Moal, Elise P Sauvadet, Adrien Robine, Virginie Lemiale, Danielle Reuter, Martin Dres, Alexandre Demoule, Dany Goldgran-Toledano, Loredana Baboi, Claude Guérin, Ralph Lohner, Jens Kraßler, Susanne Schäfer, Kai D Zacharowski, Patrick Meybohm, Andreas W Reske, Philipp Simon, HansBernd F Hopf, Michael Schuetz, Thomas Baltus, Metaxia N Papanikolaou, Theonymfi G Papavasilopoulou, Giannis A Zacharas, Vasilis Ourailogloy, Eleni K Mouloudi, Eleni V Massa, Eva O Nagy, Electra E Stamou, Ellada V Kiourtzieva, Marina A Oikonomou, Luis E Avila, Cesar A Cortez, Johanna E Citalán, Sameer A Jog, Safal D Sable, Bhagyesh Shah, Mohan Gurjar, Arvind K Baronia, Mohammedfaruk Memon, Radhakrishnan Muthuchellappan, Venkatapura J Ramesh, Anitha Shenoy, Ramesh Unnikrishnan, Subhal B Dixit, Rachana V Rhayakar, Nagarajan Ramakrishnan, Vallish K Bhardwaj, Heera L Mahto, Sudha V Sagar, Vijayanand Palaniswamy, Deeban Ganesan, Seyed Mohammadreza Hashemian, Hamidreza Jamaati, Farshad Heidari, Edel A Meaney, Alistair Nichol, Karl M Knapman, Donall O'Croinin, Eimhin S Dunne, Dorothy M Breen, Kevin P Clarkson, Rola F Jaafar, Rory Dwyer, Fahd Amir, Olaitan O Ajetunmobi, Aogan C O'Muircheartaigh, Colin S Black, Nuala Treanor, Daniel V Collins, Wahid Altaf, Gianluca Zani, Maurizio Fusari, Savino Spadaro, Carlo A Volta, Romano Graziani, Barbara Brunettini, Salvatore Palmese, Paolo Formenti, Michele Umbrello, Andrea Lombardo, Elisabetta Pecci, Marco Botteri, Monica Savioli, Alessandro Protti, Alessia Mattei, Lorenzo Schiavoni, Andrea Tinnirello, Manuel Todeschini, Antonino Giarratano, Andrea Cortegiani, Massimo M Antonelli, Luca M Montini, Paolo Casalena, Sergio Scafetti, Giovanna Panarello, Giovanna Occhipinti, Nicolò Patroniti, Matteo Pozzi, Roberto R Biscione, Michela M Poli, Ferdinando Raimondi, Daniela Albiero, Giulia Crapelli, Eduardo Beck, Vincenzo Pota, Vincenzo Schiavone, Alexandre Molin, Fabio Tarantino, Giacomo Monti, Elena Frati, Lucia Mirabella, Gilda Cinnella, Tommaso Fossali, Riccardo Colombo, Pierpaolo Terragni, Ilaria Pattarino, Francesco Mojoli, Antonio Braschi, Erika E Borotto, Andrea N Cracchiolo, Daniela M Palma, Francesco Raponi, Giuseppe Foti, Ettore R Vascotto, Andrea Coppadoro, Luca Brazzi, Leda Floris, Giorgio A Iotti, Aaron Venti, Osamu Yamaguchi, Shunsuke Takagi, Hiroki N Maeyama, Eizo Watanabe, Yoshihiro Yamaji, Kazuyoshi Shimizu, Kyoko Shiozaki, Satoru Futami, Sekine Ryosuke, Koji Saito, Yoshinobu Kameyama, Keiko Ueno, Masayo Izawa, Nao Okuda, Hiroyuki Suzuki, Tomofumi Harasawa, Michitaka Nasu, Tadaaki Takada, Fumihito Ito, Shin Nunomiya, Kansuke Koyama, Toshikazu Abe, Kohkichi Andoh, Kohei Kusumoto, Akira Hirata, Akihiro Takaba, Hiroyasu Kimura, Shuhei Matsumoto, Ushio Higashijima, Hiroyuki Honda, Nobumasa Aoki, Hiroshi Imai, Yasuaki Ogino, Ichiko Mizuguchi, Kazuya Ichikado, Kenichi Nitta, Katsunori Mochizuki, Tomoaki Hashida, Hiroyuki Tanaka, Tomoyuki Nakamura, Daisuke Niimi, Takeshi Ueda, Yozo Kashiwa, Akinori Uchiyama, Olegs Sabelnikovs, Peteris Oss, Youssef Haddad, Kong Y Liew, Silvio A Ñamendys-Silva, Yves D Jarquin-Badiola, Luis A Sanchez-Hurtado, Saira S Gomez-Flores, Maria C Marin, Asisclo J Villagomez, Jordana S Lemus, Jonathan M Fierro, Mavy Ramirez Cervantes, Francisco Javier Flores Mejia, Dulce Dector, Alejandro Rojas, Daniel R Gonzalez, Claudia R Estrella, Jorge R Sanchez-Medina, Alvaro Ramirez-Gutierrez, Fernando G George, Janet S Aguirre, Juan A Buensuseso, Manuel Poblano, Tarek Dendane, Hicham Balkhi, Mina Elkhayari, Nacer Samkaoui, Hanane Ezzouine, Abdellatif Benslama, Mourad Amor, Wajdi Maazouzi, Nedim Cimic, Oliver Beck, Monique M Bruns, Jeroen A Schouten, Myra Rinia, Monique Raaijmakers, Hellen M van Wezel, Serge J Heines, Ulrich Strauch, Marc P Buise, Fabienne D Simonis, Marcus J Schultz, Jennifer C Goodson, Troy S Browne, Leanlove Navarra, Anna Hunt, Robyn A Hutchison, Mathew B Bailey, Lynette Newby, Colin McArthur, Michael Kalkoff, Alex Mcleod, Jonathan Casement, Danielle J Hacking, Finn H Andersen, Merete S Dolva, Jon H Laake, Andreas Barratt-Due, Kim Andre L Noremark, Eldar Søreide, Brit Å Sjøbø, Anne B Guttormsen, Hector H Leon Yoshido, Ronald Zumaran Aguilar, Fredy A Montes Oscanoa, Alain U Alisasis, Joanne B Robles, Rossini Abbie B Pasanting-Lim, Beatriz C Tan, Pawel Andruszkiewicz, Karina Jakubowska, Cristina M Coxo, António M Alvarez, Bruno S Oliveira, Gustavo M Montanha, Nelson C Barros, Carlos S Pereira, António M Messias, Jorge M Monteiro, Ana M Araujo, Nuno T Catorze, Susan M Marum, Maria J Bouw, Rui M Gomes, Vania A Brito, Silvia Castro, Joana M Estilita, Filipa M Barros, Isabel M Serra, Aurelia M Martinho, Dana R Tomescu, Alexandra Marcu, Ovidiu H Bedreag, Marius Papurica, Dan E Corneci, Silvius Ioan Negoita, Evgeny Grigoriev, Alexey I Gritsan, Andrey A Gazenkampf, Ghaleb Almekhlafi, Mohamad M Albarrak, Ghanem M Mustafa, Khalid A Maghrabi, Nawal Salahuddin, Tharwat M Aisa, Ahmed S Al Jabbary, Edgardo Tabhan, Yaseen M Arabi, Olivia A Trinidad, Hasan M Al Dorzi, Edgardo E Tabhan, Vesna Bumbasirevic, Bojan Jovanovic, Stefan Bolon, Oliver Smith, Jordi Mancebo, Hernan Aguirre-Bermeo, Juan C Lopez-Delgado, Francisco Esteve, Gemma Rialp, Catalina Forteza, Candelaria De Haro, Antonio Artigas, Guillermo M Albaiceta, Sara De Cima-Iglesias, Leticia Seoane-Quiroga, Alexandra Ceniceros-Barros, Antonio L RuizAguilar, Luis M Claraco-Vega, Juan Alfonso Soler, Maria Del Carmen Lorente, Cecilia Hermosa, Federico Gordo, Miryam PrietoGonzález, Juan B López-Messa, Manuel P Perez, Cesar P Perez, Raquel Montoiro Allue, Ferran RocheCampo, Marcos Ibañez-Santacruz, Susana TempranoSusana, Maria C Pintado, Raul De Pablo, Pilar Ricart Aroa Gómez, Silvia Rodriguez Ruiz, Silvia Iglesias Moles, Mª Teresa Jurado, Alfons Arizmendi, Enrique A Piacentini, Nieves Franco, Teresa Honrubia, Meisy Perez Cheng, Elena Perez Losada, Javier Blanco, Luis J Yuste, Cecilia Carbayo-Gorriz, Francisca G Cazorla-Barranquero, Javier G Alonso, Rosa S Alda, Ángela Algaba, Gonzalo Navarro, Enrique Cereijo, Esther Diaz-Rodriguez, Diego Pastor Marcos, Laura Alvarez Montero, Luis Herrera Para, Roberto Jimenez Sanchez, Miguel Angel Blasco Navalpotro, Ricardo Diaz Abad, Raquel Montiel González, Dácil Parrilla Toribio, Alejandro G Castro, Maria Jose D Artiga, Oscar Penuelas, Tomas P Roser, Moreno F Olga, Elena Gallego Curto, Rocío Manzano Sánchez, Vallverdu P Imma, Garcia M Elisabet, Laura Claverias, Monica Magret, Ana M Pellicer, Lucia L Rodriguez, Jesús Sánchez-Ballesteros, Ángela González-Salamanca, Antonio G Jimenez, Francisco P Huerta, Juan Carlos J Sotillo Diaz, Esther Bermejo Lopez, David D Llinares Moya, Alec A Tallet Alfonso, Palazon Sanchez Eugenio Luis, Palazon Sanchez Cesar, Sánchez I Rafael, Corcoles G Virgilio, Noelia N Recio, Christian C Rylander, Bernhard Holzgraefe, Lars M Broman, Joanna Wessbergh, Linnea Persson, Fredrik Schiöler, Hans Kedelv, Anna Oscarsson Tibblin, Henrik Appelberg, Lars Hedlund, Johan Helleberg, Karin E Eriksson, Rita Glietsch, Niklas Larsson, Ingela Nygren, Silvia L Nunes, Anna-Karin Morin, Thomas Kander, Anne Adolfsson, Hervé O Zender, Corinne Leemann-Refondini, Souheil Elatrous, Slaheddine Bouchoucha, Imed Chouchene, Islem Ouanes, Asma Ben Souissi, Salma Kamoun, Oktay Demirkiran, Mustafa Aker, Emre Erbabacan, Ilkay Ceylan, Nermin Kelebek Girgin, Menekse Ozcelik, Necmettin Ünal, Basak Ceyda Meco, Onat O Akyol, Suleyman S Derman, Barry Kennedy, Ken Parhar, Latha Srinivasa, Danny McAuley, Phil Hopkins, Clare Mellis, Vivek Kakar, Dan Hadfield, Andre Vercueil, Kaushik Bhowmick, Sally K Humphreys, Andrew Ferguson, Raymond Mckee, Ashok S Raj, Danielle A Fawkes, Philip Watt, Linda Twohey, Rajeev R Jha, Matthew Thomas, Alex Morton, Varsha Kadaba, Mark J Smith, Anil P Hormis, Santhana G Kannan, Miriam Namih, Henrik Reschreiter, Julie Camsooksai, Alek Kumar, Szabolcs Rugonfalvi, Christopher Nutt, Orla Oneill, Colette Seasman, Ged Dempsey, Christopher J Scott, Helen E Ellis, Stuart Mckechnie, Paula J Hutton, Nora N Di Tomasso, Michela N Vitale, Ruth O Griffin, Michael N Dean, Julius H Cranshaw, Emma L Willett, Nicholas Ioannou, Sarah Gillis, Peter Csabi, Rosaleen Macfadyen, Heidi Dawson, Pieter D Preez, Alexandra J Williams, Owen Boyd, Laura Ortiz-Ruiz de Gordoa, Jon Bramall, Sophie Symmonds, Simon K Chau, Tim Wenham, Tamas Szakmany, Piroska Toth-Tarsoly, Katie H McCalman, Peter Alexander, Lorraine Stephenson, Thomas Collyer, Rhiannon Chapman, Raphael Cooper, Russell M Allan, Malcolm Sim, David W Wrathall, Donald A Irvine, Kim S Zantua, John C Adams, Andrew J Burtenshaw, Gareth P Sellors, Ingeborg D Welters, Karen E Williams, Robert J Hessell, Matthew G Oldroyd, Ceri E Battle, Suresh Pillai, Istvan Kajtor, Mageswaran Sivashanmugavel, Sinead C Okane, Adrian Donnelly, Aniko D Frigyik, Jon P Careless, Martin M May, Richard Stewart, T John Trinder, Samantha J Hagan, Jade M Cole, Caroline C MacFie, Anna T Dowling, Nicolás Nin, Edgardo Nuñez, Gustavo Pittini, Ruben Rodriguez, María C Imperio, Cristina Santos, Ana G França, Alejandro Ebeid, Alberto Deicas, Carolina Serra, Aditya Uppalapati, Ghassan Kamel, Valerie M Banner-Goodspeed, Jeremy R Beitler, Satyanarayana Reddy Mukkera, Shreedhar Kulkarni, John O Shinn Iii, Dina Gomaa, Christopher Tainter, Jarone Lee, Tomaz MesarJarone Lee, Dale J Yeatts, Jessica Warren, Michael J Lanspa, Russel R Miller, Colin K Grissom, Samuel M Brown, Philippe R Bauer, Ryan J Gosselin, Barrett T Kitch, Jason E Cohen, Scott H Beegle, Shazia Choudry, Renaud M Gueret, Aiman Tulaimat, William Stigler, Hitesh Batra, Nidhi G Huff, Keith D Lamb, Trevor W Oetting, Nicholas M Mohr, Claine Judy, Shigeki Saito, Fayez M Kheir, Fayez Kheir, Adam B Schlichting, Angela Delsing, Daniel R Crouch, Mary Elmasri, Dina Ismail, Kyle R Dreyer, Thomas C Blakeman, Rebecca M Baro, Carolina Quintana Grijalba, Peter C Hou, Raghu Seethala, Imo Aisiku, Galen Henderson, Gyorgy Frendl, Sen-Kuang Hou, Robert L Owens, Ashley Schomer, Pham, Tài, Pesenti, Antonio, Bellani, Giacomo, Rubenfeld, Gordon, Fan, Eddy, Bugedo, Guillermo, Lorente, José Angel, Fernandes, Antero do Vale, Van Haren, Frank, Bruhn, Alejandro, Rios, Fernando, Esteban, Andre, Gattinoni, Luciano, Larsson, Ander, McAuley, Daniel F., Ranieri, Marco, Thompson, B. Taylor, Wrigge, Hermann, Brochard, Laurent J., Laffey, John G, Antonio Pesenti, John G Laffey, Laurent Brochard, Andres Esteban, Luciano Gattinoni, Frank van Haren, Anders Larsson, Daniel F McAuley, Marco Ranieri, Gordon Rubenfeld, B Taylor Thompson, Hermann Wrigge, Arthur S Slutsky, John G Laffey, Giacomo Bellani, Tài Pham, Eddy Fan, Fernando Rios, Frank van Haren, Thierry Sottiaux, Pieter Depuydt, Fredy S Lora, Luciano Cesar Azevedo, Eddy Fan, Guillermo Bugedo, Haibo Qiu, Marcos Gonzalez, Juan Silesky, Vladimir Cerny, Jonas Nielsen, Manuel Jibaja, Tài Pham, Hermann Wrigge, Dimitrios Matamis, Jorge Luis Ranero, Pravin Amin, S M Hashemian, Kevin Clarkson, Giacomo Bellani, Kiyoyasu Kurahashi, Asisclo Villagomez, Amine Ali Zeggwagh, Leo M Heunks, Jon Henrik Laake, Jose Emmanuel Palo, Antero do Vale Fernandes, Dorel Sandesc, Yaasen Arabi, Vesna Bumbasierevic, Nicolas Nin, Jose A Lorente, Anders Larsson, Lise Piquilloud, Fekri Abroug, Daniel F McAuley, Lia McNamee, Javier Hurtado, Ed Bajwa, Gabriel Démpaire, Hektor Sula, Lordian Nunci, Alma Cani, Alan Zazu, Christian Dellera, Carolina S Insaurralde, Risso V Alejandro, Julio Daldin, Mauricio Vinzio, Ruben O Fernandez, Luis P Cardonnet, Lisandro R Bettini, Mariano Carboni Bisso, Emilio M Osman, Mariano G Setten, Pablo Lovazzano, Javier Alvarez, Veronica Villar, Norberto C Pozo, Nicolas Grubissich, Gustavo A Plotnikow, Daniela N Vasquez, Santiago Ilutovich, Norberto Tiribelli, Ariel Chena, Carlos A Pellegrini, María G Saenz, Elisa Estenssoro, Matias Brizuela, Hernan Gianinetto, Pablo E Gomez, Valeria I Cerrato, Marco G Bezzi, Silvina A Borello, Flavia A Loiacono, Adriana M Fernandez, Serena Knowles, Claire Reynolds, Deborah M Inskip, Jennene J Miller, Jing Kong, Christina Whitehead, Shailesh Bihari, Aylin Seven, Amanda Krstevski, Helen J Rodgers, Rebecca T Millar, Toni E McKenna, Irene M Bailey, Gabrielle C Hanlon, Anders Aneman, Joan M Lynch, Raman Azad, John Neal, Paul W Woods, Brigit L Roberts, Mark R Kol, Helen S Wong, Katharina C Riss, Thomas Staudinger, Xavier Wittebole, Caroline Berghe, Pierre A Bulpa, Alain M Dive, Rik Verstraete, Herve Lebbinck, Pieter Depuydt, Joris Vermassen, Philippe Meersseman, Helga Ceunen, Jonas I Rosa, Daniel O Beraldo, Claudio Piras, Adenilton M Rampinelli, Antonio P Nassar Jr, Sergio Mataloun, Marcelo Moock, Marlus M Thompson, Claudio H Gonçalves, Ana Carolina P Antônio, Aline Ascoli, Rodrigo S Biondi, Danielle C Fontenele, Danielle Nobrega, Vanessa M Sales, Ahmad Yazid Bin Hj Abul Wahab, Maizatul Ismail, Suresh Shindhe, John Laffey, Francois Beloncle, Kyle G Davies, Rob Cirone, Venika Manoharan, Mehvish Ismail, Ewan C Goligher, Mandeep Jassal, Erin Nishikawa, Areej Javeed, Gerard Curley, Nuttapol Rittayamai, Matteo Parotto, Niall D Ferguson, Sangeeta Mehta, Jenny Knoll, Antoine Pronovost, Sergio Canestrini, Alejandro R Bruhn, Patricio H Garcia, Felipe A Aliaga, Pamela A Farías, Jacob S Yumha, Claudia A Ortiz, Javier E Salas, Alejandro A Saez, Luis D Vega, Eduardo F Labarca, Felipe T Martinez, Nicolás G Carreño, Pilar Lora, Haitao Liu, Haibo Qiu, Ling Liu, Rui Tang, Xiaoming Luo, Youzhong An, Huiying Zhao, Yan Gao, Zhe Zhai, Zheng L Ye, Wei Wang, Wenwen Li, Qingdong Li, Ruiqiang Zheng, Wenkui Yu, Juanhong Shen, Xinyu Li, Tao Yu, Weihua Lu, Ya Q Wu, Xiao B Huang, Zhenyang He, Yuanhua Lu, Hui Han, Fan Zhang, Renhua Sun, Hua X Wang, Shu H Qin, Bao H Zhu, Jun Zhao, Jian Liu, Bin Li, Jing L Liu, Fa C Zhou, Qiong J Li, Xing Y Zhang, Zhou Li-Xin, Qiang Xin-Hua, Liangyan Jiang, Yuan N Gao, Xian Y Zhao, Yuan Y Li, Xiao L Li, Chunting Wang, Qingchun Yao, Rongguo Yu, Kai Chen, Huanzhang Shao, Bingyu Qin, Qing Q Huang, Wei H Zhu, Ai Y Hang, Ma X Hua, Yimin Li, Yonghao Xu, Yu D Di, Long L Ling, Tie H Qin, Shou H Wang, Junping Qin, Yi Han, Suming Zhou, Monica P Vargas, Juan I Silesky Jimenez, Manuel A González Rojas, Jaime E SolisQuesada, Christian M Ramirez-Alfaro, Jan Máca, Peter Sklienka, Jakob Gjedsted, Aage Christiansen, Jonas Nielsen, Boris G Villamagua, Iguel Llano, Philippe Burtin, Gautier Buzancais, Pascal Beuret, Nicolas Pelletier, Satar Mortaza, Alain Mercat, Jonathan Chelly, Sébastien Jochmans, Nicolas Terzi, Cédric Daubin, Guillaume Carteaux, Nicolas de Prost, Jean-Daniel Chiche, Fabrice Daviaud, Tài Pham, Muriel Fartoukh, Guillaume Barberet, Jerome Biehler, Jean Dellamonica, Denis Doyen, Jean-Michel Arnal, Anais Briquet, Sami Hraiech, Laurent Papazian, Arnaud Follin, Damien Roux, Jonathan Messika, Evangelos Kalaitzis, Laurence Dangers, Alain Combes, Siu-Ming Au, Gaetan Béduneau, Dorothée Carpentier, Elie H Zogheib, Herve Dupont, Sylvie Ricome, Francesco L Santoli, Sebastien L Besset, Philippe Michel, Bruno Gelée, Pierre-Eric Danin, Bernard Goubaux, Philippe J Crova, Nga T Phan, Frantz Berkelmans, Julio C Badie, Romain Tapponnier, Josette Gally, Samy Khebbeb, Jean-Etienne Herbrecht, Francis Schneider, PierreLouis M Declercq, Jean-Philippe Rigaud, Jacques Duranteau, Anatole Harrois, Russell Chabanne, Julien Marin, 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Mahto, Sudha V Sagar, Vijayanand Palaniswamy, Deeban Ganesan, Seyed Mohammadreza Hashemian, Hamidreza Jamaati, Farshad Heidari, Edel A Meaney, Alistair Nichol, Karl M Knapman, Donall O'Croinin, Eimhin S Dunne, Dorothy M Breen, Kevin P Clarkson, Rola F Jaafar, Rory Dwyer, Fahd Amir, Olaitan O Ajetunmobi, Aogan C O'Muircheartaigh, Colin S Black, Nuala Treanor, Daniel V Collins, Wahid Altaf, Gianluca Zani, Maurizio Fusari, Savino Spadaro, Carlo A Volta, Romano Graziani, Barbara Brunettini, Salvatore Palmese, Paolo Formenti, Michele Umbrello, Andrea Lombardo, Elisabetta Pecci, Marco Botteri, Monica Savioli, Alessandro Protti, Alessia Mattei, Lorenzo Schiavoni, Andrea Tinnirello, Manuel Todeschini, Antonino Giarratano, Andrea Cortegiani, Massimo M Antonelli, Luca M Montini, Paolo Casalena, Sergio Scafetti, Giovanna Panarello, Giovanna Occhipinti, Nicolò Patroniti, Matteo Pozzi, Roberto R Biscione, Michela M Poli, Ferdinando Raimondi, Daniela Albiero, Giulia Crapelli, Eduardo Beck, Vincenzo 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C Rylander, Bernhard Holzgraefe, Lars M Broman, Joanna Wessbergh, Linnea Persson, Fredrik Schiöler, Hans Kedelv, Anna Oscarsson Tibblin, Henrik Appelberg, Lars Hedlund, Johan Helleberg, Karin E Eriksson, Rita Glietsch, Niklas Larsson, Ingela Nygren, Silvia L Nunes, Anna-Karin Morin, Thomas Kander, Anne Adolfsson, Lise Piquilloud, Hervé O Zender, Corinne Leemann-Refondini, Souheil Elatrous, Slaheddine Bouchoucha, Imed Chouchene, Islem Ouanes, Asma Ben Souissi, Salma Kamoun, Oktay Demirkiran, Mustafa Aker, Emre Erbabacan, Ilkay Ceylan, Nermin Kelebek Girgin, Menekse Ozcelik, Necmettin Ünal, Basak Ceyda Meco, Onat O Akyol, Suleyman S Derman, Barry Kennedy, Ken Parhar, Latha Srinivasa, Lia McNamee, Danny McAuley, Phil Hopkins, Clare Mellis, Vivek Kakar, Dan Hadfield, Andre Vercueil, Kaushik Bhowmick, Sally K Humphreys, Andrew Ferguson, Raymond Mckee, Ashok S Raj, Danielle A Fawkes, Philip Watt, Linda Twohey, Rajeev R Jha, Matthew Thomas, Alex Morton, Varsha Kadaba, Mark J Smith, Anil P Hormis, Santhana G Kannan, Miriam Namih, Henrik Reschreiter, Julie Camsooksai, Alek Kumar, Szabolcs Rugonfalvi, Christopher Nutt, Orla Oneill, Colette Seasman, Ged Dempsey, Christopher J Scott, Helen E Ellis, Stuart Mckechnie, Paula J Hutton, Nora N Di Tomasso, Michela N Vitale, Ruth O Griffin, Michael N Dean, Julius H Cranshaw, Emma L Willett, Nicholas Ioannou, Sarah Gillis, Peter Csabi, Rosaleen Macfadyen, Heidi Dawson, Pieter D Preez, Alexandra J Williams, Owen Boyd, Laura Ortiz-Ruiz de Gordoa, Jon Bramall, Sophie Symmonds, Simon K Chau, Tim Wenham, Tamas Szakmany, Piroska Toth-Tarsoly, Katie H McCalman, Peter Alexander, Lorraine Stephenson, Thomas Collyer, Rhiannon Chapman, Raphael Cooper, Russell M Allan, Malcolm Sim, David W Wrathall, Donald A Irvine, Kim S Zantua, John C Adams, Andrew J Burtenshaw, Gareth P Sellors, Ingeborg D Welters, Karen E Williams, Robert J Hessell, Matthew G Oldroyd, Ceri E Battle, Suresh Pillai, Istvan Kajtor, Mageswaran Sivashanmugavel, Sinead C Okane, Adrian Donnelly, Aniko D Frigyik, Jon P Careless, Martin M May, Richard Stewart, T John Trinder, Samantha J Hagan, Jade M Cole, Caroline C MacFie, Anna T Dowling, Javier Hurtado, Nicolás Nin, Javier Hurtado, Edgardo Nuñez, Gustavo Pittini, Ruben Rodriguez, María C Imperio, Cristina Santos, Ana G França, Alejandro Ebeid, Alberto Deicas, Carolina Serra, Aditya Uppalapati, Ghassan Kamel, Valerie M Banner-Goodspeed, Jeremy R Beitler, Satyanarayana Reddy Mukkera, Shreedhar Kulkarni, John O Shinn Iii, Dina Gomaa, Christopher Tainter, Jarone Lee, Tomaz MesarJarone Lee, Dale J Yeatts, Jessica Warren, Michael J Lanspa, Russel R Miller, Colin K Grissom, Samuel M Brown, Philippe R Bauer, Ryan J Gosselin, Barrett T Kitch, Jason E Cohen, Scott H Beegle, Shazia Choudry, Renaud M Gueret, Aiman Tulaimat, William Stigler, Hitesh Batra, Nidhi G Huff, Keith D Lamb, Trevor W Oetting, Nicholas M Mohr, Claine Judy, Shigeki Saito, Fayez M Kheir, Fayez Kheir, Adam B Schlichting, Angela Delsing, Daniel R Crouch, Mary Elmasri, Daniel R Crouch, Dina Ismail, Kyle R Dreyer, Thomas C Blakeman, Dina Gomaa, Rebecca M Baro, Carolina Quintana Grijalba, Peter C Hou, Raghu Seethala, Imo Aisiku, Galen Henderson, Gyorgy Frendl, Sen-Kuang Hou, Robert L Owens, Ashley Schomer, Intensive Care Medicine, ACS - Diabetes & metabolism, ACS - Pulmonary hypertension & thrombosis, ACS - Microcirculation, Pham, T, Pesenti, A, Bellani, G, Rubenfeld, G, Fan, E, Bugedo, G, Lorente, J, Fernandes, A, Van Haren, F, Bruhn, A, Rios, F, Esteban, A, Gattinoni, L, Larsson, A, Mcauley, D, Ranieri, M, Thompson, B, Wrigge, H, Brochard, L, Laffey, J, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), St. Michael's Hospital, University of Toronto, Groupe de recherche clinique CARMAS, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Università degli Studi di Milano [Milano] (UNIMI), University of Milan, San Gerardo Hospital, Sunnybrook Health Sciences Center, Mount Sinai Hospital [Toronto, Canada] (MSH), Pontificia Universidad Católica de Chile (UC), University Hospital of Getafe, CIBER Enfermedades Respiratorias (CIBERES), Universidad Europea de Madrid, Hospital Garcia de Orta (EPE), Canberra Hospital, Medical School [Australian National University - ANU], Australian National University (ANU), University of Canberra, Centro de Investigación Biomédica en Red Enfermedades Respiratorias (CIBERES), University of Göttingen - Georg-August-Universität Göttingen, Uppsala University, Queen's University [Belfast] (QUB), Royal Victoria Hospital, McGill University Health Center [Montreal] (MUHC), Università degli Studi di Bologna, Massachusetts General Hospital [Boston], University Hospital Leipzig, Department of Anaesthesiology, Intensive Care and Emergency Medicine, Pain Therapy, Bergmannstrost Hospital Halle, 06112, Halle, National University of Ireland [Galway] (NUI Galway), Bayer GlaxoSmithKline, GSK Baxter International Boehringer Ingelheim Wellcome Trust, WT National Institute for Health Research, NIHR Queen's University Belfast, QUB Medical Research Council Canada, MRC European Society of Intensive Care Medicine, ESICM, Support statement: This work was supported by the European Society of Intensive Care Medicine. Funding information for this article has been deposited with the Crossref Funder Registry., Conflict of interest: T. Pham has nothing to disclose. A. Pesenti reports personal fees from Maquet, Novalung/Xenios, Baxter, Gilead and Boehringer Ingelheim, outside the submitted work. G. Bellani reports grants and personal fees from Draeger Medical, personal fees from Getinge, Hamilton, GE Healthcare, Dimar SRL, Intersurgical and Flowmeter SPA, outside the submitted work. G. Rubenfeld has nothing to disclose. E. Fan reports personal fees from ALung Technologies, Getinge and MC3 Cardiopulmonary, grants, personal fees and non-financial support from Fresenius Medical Care, outside the submitted work. G. Bugedo has nothing to disclose. J.A. Lorente has nothing to disclose. A.D. V. Fernandes has nothing to disclose. F. Van Haren has nothing to disclose. A. Bruhn has nothing to disclose. F. Rios has nothing to disclose. A. Esteban has nothing to disclose. L. Gattinoni has nothing to disclose. A. Larsson reports grants from the Swedish Heart and Lung Foundation, during the conduct of the study. D.F. McAuley reports personal fees from consultancy for GlaxoSmithKline, Boehringer Ingelheim and Bayer, outside the submitted work, in addition, his institution has received funds from grants from the UK NIHR, Wellcome Trust, Innovate UK, NI HSC R&D Division, NI Chest Heart and Stroke, and MRC, is one of four named inventors on a patent US8962032 covering the use of sialic acid-bearing nanoparticles as anti-inflammatory agents issued to his institution, The Queen’s University of Belfast (http://www.google.com/patents/US8962032), and is a Director of Research for the Intensive Care Society and NIHR EME Programme Director. M. Ranieri has nothing to disclose. B.T. Thompson reports personal fees from Bayer, Thetis and Novartis, outside the submitted work. H. Wrigge reports personal fees for consultancy from Dräger Medical, personal fees for advisory board work from Liberate Medical, grants and personal fees for lectures from InfectoPharm, personal fees for lectures from MSD and GE, outside the submitted work. L.J. Brochard reports grants from Medtronic Covidien, grants and non-financial support from Fisher Paykel, non-financial support from Air Liquide, Sentec and Philips, other (patent) from General Electric, outside the submitted work. J.G. Laffey reports grants and personal fees from Baxter, grants and non-financial support from Aerogen and Factor Biosciences, outside the submitted work., LUNG SAFE Investigators and the European Society of Intensive Care Medicine Trials Group: Antonio Pesenti, John G Laffey, Laurent Brochard, Andres Esteban, Luciano Gattinoni, Frank van Haren, Anders Larsson, Daniel F McAuley, Marco Ranieri, Gordon Rubenfeld, B Taylor Thompson, Hermann Wrigge, Arthur S Slutsky, John G Laffey, Giacomo Bellani, Tài Pham, Eddy Fan, Fernando Rios, Frank van Haren, Thierry Sottiaux, Pieter Depuydt, Fredy S Lora, Luciano Cesar Azevedo, Eddy Fan, Guillermo Bugedo, Haibo Qiu, Marcos Gonzalez, Juan Silesky, Vladimir Cerny, Jonas Nielsen, Manuel Jibaja, Tài Pham, Hermann Wrigge, Dimitrios Matamis, Jorge Luis Ranero, Pravin Amin, S M Hashemian, Kevin Clarkson, Giacomo Bellani, Kiyoyasu Kurahashi, Asisclo Villagomez, Amine Ali Zeggwagh, Leo M Heunks, Jon Henrik Laake, Jose Emmanuel Palo, Antero do Vale Fernandes, Dorel Sandesc, Yaasen Arabi, Vesna Bumbasierevic, Nicolas Nin, Jose A Lorente, Anders Larsson, Lise Piquilloud, Fekri Abroug, Daniel F McAuley, Lia McNamee, Javier Hurtado, Ed Bajwa, Gabriel Démpaire, Hektor Sula, Lordian Nunci, Alma Cani, Alan Zazu, Christian Dellera, Carolina S Insaurralde, Risso V Alejandro, Julio Daldin, Mauricio Vinzio, Ruben O Fernandez, Luis P Cardonnet, Lisandro R Bettini, Mariano Carboni Bisso, Emilio M Osman, Mariano G Setten, Pablo Lovazzano, Javier Alvarez, Veronica Villar, Norberto C Pozo, Nicolas Grubissich, Gustavo A Plotnikow, Daniela N Vasquez, Santiago Ilutovich, Norberto Tiribelli, Ariel Chena, Carlos A Pellegrini, María G Saenz, Elisa Estenssoro, Matias Brizuela, Hernan Gianinetto, Pablo E Gomez, Valeria I Cerrato, Marco G Bezzi, Silvina A Borello, Flavia A Loiacono, Adriana M Fernandez, Serena Knowles, Claire Reynolds, Deborah M Inskip, Jennene J Miller, Jing Kong, Christina Whitehead, Shailesh Bihari, Aylin Seven, Amanda Krstevski, Helen J 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Pronovost, Sergio Canestrini, Alejandro R Bruhn, Patricio H Garcia, Felipe A Aliaga, Pamela A Farías, Jacob S Yumha, Claudia A Ortiz, Javier E Salas, Alejandro A Saez, Luis D Vega, Eduardo F Labarca, Felipe T Martinez, Nicolás G Carreño, Pilar Lora, Haitao Liu, Haibo Qiu, Ling Liu, Rui Tang, Xiaoming Luo, Youzhong An, Huiying Zhao, Yan Gao, Zhe Zhai, Zheng L Ye, Wei Wang, Wenwen Li, Qingdong Li, Ruiqiang Zheng, Wenkui Yu, Juanhong Shen, Xinyu Li, Tao Yu, Weihua Lu, Ya Q Wu, Xiao B Huang, Zhenyang He, Yuanhua Lu, Hui Han, Fan Zhang, Renhua Sun, Hua X Wang, Shu H Qin, Bao H Zhu, Jun Zhao, Jian Liu, Bin Li, Jing L Liu, Fa C Zhou, Qiong J Li, Xing Y Zhang, Zhou Li-Xin, Qiang Xin-Hua, Liangyan Jiang, Yuan N Gao, Xian Y Zhao, Yuan Y Li, Xiao L Li, Chunting Wang, Qingchun Yao, Rongguo Yu, Kai Chen, Huanzhang Shao, Bingyu Qin, Qing Q Huang, Wei H Zhu, Ai Y Hang, Ma X Hua, Yimin Li, Yonghao Xu, Yu D Di, Long L Ling, Tie H Qin, Shou H Wang, Junping Qin, Yi Han, Suming Zhou, Monica P Vargas, Juan I Silesky Jimenez, Manuel A González Rojas, Jaime E SolisQuesada, Christian M Ramirez-Alfaro, Jan Máca, Peter Sklienka, Jakob Gjedsted, Aage Christiansen, Jonas Nielsen, Boris G Villamagua, Iguel Llano, Philippe Burtin, Gautier Buzancais, Pascal Beuret, Nicolas Pelletier, Satar Mortaza, Alain Mercat, Jonathan Chelly, Sébastien Jochmans, Nicolas Terzi, Cédric Daubin, Guillaume Carteaux, Nicolas de Prost, Jean-Daniel Chiche, Fabrice Daviaud, Tài Pham, Muriel Fartoukh, Guillaume Barberet, Jerome Biehler, Jean Dellamonica, Denis Doyen, Jean-Michel Arnal, Anais Briquet, Sami Hraiech, Laurent Papazian, Arnaud Follin, Damien Roux, Jonathan Messika, Evangelos Kalaitzis, Laurence Dangers, Alain Combes, Siu-Ming Au, Gaetan Béduneau, Dorothée Carpentier, Elie H Zogheib, Herve Dupont, Sylvie Ricome, Francesco L Santoli, Sebastien L Besset, Philippe Michel, Bruno Gelée, Pierre-Eric Danin, Bernard Goubaux, Philippe J Crova, Nga T Phan, Frantz Berkelmans, Julio C Badie, Romain Tapponnier, Josette Gally, Samy Khebbeb, Jean-Etienne Herbrecht, Francis Schneider, PierreLouis M Declercq, Jean-Philippe Rigaud, Jacques Duranteau, Anatole Harrois, Russell Chabanne, Julien Marin, Charlene Bigot, Sandrine Thibault, Mohammed Ghazi, Messabi Boukhazna, Salem Ould Zein, Jack R Richecoeur, Daniele M Combaux, Fabien Grelon, Charlene Le Moal, Elise P Sauvadet, Adrien Robine, Virginie Lemiale, Danielle Reuter, Martin Dres, Alexandre Demoule, Dany Goldgran-Toledano, Loredana Baboi, Claude Guérin, Ralph Lohner, Jens Kraßler, Susanne Schäfer, Kai D Zacharowski, Patrick Meybohm, Andreas W Reske, Philipp Simon, HansBernd F Hopf, Michael Schuetz, Thomas Baltus, Metaxia N Papanikolaou, Theonymfi G Papavasilopoulou, Giannis A Zacharas, Vasilis Ourailogloy, Eleni K Mouloudi, Eleni V Massa, Eva O Nagy, Electra E Stamou, Ellada V Kiourtzieva, Marina A Oikonomou, Luis E Avila, Cesar A Cortez, Johanna E Citalán, Sameer A Jog, Safal D Sable, Bhagyesh Shah, Mohan Gurjar, Arvind K Baronia, Mohammedfaruk Memon, Radhakrishnan Muthuchellappan, Venkatapura J Ramesh, Anitha Shenoy, Ramesh Unnikrishnan, Subhal B Dixit, Rachana V Rhayakar, Nagarajan Ramakrishnan, Vallish K Bhardwaj, Heera L Mahto, Sudha V Sagar, Vijayanand Palaniswamy, Deeban Ganesan, Seyed Mohammadreza Hashemian, Hamidreza Jamaati, Farshad Heidari, Edel A Meaney, Alistair Nichol, Karl M Knapman, Donall O'Croinin, Eimhin S Dunne, Dorothy M Breen, Kevin P Clarkson, Rola F Jaafar, Rory Dwyer, Fahd Amir, Olaitan O Ajetunmobi, Aogan C O'Muircheartaigh, Colin S Black, Nuala Treanor, Daniel V Collins, Wahid Altaf, Gianluca Zani, Maurizio Fusari, Savino Spadaro, Carlo A Volta, Romano Graziani, Barbara Brunettini, Salvatore Palmese, Paolo Formenti, Michele Umbrello, Andrea Lombardo, Elisabetta Pecci, Marco Botteri, Monica Savioli, Alessandro Protti, Alessia Mattei, Lorenzo Schiavoni, Andrea Tinnirello, Manuel Todeschini, Antonino Giarratano, Andrea Cortegiani, Antonino Giarratano, Andrea Cortegiani, Massimo M Antonelli, Luca M Montini, Paolo Casalena, Sergio Scafetti, Giovanna Panarello, Giovanna Occhipinti, Nicolò Patroniti, Matteo Pozzi, Roberto R Biscione, Michela M Poli, Ferdinando Raimondi, Daniela Albiero, Giulia Crapelli, Eduardo Beck, Vincenzo Pota, Vincenzo Schiavone, Alexandre Molin, Fabio Tarantino, Giacomo Monti, Elena Frati, Lucia Mirabella, Gilda Cinnella, Tommaso Fossali, Riccardo Colombo, Pierpaolo Terragni, Ilaria Pattarino, Francesco Mojoli, Antonio Braschi, Erika E Borotto, Andrea N Cracchiolo, Daniela M Palma, Francesco Raponi, Giuseppe Foti, Ettore R Vascotto, Andrea Coppadoro, Luca Brazzi, Leda Floris, Giorgio A Iotti, Aaron Venti, Osamu Yamaguchi, Shunsuke Takagi, Hiroki N Maeyama, Eizo Watanabe, Yoshihiro Yamaji, Kazuyoshi Shimizu, Kyoko Shiozaki, Satoru Futami, Sekine Ryosuke, Koji Saito, Yoshinobu Kameyama, Keiko Ueno, Masayo Izawa, Nao Okuda, Hiroyuki Suzuki, Tomofumi Harasawa, Michitaka Nasu, Tadaaki Takada, Fumihito Ito, Shin Nunomiya, Kansuke Koyama, Toshikazu Abe, Kohkichi Andoh, Kohei Kusumoto, Akira Hirata, Akihiro Takaba, Hiroyasu Kimura, Shuhei Matsumoto, Ushio Higashijima, Hiroyuki Honda, Nobumasa Aoki, Hiroshi Imai, Yasuaki Ogino, Ichiko Mizuguchi, Kazuya Ichikado, Kenichi Nitta, Katsunori Mochizuki, Tomoaki Hashida, Hiroyuki Tanaka, Tomoyuki Nakamura, Daisuke Niimi, Takeshi Ueda, Yozo Kashiwa, Akinori Uchiyama, Olegs Sabelnikovs, Peteris Oss, Youssef Haddad, Kong Y Liew, Silvio A Ñamendys-Silva, Yves D Jarquin-Badiola, Luis A Sanchez-Hurtado, Saira S Gomez-Flores, Maria C Marin, Asisclo J Villagomez, Jordana S Lemus, Jonathan M Fierro, Mavy Ramirez Cervantes, Francisco Javier Flores Mejia, Dulce Dector, Alejandro Rojas, Daniel R Gonzalez, Claudia R Estrella, Jorge R Sanchez-Medina, Alvaro Ramirez-Gutierrez, Fernando G George, Janet S Aguirre, Juan A Buensuseso, Manuel Poblano, Juan A Buensuseso, Manuel Poblano, Tarek Dendane, Amine Ali Zeggwagh, Hicham Balkhi, Mina Elkhayari, Nacer Samkaoui, Hanane Ezzouine, Abdellatif Benslama, Mourad Amor, Wajdi Maazouzi, Nedim Cimic, Oliver Beck, Monique M Bruns, Jeroen A Schouten, Myra Rinia, Monique Raaijmakers, Leo M Heunks, Hellen M van Wezel, Serge J Heines, Ulrich Strauch, Marc P Buise, Fabienne D Simonis, Marcus J Schultz, Jennifer C Goodson, Troy S Browne, Leanlove Navarra, Anna Hunt, Robyn A Hutchison, Mathew B Bailey, Lynette Newby, Colin McArthur, Michael Kalkoff, Alex Mcleod, Jonathan Casement, Danielle J Hacking, Finn H Andersen, Merete S Dolva, Jon H Laake, Andreas Barratt-Due, Kim Andre L Noremark, Eldar Søreide, Brit Å Sjøbø, Anne B Guttormsen, Hector H Leon Yoshido, Ronald Zumaran Aguilar, Fredy A Montes Oscanoa, Alain U Alisasis, Joanne B Robles, Rossini Abbie B Pasanting-Lim, Beatriz C Tan, Pawel Andruszkiewicz, Karina Jakubowska, Cristina M Coxo, António M Alvarez, Bruno S Oliveira, Gustavo M Montanha, Nelson C Barros, Carlos S Pereira, António M Messias, Jorge M Monteiro, Ana M Araujo, Nuno T Catorze, Susan M Marum, Maria J Bouw, Rui M Gomes, Vania A Brito, Silvia Castro, Joana M Estilita, Filipa M Barros, Isabel M Serra, Aurelia M Martinho, Dana R Tomescu, Alexandra Marcu, Ovidiu H Bedreag, Marius Papurica, Dan E Corneci, Silvius Ioan Negoita, Evgeny Grigoriev, Alexey I Gritsan, Andrey A Gazenkampf, Ghaleb Almekhlafi, Mohamad M Albarrak, Ghanem M Mustafa, Khalid A Maghrabi, Nawal Salahuddin, Tharwat M Aisa, Ahmed S Al Jabbary, Edgardo Tabhan, Yaseen M Arabi, Yaseen M Arabi, Olivia A Trinidad, Hasan M Al Dorzi, Edgardo E Tabhan, Vesna Bumbasirevic, Bojan Jovanovic, Stefan Bolon, Oliver Smith, Jordi Mancebo, Hernan Aguirre-Bermeo, Juan C Lopez-Delgado, Francisco Esteve, Gemma Rialp, Catalina Forteza, Candelaria De Haro, Antonio Artigas, Guillermo M Albaiceta, Sara De Cima-Iglesias, Leticia Seoane-Quiroga, Alexandra Ceniceros-Barros, Antonio L RuizAguilar, Luis M Claraco-Vega, Juan Alfonso Soler, Maria Del Carmen Lorente, Cecilia Hermosa, Federico Gordo, Miryam PrietoGonzález, Juan B López-Messa, Manuel P Perez, Cesar P Perez, Raquel Montoiro Allue, Ferran RocheCampo, Marcos Ibañez-Santacruz, Susana TempranoSusana, Maria C Pintado, Raul De Pablo, Pilar Ricart Aroa Gómez, Silvia Rodriguez Ruiz, Silvia Iglesias Moles, Mª Teresa Jurado, Alfons Arizmendi, Enrique A Piacentini, Nieves Franco, Teresa Honrubia, Meisy Perez Cheng, Elena Perez Losada, Javier Blanco, Luis J Yuste, Cecilia Carbayo-Gorriz, Francisca G Cazorla-Barranquero, Javier G Alonso, Rosa S Alda, Ángela Algaba, Gonzalo Navarro, Enrique Cereijo, Esther Diaz-Rodriguez, Diego Pastor Marcos, Laura Alvarez Montero, Luis Herrera Para, Roberto Jimenez Sanchez, Miguel Angel Blasco Navalpotro, Ricardo Diaz Abad, Raquel Montiel González, Dácil Parrilla Toribio, Alejandro G Castro, Maria Jose D Artiga, Oscar Penuelas, Tomas P Roser, Moreno F Olga, Elena Gallego Curto, Rocío Manzano Sánchez, Vallverdu P Imma, Garcia M Elisabet, Laura Claverias, Monica Magret, Ana M Pellicer, Lucia L Rodriguez, Jesús Sánchez-Ballesteros, Ángela González-Salamanca, Antonio G Jimenez, Francisco P Huerta, Juan Carlos J Sotillo Diaz, Esther Bermejo Lopez, David D Llinares Moya, Alec A Tallet Alfonso, Palazon Sanchez Eugenio Luis, Palazon Sanchez Cesar, Sánchez I Rafael, Corcoles G Virgilio, Noelia N Recio, Christian C Rylander, Bernhard Holzgraefe, Lars M Broman, Joanna Wessbergh, Linnea Persson, Fredrik Schiöler, Hans Kedelv, Anna Oscarsson Tibblin, Henrik Appelberg, Lars Hedlund, Johan Helleberg, Karin E Eriksson, Rita Glietsch, Niklas Larsson, Ingela Nygren, Silvia L Nunes, Anna-Karin Morin, Thomas Kander, Anne Adolfsson, Lise Piquilloud, Hervé O Zender, Corinne Leemann-Refondini, Souheil Elatrous, Slaheddine Bouchoucha, Imed Chouchene, Islem Ouanes, Asma Ben Souissi, Salma Kamoun, Oktay Demirkiran, Mustafa Aker, Emre Erbabacan, Ilkay Ceylan, Nermin Kelebek Girgin, Menekse Ozcelik, Necmettin Ünal, Basak Ceyda Meco, Onat O Akyol, Suleyman S Derman, Barry Kennedy, Ken Parhar, Latha Srinivasa, Lia McNamee, Danny McAuley, Phil Hopkins, Clare Mellis, Vivek Kakar, Dan Hadfield, Andre Vercueil, Kaushik Bhowmick, Sally K Humphreys, Andrew Ferguson, Raymond Mckee, Ashok S Raj, Danielle A Fawkes, Philip Watt, Linda Twohey, Rajeev R Jha, Matthew Thomas, Alex Morton, Varsha Kadaba, Mark J Smith, Anil P Hormis, Santhana G Kannan, Miriam Namih, Henrik Reschreiter, Julie Camsooksai, Alek Kumar, Szabolcs Rugonfalvi, Christopher Nutt, Orla Oneill, Colette Seasman, Ged Dempsey, Christopher J Scott, Helen E Ellis, Stuart Mckechnie, Paula J Hutton, Nora N Di Tomasso, Michela N Vitale, Ruth O Griffin, Michael N Dean, Julius H Cranshaw, Emma L Willett, Nicholas Ioannou, Sarah Gillis, Peter Csabi, Rosaleen Macfadyen, Heidi Dawson, Pieter D Preez, Alexandra J Williams, Owen Boyd, Laura Ortiz-Ruiz de Gordoa, Jon Bramall, Sophie Symmonds, Simon K Chau, Tim Wenham, Tamas Szakmany, Piroska Toth-Tarsoly, Katie H McCalman, Peter Alexander, Lorraine Stephenson, Thomas Collyer, Rhiannon Chapman, Raphael Cooper, Russell M Allan, Malcolm Sim, David W Wrathall, Donald A Irvine, Kim S Zantua, John C Adams, Andrew J Burtenshaw, Gareth P Sellors, Ingeborg D Welters, Karen E Williams, Robert J Hessell, Matthew G Oldroyd, Ceri E Battle, Suresh Pillai, Istvan Kajtor, Mageswaran Sivashanmugavel, Sinead C Okane, Adrian Donnelly, Aniko D Frigyik, Jon P Careless, Martin M May, Richard Stewart, T John Trinder, Samantha J Hagan, Jade M Cole, Caroline C MacFie, Anna T Dowling, Javier Hurtado, Nicolás Nin, Javier Hurtado, Edgardo Nuñez, Gustavo Pittini, Ruben Rodriguez, María C Imperio, Cristina Santos, Ana G França, Alejandro Ebeid, Alberto Deicas, Carolina Serra, Aditya Uppalapati, Ghassan Kamel, Valerie M Banner-Goodspeed, Jeremy R Beitler, Satyanarayana Reddy Mukkera, Shreedhar Kulkarni, John O Shinn Iii, Dina Gomaa, Christopher Tainter, Jarone Lee, Tomaz MesarJarone Lee, Dale J Yeatts, Jessica Warren, Michael J Lanspa, Russel R Miller, Colin K Grissom, Samuel M Brown, Philippe R Bauer, Ryan J Gosselin, Barrett T Kitch, Jason E Cohen, Scott H Beegle, Shazia Choudry, Renaud M Gueret, Aiman Tulaimat, William Stigler, Hitesh Batra, Nidhi G Huff, Keith D Lamb, Trevor W Oetting, Nicholas M Mohr, Claine Judy, Shigeki Saito, Fayez M Kheir, Fayez Kheir, Adam B Schlichting, Angela Delsing, Daniel R Crouch, Mary Elmasri, Daniel R Crouch, Dina Ismail, Kyle R Dreyer, Thomas C Blakeman, Dina Gomaa, Rebecca M Baro, Carolina Quintana Grijalba, Peter C Hou, Raghu Seethala, Imo Aisiku, Galen Henderson, Gyorgy Frendl, Sen-Kuang Hou, Robert L Owens, Ashley Schomer, UCL - SSS/IREC/MEDA - Pôle de médecine aiguë, UCL - (MGD) Services des soins intensifs, and UCL - (SLuc) Service de soins intensifs

Subjects
Pulmonary and Respiratory Medicine, ARDS, Unidades de cuidados intensivos, [SDV]Life Sciences [q-bio], medicine.medical_treatment, mechanical ventilation, NO, law.invention, 03 medical and health sciences, Tratamiento médico, 0302 clinical medicine, law, Settore MED/41 - ANESTESIOLOGIA, Insuficiencia respiratoria, Medicine, Humans, 030212 general & internal medicine, Prospective Studies, Prospective cohort study, Lung, Mechanical ventilation, Respiratory Distress Syndrome, business.industry, Respiration, Incidence (epidemiology), medicine.disease, Intensive care unit, Respiration, Artificial, 3. Good health, Intensive Care Units, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], medicine.anatomical_structure, 030228 respiratory system, Respiratory failure, Heart failure, Anesthesia, Artificial, ards, business, Respiratory Insufficiency, Enfermedad
Abstract

BackgroundCurrent incidence and outcome of patients with acute hypoxaemic respiratory failure requiring mechanical ventilation in the intensive care unit (ICU) are unknown, especially for patients not meeting criteria for acute respiratory distress syndrome (ARDS).MethodsAn international, multicentre, prospective cohort study of patients presenting with hypoxaemia early in the course of mechanical ventilation, conducted during four consecutive weeks in the winter of 2014 in 459 ICUs from 50 countries (LUNG SAFE). Patients were enrolled with arterial oxygen tension/inspiratory oxygen fraction ratio ≤300 mmHg, new pulmonary infiltrates and need for mechanical ventilation with a positive end-expiratory pressure of ≥5 cmH2O. ICU prevalence, causes of hypoxaemia, hospital survival and factors associated with hospital mortality were measured. Patients with unilateral versus bilateral opacities were compared.Findings12 906 critically ill patients received mechanical ventilation and 34.9% with hypoxaemia and new infiltrates were enrolled, separated into ARDS (69.0%), unilateral infiltrate (22.7%) and congestive heart failure (CHF; 8.2%). The global hospital mortality was 38.6%. CHF patients had a mortality comparable to ARDS (44.1% versus 40.4%). Patients with unilateral-infiltrate had lower unadjusted mortality, but similar adjusted mortality compared to those with ARDS. The number of quadrants on chest imaging was associated with an increased risk of death. There was no difference in mortality comparing patients with unilateral-infiltrate and ARDS with only two quadrants involved.InterpretationMore than one-third of patients receiving mechanical ventilation have hypoxaemia and new infiltrates with a hospital mortality of 38.6%. Survival is dependent on the degree of pulmonary involvement whether or not ARDS criteria are reached.

Published
2021

31. Philips Respironics Recall of Positive Airway Pressure and Noninvasive Ventilation Devices: A Brief Statement to Inform Response Efforts and Identify Key Steps Forward

Author

Indira Gurubhagavatula, Robert L. Owens, Kevin C. Wilson, and Reena Mehra

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, Statement (logic), Critical Care and Intensive Care Medicine, Patient-Centered Care, Positive airway pressure, Medicine, Humans, Practice Patterns, Physicians', Intensive care medicine, Societies, Medical, Informed Consent, Noninvasive Ventilation, Ventilators, Mechanical, Recall, Continuous Positive Airway Pressure, business.industry, Editorials, United States, Hypoventilation, Safety-Based Medical Device Withdrawals, Practice Guidelines as Topic, Key (cryptography), Sleep disordered breathing, Noninvasive ventilation, medicine.symptom, Patient Participation, business
Published
2021

32. Supplemental oxygen and noninvasive ventilation

Author

Robert L. Owens, Eric Derom, and Nicolino Ambrosino

Subjects
Pulmonary and Respiratory Medicine
Abstract

The respiratory system attempts to maintain normal levels of oxygen and carbon dioxide. However, airflow limitation, parenchymal abnormalities and dysfunction of the respiratory pump may be compromised in individuals with advanced COPD, eventually leading to respiratory failure, with reduced arterial oxygen tension (hypoxaemia) and/or increased arterial carbon dioxide tension (PaCO2; hypercapnia). Hypoxaemia may persist in individuals with severe COPD despite smoking cessation and optimisation of pharmacotherapy. Long-term oxygen therapy (LTOT) can improve survival in those with severe daytime hypoxaemia, whereas those with less severe hypoxaemia may only have improved exercise capacity and dyspnoea. Changes in respiratory physiology that occur during sleep further predispose to hypoxaemia, particularly in individuals with COPD. However, the major cause of hypoxaemia is hypoventilation. Noninvasive ventilation (NIV) may reduce mortality and need for intubation in individuals with COPD and acute hypercapnic respiratory failure. However, NIV may also improve survival and quality of life in individuals with stable, chronic hypercapnia and is now suggested for those with prolonged hypercapnia (e.g.PaCO2>55 mmHg 2–6 weeks after hospital discharge) when clinically stable and after optimisation of medical therapy including LTOT if indicated. Many questions remain about the optimal mode, settings and goal of NIV therapy.

Published
2023

34. The Arousal Threshold as a Drug Target to Improve Continuous Positive Airway Pressure Adherence: Secondary Analysis of a Randomized Trial

Author

Christopher N. Schmickl, Jeremy E. Orr, Robert L. Owens, Pamela N. DeYoung, Bradley A. Edwards, Christopher J. Lettieri, and Atul Malhotra

Subjects
Adult, Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, medicine.medical_treatment, Drug target, MEDLINE, Critical Care and Intensive Care Medicine, Arousal, law.invention, Text mining, Randomized controlled trial, law, Internal medicine, Secondary analysis, Correspondence, Humans, Hypnotics and Sedatives, Medicine, Continuous positive airway pressure, Eszopiclone, Sleep Apnea, Obstructive, Continuous Positive Airway Pressure, business.industry, Middle Aged, Treatment Outcome, Patient Compliance, Female, business
Published
2020

35. Acetazolamide for OSA and Central Sleep Apnea

Author

Bradley A. Edwards, Christopher N. Schmickl, Kimihiko Murase, Shahrokh Javaheri, Robert L. Owens, Jeremy E. Orr, Johan Verbraecken, Shane A. Landry, Kazuo Chin, and Atul Malhotra

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, Central sleep apnea, business.industry, Sleep apnea, Critical Care and Intensive Care Medicine, medicine.disease, respiratory tract diseases, law.invention, Clinical trial, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, Apnea–hypopnea index, Randomized controlled trial, law, Internal medicine, Meta-analysis, medicine, Number needed to treat, 030212 general & internal medicine, Cardiology and Cardiovascular Medicine, business, Acetazolamide, medicine.drug
Abstract

Background Therapy options for OSA and central sleep apnea (CSA) are limited, thus many patients remain untreated. Clinically, acetazolamide is sometimes used for CSA; however, given overlapping pathophysiologic properties of OSA and CSA, we hypothesized that acetazolamide is equally effective for both types. Prior reviews focused on specific subtypes of sleep apnea, study designs, and languages, thus including few studies (typically ≤3) limiting insights. Research Question How efficacious is acetazolamide for sleep apnea, and is its effect modified by sleep apnea type or acetazolamide dose? Study Design and Methods We queried MEDLINE, EMBASE, and ClinicalTrials.gov from inception until March 11, 2019. Any study in which adults with OSA/CSA received oral acetazolamide vs no acetazolamide (control) that reported sleep apnea-related outcomes was eligible, independent of study design or language. Two reviewers independently assessed eligibility and abstracted data. Primary outcomes were apnea-hypopnea index (AHI) and oxygen saturation nadir. Quality of evidence (QoE) was rated with the use of Grades of Recommendation Assessment, Development and Evaluation methods. Results We included 28 studies (13 OSA/15 CSA; NSubjects,Acetazolamide = 542; NSubjects,Control = 553) that enabled meta-analyses for 24 outcomes. Acetazolamide doses ranged from 36 to 1000 mg/d and treatment duration from 1 to 90 d (median, 6 d). Overall, acetazolamide vs control lowered the AHI by −0.7 effect sizes (95% CI, −0.83 to −0.58; I2 = 0%; moderate QoE) that corresponded to a reduction of 37.7% (95% CI, −44.7 to −31.3) or 13.8/h (95% CI, −16.3 to −11.4; AHIControl = 36.5/h). The AHI reduction was similar in OSA vs CSA, but significantly greater with higher doses (at least up to 500 mg/d). Furthermore, acetazolamide improved oxygen saturation nadir by +4.4% (95% CI, 2.3 to 6.5; I2 = 63%; no evidence of effect modification; very low QoE) and several secondary outcomes that included sleep quality measures and BP (mostly low QoE). Interpretation Short-term acetazolamide improved both OSA and CSA. Rigorous studies with long-term follow up are warranted to assess Acetazolamide’s value for the chronic treatment of patients with sleep apnea. Clinical Trial Registration PROSPERO (CRD42019147504)

Published
2020

36. Screening for Obstructive Sleep Apnea in a Diverse Bariatric Surgery Population

Author

Macy Mei Sze Lui, Santiago Horgan, Atul Malhotra, Janna R Raphelson, Christopher N. Schmickl, Eduardo Grunvald, Kimberly Y Kreitinger, and Robert L. Owens

Subjects
Adult, Male, medicine.medical_specialty, Polysomnography, Endocrinology, Diabetes and Metabolism, Population, Bariatric Surgery, Medicine (miscellaneous), 030209 endocrinology & metabolism, Article, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Surveys and Questionnaires, medicine, Humans, Mass Screening, 030212 general & internal medicine, Sleep study, education, Retrospective Studies, Sleep Apnea, Obstructive, education.field_of_study, Nutrition and Dietetics, Receiver operating characteristic, business.industry, Epworth Sleepiness Scale, Perioperative, medicine.disease, Obesity, respiratory tract diseases, Surgery, Obstructive sleep apnea, Cohort, Female, business
Abstract

OBJECTIVE: Obstructive sleep apnea (OSA) is common among bariatric surgery patients and is associated with perioperative risk. Preoperative screening is recommended, but some screening tools lack validation, and their relative performance is unclear in this population. The study objective was to compare the ability of four existing tools (STOP-BANG, NO-OSAS, No-Apnea, and the Epworth Sleepiness Scale [ESS]) to screen for moderate to severe OSA in a diverse bariatric cohort. METHODS: Data from patients presenting for first-time bariatric surgery who underwent a sleep study within 1 year of the initial encounter were retrospectively reviewed. Performance of the four tools for detecting moderate to severe OSA was compared based on the area under the receiver operating characteristic curves (AUC). RESULTS: Of the included 214 patients (83.2% female, median age 39 years), 45.3% had moderate to severe OSA. Based on AUC, STOP-BANG (0.75 [95% CI: 0.68–0.81], N = 185), NO-OSAS (0.76 [95% CI: 0.69–0.82], N = 185), and No-Apnea (0.69 [95% CI: 0.62–0.76], N = 190) had similar performance (P > 0.16). Compared with STOP-BANG and NO-OSAS, ESS (0.61 [95% CI: 0.54–0.68], N = 198) had a significantly lower AUC (P < 0.01). Hispanic/Latino self-identification, sex, or obesity class did not significantly modify test performance. CONCLUSIONS: STOP-BANG and NO-OSAS may be preferable to No-Apnea and ESS when screening bariatric surgery patients for moderate to severe OSA. Efforts to screen bariatric patients for OSA are recommended.

Published
2020

38. Nocturnal Respiratory Rate Dynamics Enable Early Recognition of Impending Hospitalizations

Author

Nicholas Harrington, David Torres Barba, Quan M. Bui, Andrew Wassell, Sukhdeep Khurana, Rodrigo B. Rubarth, Kevin Sung, Robert L. Owens, Parag Agnihotri, and Kevin R. King

Abstract

The days and weeks preceding hospitalization are poorly understood because they transpire before patients are seen in conventional clinical care settings. Home health sensors offer opportunities to learn signatures of impending hospitalizations and facilitate early interventions, however the relevant biomarkers are unknown. Nocturnal respiratory rate (NRR) is an activity-independent biomarker that can be measured by adherence-independent sensors in the home bed. Here, we report automated longitudinal monitoring of NRR dynamics in a cohort of high-risk recently hospitalized patients using non-contact mechanical sensors under patients’ home beds. Since the distribution of nocturnal respiratory rates in populations is not well defined, we first quantified it in 2,000 overnight sleep studies from the NHLBI Sleep Heart Health Study. This revealed that interpatient variability was significantly greater than intrapatient variability (NRR variances of 11.7 brpm2and 5.2 brpm2respectively, n=1,844,110 epochs), which motivated the use of patient-specific references when monitoring longitudinally. We then performed adherence-independent longitudinal monitoring in the home beds of 34 high-risk patients and collected raw waveforms (sampled at 80 Hz) and derived quantitative NRR statistics and dynamics across 3,403 patient-nights (n= 4,326,167 epochs). We observed 23 hospitalizations for diverse causes (a 30-day hospitalization rate of 20%). Hospitalized patients had significantly greater NRR deviations from baseline compared to those who were not hospitalized (NRR variances of 3.78 brpm2and 0.84 brpm2respectively, n= 2,920 nights). These deviations were concentrated prior to the clinical event, suggesting that NRR can identify impending hospitalizations. We analyzed alarm threshold tradeoffs and demonstrated that nominal values would detect 11 of the 23 clinical events while only alarming 2 times in non-hospitalized patients. Taken together, our data demonstrate that NRR dynamics change days to weeks in advance of hospitalizations, with longer prodromes associating with volume overload and heart failure, and shorter prodromes associating with acute infections (pneumonia, septic shock, and covid-19), inflammation (diverticulitis), and GI bleeding. In summary, adherence-independent longitudinal NRR monitoring has potential to facilitate early recognition and management of pre-symptomatic disease.

Published
2022

39. The AWAKE-HF Study: Sacubitril/Valsartan Impact on Daily Physical Activity and Sleep in Heart Failure

Author

Awake-H. F. Study Investigators, Raj M. Khandwalla, Emmanuel Fombu, Kade Birkeland, J. Thomas Heywood, Daniel Grant, Steven R. Steinhubl, and Robert L. Owens

Subjects
medicine.medical_specialty, Ejection fraction, business.industry, General Medicine, 030204 cardiovascular system & hematology, medicine.disease, Confidence interval, Sacubitril, 03 medical and health sciences, 0302 clinical medicine, Valsartan, Heart failure, Internal medicine, medicine, Cardiology, Clinical endpoint, Pharmacology (medical), 030212 general & internal medicine, Enalapril, Cardiology and Cardiovascular Medicine, business, Sacubitril, Valsartan, medicine.drug
Abstract

AWAKE-HF evaluated the effect of the initiation of sacubitril/valsartan versus enalapril on activity and sleep using actigraphy in patients who have heart failure with reduced ejection fraction (HFrEF). In this randomized, double-blind study, patients with HFrEF (n = 140) were randomly assigned to sacubitril/valsartan or enalapril for 8 weeks, followed by an 8-week open-label phase with sacubitril/valsartan. Primary endpoint was change from baseline in mean activity counts during the most active 30 min/day at week 8. The key secondary endpoint was change in mean nightly activity counts/minute from baseline to week 8. Kansas City Cardiomyopathy Questionnaire-23 (KCCQ-23) was an exploratory endpoint. There were no detectable differences between groups in geometric mean ratio of activity counts during the most active 30 min/day at week 8 compared with baseline (0.9456 [sacubitril/valsartan:enalapril]; 95% confidence interval [CI] 0.8863–1.0088; P = 0.0895) or in mean change from baseline in activity during sleep (difference: 2.038 counts/min; 95% CI − 0.062 to 4.138; P = 0.0570). Change from baseline to week 8 in KCCQ-23 was 2.89 for sacubitril/valsartan and 4.19 for enalapril, both nonsignificant. In AWAKE-HF, no detectable differences in activity and sleep were observed when comparing sacubitril/valsartan with enalapril in patients with HFrEF using a wearable biosensor. ClinicalTrials.gov, NCT02970669.

Published
2020

40. Long-Term Noninvasive Ventilation in Chronic Stable Hypercapnic Chronic Obstructive Pulmonary Disease. An Official American Thoracic Society Clinical Practice Guideline

Author

Robert L. Owens, Shandra L Knight, Richard D. Branson, Simon Oczkowski, Shilpa Rahangdale, John M. Coleman, M. Bradley Drummond, Madalina Macrea, Amanda J. Piper, Dean R. Hess, Bram Rochwerg, Bartolome R. Celli, Naresh M. Punjabi, Jill A. Ohar, Susie Yim-Yeh, Peter J. Wijkstra, and Jeremy E. Orr

Subjects
Pulmonary and Respiratory Medicine, American Thoracic Society Documents, medicine.medical_specialty, COPD, business.industry, Epworth Sleepiness Scale, medicine.medical_treatment, Polysomnogram, noninvasive ventilation, Guideline, Critical Care and Intensive Care Medicine, medicine.disease, hypercapnic respiratory failure, chronic obstructive pulmonary disease, Obstructive sleep apnea, Respiratory failure, Oxygen therapy, Medicine, Noninvasive ventilation, business, Intensive care medicine
Abstract

Background: Noninvasive ventilation (NIV) is used for patients with chronic obstructive pulmonary disease (COPD) and chronic hypercapnia. However, evidence for clinical efficacy and optimal management of therapy is limited. Target Audience: Patients with COPD, clinicians who care for them, and policy makers. Methods: We summarized evidence addressing five PICO (patients, intervention, comparator, and outcome) questions. The GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach was used to evaluate the certainty in evidence and generate actionable recommendations. Recommendations were formulated by a panel of pulmonary and sleep physicians, respiratory therapists, and methodologists using the Evidence-to-Decision framework. Recommendations: 1) We suggest the use of nocturnal NIV in addition to usual care for patients with chronic stable hypercapnic COPD (conditional recommendation, moderate certainty); 2) we suggest that patients with chronic stable hypercapnic COPD undergo screening for obstructive sleep apnea before initiation of long-term NIV (conditional recommendation, very low certainty); 3) we suggest not initiating long-term NIV during an admission for acute-on-chronic hypercapnic respiratory failure, favoring instead reassessment for NIV at 2–4 weeks after resolution (conditional recommendation, low certainty); 4) we suggest not using an in-laboratory overnight polysomnogram to titrate NIV in patients with chronic stable hypercapnic COPD who are initiating NIV (conditional recommendation, very low certainty); and 5) we suggest NIV with targeted normalization of PaCO2 in patients with hypercapnic COPD on long-term NIV (conditional recommendation, low certainty). Conclusions: This expert panel provides evidence-based recommendations addressing the use of NIV in patients with COPD and chronic stable hypercapnic respiratory failure.

Published
2020

41. Effect of Venlafaxine on Apnea-Hypopnea Index in Patients With Sleep Apnea

Author

Yanru Li, Christopher N. Schmickl, Jeremy E. Orr, Bradley A. Edwards, Scott A. Sands, Atul Malhotra, Robert L. Owens, Rachel Jen, and Pamela N. DeYoung

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, business.industry, Sleep apnea, Venlafaxine, Critical Care and Intensive Care Medicine, Placebo, medicine.disease, Non-rapid eye movement sleep, Crossover study, 03 medical and health sciences, 0302 clinical medicine, Before Bedtime, 030228 respiratory system, Apnea–hypopnea index, Internal medicine, Cardiology, Medicine, 030212 general & internal medicine, Cardiology and Cardiovascular Medicine, business, Reuptake inhibitor, medicine.drug
Abstract

Background One of the key mechanisms underlying OSA is reduced pharyngeal muscle tone during sleep. Data suggest that pharmacologic augmentation of central serotonergic/adrenergic tone increases pharyngeal muscle tone. Research Question We hypothesized that venlafaxine, a serotonin-norepinephrine reuptake inhibitor, would improve OSA severity. Study Design and Methods In this mechanistic, randomized, double-blind, placebo-controlled crossover trial, 20 patients with OSA underwent two overnight polysomnograms ≥ 4 days apart, receiving either 50 mg of immediate-release venlafaxine or placebo before bedtime. Primary outcomes were the apnea-hypopnea index (AHI) and peripheral oxygen saturation (Sp o 2) nadir, and secondary outcomes included sleep parameters and pathophysiologic traits with a view toward understanding the impact of venlafaxine on mechanisms underlying OSA. Results Overall, there was no significant difference between venlafaxine and placebo regarding AHI (mean reduction, –5.6 events/h [95% CI, –12.0 to 0.9]; P = .09) or Sp o 2 nadir (median increase, +1.0% [–0.5 to 5]; P = .11). Venlafaxine reduced total sleep time, sleep efficiency, and rapid eye movement (REM) sleep, while increasing non-REM stage 1 sleep (Pall 0.5, P ≤ .02). Interpretation In unselected patients, venlafaxine simultaneously worsened and improved various pathophysiologic traits, resulting in a zero net effect. Careful patient selection based on pathophysiologic traits, or combination therapy with drugs countering its alerting effects, may produce a more robust response. Trial Registry ClinicalTrials.gov; No.: NCT02714400 ; URL: www.clinicaltrials.gov .

Published
2020

42. Revisiting Reliability: Using Sampling Utterances and Grammatical Analysis Revised (SUGAR) to Compare 25- and 50-Utterance Language Samples

Author

Larry R. Price, Robert E. Owens, and Stacey L. Pavelko

Subjects
Male, Linguistics and Language, Language Tests, Grammar, media_common.quotation_subject, Linear model, Reproducibility of Results, Contrast (statistics), Linguistics, Sample (statistics), Language and Linguistics, Speech and Hearing, Child, Preschool, Scatter plot, Statistics, Linear Models, Humans, Female, Child, Psychology, Child Language, Reliability (statistics), Utterance, Sentence, media_common
Abstract

Purpose The goal of this study was to determine whether the results obtained from a 25-utterance conversational language sample were as reliable as those obtained from a 50-utterance sample. Method Robust conversational language samples from 220 children with typically developing language (106 boys, 114 girls) ranging in age from 3;2 to 7;10 (years;months) were collected. The language samples were randomly assigned to one of two conditions: a 25-utterance condition and a 50-utterance condition. Transcripts were examined for three metrics, including mean length of utterance SUGAR , words per sentence, and clauses per sentence. Results Data were analyzed using two methods. A linear mixed-model analysis was used to assess absolute and relative reliability, and the Bland–Altman procedure was used to assess absolute reliability and clinical acceptability. Results of the mixed-model analysis indicated that mean length of utterance SUGAR and words per sentence demonstrated relative reliability; however, none of the metrics demonstrated absolute reliability. In contrast, results of the Bland–Altman scatter plots indicated that all three metrics demonstrated absolute reliability because 94%–96% of participants' scores fell within the limits of agreement. Taken together, the results suggested that the statistically significant differences indicated by the mixed-model analysis were not clinically significant. Conclusion These results highlighted the importance of using different methods of analysis in studies of reliability. The findings indicated that reliable language sample results can be obtained from 25-utterance samples. Furthermore, by including practices already in use (e.g., collecting samples ≤ 50 utterances) and including only minimal changes to current practices, the methods used in this study are feasible for school-based clinicians, could be easily integrated into clinical practice, and could increase the use of evidence-based assessment practices in schools.

Published
2020

43. Accuracy of WatchPAT for the Diagnosis of Obstructive Sleep Apnea in Patients with Chronic Obstructive Pulmonary Disease

Author

Jeremy E. Orr, Yanru Li, Atul Malhotra, Pamela N. DeYoung, Erik Smales, Robert L. Owens, and Rachel Jen

Subjects
Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Manometry, Polysomnography, Population, Monitoring, Ambulatory, Non-rapid eye movement sleep, Article, Pulmonary function testing, Pulmonary Disease, Chronic Obstructive, Wearable Electronic Devices, Heart Rate, Forced Expiratory Volume, Surveys and Questionnaires, Internal medicine, medicine, Humans, Oximetry, Lead (electronics), education, Aged, Sleep Apnea, Obstructive, COPD, education.field_of_study, medicine.diagnostic_test, business.industry, Snoring, Overlap syndrome, Middle Aged, medicine.disease, Actigraphy, nervous system diseases, respiratory tract diseases, Obstructive sleep apnea, Cardiology, Female, business, psychological phenomena and processes
Abstract

The co-existence of chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA), termed the overlap syndrome (OVS), is associated with adverse outcomes that may be reversed with treatment. However, diagnosis is limited by the apparent need for in-laboratory polysomnography (PSG). WatchPAT is a portable diagnostic device that is validated for the diagnosis of OSA that might represent an attractive tool for the diagnosis of OVS. Subjects with established COPD were recruited from a general population. Subjects underwent PSG and simultaneous recording with WatchPAT. Pulmonary function testing and questionnaires were also performed. A total of 36 subjects were recruited and valid data was obtained on 33 (age 63 ± 7, BMI 28 ± 7, 61% male, FEV(1) 56 ± 20% predicted). There was no significant difference in the apnea–hypopnea index (AHI) between PSG and WatchPAT (19 ± 20 versus 20 ± 15 events/h; mean difference 2(−2, 5) events/h; p = 0.381). The AHI was not significantly different in rapid eye movement (REM) and non-rapid eye movement (NREM) determined by PSG versus REM and NREM determined by WatchPAT. WatchPAT slightly overestimated total and REM sleep time, and sleep efficiency. The sensitivity of WatchPAT at an AHI cut-off of ≥5, ≥15, and ≥30 events/h for corresponding PSG AHI cut-offs was 95.8, 92.3, and 88.9, respectively; specificity was 55, 65.0, and 95.8, respectively. WatchPAT is able to determine OSA reliably in patients with COPD. The availability of this additional diagnostic modality may lead to improved detection of OVS, which may in turn lead to improved outcomes for a group of COPD patients at high risk of poor outcomes.

Published
2020

45. The impact of sleep disordered breathing on cardiac troponin in acutely decompensated heart failure

Author

Matthew P. Light, Kimberly Y. Kreitinger, Euyhyun Lee, Pamela N. DeYoung, Avni Lakhani, Brent Siegel, Lori B. Daniels, Atul Malhotra, and Robert L. Owens

Subjects
Adult, Heart Failure, Aging, Sleep Apnea, Polysomnography, Clinical Sciences, Respiratory System, Cheyne-Stokes, Cardiovascular, Troponin, Sleep Apnea Syndromes, Heart Disease, Otorhinolaryngology, Clinical Research, Humans, Psychology, Neurology (clinical), Sleep, Sleep Research, Central, Lung
Abstract

Purpose Sleep disordered breathing in decompensated heart failure has physiological consequences (e.g., intermittent hypoxemia) that may predispose to subclinical myocardial injury, yet a temporal relationship between sleep apnea and troponin elevation has not been established. Methods We assessed the feasibility of performing respiratory polygraphy and measuring overnight high-sensitivity cardiac troponin T change in adults admitted to the hospital with acutely decompensated heart failure. Repeat sleep apnea tests (SATs) were performed to determine response to optimal medical heart failure therapy. Multivariable logistic regression was used to identify associations between absolute overnight troponin change and sleep apnea characteristics. Results Among the 19 subjects with acutely decompensated heart failure, 92% of SATs demonstrated sleep disordered breathing (apnea–hypopnea index [AHI] > 5 events/h). For those with repeat SATs, AHI increased in 67% despite medical management of heart failure. Overnight troponin increase was associated with moderate to severe sleep apnea (vs. no to mild sleep apnea, odds ratio (OR = 18.4 [1.51–224.18]), central apnea index (OR = 1.11 [1.01–1.22]), and predominantly central sleep apnea (vs. obstructive, OR = 22.9 [1.29–406.32]). Conclusions Sleep apnea severity and a central apnea pattern may be associated with myocardial injury. Respiratory polygraphy with serial biomarker assessment is feasible in this population, and combining this approach with interventions (e.g., positive airway pressure) may help establish if a link exists between sleep apnea and subclinical myocardial injury.

Published
2022

47. Activity Sensors to Evaluate the Effect of Sacubitril/Valsartan on Quality‐of‐Life in Heart Failure: rational and design of the AWAKE‐HF study

Author

Raj M. Khandwalla, Kade Birkeland, Steven R. Steinhubl, Emmanuel Fombu, Jerome B. Riebman, J. Thomas Heywood, Kevin McCague, Daniel Grant, and Robert L. Owens

Subjects
Adult, Male, medicine.medical_specialty, lcsh:Diseases of the circulatory (Cardiovascular) system, Adolescent, Study Designs, Tetrazoles, Context (language use), Heart failure, 030204 cardiovascular system & hematology, Sacubitril, Angiotensin Receptor Antagonists, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Quality of life, Accelerometry, Humans, Medicine, 030212 general & internal medicine, Sacubitril/valsartan, Aged, Monitoring, Physiologic, Aged, 80 and over, Study Design, business.industry, Physical activity, Aminobutyrates, Biphenyl Compounds, Actigraphy, Middle Aged, Drug Combinations, Valsartan, Health‐related quality of life, lcsh:RC666-701, Ambulatory, Quality of Life, Physical therapy, Female, Observational study, Cardiology and Cardiovascular Medicine, business, Sleep, Sacubitril, Valsartan, Biosensor, medicine.drug
Abstract

Aims Limited data are available regarding the ability of sacubitril/valsartan to provide clinically meaningful health‐related quality of life (HRQoL) improvements among individuals with heart failure (HF). Objective measurement of physical activity and sleep using actigraphy can provide insight into daily functioning and HRQoL. Methods and results We designed an 18 week, multicenter, randomized, double‐blind, double‐dummy, parallel‐group study to objectively assess changes in function and HRQoL directly after initiating sacubitril/valsartan vs. enalapril in participants with HF in their home environments. A total of 136 outpatient, ambulatory participants with New York Heart Association Class II or III HF with reduced ejection fraction (HFrEF) will be included in the study. Patients will undergo a 2 week baseline observational phase (continuing current HF treatment); data from the second week of this phase will be the baseline value for comparison with those of subsequent periods. Patients will then enter an 8 week blinded‐treatment phase (randomly assigned 1:1 to sacubitril/valsartan or enalapril), followed by an 8 week open‐label extension phase (treatment with only sacubitril/valsartan). The primary efficacy endpoint is the change in mean activity counts during the most active 30 min of the participant's day between baseline and the final randomized treatment phase measurement. Secondary endpoints include the change in mean sleep activity during the randomized and open‐label phases; questionnaires will also assess HRQoL measures. Rather than analysing pooled actigraphy data, the researchers are considering each participant to be acting as his or her own control. Conclusions This will be the first study to assess the effects of sacubitril/valsartan on objective measures of sleep and activity in individuals with HFrEF within the context of their daily lives. Wearable accelerometer devices will be used to gain insight into how the medication affects physical activity and sleep.

Published
2019

48. Ramelteon for Prevention of Postoperative Delirium

Author

Andrew J Heisel, Robert L. Owens, Michael M. Madani, Anuja Vyas, Stuti J. Jaiswal, Victor Pretorius, Atul Malhotra, Nick H. Kim, Ashna Aggarwal, Timothy M. Fernandes, Kim M. Kerr, William R. Auger, and Haritha Ackula

Subjects
Adult, Male, medicine.medical_treatment, Ramelteon, MEDLINE, Endarterectomy, Critical Care and Intensive Care Medicine, law.invention, 03 medical and health sciences, Postoperative Complications, 0302 clinical medicine, Double-Blind Method, Randomized controlled trial, law, mental disorders, Humans, Medicine, Aged, Pulmonary thromboendarterectomy, business.industry, Delirium, 030208 emergency & critical care medicine, Perioperative, Middle Aged, Indenes, 030228 respiratory system, Elective Surgical Procedures, Anesthesia, Female, medicine.symptom, business, Elective Surgical Procedure, medicine.drug
Abstract

To assess the efficacy of ramelteon in preventing delirium, an acute neuropsychiatric condition associated with increased morbidity and mortality, in the perioperative, ICU setting.Parallel-arm, randomized, double-blinded, placebo-controlled trial.Academic medical center in La Jolla, California.Patients greater than or equal to 18 years undergoing elective pulmonary thromboendarterectomy.Ramelteon 8 mg or matching placebo starting the night prior to surgery and for a maximum of six nights while in the ICU.Incident delirium was measured twice daily using the Confusion Assessment Method-ICU. The safety outcome was coma-free days assessed by the Richmond Agitation-Sedation Scale. One-hundred twenty participants were enrolled and analysis completed in 117. Delirium occurred in 22 of 58 patients allocated to placebo versus 19 of 59 allocated to ramelteon (relative risk, 0.8; 95% CI, 0.5-1.4; p = 0.516). Delirium duration, as assessed by the number of delirium-free days was also similar in both groups (placebo median 2 d [interquartile range, 2-3 d] vs ramelteon 3 d [2-5 d]; p = 0.181). Coma-free days was also similar between groups (placebo median 2 d [interquartile range, 1-3 d] vs ramelteon 3 d [2-4 d]; p = 0.210). We found no difference in ICU length of stay (median 4 d [interquartile range, 3-5 d] vs 4 d [3-6 d]; p = 0.349), or in-hospital mortality (four vs three deaths; relative risk ratio, 0.7; 95% CI, 0.2-3.2; p = 0.717), all placebo versus ramelteon, respectively.Ramelteon 8 mg did not prevent postoperative delirium in patients admitted for elective cardiac surgery.

Published
2019

49. Effects of acetazolamide on control of breathing in sleep apnea patients: Mechanistic insights using meta‐analyses and physiological model simulations

Author

Shane A. Landry, Robert L. Owens, Jeremy E. Orr, Bradley A. Edwards, Christopher N. Schmickl, Brandon Nokes, and Atul Malhotra

Subjects
medicine.medical_specialty, Central sleep apnea, Physiology, Clinical Sciences, Medical Physiology, Models, Biological, Sleep Apnea Syndromes, Models, Physiology (medical), Internal medicine, medicine, QP1-981, Humans, Computer Simulation, Carbonic Anhydrase Inhibitors, Lead (electronics), Lung, business.industry, Respiration, Sleep apnea, Original Articles, Biological, medicine.disease, Acetazolamide, Control of respiration, Breathing, Cardiology, Original Article, Sleep Research, business, Neurocognitive, medicine.drug, Loop gain
Abstract

Obstructive and central sleep apnea affects ~1 billion people globally and may lead to serious cardiovascular and neurocognitive consequences, but treatment options are limited. High loop gain (ventilatory instability) is a major pathophysiological mechanism underlying both types of sleep apnea and can be lowered pharmacologically with acetazolamide, thereby improving sleep apnea severity. However, individual responses vary and are strongly correlated with the loop gain reduction achieved by acetazolamide. To aid with patient selection for long‐term trials and clinical care, our goal was to understand better the factors that determine the change in loop gain following acetazolamide in human subjects with sleep apnea. Thus, we (i) performed several meta‐analyses to clarify how acetazolamide affects ventilatory control and loop gain (including its primary components controller/plant gain), and based on these results, we (ii) performed physiological model simulations to assess how different baseline conditions affect the change in loop gain. Our results suggest that (i) acetazolamide primarily causes a left shift of the chemosensitivity line thus lowering plant gain without substantially affecting controller gain; and (ii) higher controller gain, higher paCO2 at eupneic ventilation, and lower CO2 production at baseline result in a more pronounced loop gain reduction with acetazolamide. In summary, the combination of mechanistic meta‐analyses with model simulations provides a unified framework of acetazolamide’s effects on ventilatory control and revealed physiological predictors of response, which are consistent with empirical observations of acetazolamide's effects in different sleep apnea subgroups. Prospective studies are needed to validate these predictors and assess their value for patient selection., (a) Based on mechanistic meta‐analyses in patients with sleep apnea, acetazolamide primarily causes a left‐shift of the chemosensitivity line thus lowering plant gain without substantially affecting controller gain; the net effect is a relative reduction in overall loop gain similar to the reduction in plant gain. (b) Based on model simulations, a higher controller gain, higher paCO2 at eupneic ventilation, and lower CO2 production at baseline each result in a more pronounced loop gain reduction with acetazolamide, and thus may predict response to acetazolamide.

Published
2021

50. Statistical uncertainty quantification to augment clinical decision support: a first implementation in sleep medicine

Author

Pamela N. DeYoung, Dae Y. Kang, Robert L. Owens, Todd P. Coleman, and Justin Tantiongloc

Subjects
medicine.medical_specialty, Computer science, Computer applications to medicine. Medical informatics, R858-859.7, Medicine (miscellaneous), Bioengineering, Health Informatics, Medical classification, Machine learning, computer.software_genre, Clinical decision support system, Sleep medicine, Article, Health Information Management, medicine, Human-in-the-loop, Fraction (mathematics), Uncertainty quantification, business.industry, Diagnostic markers, Sleep disorders, Gold standard (test), Translational research, Computer Science Applications, Pattern recognition (psychology), Artificial intelligence, Sleep Research, business, computer
Abstract

Machine learning has the potential to change the practice of medicine, particularly in areas that require pattern recognition (e.g. radiology). Although automated classification is unlikely to be perfect, few modern machine learning tools have the ability to assess their own classification confidence to recognize uncertainty that might need human review. Using automated single-channel sleep staging as a first implementation, we demonstrated that uncertainty information (as quantified using Shannon entropy) can be utilized in a “human in the loop” methodology to promote targeted review of uncertain sleep stage classifications on an epoch-by-epoch basis. Across 20 sleep studies, this feedback methodology proved capable of improving scoring agreement with the gold standard over automated scoring alone (average improvement in Cohen’s Kappa of 0.28), in a fraction of the scoring time compared to full manual review (60% reduction). In summary, our uncertainty-based clinician-in-the-loop framework promotes the improvement of medical classification accuracy/confidence in a cost-effective and economically resourceful manner.

Published
2021

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