Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Rest energy expenditure under brain death condition

Introduction: Brain metabolism deteriorates during brain death, suggesting that cerebral metabolic measurements could serve as a prognostic factor. The application of transcranial Doppler can be useful in evaluating patients evolving to brain death. Resting energy expenditure is lower than expected in patients with brain death, and this is cause by the decrease in cerebral blood flow and consequently lower oxygen supply. The primary aim of this retrospective study is to investigate the early metabolic changes in patients with clinical criteria of brain death and examine if these changes a rerelated to a gradual decrease in blood flow velocities in the middle cerebral artery. Methods: All consecutive patients from 1st June 2018 to 30th April 2022, admitted to the ICU with brain injury and a GCS ≤ 8, were included retrospectively in the study. Patients were allocated into two groups: Group A, patients without clinical signs of brain death (n = 32), and Group B, patients with brain death (n = 34). In each group, three sets of metabolic measurements were performed concomitantly with cerebral blood flow velocities using transcranial Doppler (a) up on admission to the ICU, (b) once hemodynamic stabilization was158obtained, and (c) 48 hours after their hemodynamic stabilization or when brain death was confirmed by clinical criteria. Resting energy expenditure (REE) measurements were performed using a metabolic computer. Cerebral blood flow velocities were measured after a period of 30 min using a 2-MHZ 2D ultrasound probe. Results: Brain death patients had a significant decrease in their metabolic parameters as the cerebral blood flow velocities recorded with the transcranial Doppler deteriorated, (REE Group A = 1667.65 ± 597 vs Group B = 1376.12 ± 615, p = 0.05 and REE predicted Group A = 113.19 ± 44.9 vs Group B = 93.29 ± 41.5, p = 0.066 for measurement 1; REE Group A = 1844 ± 530.9 vs Group B = 1219.97 ± 489, p < 0.001 and REE predicted Group A = 124.38 ± 39 vs Group B = 81.35 ± 30.4, p < 0.001 for measurement 2; REE Group A = 1750.97 ± 414, p < 0.001 and REE predicted Group A = 116.38 ± 19.2 vs Group B = 56.09 ± 19.6, p < 0.001 for measurement 3). Multiple step wise regression analysis evealed a strong relationship between age, the worsening of the blood flow velocities pattern, and the decrease in REE (multiple R = 0.264, F = 5.55, p = 0.009). Furthermore, a statistically significant correlation was found between temperature and REE (correlation coefficient = 0.500, 0.674, 0.784 for measurements 1, 2, and 3, respectively, and p < 0.001 for all measures). Conclusions: In brain-dead patients, the gradual decrease in cerebral blood flow leads to a decrease in REE as well as thermogenetic control. These changes can be detected early after the patient's admission to the ICU.Εισαγωγή: Ο εγκεφαλικός μεταβολισμός απορρυθμίζεται κατά τη διάρκεια του εγκεφαλικού θανάτου, υποδηλώνοντας ότι οι μετρήσεις της σωστής λειτουργίας του θα μπορούσαν να χρησιμεύσουν ως προγνωστικός παράγοντας. Η βασική ενεργειακή δαπάνη κατά την ανάπαυση είναι χαμηλότερη από το αναμενόμενο σε ασθενείς με εγκεφαλικό θάνατο, και αυτό οφείλεται στη μείωση της ροής του αίματος στον εγκέφαλο και συνεπώς στη μειωμένη προσφορά οξυγόνου. Η εφαρμογή της διακρανιακής υπερηχογραφίας doppler μπορεί να είναι χρήσιμη στην αξιολόγηση ασθενών που εξελίσσονται προς εγκεφαλικό θάνατο. Ο κύριος σκοπός της παρούσας αναδρομικής μελέτης ήταν να διερευνήσει τις πρώιμες μεταβολικές αλλαγές σε ασθενείς με κλινικά κριτήρια εγκεφαλικού θανάτου και να εξετάσει αν αυτές οι αλλαγές σχετίζονται με μια σταδιακή μείωση της ροής του αίματος στη μέση εγκεφαλική αρτηρία. Μεθοδολογία: Όλοι οι ασθενείς από 1η Ιουνίου 2018 έως 30η Απριλίου 2022, που εισήχθησαν στη ΜΕΘ του ΓΝ Παπαγεωργίου, με εγκεφαλική βλάβη και GCS ≤ 8, συμπεριλήφθηκαν αναδρομικά στη μελέτη. Οι ασθενείς κατανεμήθηκαν σε δύο ομάδες: Ομάδα Α, ασθενείς χωρίς κλινικά σημεία εγκεφαλικού θανάτου (n = 32), και Ομάδα Β, ασθενείς με εγκεφαλικό θάνατο (n = 34). Σε κάθε ομάδα, διενεργήθηκαν τρία σύνολα μεταβολικών μετρήσεων ταυτόχρονα με τον υπολογισμό των ταχυτήτων ροής του αίματος στον εγκέφαλο χρησιμοποιώντας διακρανιακόdoppler (α) κατά την εισαγωγή στη ΜΕΘ, (β) μόλις επιτεύχθηκε αιμοδυναμική σταθεροποίηση, και (γ) 48 ώρες μετά την αιμοδυναμική σταθεροποίηση ή όταν ο εγκεφαλικός θάνατος επιβεβαιώθηκε με κλινικά κριτήρια. Οι μετρήσεις της ενεργειακής δαπάνης σε ανάπαυση (REE) διενεργήθηκαν χρησιμοποιώντας υπολογιστή 154 μεταβολικού ρυθμού. Οι ταχύτητες ροής του αίματος στον εγκέφαλο μετρήθηκαν μετά από περίοδο 30 λεπτών χρησιμοποιώντας έναν υπέρηχο 2D 2-MHZ. Αποτελέσματα: Οι ασθενείς με εγκεφαλικό θάνατο είχαν σημαντική μείωση των μεταβολικών τους παραμέτρων καθώς η ταχύτητα ροής του αίματος στον εγκέφαλο επιδεινωνόταν (REE της ομάδας Α 1667.65 ± 597 έναντι της ομάδας Β 1376.12 ± 615, p = 0.05 και της προβλεπόμενης REE (13.19 ± 44.9 ομάδας Α έναντι 93.29 ± 41.5 για την ομάδα Β, p = 0.066 για τη μέτρηση 1), (REE ομάδας A = 1844 ± 530.9 έναντι ομάδας B = 1219.97 ± 489, p < 0.001 και προβλεπόμενη REE ομάδας A = 124.38 ± 39 έναντι ομάδας B = 81.35 ± 30.4, p < 0.001 για τη μέτρηση 2), (REE ομάδας A = 1750.97 ± 414, p < 0.001 και REE predicted Group A = 116.38 ± 19.2 έναντι ομάδας B = 56.09 ± 19.6, p < 0.001 για τη μέτρηση 3). Η λογαριθμική πολλαπλή ανάλυση παλινδρόμησης έδειξε μια ισχυρή συσχέτιση μεταξύ της ηλικίας, της επιδείνωσης της ταχύτητας ροής του αίματος και της μείωσης της REE (πολλαπλή R = 0.264, F = 5.55, p = 0.009). Επιπλέον, βρέθηκε στατιστικώς σημαντική συσχέτιση μεταξύ της θερμοκρασίας και της REE (συντελεστής συσχέτισης = 0.500, 0.674, 0.784 για τις μετρήσεις 1, 2 και 3 αντίστοιχα, και p < 0.001 για όλες τις μετρήσεις). Συμπεράσματα: Στους ασθενείς με εγκεφαλικό θάνατο, η σταδιακή μείωση της ροής αίματος στον εγκέφαλο οδηγεί σε μείωση της REE καθώς και δυσλειτουργία του ελέγχου της θερμογένεσης. Αυτές οι αλλαγές μπορούν να ανιχνευθούν νωρίς μετά την εισαγωγή του ασθενή με εγκεφαλική βλάβη στη Μονάδα Εντατικής Θεραπείας (ΜΕΘ)

Immunocompromised patients with acute respiratory distress syndrome : Secondary analysis of the LUNG SAFE database

The aim of this study was to describe data on epidemiology, ventilatory management, and outcome of acute respiratory distress syndrome (ARDS) in immunocompromised patients. Methods: We performed a post hoc analysis on the cohort of immunocompromised patients enrolled in the Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE) study. The LUNG SAFE study was an international, prospective study including hypoxemic patients in 459 ICUs from 50 countries across 5 continents. Results: Of 2813 patients with ARDS, 584 (20.8%) were immunocompromised, 38.9% of whom had an unspecified cause. Pneumonia, nonpulmonary sepsis, and noncardiogenic shock were their most common risk factors for ARDS. Hospital mortality was higher in immunocompromised than in immunocompetent patients (52.4% vs 36.2%; p < 0.0001), despite similar severity of ARDS. Decisions regarding limiting life-sustaining measures were significantly more frequent in immunocompromised patients (27.1% vs 18.6%; p < 0.0001). Use of noninvasive ventilation (NIV) as first-line treatment was higher in immunocompromised patients (20.9% vs 15.9%; p = 0.0048), and immunodeficiency remained independently associated with the use of NIV after adjustment for confounders. Forty-eight percent of the patients treated with NIV were intubated, and their mortality was not different from that of the patients invasively ventilated ab initio. Conclusions: Immunosuppression is frequent in patients with ARDS, and infections are the main risk factors for ARDS in these immunocompromised patients. Their management differs from that of immunocompetent patients, particularly the greater use of NIV as first-line ventilation strategy. Compared with immunocompetent subjects, they have higher mortality regardless of ARDS severity as well as a higher frequency of limitation of life-sustaining measures. Nonetheless, nearly half of these patients survive to hospital discharge. Trial registration: ClinicalTrials.gov, NCT02010073. Registered on 12 December 2013

Immunocompromised patients with acute respiratory distress syndrome: Secondary analysis of the LUNG SAFE database

Background: The aim of this study was to describe data on epidemiology, ventilatory management, and outcome of acute respiratory distress syndrome (ARDS) in immunocompromised patients. Methods: We performed a post hoc analysis on the cohort of immunocompromised patients enrolled in the Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE) study. The LUNG SAFE study was an international, prospective study including hypoxemic patients in 459 ICUs from 50 countries across 5 continents. Results: Of 2813 patients with ARDS, 584 (20.8%) were immunocompromised, 38.9% of whom had an unspecified cause. Pneumonia, nonpulmonary sepsis, and noncardiogenic shock were their most common risk factors for ARDS. Hospital mortality was higher in immunocompromised than in immunocompetent patients (52.4% vs 36.2%; p &lt; 0.0001), despite similar severity of ARDS. Decisions regarding limiting life-sustaining measures were significantly more frequent in immunocompromised patients (27.1% vs 18.6%; p &lt; 0.0001). Use of noninvasive ventilation (NIV) as first-line treatment was higher in immunocompromised patients (20.9% vs 15.9%; p = 0.0048), and immunodeficiency remained independently associated with the use of NIV after adjustment for confounders. Forty-eight percent of the patients treated with NIV were intubated, and their mortality was not different from that of the patients invasively ventilated ab initio. Conclusions: Immunosuppression is frequent in patients with ARDS, and infections are the main risk factors for ARDS in these immunocompromised patients. Their management differs from that of immunocompetent patients, particularly the greater use of NIV as first-line ventilation strategy. Compared with immunocompetent subjects, they have higher mortality regardless of ARDS severity as well as a higher frequency of limitation of life-sustaining measures. Nonetheless, nearly half of these patients survive to hospital discharge. Trial registration: ClinicalTrials.gov, NCT02010073. Registered on 12 December 2013

Mechanical ventilation in patients with cardiogenic pulmonary edema: a sub-analysis of the LUNG SAFE study

International audienceBackground: Patients with acute respiratory failure caused by cardiogenic pulmonary edema (CPE) may require mechanical ventilation that can cause further lung damage. Our aim was to determine the impact of ventilatory settings on CPE mortality. Methods: Patients from the LUNG SAFE cohort, a multicenter prospective cohort study of patients undergoing mechanical ventilation, were studied. Relationships between ventilatory parameters and outcomes (ICU discharge/ hospital mortality) were assessed using latent mixture analysis and a marginal structural model. Results: From 4499 patients, 391 meeting CPE criteria (median age 70 [interquartile range 59-78], 40% female) were included. ICU and hospital mortality were 34% and 40%, respectively. ICU survivors were younger (67 [57-77] vs 74 [64-80] years, p < 0.001) and had lower driving (12 [8-16] vs 15 [11-17] cmH 2 O, p < 0.001), plateau (20 [15-23] vs 22 [19-26] cmH 2 O, p < 0.001) and peak (21 [17-27] vs 26 [20-32] cmH 2 O, p < 0.001) pressures. Latent mixture analysis of patients receiving invasive mechanical ventilation on ICU day 1 revealed a subgroup ventilated with high pressures with lower probability of being discharged alive from the ICU (hazard ratio [HR] 0.79 [95% confidence interval 0.60-1.05], p = 0.103) and increased hospital mortality (HR 1.65 [1.16-2.36], p = 0.005). In a marginal structural model, driving pressures in the first week (HR 1.12 [1.06-1.18], p < 0.001) and tidal volume after day 7 (HR 0.69 [0.52-0.93], p = 0.015) were related to survival. Conclusions: Higher airway pressures in invasively ventilated patients with CPE are related to mortality. These patients may be exposed to an increased risk of ventilator-induced lung injury

Outcomes of Patients Presenting with Mild Acute Respiratory Distress Syndrome Insights from the LUNG SAFE Study

BACKGROUND: Patients with initial mild acute respiratory distress syndrome are often underrecognized and mistakenly considered to have low disease severity and favorable outcomes. They represent a relatively poorly characterized population that was only classified as having acute respiratory distress syndrome in the most recent definition. Our primary objective was to describe the natural course and the factors associated with worsening and mortality in this population. METHODS: This study analyzed patients from the international prospective Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE) who had initial mild acute respiratory distress syndrome in the first day of inclusion. This study defined three groups based on the evolution of severity in the first week: "worsening" if moderate or severe acute respiratory distress syndrome criteria were met, "persisting" if mild acute respiratory distress syndrome criteria were the most severe category, and "improving" if patients did not fulfill acute respiratory distress syndrome criteria any more from day 2. RESULTS: Among 580 patients with initial mild acute respiratory distress syndrome, 18% (103 of 580) continuously improved, 36% (210 of 580) had persisting mild acute respiratory distress syndrome, and 46% (267 of 580) worsened in the first week after acute respiratory distress syndrome onset. Global in-hospital mortality was 30% (172 of 576; specifically 10% [10 of 101], 30% [63 of 210], and 37% [99 of 265] for patients with improving, persisting, and worsening acute respiratory distress syndrome, respectively), and the median (interquartile range) duration of mechanical ventilation was 7 (4, 14) days (specifically 3 [2, 5], 7 [4, 14], and 11 [6, 18] days for patients with improving, persisting, and worsening acute respiratory distress syndrome, respectively). Admissions for trauma or pneumonia, higher nonpulmonary sequential organ failure assessment score, lower partial pressure of alveolar oxygen/fraction of inspired oxygen, and higher peak inspiratory pressure were independently associated with worsening. CONCLUSIONS: Most patients with initial mild acute respiratory distress syndrome continue to fulfill acute respiratory distress syndrome criteria in the first week, and nearly half worsen in severity. Their mortality is high, particularly in patients with worsening acute respiratory distress syndrome, emphasizing the need for close attention to this patient population.status: publishe

Correction to: Potentially modifiable factors contributing to outcome from acute respiratory distress syndrome: the LUNG SAFE study (Intensive Care Medicine, (2016), 42, 12, (1865-1876), 10.1007/s00134-016-4571-5)

The members of the LUNG SAFE Investigators and the ESICM Trials Group were provided in such a way that they could not be indexed as collaborators on PubMed. The publisher apologizes for this error

Resolved versus confirmed ARDS after 24 h: insights from the LUNG SAFE study

Purpose: To evaluate patients with resolved versus confirmed ARDS, identify subgroups with substantial mortality risk, and to determine the utility of day 2 ARDS reclassification. Methods: Our primary objective, in this secondary LUNG SAFE analysis, was to compare outcome in patients with resolved versus confirmed ARDS after 24 h. Secondary objectives included identifying factors associated with ARDS persistence and mortality, and the utility of day 2 ARDS reclassification. Results: Of 2377 patients fulfilling the ARDS definition on the first day of ARDS (day 1) and receiving invasive mechanical ventilation, 503 (24%) no longer fulfilled the ARDS definition the next day, 52% of whom initially had moderate or severe ARDS. Higher tidal volume on day 1 of ARDS was associated with confirmed ARDS [OR 1.07 (CI 1.01–1.13), P = 0.035]. Hospital mortality was 38% overall, ranging from 31% in resolved ARDS to 41% in confirmed ARDS, and 57% in confirmed severe ARDS at day 2. In both resolved and confirmed ARDS, age, non-respiratory SOFA score, lower PEEP and P/F ratio, higher peak pressure and respiratory rate were each associated with mortality. In confirmed ARDS, pH and the presence of immunosuppression or neoplasm were also associated with mortality. The increase in area under the receiver operating curve for ARDS reclassification on day 2 was marginal. Conclusions: ARDS, whether resolved or confirmed at day 2, has a high mortality rate. ARDS reclassification at day 2 has limited predictive value for mortality. The substantial mortality risk in severe confirmed ARDS suggests that complex interventions might best be tested in this population. Trial Registration: ClinicalTrials.gov NCT02010073

Validation and utility of ARDS subphenotypes identified by machine-learning models using clinical data: an observational, multicohort, retrospective analysis

International audienceTwo acute respiratory distress syndrome (ARDS) subphenotypes (hyperinflammatory and hypoinflammatory) with distinct clinical and biological features and differential treatment responses have been identified using latent class analysis (LCA) in seven individual cohorts. To facilitate bedside identification of subphenotypes, clinical classifier models using readily available clinical variables have been described in four randomised controlled trials. We aimed to assess the performance of these models in observational cohorts of ARDS. Methods: In this observational, multicohort, retrospective study, we validated two machine-learning clinical classifier models for assigning ARDS subphenotypes in two observational cohorts of patients with ARDS: Early Assessment of Renal and Lung Injury (EARLI; n=335) and Validating Acute Lung Injury Markers for Diagnosis (VALID; n=452), with LCA-derived subphenotypes as the gold standard. The primary model comprised only vital signs and laboratory variables, and the secondary model comprised all predictors in the primary model, with the addition of ventilatory variables and demographics. Model performance was assessed by calculating the area under the receiver operating characteristic curve (AUC) and calibration plots, and assigning subphenotypes using a probability cutoff value of 0·5 to determine sensitivity, specificity, and accuracy of the assignments. We also assessed the performance of the primary model in EARLI using data automatically extracted from an electronic health record (EHR; EHR-derived EARLI cohort). In Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE; n=2813), a multinational, observational ARDS cohort, we applied a custom classifier model (with fewer variables than the primary model) to determine the prognostic value of the subphenotypes and tested their interaction with the positive end-expiratory pressure (PEEP) strategy, with 90-day mortality as the dependent variable. Findings: The primary clinical classifier model had an area under receiver operating characteristic curve (AUC) of 0·92 (95% CI 0·90–0·95) in EARLI and 0·88 (0·84–0·91) in VALID. Performance of the primary model was similar when using exclusively EHR-derived predictors compared with manually curated predictors (AUC=0·88 [95% CI 0·81–0·94] vs 0·92 [0·88–0·97]). In LUNG SAFE, 90-day mortality was higher in patients assigned the hyperinflammatory subphenotype than in those with the hypoinflammatory phenotype (414 [57%] of 725 vs 694 [33%] of 2088; p<0·0001). There was a significant treatment interaction with PEEP strategy and ARDS subphenotype (p=0·041), with lower 90-day mortality in the high PEEP group of patients with the hyperinflammatory subphenotype (hyperinflammatory subphenotype: 169 [54%] of 313 patients in the high PEEP group vs 127 [62%] of 205 patients in the low PEEP group; hypoinflammatory subphenotype: 231 [34%] of 675 patients in the high PEEP group vs 233 [32%] of 734 patients in the low PEEP group). Interpretation: Classifier models using clinical variables alone can accurately assign ARDS subphenotypes in observational cohorts. Application of these models can provide valuable prognostic information and could inform management strategies for personalised treatment, including application of PEEP, once prospectively validated. Funding: US National Institutes of Health and European Society of Intensive Care Medicine

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

Background: Current 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). Methods: An 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. Findings: 12 906 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. Interpretation: More 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