EDITORIALS Biomarkers to Guide Ventilation Management and Readiness for Extubation Weaning from ventilatory support is a constant challenge for epithelial and endothelial lung injury, coagulation, and inflammation clinicians, especially in patients with acute hypoxemic respiratory and has shown that a combination of clinical predictors with failure (AHRF). Even in patients who succeed in a spontaneous biomarkers predicted mortality better than clinical or biomarker breathing trial (SBT), failure of planned extubation occurs in up to assessment alone (9). In another study, direct lung injury caused by 20% of the patients (1, 2). Importantly, failed extubation is associated pneumonia and aspiration was characterized by more severe lung with increased hospital mortality, prolonged ICU and hospital length epithelial and less severe endothelial injury, with higher plasma levels of stay, and increased need for tracheostomy (3, 4). Despite the of sRAGE (soluble for advanced glycation end-products) and lower assessment of several respiratory and hemodynamic variables for levels of Ang-2 (angiopoietin-2) when compared with indirect lung predicting weaning success, few parameters present a substantial injury (10). Plasma levels of sRAGE reflect the extent and severity of predictive power (1, 2). In addition, physiologic parameters may not lung epithelial injury, and higher levels were strongly associated with reflect the degree of underlying lung injury, and new predictive tools impaired alveolar fluid clearance (11). sST2 and IL-6, as assessed in are urgently needed. the study by Alladina and colleagues, are biomarkers that are elevated Plasma biomarkers of lung injury are attractive tools for in lung inflammation and may provide measures of ongoing lung determining readiness for liberation from ventilator. Because injury. However, it is important to emphasize that the present study common causes of AHRF are frequently associated with elements of did not include biomarkers of epithelial lung damage as a potential lung inflammation and cardiac dysfunction (5, 6), circulating comparator. There is a potential difference between the systemic biomarkers of cardiovascular stress and inflammation can provide reaction and the local alveolar reaction associated with AHRF and objective measures of time to resolution of AHRF and potentially ARDS, emphasizing the importance of assessing biomarkers of the predict liberation from the ventilator (6). Among several biomarkers, alveolar compartment in future research. Also, another important sST2 (suppression of tumorigenicity-2), which is a member of the IL-1 element that has been studied recently in the field of lung injury is receptor family, has been implicated in signaling pathways of cardiac volatile organic compounds from exhaled breath analysis, and this and vascular stress as well as inflammation (6, 7). In patients with could be considered in future research (12). acute respiratory distress syndrome (ARDS), higher sST2 The development and clinical utility of point-of-care or clinical- concentrations were associated with worse outcomes during weaning grade assays of biomarkers, including the potential of an “acute lung of ventilation and increased need for reintubation (6). Measurement injury or extubation chip,” must first be confirmed to improve patient of sST2 level in AHRF could provide real-time prognostic information outcomes in well-powered studies. sST2 is still not widely available in on the patient’s clinical trajectory and readiness for extubation. clinical practice, and this should be taken into account when In this issue of the Journal, Alladina and colleagues interpreting the results of the present study. In addition, the study (pp. 1257–1265) published the first prospective observational focuses more on lung injury as a cause for failed extubation. However, study to investigate a biomarker-direct approach to bedside other reasons not directly related to lung injury may contribute to ventilator management in patients with AHRF (8). In this study, extubation failure, such as respiratory muscle weakness or heart failure. 200 adult patients with AHRF (95.2% with ARDS) were included, Indeed, the SBT is a cardiovascular stress test, and failure to wean from and daily measurements of sST2 and IL-6 were assessed. Baseline mechanical ventilation often reflects cardiovascular insufficiency to sST2 concentrations were higher in nonsurvivors and in patients cope with an increased oxygen demand from increased work of still receiving ventilation on Day 29. In addition, higher breathing. The relationship between sST2 and extubation failure related concentrations of sST2 over time were associated with a to other factors than lung injury is still a matter of study. decreased chance of liberation from the ventilator. Furthermore, During the study period, Alladina and colleagues enrolled a higher sST2 at the day of extubation predicted failed patients from November 2015 to January 2017. Over this period, extubation. Based on their findings, the authors concluded that some changes in the weaning process have occurred, mainly focused using sST2 concentrations to guide ventilator management may on the prevention of failed extubation (13–15). The main changes are more accurately reflect underlying lung injury and outperform related to a shorter and less demanding ventilation strategy for SBT traditional measures of readiness for ventilator liberation. (13), the use of a 1-hour rest after a successful SBT and before In recent years, several biomarkers were assessed in patients with extubation (14), and the use of high-flow nasal cannula or AHRF and ARDS. A recent study has looked into biomarkers of noninvasive ventilation after extubation in patients at low or high risk for extubation failure (15). The implementation of these recommendations was very low in the patients included in the This article is open access and distributed under the terms of the present study. Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/). There is an urgent need for future randomized clinical trials For commercial usage and reprints, please contact Diane comparing the performance of pulmonary and blood biomarkers Gern (dgern@thoracic.org). combined with precise physiological criteria to guide ventilator Originally Published in Press as DOI: 10.1164/rccm.202101-0093ED management and to determine readiness for extubation in on January 27, 2021 patients with AHRF at high risk for extubation failure. The Editorials 1211 EDITORIALS present study from Alladina and colleagues is another important 6. Alladina JW, Levy SD, Hibbert KA, Januzzi JL, Harris RS, Matthay MA, piece in this field. 䊏 et al.; National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Network. Plasma concentrations of soluble soluble suppression of tumorigenicity-2 and IL-6 are predictive of successful Author disclosures are available with the text of this article at liberation from mechanical ventilation in patients with the acute www.atsjournals.org. respiratory distress syndrome. Crit Care Med 2016;44:1735–1743. 7. Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 s, M.D., Ph.D. Antonio Artigas Ravento receptor-related protein ST2 and induces T helper type 2-associated Critical Care Department cytokines. Immunity 2005;23:479–490. Autonomous University of Barcelona 8. Alladina J, Levy SD, Cho JL, Brait KL, Rao SR, Camacho A, et al. Plasma Sabadell, Spain soluble suppression of tumorigenicity-2 associates with ventilator Ary Serpa Neto, M.D., M.Sc., Ph.D. liberation in acute hypoxemic respiratory failure. Am J Respir Crit Care Australian and New Zealand Intensive Care Research Centre Med 2021;203:1257–1265. Monash University 9. Calfee CS, Ware LB, Glidden DV, Eisner MD, Parsons PE, Thompson BT, Melbourne, Victoria, Australia et al.; National Heart, Blood, and Lung Institute Acute Respiratory Distress Syndrome Network. Use of risk reclassification with multiple Data Analytics Research and Evaluation Centre biomarkers improves mortality prediction in acute lung injury. Crit Care Austin Hospital Med 2011;39:711–717. Heidelberg, Victoria, Australia 10. Ware LB, Koyama T, Zhao Z, Janz DR, Wickersham N, Bernard GR, Department of Critical Care et al. Biomarkers of lung epithelial injury and inflammation distinguish University of Melbourne severe sepsis patients with acute respiratory distress syndrome. Crit Heidelberg, Victoria, Australia Care 2013;17:R253. and 11. Jabaudon M, Blandonnet R, Roszyk L, Bouvier D, Audard J, Clairefond Department of Critical Care Medicine G, et al. Soluble receptor for advanced glycation end-products predicts Hospital Israelita Albert Einstein impaired alveolar fluid clearance in acute respiratory distress syndrome. ~ o Paulo, Brazil Sa Am J Respir Crit Care Med 2015;192:191–199. 12. Bos LD, Weda H, Wang Y, Knobel HH, Nijsen TM, Vink TJ, et al. Exhaled breath metabolomics as a noninvasive diagnostic tool for acute respiratory distress syndrome. Eur Respir J 2014;44:188–197. 13. Subira  C, Herna ndez G, Va zquez A, Rodrıguez-Garcıa R, Gonza lez- References Castro A, Garcıa C, et al. Effect of pressure support vs t-piece ventilation strategies during spontaneous breathing trials on successful 1. Thille AW, Cortes-Puch I, Esteban A. Weaning from the ventilator and extubation among patients receiving mechanical ventilation: a extubation in ICU. Curr Opin Crit Care 2013;19:57–64. randomized clinical trial. JAMA 2019;321:2175–2182. 2. Thille AW, Harrois A, Schortgen F, Brun-Buisson C, Brochard L. Outcomes lez-Castro A, Magret M, Bouza MT, Iban ~ez M, 14. Fernandez MM, Gonza of extubation failure in medical intensive care unit patients. Crit Care Garcıa C, et al. Reconnection to mechanical ventilation for 1 h after a Med 2011;39:2612–2618. 3. Frutos-Vivar F, Esteban A, Apezteguia C, Gonza  lez M, Arabi Y, Restrepo successful spontaneous breathing trial reduces reintubation in critically ill MI, et al. Outcome of reintubated patients after scheduled extubation. patients: a multicenter randomized controlled trial. Intensive Care Med J Crit Care 2011;26:502–509. 2017;43:1660–1667. 15. Hernandez G, Vaquero C, Colinas L, Cuena R, Gonza lez P, Canabal A, 4. Funk GC, Anders S, Breyer MK, Burghuber OC, Edelmann G, Heindl W, et al. Incidence and outcome of weaning from mechanical ventilation et al. Effect of postextubation high-flow nasal cannula vs noninvasive according to new categories. Eur Respir J 2010;35:88–94. ventilation on reintubation and postextubation respiratory failure in high- 5. Bajwa EK, Boyce PD, Januzzi JL, Gong MN, Thompson BT, Christiani DC. risk patients: a randomized clinical trial. JAMA 2016;316:1565–1574. Biomarker evidence of myocardial cell injury is associated with mortality in acute respiratory distress syndrome. Crit Care Med 2007;35:2484–2490. Copyright © 2021 by the American Thoracic Society Smoothing the Edges of Lung Protection Two deceptively simple tools for improving the gas exchange and simultaneously influence global lung mechanics, gas exchange, and mechanics of patients with the acute respiratory distress syndrome hemodynamics (2), our understanding of its regional actions in ARDS (ARDS)—positive end-expiratory pressure (PEEP) and prone and its relationship to body position has been slow to evolve. The early positioning—were brought to clinical attention nearly 50 years ago and elegant physiologic investigation of Suter and colleagues (1). Although the potential was soon recognized for PEEP to demonstrated that the PEEP associated with best tidal compliance during volume-controlled ventilation (lowest driving pressure) held simultaneous benefits for gas exchange efficiency and oxygen delivery. This article is open access and distributed under the terms of the At the time, lung protection against ventilator-induced lung injury Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/). was not a recognized priority, and by today’s standards, a large VT was For commercial usage and reprints, please contact Diane in use. It is interesting to note that the compliance-defined optimal Gern (dgern@thoracic.org). value of PEEP was first shown in that early era (3) to be a function of Originally Published in Press as DOI: 10.1164/rccm.202101-0111ED the VT delivered, a relationship that has been more recently confirmed on January 27, 2021 (4). In today’s routine practice, the effects of PEEP on the lung 1212 American Journal of Respiratory and Critical Care Medicine Volume 203 Number 10 | May 15 2021