Online Letters to the Editor
New Classification of Acute Respiratory Distress Syndrome: Not So Convincing To the Editor:
W
e read with interest the study by Villar et al (1) on the clinical classification of acute respiratory distress syndrome (ARDS). The authors have categorized ARDS based on Pao2/Fio2 ratio and the level of positive end-expiratory pressure after 24 hours of mechanical ventilation. Although the current classification may predict severe lung damage in a subset of patients, it is of limited utility in patient management unlike the lung injury score (LIS) (2). A reduction by greater than or equal to 1 point in LIS is associated with better clinical outcomes in patients when compared with patients who do not demonstrate an improvement in LIS; this may help in the choice of additional therapy in ARDS (3). The overall mortality in the current study was 46.3%, which is higher than the mortality rate in ARDS after application of the Acute Respiratory Distress Syndrome Network (ARDSNet) low tidal volume strategy, and is in fact even higher than the control arm of ARDSNet trial (39.8% vs 31%) (4) and other centers (5, 6). Furthermore, patients who died were significantly older than those who survived. This is important as elderly may not only behave differently from younger individuals but also have several comorbidities that may contribute to a higher mortality and prolonged need for ventilation and hospitalization (7, 8). Also, patients in group IV had a significantly higher Acute Physiology and Chronic Health Evaluation (APACHE) II score when compared with other groups of the study. Each unit increase in baseline ICU severity score is associated with an odds ratio of death of 1.18 (95% CI, 1.07–1.3) (9). Thus, the results of this study need validation across other centers due to the presence of several confounding factors (age, disease severity scores at baseline, trends in ARDS severity with duration of mechanical ventilation, pulmonary and extrapulmonary etiology of ARDS, and others). Finally, we would also be interested to know if the authors are able to reproduce their results after adjusting for confounding factors such as age and APACHE II score. The authors have disclosed that they do not have any potential conflicts of interest. Inderpaul Singh Sehgal, MD, DM, Ritesh Agarwal, MD, DM, Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
REFERENCES
1. Villar J, Fernández RL, Ambrós A, et al; Acute Lung Injury: Epidemiology and Natural history (ALIEN) Network; Acute Lung Injury Epidemiology and Natural history ALIEN Network: A Clinical Classification of the Acute Respiratory Distress Syndrome for Predicting Outcome and Guiding Medical Therapy. Crit Care Med 2015; 43:346–353 2. Murray JF, Matthay MA, Luce JM, et al: An expanded definition of the adult respiratory distress syndrome. Am Rev Respir Dis 1988; 138:720–723 3. Meduri GU, Golden E, Freire AX, et al: Methylprednisolone infusion in early severe ARDS: Results of a randomized controlled trial. Chest 2007; 131:954–963
e214
www.ccmjournal.org
4. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000; 342:1301–1308 5. Erickson SE, Martin GS, Davis JL, et al; NIH NHLBI ARDS Network: Recent trends in acute lung injury mortality: 1996-2005. Crit Care Med 2009; 37:1574–1579 6. Agarwal R, Srinivasan A, Aggarwal AN, et al: Adaptive support ventilation for complete ventilatory support in acute respiratory distress syndrome: A pilot, randomized controlled trial. Respirology 2013; 18:1108–1115 7. Martin GS, Mannino DM, Moss M: The effect of age on the development and outcome of adult sepsis. Crit Care Med 2006; 34:15–21 8. Ely EW, Wheeler AP, Thompson BT, et al: Recovery rate and prognosis in older persons who develop acute lung injury and the acute respiratory distress syndrome. Ann Intern Med 2002; 136:25–36 9. Agarwal R, Aggarwal AN, Gupta D, et al: Etiology and outcomes of pulmonary and extrapulmonary acute lung injury/ARDS in a respiratory ICU in North India. Chest 2006; 130:724–729 DOI: 10.1097/CCM.0000000000000918
The authors reply:
W
e thank Singh Sehgal and Agarwal (1) for their interest in our study (2). In 1977, Forrester et al (3, 4) classified 200 patients with acute myocardial infarction into four hemodynamic subsets based on a threshold value for cardiac index and pulmonary artery occlusion pressure. Although patients had a wide degree of variability in left ventricular function, the level of cardiac performance assessed by these two parameters showed a direct relation to hospital mortality. Those four subgroups were of substantial value because in addition to assessing short-term prognosis, each subgroup established a distinct level of optimal care. The management of patients with acute coronary artery disease has changed dramatically and mortality has decreased, but this classification is still in use because it predicts mortality for each subgroup of myocardial infarction, independently of the patient’s age, gender, precipitating factors, and location of the myocardial infarction. To this end, we investigated whether a threshold value of 150 mm Hg for Pao2/Fio2 and of 10 cmH2O for positive end-expiratory pressure (PEEP) would classify 300 patients with the acute respiratory distress syndrome (ARDS) into subsets for predicting outcome and guiding therapy, independent of age, gender, underlying disease, or specific therapy. In general, outcome of critically ill patients is worse with increasing age and Acute Physiology and Chronic Health Evaluation (APACHE) score, but we do not think that patient’s age and APACHE score should prevent clinicians from applying the appropriate ventilator management in patients with ARDS, as is true in patients with myocardial infarction! Our classification will help in identifying patients in whom benefit from treatment may be limited or disproportional to the resources used. Also, our classification system could facilitate the standardization of future epidemiological studies, clinical trials, clinical practice, and reporting outcome when focusing on a given group. Clearly, the selection of therapy for an individual patient with ARDS involves both assessment of the degree of respiratory dysfunction, as measured by Pao2/Fio2 June 2015 • Volume 43 • Number 6
Copyright © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Online Letters to the Editor
after 24 hours of routine clinical care, and evaluation of the response to PEEP therapy. ARDS categorization should be simple and quickly assessed at the bedside by calculating the Pao2/ Fio2 ratio as an indicator of treatment effect in clinical trials of therapies thought to have greater impact in sicker patients with ARDS (5). The lung injury severity score (LISS) has been and continues to be used in many reports, but it has not been validated, it is not clear whether patients with identical LISS have similar degrees of lung injury and the same prognosis, it does not consider the effects of time on the designation of severity, and it is not specific for ARDS. The combined in-hospital mortality rate of our cohort of patients with moderate and severe ARDS (46.3%) is in the range of recent reports in which the pooled mortality for moderate and severe ARDS in observational studies ranged between 44% and 55% (6, 7). It is important to remember that regardless of the number of patients enrolled in ARDS randomized controlled trials (RCTs), the enrolled number represents only a small portion of the patients with ARDS requiring treatment. The reported mortality rates for ARDS in RCTs do not represent true disease mortality. Among other considerations, these studies do not include all consecutive patients with ARDS admitted into the ICU, as we did in our study. The strict inclusion and exclusion criteria eliminate patients with the highest probability of death, the very patients clinicians are obliged to treat (8). Currently, we are in a process of validating this simple and highly predictive classification tool for identifying four distinct clinical subsets of patients with ARDS, independent of age, gender, and precipitating factors. The authors have disclosed that they do not have any potential conflicts of interest. Jesús Villar, MD, PhD, FCCM, CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain and Research Unit, Hospital Universitario Dr. Negrín, Las Palmas de Gran Canaria, Spain; Robert M. Kacmarek, PhD, RTT, Department of Respiratory Care, Massachusetts General Hospital, Boston, MA and Department of Anesthesiology, Harvard University, Boston, MA
REFERENCES
1. Singh Sehgal I, Agarwal R: New Classification of Acute Respiratory Distress Syndrome: Not So Convincing. Crit Care Med 2015; 43:e214 2. Villar J, Fernández RL, Ambrós A, et al; Acute Lung Injury: Epidemiology and Natural history (ALIEN) Network; Acute Lung Injury Epidemiology and Natural history ALIEN Network: A clinical classification of the acute respiratory distress syndrome for predicting outcome and guiding medical therapy*. Crit Care Med 2015; 43:346–353 3. Forrester JS, Diamond G, Chatterjee K, et al: Medical therapy of acute myocardial infarction by application of hemodynamic subsets (first of two parts). N Engl J Med 1976; 295:1356–1362 4. Forrester JS, Diamond GA, Swan HJ: Correlative classification of clinical and hemodynamic function after acute myocardial infarction. Am J Cardiol 1977; 39:137–145 5. Cooke CR: The siren song of simple tools that predict mortality. Respir Care 2011; 56:533–535 6. Phua J, Badia JR, Adhikari NK, et al: Has mortality from acute respiratory distress syndrome decreased over time? A systematic review. Am J Respir Crit Care Med 2009; 179:220–227
Critical Care Medicine
7. Caser EB, Zandonade E, Pereira E, et al: Impact of distinct definitions of acute lung injury on its incidence and outcomes in Brazilian ICUs: Prospective evaluation of 7,133 patients*. Crit Care Med 2014; 42:574–582 8. Villar J, Pérez-Méndez L, Aguirre-Jaime A, et al: Why are physicians so skeptical about positive randomized controlled clinical trials in critical care medicine? Intensive Care Med 2005; 31:196–204 DOI: 10.1097/CCM.0000000000000983
Oxygenation During High-Flow Nasal Cannula in Tracheal Intubation: Do We Know the “Red Desaturation Line”? To the Editor:
P
reoxygenation techniques are essential for minimizing the risk of critical hypoxia during emergency airway management (1). Therefore, we have read with interest the recently published study by Miguel-Montanes et al (2), which compares preoxygenation via nonrebreathing bag reservoir mask (NRM) in the control period with a highflow nasal cannula (HFNC) preoxygenation in the “change of practice” period. Although the study was nonrandomized, we consider it an important proof of principle that HFNC can maintain oxygenation throughout the peri-intubation period. We wish to raise several considerations related to this study. The HFNC technique may maintain oxygenation by a number of possible mechanisms. Compared with NRM, the HFNC can provide increased airflow as well as alveolar recruitment by creating positive end-expiratory pressure (PEEP). The Fio2 delivered by NRM and HFNC will vary significantly depending on the pattern and rate of inspiratory flow created by the patient’s effort. HFNC systems provide a low PEEP (< 4 cm H2O) but are highly dependent on mouth closing (3). As HFNC technique can provide apneic oxygenation during the peri-intubation period as well, it is not possible to know the relative contributions of high flow, PEEP, and apneic oxygenation in the present study. Independent from the exact mechanism of its action, the real benefits of HFNC should be seen in patients with severe hypoxemic respiratory failure, the group of patients excluded from this study (2). Other strategies may also provide recruitment throughout the intubation. We have previously reported the use of nasal NIPPV during intubation in patients with severe hypoxemic respiratory failure dependent on external PEEP prior to intubation (4). Noninvasive positive pressure ventilation during preoxygenation or other forms of apneic oxygenation may also be equally effective (1). Therefore, we encourage additional research to understand the mechanism of HFNC during intubation and identify which patient subpopulations may benefit from it or alternative oxygenation strategies. The authors received support for article research from the National Institutes of Health and the Research Councils UK. Antonio M. Esquinas, MD, PhD, FCCP, Intensive Care Unit, Hospital Morales Meseguer, Murcia, Spain; David A. Berlin, MD, Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, Cornell University, www.ccmjournal.org
Copyright © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
e215
New Classification of Acute Respiratory Distress Syndrome: Not So Convincing To the Editor:
W
e read with interest the study by Villar et al (1) on the clinical classification of acute respiratory distress syndrome (ARDS). The authors have categorized ARDS based on Pao2/Fio2 ratio and the level of positive end-expiratory pressure after 24 hours of mechanical ventilation. Although the current classification may predict severe lung damage in a subset of patients, it is of limited utility in patient management unlike the lung injury score (LIS) (2). A reduction by greater than or equal to 1 point in LIS is associated with better clinical outcomes in patients when compared with patients who do not demonstrate an improvement in LIS; this may help in the choice of additional therapy in ARDS (3). The overall mortality in the current study was 46.3%, which is higher than the mortality rate in ARDS after application of the Acute Respiratory Distress Syndrome Network (ARDSNet) low tidal volume strategy, and is in fact even higher than the control arm of ARDSNet trial (39.8% vs 31%) (4) and other centers (5, 6). Furthermore, patients who died were significantly older than those who survived. This is important as elderly may not only behave differently from younger individuals but also have several comorbidities that may contribute to a higher mortality and prolonged need for ventilation and hospitalization (7, 8). Also, patients in group IV had a significantly higher Acute Physiology and Chronic Health Evaluation (APACHE) II score when compared with other groups of the study. Each unit increase in baseline ICU severity score is associated with an odds ratio of death of 1.18 (95% CI, 1.07–1.3) (9). Thus, the results of this study need validation across other centers due to the presence of several confounding factors (age, disease severity scores at baseline, trends in ARDS severity with duration of mechanical ventilation, pulmonary and extrapulmonary etiology of ARDS, and others). Finally, we would also be interested to know if the authors are able to reproduce their results after adjusting for confounding factors such as age and APACHE II score. The authors have disclosed that they do not have any potential conflicts of interest. Inderpaul Singh Sehgal, MD, DM, Ritesh Agarwal, MD, DM, Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
REFERENCES
1. Villar J, Fernández RL, Ambrós A, et al; Acute Lung Injury: Epidemiology and Natural history (ALIEN) Network; Acute Lung Injury Epidemiology and Natural history ALIEN Network: A Clinical Classification of the Acute Respiratory Distress Syndrome for Predicting Outcome and Guiding Medical Therapy. Crit Care Med 2015; 43:346–353 2. Murray JF, Matthay MA, Luce JM, et al: An expanded definition of the adult respiratory distress syndrome. Am Rev Respir Dis 1988; 138:720–723 3. Meduri GU, Golden E, Freire AX, et al: Methylprednisolone infusion in early severe ARDS: Results of a randomized controlled trial. Chest 2007; 131:954–963
e214
www.ccmjournal.org
4. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000; 342:1301–1308 5. Erickson SE, Martin GS, Davis JL, et al; NIH NHLBI ARDS Network: Recent trends in acute lung injury mortality: 1996-2005. Crit Care Med 2009; 37:1574–1579 6. Agarwal R, Srinivasan A, Aggarwal AN, et al: Adaptive support ventilation for complete ventilatory support in acute respiratory distress syndrome: A pilot, randomized controlled trial. Respirology 2013; 18:1108–1115 7. Martin GS, Mannino DM, Moss M: The effect of age on the development and outcome of adult sepsis. Crit Care Med 2006; 34:15–21 8. Ely EW, Wheeler AP, Thompson BT, et al: Recovery rate and prognosis in older persons who develop acute lung injury and the acute respiratory distress syndrome. Ann Intern Med 2002; 136:25–36 9. Agarwal R, Aggarwal AN, Gupta D, et al: Etiology and outcomes of pulmonary and extrapulmonary acute lung injury/ARDS in a respiratory ICU in North India. Chest 2006; 130:724–729 DOI: 10.1097/CCM.0000000000000918
The authors reply:
W
e thank Singh Sehgal and Agarwal (1) for their interest in our study (2). In 1977, Forrester et al (3, 4) classified 200 patients with acute myocardial infarction into four hemodynamic subsets based on a threshold value for cardiac index and pulmonary artery occlusion pressure. Although patients had a wide degree of variability in left ventricular function, the level of cardiac performance assessed by these two parameters showed a direct relation to hospital mortality. Those four subgroups were of substantial value because in addition to assessing short-term prognosis, each subgroup established a distinct level of optimal care. The management of patients with acute coronary artery disease has changed dramatically and mortality has decreased, but this classification is still in use because it predicts mortality for each subgroup of myocardial infarction, independently of the patient’s age, gender, precipitating factors, and location of the myocardial infarction. To this end, we investigated whether a threshold value of 150 mm Hg for Pao2/Fio2 and of 10 cmH2O for positive end-expiratory pressure (PEEP) would classify 300 patients with the acute respiratory distress syndrome (ARDS) into subsets for predicting outcome and guiding therapy, independent of age, gender, underlying disease, or specific therapy. In general, outcome of critically ill patients is worse with increasing age and Acute Physiology and Chronic Health Evaluation (APACHE) score, but we do not think that patient’s age and APACHE score should prevent clinicians from applying the appropriate ventilator management in patients with ARDS, as is true in patients with myocardial infarction! Our classification will help in identifying patients in whom benefit from treatment may be limited or disproportional to the resources used. Also, our classification system could facilitate the standardization of future epidemiological studies, clinical trials, clinical practice, and reporting outcome when focusing on a given group. Clearly, the selection of therapy for an individual patient with ARDS involves both assessment of the degree of respiratory dysfunction, as measured by Pao2/Fio2 June 2015 • Volume 43 • Number 6
Copyright © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Online Letters to the Editor
after 24 hours of routine clinical care, and evaluation of the response to PEEP therapy. ARDS categorization should be simple and quickly assessed at the bedside by calculating the Pao2/ Fio2 ratio as an indicator of treatment effect in clinical trials of therapies thought to have greater impact in sicker patients with ARDS (5). The lung injury severity score (LISS) has been and continues to be used in many reports, but it has not been validated, it is not clear whether patients with identical LISS have similar degrees of lung injury and the same prognosis, it does not consider the effects of time on the designation of severity, and it is not specific for ARDS. The combined in-hospital mortality rate of our cohort of patients with moderate and severe ARDS (46.3%) is in the range of recent reports in which the pooled mortality for moderate and severe ARDS in observational studies ranged between 44% and 55% (6, 7). It is important to remember that regardless of the number of patients enrolled in ARDS randomized controlled trials (RCTs), the enrolled number represents only a small portion of the patients with ARDS requiring treatment. The reported mortality rates for ARDS in RCTs do not represent true disease mortality. Among other considerations, these studies do not include all consecutive patients with ARDS admitted into the ICU, as we did in our study. The strict inclusion and exclusion criteria eliminate patients with the highest probability of death, the very patients clinicians are obliged to treat (8). Currently, we are in a process of validating this simple and highly predictive classification tool for identifying four distinct clinical subsets of patients with ARDS, independent of age, gender, and precipitating factors. The authors have disclosed that they do not have any potential conflicts of interest. Jesús Villar, MD, PhD, FCCM, CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain and Research Unit, Hospital Universitario Dr. Negrín, Las Palmas de Gran Canaria, Spain; Robert M. Kacmarek, PhD, RTT, Department of Respiratory Care, Massachusetts General Hospital, Boston, MA and Department of Anesthesiology, Harvard University, Boston, MA
REFERENCES
1. Singh Sehgal I, Agarwal R: New Classification of Acute Respiratory Distress Syndrome: Not So Convincing. Crit Care Med 2015; 43:e214 2. Villar J, Fernández RL, Ambrós A, et al; Acute Lung Injury: Epidemiology and Natural history (ALIEN) Network; Acute Lung Injury Epidemiology and Natural history ALIEN Network: A clinical classification of the acute respiratory distress syndrome for predicting outcome and guiding medical therapy*. Crit Care Med 2015; 43:346–353 3. Forrester JS, Diamond G, Chatterjee K, et al: Medical therapy of acute myocardial infarction by application of hemodynamic subsets (first of two parts). N Engl J Med 1976; 295:1356–1362 4. Forrester JS, Diamond GA, Swan HJ: Correlative classification of clinical and hemodynamic function after acute myocardial infarction. Am J Cardiol 1977; 39:137–145 5. Cooke CR: The siren song of simple tools that predict mortality. Respir Care 2011; 56:533–535 6. Phua J, Badia JR, Adhikari NK, et al: Has mortality from acute respiratory distress syndrome decreased over time? A systematic review. Am J Respir Crit Care Med 2009; 179:220–227
Critical Care Medicine
7. Caser EB, Zandonade E, Pereira E, et al: Impact of distinct definitions of acute lung injury on its incidence and outcomes in Brazilian ICUs: Prospective evaluation of 7,133 patients*. Crit Care Med 2014; 42:574–582 8. Villar J, Pérez-Méndez L, Aguirre-Jaime A, et al: Why are physicians so skeptical about positive randomized controlled clinical trials in critical care medicine? Intensive Care Med 2005; 31:196–204 DOI: 10.1097/CCM.0000000000000983
Oxygenation During High-Flow Nasal Cannula in Tracheal Intubation: Do We Know the “Red Desaturation Line”? To the Editor:
P
reoxygenation techniques are essential for minimizing the risk of critical hypoxia during emergency airway management (1). Therefore, we have read with interest the recently published study by Miguel-Montanes et al (2), which compares preoxygenation via nonrebreathing bag reservoir mask (NRM) in the control period with a highflow nasal cannula (HFNC) preoxygenation in the “change of practice” period. Although the study was nonrandomized, we consider it an important proof of principle that HFNC can maintain oxygenation throughout the peri-intubation period. We wish to raise several considerations related to this study. The HFNC technique may maintain oxygenation by a number of possible mechanisms. Compared with NRM, the HFNC can provide increased airflow as well as alveolar recruitment by creating positive end-expiratory pressure (PEEP). The Fio2 delivered by NRM and HFNC will vary significantly depending on the pattern and rate of inspiratory flow created by the patient’s effort. HFNC systems provide a low PEEP (< 4 cm H2O) but are highly dependent on mouth closing (3). As HFNC technique can provide apneic oxygenation during the peri-intubation period as well, it is not possible to know the relative contributions of high flow, PEEP, and apneic oxygenation in the present study. Independent from the exact mechanism of its action, the real benefits of HFNC should be seen in patients with severe hypoxemic respiratory failure, the group of patients excluded from this study (2). Other strategies may also provide recruitment throughout the intubation. We have previously reported the use of nasal NIPPV during intubation in patients with severe hypoxemic respiratory failure dependent on external PEEP prior to intubation (4). Noninvasive positive pressure ventilation during preoxygenation or other forms of apneic oxygenation may also be equally effective (1). Therefore, we encourage additional research to understand the mechanism of HFNC during intubation and identify which patient subpopulations may benefit from it or alternative oxygenation strategies. The authors received support for article research from the National Institutes of Health and the Research Councils UK. Antonio M. Esquinas, MD, PhD, FCCP, Intensive Care Unit, Hospital Morales Meseguer, Murcia, Spain; David A. Berlin, MD, Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, Cornell University, www.ccmjournal.org
Copyright © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
e215
