Editorials
seasonal one, the same old challenges of critical care medicine exist and improvements in supportive care, modes of ventilation, and treatment of SIRS, sepsis, and multiple organ dysfunction will likely have the greatest impact on reducing ICU morbidity and mortality.
REFERENCES
1. Gao R, Cao B, Hu Y, et al: Human infection with a novel avian-origin influenza A (H7N9) virus. N Engl J Med 2013; 368:1888–1897 2. Yang Y, Guo F, Zhao W, et al: Novel Avian-Origin Influenza A (H7N9) in Critically Ill Patients in China. Crit Care Med 2015; 43:339–345 3. Su S, Chaves SS, Perez A, et al: Comparing clinical characteristics between hospitalized adults with laboratory-confirmed influenza A and B virus infection. Clin Infect Dis 2014; 59:252–255 4. Hu J, Zhu Y, Zhao B, et al: Limited human-to-human transmission of avian influenza A(H7N9) virus, Shanghai, China, March to April 2013. Euro Surveill 2014; 19:20838 5. Qiu C, Yuan S, Tian D, et al: Epidemiologic report and serologic findings for household contacts of three cases of influenza A (H7N9) virus infection. J Clin Virol 2014; 59:129–131
6. Zeng X, Mai W, Shu B, et al: Mild influenza A/H7N9 infection among children in Guangdong Province. Pediatr Infect Dis J 2014 Jul 25. [Epub ahead of print] 7. Cowling BJ, Jin L, Lau EH, et al: Comparative epidemiology of human infections with avian influenza A H7N9 and H5N1 viruses in China: A population-based study of laboratory-confirmed cases. Lancet 2013; 382:129–137 8. Gao HN, Lu HZ, Cao B, et al: Clinical findings in 111 cases of influenza A (H7N9) virus infection. N Engl J Med 2013; 368:2277–2285 9. Centers for Disease Control and Prevention: Bacterial coinfections in lung tissue specimens from fatal cases of 2009 pandemic influenza A (H1N1) - United States, May-August 2009. MMWR Morb Mortal Wkly Rep 2009; 58:1071–1074 10. Morens DM, Taubenberger JK, Fauci AS: Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: Implications for pandemic influenza preparedness. J Infect Dis 2008; 198:962–970 11. García-Vázquez E, Marcos MA, Mensa J, et al: Assessment of the usefulness of sputum culture for diagnosis of community-acquired pneumonia using the PORT predictive scoring system. Arch Intern Med 2004; 164:1807–1811 12. Martin-Loeches I, Díaz E, Vidaur L, et al; H1N1 SEMICYUC/REIPI/ CIBERES Working Group: Pandemic and post-pandemic influenza A (H1N1) infection in critically ill patients. Crit Care 2011; 15:R286
The Pao2/Fio2 Ratio Categorization of Patients With Acute Respiratory Distress Syndrome Is Suboptimal* Michael J. Lanspa, MD Alan H. Morris, MD Pulmonary and Critical Care Division, Department of Medicine Intermountain Medical Center and University of Utah School of Medicine Salt Lake City, UT
I
n this issue of Critical Care Medicine, Villar et al (1) explore the relationship of Pao2/Fio2, positive end-expiratory pressure (PEEP), and mortality in patients with acute respiratory distress syndrome (ARDS). This multicenter study categorized patients into four groups based on thresholds of Pao2/Fio2 of 150 mm Hg and PEEP of 10 cm H2O. At the onset *See also p. 346. Key Words: acute respiratory distress syndrome; categorization; Pao2/Fio2; short-term response to ICU care Dr. Morris’ institution received grant support from the National Institutes of Health (NIH/National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Network funding). Dr. Lanspa has disclosed that he does not have any potential conflicts of interest. Drs. Lanspa and Morris participated in the conceptualization and design, data acquisition, analysis, and interpretation. They participated in drafting the work and revising it for important intellectual content. They approved the final version and are accountable for all aspects of the work including accuracy and integrity. Copyright © 2015 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.0000000000000816
488
www.ccmjournal.org
of ARDS, Villar et al (1) found no difference in hospital mortality for multiple analyses of data, with one exception: those with a Pao2/Fio2 less than 150 had greater hospital mortality. By contrast, the mortalities of the four groups were different after 24 hours of ICU care. These groups were also different in regard to Acute Physiology and Chronic Health Evaluation II scores, numbers of organ failures, plateau pressures, Fio2, and days of mechanical ventilation. Villar et al (1) concluded that response to 24 hours of ICU care allows distinction of important subgroups of patients with ARDS with different mortalities. This study has many virtues. Patient enrollment was prospective. The entry criteria were explicit and in accordance with the American-European Consensus Conference definition (2), although this definition has been abandoned in favor of the Berlin Definition (3). Clinicians were instructed to adopt lungprotective mechanical ventilation strategies and to obtain representative Pao2/Fio2 measurements instead of those stemming from acute events unrelated to the disease. However, clinician compliance was not assessed, and this remains a methodological limitation. Based on the conclusions of Villar et al (1), it might appear that we should wait 24 hours to distinguish subgroups of ARDS for future investigation or tailoring treatment. Perhaps we would get even greater separation of groups if we were to wait 48 hours or 1 week. The relationship between Pao2/Fio2, PEEP, and mortality will likely be even stronger in the hour immediately preceding death or preceding liberation from mechanical ventilation. Such reductio ad absurdum argument February 2015 • Volume 43 • Number 2
Editorials
is meant to illustrate that a measurement that occurs well after the disease identification (and occasionally after an outcome of interest) is of limited utility for clinical decision making at the time of identification. Measurement of Pao2/Fio2 at 24 hours will be of small help to the patient who dies within 24 hours. ARDS is a syndrome already fraught with problems of leadtime bias because the onset of disease precedes the fulfillment of ARDS criteria for an unknown period of time. A more reasonable conclusion to take away from the study of Villar et al (1) is that our current method of grading the severity of ARDS by Pao2/Fio2 is less reliable at the onset of disease than later in the course of the disease. We should acknowledge that severity may change within hours. Villar et al (1) demonstrate that ARDS is a heterogenous disease that evolves over time. They demonstrate that assessment at 24 hours may better approximate the course of the disease than assessment at the time the patient meets the criteria for ARDS. Of great clinical interest is whether any association exists between clinical outcome and the patient’s specific evolution of ARDS severity over 24 hours, a question unanswered in the study by Villar et al (1). Were the patients recategorized from group 3 (low Pao2/Fio2, low PEEP) to group 2 (high Pao2/Fio2, high PEEP) associated with different clinically important outcome changes? Were these outcome changes different from those recategorized from group 1 (high Pao2/Fio2, low PEEP) to group 2? It appears that the greatest amount of recategorization occurred from group 3 to group 2. This suggests that several patients may have been receiving inappropriately low PEEP when ARDS was identified. Villar et al (1), after reviewing their results, recommend that therapy should be focused on moving patients into a classification with better survival, by increasing PEEP greater than 10 in a patient with Pao2/Fio2 less than 150 mm Hg. Although their data do not directly support such a recommendation, this is a very reasonable inference from both their study and the physiologic goal of recruiting consolidated and atelectatic alveoli. As this recommendation is not novel, it is surprising that any patients at all in their study fell into the group with low Pao2/Fio2 and low PEEP at the 24-hour mark. The Berlin definition, perhaps in an attempt to simplify diagnosis, grades the severity ARDS by the Pao2/Fio2. Yet the Pao2/Fio2 is not constant across a range of Fio2 and may vary in response to ventilator settings, particularly PEEP (4, 5). Villar et al (1) demonstrate that PEEP is an important variable to consider when grading severity of ARDS. The Berlin definition of ARDS does not recognize that a patient with ARDS with a Pao2/Fio2 of 150 mm Hg at a PEEP of 15 cm H2O has greater lung disease than a patient with the same Pao2/Fio2 at a PEEP of 5 cm H2O. Both academic investigators and bedside clinicians need a better method of grading the severity of ARDS. It
Critical Care Medicine
is evident that the Pao2/Fio2 is suboptimal. Perhaps a method that incorporates both Pao2/Fio2 and airway pressure, such as the oxygenation index, is preferable (6). It is unsurprising that patients with ARDS with greater lung disease are more likely to die. Yet, after decades of research, we still do not have a reliable method to measure the amount of lung disease in these patients when they present with ARDS. We need a better categorization method in order to target patientspecific therapies. Therapies, such as recruitment maneuvers, prone positioning, or extracorporeal lung assist, might work best in patients with low Pao2/Fio2 despite high PEEP. Prone positioning was not associated with better patient outcomes when applied to a larger group of patients with ARDS (7) but was associated with survival improvement in patients with Pao2/Fio2 less than 150 mm Hg (8). The study by Villar et al (1) provides valuable illumination of our current method of assessing ARDS, but we still need a better method of assessing lung severity. Their distinction between survival of different categories after 24 hours of care versus the survival at the time of ARDS identification underscores the importance of evaluating ARDS patient response to treatment. What kind of response to what kind of care, for what period of time, remains unknown and a challenge. Future investigation may be strengthened by a definition that recognizes the evolution of lung disease throughout the course of ARDS, but this will likely depend on the experimental question and methodology.
REFERENCES
1. Villar J, Fernández RL, Ambrós A, et al; for the 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. Bernard GR, Artigas A, Brigham KL, et al: The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994; 149(3, Part 1):818–824 3. Ranieri VM, Rubenfeld GD, Thompson BT, et al; ARDS Definition Task Force: Acute respiratory distress syndrome: The Berlin Definition. JAMA 2012; 307:2526–2533 4. Gowda MS, Klocke RA: Variability of indices of hypoxemia in adult respiratory distress syndrome. Crit Care Med 1997; 25:41–45 5. Ferguson ND, Kacmarek RM, Chiche JD, et al: Screening of ARDS patients using standardized ventilator settings: Influence on enrollment in a clinical trial. Intensive Care Med 2004; 30:1111–1116 6. El-Khatib MF, Jamaleddine GW: A new oxygenation index for reflecting intrapulmonary shunting in patients undergoing open-heart surgery. Chest 2004; 125:592–596 7. Gattinoni L, Tognoni G, Pesenti A, et al; Prone-Supine Study Group: Effect of prone positioning on the survival of patients with acute respiratory failure. N Engl J Med 2001; 345:568–573 8. Guérin C, Reignier J, Richard JC, et al; PROSEVA Study Group: Prone positioning in severe acute respiratory distress syndrome. N Engl J Med 2013; 368:2159–2168
www.ccmjournal.org
489
Copyright of Critical Care Medicine is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
seasonal one, the same old challenges of critical care medicine exist and improvements in supportive care, modes of ventilation, and treatment of SIRS, sepsis, and multiple organ dysfunction will likely have the greatest impact on reducing ICU morbidity and mortality.
REFERENCES
1. Gao R, Cao B, Hu Y, et al: Human infection with a novel avian-origin influenza A (H7N9) virus. N Engl J Med 2013; 368:1888–1897 2. Yang Y, Guo F, Zhao W, et al: Novel Avian-Origin Influenza A (H7N9) in Critically Ill Patients in China. Crit Care Med 2015; 43:339–345 3. Su S, Chaves SS, Perez A, et al: Comparing clinical characteristics between hospitalized adults with laboratory-confirmed influenza A and B virus infection. Clin Infect Dis 2014; 59:252–255 4. Hu J, Zhu Y, Zhao B, et al: Limited human-to-human transmission of avian influenza A(H7N9) virus, Shanghai, China, March to April 2013. Euro Surveill 2014; 19:20838 5. Qiu C, Yuan S, Tian D, et al: Epidemiologic report and serologic findings for household contacts of three cases of influenza A (H7N9) virus infection. J Clin Virol 2014; 59:129–131
6. Zeng X, Mai W, Shu B, et al: Mild influenza A/H7N9 infection among children in Guangdong Province. Pediatr Infect Dis J 2014 Jul 25. [Epub ahead of print] 7. Cowling BJ, Jin L, Lau EH, et al: Comparative epidemiology of human infections with avian influenza A H7N9 and H5N1 viruses in China: A population-based study of laboratory-confirmed cases. Lancet 2013; 382:129–137 8. Gao HN, Lu HZ, Cao B, et al: Clinical findings in 111 cases of influenza A (H7N9) virus infection. N Engl J Med 2013; 368:2277–2285 9. Centers for Disease Control and Prevention: Bacterial coinfections in lung tissue specimens from fatal cases of 2009 pandemic influenza A (H1N1) - United States, May-August 2009. MMWR Morb Mortal Wkly Rep 2009; 58:1071–1074 10. Morens DM, Taubenberger JK, Fauci AS: Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: Implications for pandemic influenza preparedness. J Infect Dis 2008; 198:962–970 11. García-Vázquez E, Marcos MA, Mensa J, et al: Assessment of the usefulness of sputum culture for diagnosis of community-acquired pneumonia using the PORT predictive scoring system. Arch Intern Med 2004; 164:1807–1811 12. Martin-Loeches I, Díaz E, Vidaur L, et al; H1N1 SEMICYUC/REIPI/ CIBERES Working Group: Pandemic and post-pandemic influenza A (H1N1) infection in critically ill patients. Crit Care 2011; 15:R286
The Pao2/Fio2 Ratio Categorization of Patients With Acute Respiratory Distress Syndrome Is Suboptimal* Michael J. Lanspa, MD Alan H. Morris, MD Pulmonary and Critical Care Division, Department of Medicine Intermountain Medical Center and University of Utah School of Medicine Salt Lake City, UT
I
n this issue of Critical Care Medicine, Villar et al (1) explore the relationship of Pao2/Fio2, positive end-expiratory pressure (PEEP), and mortality in patients with acute respiratory distress syndrome (ARDS). This multicenter study categorized patients into four groups based on thresholds of Pao2/Fio2 of 150 mm Hg and PEEP of 10 cm H2O. At the onset *See also p. 346. Key Words: acute respiratory distress syndrome; categorization; Pao2/Fio2; short-term response to ICU care Dr. Morris’ institution received grant support from the National Institutes of Health (NIH/National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Network funding). Dr. Lanspa has disclosed that he does not have any potential conflicts of interest. Drs. Lanspa and Morris participated in the conceptualization and design, data acquisition, analysis, and interpretation. They participated in drafting the work and revising it for important intellectual content. They approved the final version and are accountable for all aspects of the work including accuracy and integrity. Copyright © 2015 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.0000000000000816
488
www.ccmjournal.org
of ARDS, Villar et al (1) found no difference in hospital mortality for multiple analyses of data, with one exception: those with a Pao2/Fio2 less than 150 had greater hospital mortality. By contrast, the mortalities of the four groups were different after 24 hours of ICU care. These groups were also different in regard to Acute Physiology and Chronic Health Evaluation II scores, numbers of organ failures, plateau pressures, Fio2, and days of mechanical ventilation. Villar et al (1) concluded that response to 24 hours of ICU care allows distinction of important subgroups of patients with ARDS with different mortalities. This study has many virtues. Patient enrollment was prospective. The entry criteria were explicit and in accordance with the American-European Consensus Conference definition (2), although this definition has been abandoned in favor of the Berlin Definition (3). Clinicians were instructed to adopt lungprotective mechanical ventilation strategies and to obtain representative Pao2/Fio2 measurements instead of those stemming from acute events unrelated to the disease. However, clinician compliance was not assessed, and this remains a methodological limitation. Based on the conclusions of Villar et al (1), it might appear that we should wait 24 hours to distinguish subgroups of ARDS for future investigation or tailoring treatment. Perhaps we would get even greater separation of groups if we were to wait 48 hours or 1 week. The relationship between Pao2/Fio2, PEEP, and mortality will likely be even stronger in the hour immediately preceding death or preceding liberation from mechanical ventilation. Such reductio ad absurdum argument February 2015 • Volume 43 • Number 2
Editorials
is meant to illustrate that a measurement that occurs well after the disease identification (and occasionally after an outcome of interest) is of limited utility for clinical decision making at the time of identification. Measurement of Pao2/Fio2 at 24 hours will be of small help to the patient who dies within 24 hours. ARDS is a syndrome already fraught with problems of leadtime bias because the onset of disease precedes the fulfillment of ARDS criteria for an unknown period of time. A more reasonable conclusion to take away from the study of Villar et al (1) is that our current method of grading the severity of ARDS by Pao2/Fio2 is less reliable at the onset of disease than later in the course of the disease. We should acknowledge that severity may change within hours. Villar et al (1) demonstrate that ARDS is a heterogenous disease that evolves over time. They demonstrate that assessment at 24 hours may better approximate the course of the disease than assessment at the time the patient meets the criteria for ARDS. Of great clinical interest is whether any association exists between clinical outcome and the patient’s specific evolution of ARDS severity over 24 hours, a question unanswered in the study by Villar et al (1). Were the patients recategorized from group 3 (low Pao2/Fio2, low PEEP) to group 2 (high Pao2/Fio2, high PEEP) associated with different clinically important outcome changes? Were these outcome changes different from those recategorized from group 1 (high Pao2/Fio2, low PEEP) to group 2? It appears that the greatest amount of recategorization occurred from group 3 to group 2. This suggests that several patients may have been receiving inappropriately low PEEP when ARDS was identified. Villar et al (1), after reviewing their results, recommend that therapy should be focused on moving patients into a classification with better survival, by increasing PEEP greater than 10 in a patient with Pao2/Fio2 less than 150 mm Hg. Although their data do not directly support such a recommendation, this is a very reasonable inference from both their study and the physiologic goal of recruiting consolidated and atelectatic alveoli. As this recommendation is not novel, it is surprising that any patients at all in their study fell into the group with low Pao2/Fio2 and low PEEP at the 24-hour mark. The Berlin definition, perhaps in an attempt to simplify diagnosis, grades the severity ARDS by the Pao2/Fio2. Yet the Pao2/Fio2 is not constant across a range of Fio2 and may vary in response to ventilator settings, particularly PEEP (4, 5). Villar et al (1) demonstrate that PEEP is an important variable to consider when grading severity of ARDS. The Berlin definition of ARDS does not recognize that a patient with ARDS with a Pao2/Fio2 of 150 mm Hg at a PEEP of 15 cm H2O has greater lung disease than a patient with the same Pao2/Fio2 at a PEEP of 5 cm H2O. Both academic investigators and bedside clinicians need a better method of grading the severity of ARDS. It
Critical Care Medicine
is evident that the Pao2/Fio2 is suboptimal. Perhaps a method that incorporates both Pao2/Fio2 and airway pressure, such as the oxygenation index, is preferable (6). It is unsurprising that patients with ARDS with greater lung disease are more likely to die. Yet, after decades of research, we still do not have a reliable method to measure the amount of lung disease in these patients when they present with ARDS. We need a better categorization method in order to target patientspecific therapies. Therapies, such as recruitment maneuvers, prone positioning, or extracorporeal lung assist, might work best in patients with low Pao2/Fio2 despite high PEEP. Prone positioning was not associated with better patient outcomes when applied to a larger group of patients with ARDS (7) but was associated with survival improvement in patients with Pao2/Fio2 less than 150 mm Hg (8). The study by Villar et al (1) provides valuable illumination of our current method of assessing ARDS, but we still need a better method of assessing lung severity. Their distinction between survival of different categories after 24 hours of care versus the survival at the time of ARDS identification underscores the importance of evaluating ARDS patient response to treatment. What kind of response to what kind of care, for what period of time, remains unknown and a challenge. Future investigation may be strengthened by a definition that recognizes the evolution of lung disease throughout the course of ARDS, but this will likely depend on the experimental question and methodology.
REFERENCES
1. Villar J, Fernández RL, Ambrós A, et al; for the 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. Bernard GR, Artigas A, Brigham KL, et al: The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994; 149(3, Part 1):818–824 3. Ranieri VM, Rubenfeld GD, Thompson BT, et al; ARDS Definition Task Force: Acute respiratory distress syndrome: The Berlin Definition. JAMA 2012; 307:2526–2533 4. Gowda MS, Klocke RA: Variability of indices of hypoxemia in adult respiratory distress syndrome. Crit Care Med 1997; 25:41–45 5. Ferguson ND, Kacmarek RM, Chiche JD, et al: Screening of ARDS patients using standardized ventilator settings: Influence on enrollment in a clinical trial. Intensive Care Med 2004; 30:1111–1116 6. El-Khatib MF, Jamaleddine GW: A new oxygenation index for reflecting intrapulmonary shunting in patients undergoing open-heart surgery. Chest 2004; 125:592–596 7. Gattinoni L, Tognoni G, Pesenti A, et al; Prone-Supine Study Group: Effect of prone positioning on the survival of patients with acute respiratory failure. N Engl J Med 2001; 345:568–573 8. Guérin C, Reignier J, Richard JC, et al; PROSEVA Study Group: Prone positioning in severe acute respiratory distress syndrome. N Engl J Med 2013; 368:2159–2168
www.ccmjournal.org
489
Copyright of Critical Care Medicine is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
