CORRESPONDENCE extracorporeal membrane oxygenation programs for acute respiratory failure in adult patients. Am J Respir Crit Care Med 2014;190:488–496. 2. Sharma NS, Wille KM, Bellot SC, Brodie D, Diaz-Guzman E. Role of Extracorporeal Membrane Oxygenation in Management of Refractory ARDS in the Intensive Care Unit: A National Survey of Perspective of Adult Critical Care Physicians and Trainees; 2014 Oct 25–30; Austin, Texas: Chest 2014 (A1994642). 3. Stewart GC, Stevenson LW. Keeping left ventricular assist device acceleration on track. Circulation 2011;123:1559–1568, discussion 1568. 4. Hoopes CW, Kukreja J, Golden J, Davenport DL, Diaz-Guzman E, Zwischenberger JB. Extracorporeal membrane oxygenation as a bridge to pulmonary transplantation. J Thorac Cardiovasc Surg 2013;145:862–867, discussion 867–868.
Copyright © 2014 by the American Thoracic Society
Reply From the Authors: We appreciate the interest of Diaz-Guzman and colleagues in our position paper for the organization of extracorporeal membrane oxygenation (ECMO) programs for acute respiratory failure in adult patients (1). Diaz-Guzman and colleagues disagree with our consensus statement that “optimization of conventional treatments . . . should always be undertaken prior to considering ECMO in patients with severe [acute respiratory distress syndrome (ARDS)].” They state that a consensus among critical care physicians about the use of therapies, even those considered more conventional, in patients with severe ARDS does not exist and that supportive or therapeutic modalities such as prone positioning, bilevel positive pressure ventilation, or the use of inhaled vasodilators have not demonstrated efficacy over conventional low-tidal volume ventilation. We respectfully disagree with this assertion. Although evidence for bilevel ventilation or the use of inhaled vasodilators in patients with severe ARDS is lacking, a recent, high-quality randomized trial showed that the use of prone positioning in patients with moderate to severe ARDS at centers experienced in using the technique resulted in a 50% relative reduction in mortality, the largest reduction in mortality observed in the intensive care unit literature in more than 4 decades (2). A recent meta-analysis of prone positioning further suggested that the subgroup of patients who benefited included those in whom a strategy of low-tidal volume ventilation was used, making the evidence of an effect in the Effect of Prone Positioning on Mortality in Patients With Severe and Persistent Acute Respiratory Distress Syndrome (PROSEVA) trial (2), in the era of low-volume, low-pressure ventilation, even more believable (3). Similarly, neuromuscular blockade prescribed for 48 hours in patients with moderate to severe ARDS was also associated with a significant reduction in mortality (4). These simple and relatively inexpensive interventions should be strongly considered before initiating extracorporeal gas exchange techniques in patients with ARDS, for which the current evidence remains controversial. We concur with Diaz-Guzman and colleagues that venovenous ECMO support may facilitate lung-protective ventilation and that this strategy might be associated with better outcomes, 1322
especially if applied early, and not as a “salvage therapy” for patients with disease refractory to medical therapy. However, evidence for this strategy is currently fragile. Although results of the randomized Conventional Ventilation or ECMO for Severe Adult Respiratory Failure (CESAR) trial suggested that a strategy of transferring patients with severe ARDS to an ECMO referral center for consideration of receiving ECMO was associated with better outcomes, this trial has been criticized for methodological limitations (5). Because ECMO might be associated with severe and potentially life-threatening complications, more evidence is urgently needed to evaluate the actual effect of this technique compared with optimization of conventional treatments, including prone positioning. Creating registries such as the one proposed by Diaz-Guzman and colleagues might help determine appropriate risk stratification and patient selection for ECMO. However, data derived from registries are prone to important selection biases, weakening interpretation of their results. Highquality randomized trials could provide sufficient evidence for a more widespread and earlier use of veno-venous ECMO for severe ARDS. This is the one of the main objectives of our position paper (1) and of the recently formed International ECMO Network (ECMONet) consortium. Last, more evidence is forthcoming from the ECMONetsupported and ongoing international multicenter, randomized Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome (EOLIA) trial, which will test the efficacy of early veno-venous ECMO in patients with severe ARDS with tight control of mechanical ventilation in the control group, initiation of ECMO before transportation to ECMO centers, and the use of ECMO in every patient randomly assigned to receive it (6). Innovation is seldom evidence based, but only high-quality evidence can provide the requisite proof of efficacy and high-grade evidence-based recommendations for the use of invasive and expensive devices in critically ill patients. This lesson was recently demonstrated after publication of the Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) trial (7), which led, surprisingly, to downgrading indications of the intraaortic balloon pump in patients with acute myocardial infarction with cardiogenic shock (8). n Author disclosures are available with the text of this letter at www.atsjournals.org. Alain Combes, M.D., Ph.D. Institute of Cardiometabolism and Nutrition, Groupe Hospitalier Pitie-Salp ´ etri ˆ ere ` Paris, France Dan Brodie, M.D., Ph.D. Columbia College of Physicians and Surgeons/New York Presbyterian Hospital New York, New York
References 1. Combes A, Brodie D, Bartlett R, Brochard L, Brower R, Conrad S, De Backer D, Fan E, Ferguson N, Fortenberry J, et al.; International ECMO Network (ECMONet). Position paper for the organization of extracorporeal membrane oxygenation programs for acute respiratory failure in adult patients. Am J Respir Crit Care Med 2014; 190:488–496.
American Journal of Respiratory and Critical Care Medicine Volume 190 Number 11 | December 1 2014
CORRESPONDENCE 2. Guerin ´ C, Reignier J, Richard JC, Beuret P, Gacouin A, Boulain T, Mercier E, Badet M, Mercat A, Baudin O, et al.; PROSEVA Study Group. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med 2013;368:2159–2168. 3. Sud S, Friedrich JO, Adhikari NK, Taccone P, Mancebo J, Polli F, Latini R, Pesenti A, Curley MA, Fernandez R, et al. Effect of prone positioning during mechanical ventilation on mortality among patients with acute respiratory distress syndrome: a systematic review and meta-analysis. CMAJ 2014;186:E381–E390. 4. Papazian L, Forel JM, Gacouin A, Penot-Ragon C, Perrin G, Loundou A, Jaber S, Arnal JM, Perez D, Seghboyan JM, et al.; ACURASYS Study Investigators. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med 2010;363:1107–1116. 5. Combes A, Bacchetta M, Brodie D, Muller ¨ T, Pellegrino V. Extracorporeal membrane oxygenation for respiratory failure in adults. Curr Opin Crit Care 2012;18:99–104. 6. Eolia trial [accessed 2014 Sept 14]. Available from: http://www. Clinicaltrials.Gov/ct2/show/nct01470703?Term=eolia&rank=1 7. Thiele H, Zeymer U, Neumann FJ, Ferenc M, Olbrich HG, Hausleiter J, Richardt G, Hennersdorf M, Empen K, Fuernau G, et al.; IABPSHOCK II Trial Investigators. Intraaortic balloon support for myocardial infarction with cardiogenic shock. N Engl J Med 2012; 367:1287–1296. 8. Windecker S, Kolh P, Alfonso F, Collet JP, Cremer J, Falk V, Filippatos G, Hamm C, Head SJ, Juni ¨ P, et al.; The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). 2014 ESC/EACTS Guidelines on myocardial revascularization. Eur Heart J 2014;35:2541–2619.
Copyright © 2014 by the American Thoracic Society
Neonatal Caffeine Therapy and Sleep: Important Findings to Guide New Approaches and Reduce Concerns To the Editor: Sleep is an intriguing behavior: we do not know how exactly to define it or what the real function of sleep is, yet it is widely accepted that sleep impairment is harmful to health and well being. The ontogenetic changes in sleep patterns and the large amount of sleep required during infancy indicate that sleep has an important function in development. A key question is whether sleep alterations occurring during a critical period for brain maturation could have a long-term effect on development. We read with great interest the article by Marcus and colleagues (1), which highlights this important topic in premature newborns, a population at increased risk of health complications. Apnea of prematurity is a common condition in premature infants, and the gold standard and most commonly used treatment is caffeine. Despite the beneficial effects of caffeine on respiratory response, the consequences of treatment are poorly understood in regard to the sleep–wake cycle. Marcus and colleagues conducted an elegant experiment designed to investigate the effects of caffeine treatment on the sleep pattern of preschool children. Using objective measures of sleep; actigraphy and polysomnography, they found no significant abnormalities in sleep quality or quantity as an effect of caffeine administration. For clinicians looking Supported by fellowships from National Council for Scientific and Technological Development (CNPq) and Research Fund Incentive Association (AFIP) (M.L.A. and S.T.).
Correspondence
for the best treatment for apnea of prematurity with the best health outcomes, as the authors state in the article, the results allay concerns about any adverse effects on sleep patterns. However, we believe that it would be useful to also consider electrophysiological markers that correlate brain maturation and sleep regulation to further investigate the possible effects of caffeine treatment. Caffeine acts on the sleep–wake cycle, increasing arousal and reducing sleep pressure, due to its action in the adenosinergic system. Adenosine is one of the main substances involved in the homeostatic modulation of sleep, a process defined by increased sleep pressure during wakefulness and the gradual reduction of this pressure during deep sleep. One marker of deep sleep and homeostasis response is the slow wave activity (SWA) during non–rapid eye movement sleep. SWA reflects the synchronized pattern of cortical neuronal activity (2), and some studies indicate that this electrophysiological marker can be used as a clinical tool to detect alterations in cortical maturation. In fact, there is an association between SWA and cortical maturation, in which slow waves undergo changes during development that correlate with changes in cortical maturation (3, 4). In rats, caffeine administration during a critical period for brain development delayed the physiological changes of SWA, indicating a possible impairment caused by the effects of caffeine on the regulatory response of sleep and brain maturation (5). Caffeine could interfere not only with the quantity of sleep and wakefulness, but also with the microstructure of sleep patterns. The investigation of electrophysiological markers that correlate with brain maturation and the development of sleep regulatory systems is a missing element in the Marcus study. Advances in medical conditions have increased survival rates of premature infants, but also elevated the need for better health support, due to their vulnerability to medical problems. Caffeine is the best treatment for apnea of prematurity, increasing survival and reducing morbidity. However, although lowering mortality is a significant aim in itself, we also need to ensure a good quality of life for the patient in the longer term. Given the importance of sleep for health and well being, this study (1) makes a valuable contribution to the fields of neonatology and sleep medicine. n Author disclosures are available with the text of this letter at www.atsjournals.org. Paula Araujo, Ph.D. Sergio Tufik, M.D., Ph.D. Monica Levy Andersen, Ph.D. Universidade Federal de São Paulo São Paulo, Brazil
References 1. Marcus CL, Meltzer LJ, Roberts RS, Traylor J, Dix J, D’ilario J, Asztalos E, Opie G, Doyle LW, Biggs SN, et al.; Caffeine for Apnea of Prematurity–Sleep Study. Long-term effects of caffeine therapy for apnea of prematurity on sleep at school age. Am J Respir Crit Care Med 2014;190:791–799. 2. Vyazovskiy VV, Olcese U, Lazimy YM, Faraguna U, Esser SK, Williams JC, Cirelli C, Tononi G. Cortical firing and sleep homeostasis. Neuron 2009;63:865–878.
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Copyright © 2014 by the American Thoracic Society
Reply From the Authors: We appreciate the interest of Diaz-Guzman and colleagues in our position paper for the organization of extracorporeal membrane oxygenation (ECMO) programs for acute respiratory failure in adult patients (1). Diaz-Guzman and colleagues disagree with our consensus statement that “optimization of conventional treatments . . . should always be undertaken prior to considering ECMO in patients with severe [acute respiratory distress syndrome (ARDS)].” They state that a consensus among critical care physicians about the use of therapies, even those considered more conventional, in patients with severe ARDS does not exist and that supportive or therapeutic modalities such as prone positioning, bilevel positive pressure ventilation, or the use of inhaled vasodilators have not demonstrated efficacy over conventional low-tidal volume ventilation. We respectfully disagree with this assertion. Although evidence for bilevel ventilation or the use of inhaled vasodilators in patients with severe ARDS is lacking, a recent, high-quality randomized trial showed that the use of prone positioning in patients with moderate to severe ARDS at centers experienced in using the technique resulted in a 50% relative reduction in mortality, the largest reduction in mortality observed in the intensive care unit literature in more than 4 decades (2). A recent meta-analysis of prone positioning further suggested that the subgroup of patients who benefited included those in whom a strategy of low-tidal volume ventilation was used, making the evidence of an effect in the Effect of Prone Positioning on Mortality in Patients With Severe and Persistent Acute Respiratory Distress Syndrome (PROSEVA) trial (2), in the era of low-volume, low-pressure ventilation, even more believable (3). Similarly, neuromuscular blockade prescribed for 48 hours in patients with moderate to severe ARDS was also associated with a significant reduction in mortality (4). These simple and relatively inexpensive interventions should be strongly considered before initiating extracorporeal gas exchange techniques in patients with ARDS, for which the current evidence remains controversial. We concur with Diaz-Guzman and colleagues that venovenous ECMO support may facilitate lung-protective ventilation and that this strategy might be associated with better outcomes, 1322
especially if applied early, and not as a “salvage therapy” for patients with disease refractory to medical therapy. However, evidence for this strategy is currently fragile. Although results of the randomized Conventional Ventilation or ECMO for Severe Adult Respiratory Failure (CESAR) trial suggested that a strategy of transferring patients with severe ARDS to an ECMO referral center for consideration of receiving ECMO was associated with better outcomes, this trial has been criticized for methodological limitations (5). Because ECMO might be associated with severe and potentially life-threatening complications, more evidence is urgently needed to evaluate the actual effect of this technique compared with optimization of conventional treatments, including prone positioning. Creating registries such as the one proposed by Diaz-Guzman and colleagues might help determine appropriate risk stratification and patient selection for ECMO. However, data derived from registries are prone to important selection biases, weakening interpretation of their results. Highquality randomized trials could provide sufficient evidence for a more widespread and earlier use of veno-venous ECMO for severe ARDS. This is the one of the main objectives of our position paper (1) and of the recently formed International ECMO Network (ECMONet) consortium. Last, more evidence is forthcoming from the ECMONetsupported and ongoing international multicenter, randomized Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome (EOLIA) trial, which will test the efficacy of early veno-venous ECMO in patients with severe ARDS with tight control of mechanical ventilation in the control group, initiation of ECMO before transportation to ECMO centers, and the use of ECMO in every patient randomly assigned to receive it (6). Innovation is seldom evidence based, but only high-quality evidence can provide the requisite proof of efficacy and high-grade evidence-based recommendations for the use of invasive and expensive devices in critically ill patients. This lesson was recently demonstrated after publication of the Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) trial (7), which led, surprisingly, to downgrading indications of the intraaortic balloon pump in patients with acute myocardial infarction with cardiogenic shock (8). n Author disclosures are available with the text of this letter at www.atsjournals.org. Alain Combes, M.D., Ph.D. Institute of Cardiometabolism and Nutrition, Groupe Hospitalier Pitie-Salp ´ etri ˆ ere ` Paris, France Dan Brodie, M.D., Ph.D. Columbia College of Physicians and Surgeons/New York Presbyterian Hospital New York, New York
References 1. Combes A, Brodie D, Bartlett R, Brochard L, Brower R, Conrad S, De Backer D, Fan E, Ferguson N, Fortenberry J, et al.; International ECMO Network (ECMONet). Position paper for the organization of extracorporeal membrane oxygenation programs for acute respiratory failure in adult patients. Am J Respir Crit Care Med 2014; 190:488–496.
American Journal of Respiratory and Critical Care Medicine Volume 190 Number 11 | December 1 2014
CORRESPONDENCE 2. Guerin ´ C, Reignier J, Richard JC, Beuret P, Gacouin A, Boulain T, Mercier E, Badet M, Mercat A, Baudin O, et al.; PROSEVA Study Group. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med 2013;368:2159–2168. 3. Sud S, Friedrich JO, Adhikari NK, Taccone P, Mancebo J, Polli F, Latini R, Pesenti A, Curley MA, Fernandez R, et al. Effect of prone positioning during mechanical ventilation on mortality among patients with acute respiratory distress syndrome: a systematic review and meta-analysis. CMAJ 2014;186:E381–E390. 4. Papazian L, Forel JM, Gacouin A, Penot-Ragon C, Perrin G, Loundou A, Jaber S, Arnal JM, Perez D, Seghboyan JM, et al.; ACURASYS Study Investigators. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med 2010;363:1107–1116. 5. Combes A, Bacchetta M, Brodie D, Muller ¨ T, Pellegrino V. Extracorporeal membrane oxygenation for respiratory failure in adults. Curr Opin Crit Care 2012;18:99–104. 6. Eolia trial [accessed 2014 Sept 14]. Available from: http://www. Clinicaltrials.Gov/ct2/show/nct01470703?Term=eolia&rank=1 7. Thiele H, Zeymer U, Neumann FJ, Ferenc M, Olbrich HG, Hausleiter J, Richardt G, Hennersdorf M, Empen K, Fuernau G, et al.; IABPSHOCK II Trial Investigators. Intraaortic balloon support for myocardial infarction with cardiogenic shock. N Engl J Med 2012; 367:1287–1296. 8. Windecker S, Kolh P, Alfonso F, Collet JP, Cremer J, Falk V, Filippatos G, Hamm C, Head SJ, Juni ¨ P, et al.; The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). 2014 ESC/EACTS Guidelines on myocardial revascularization. Eur Heart J 2014;35:2541–2619.
Copyright © 2014 by the American Thoracic Society
Neonatal Caffeine Therapy and Sleep: Important Findings to Guide New Approaches and Reduce Concerns To the Editor: Sleep is an intriguing behavior: we do not know how exactly to define it or what the real function of sleep is, yet it is widely accepted that sleep impairment is harmful to health and well being. The ontogenetic changes in sleep patterns and the large amount of sleep required during infancy indicate that sleep has an important function in development. A key question is whether sleep alterations occurring during a critical period for brain maturation could have a long-term effect on development. We read with great interest the article by Marcus and colleagues (1), which highlights this important topic in premature newborns, a population at increased risk of health complications. Apnea of prematurity is a common condition in premature infants, and the gold standard and most commonly used treatment is caffeine. Despite the beneficial effects of caffeine on respiratory response, the consequences of treatment are poorly understood in regard to the sleep–wake cycle. Marcus and colleagues conducted an elegant experiment designed to investigate the effects of caffeine treatment on the sleep pattern of preschool children. Using objective measures of sleep; actigraphy and polysomnography, they found no significant abnormalities in sleep quality or quantity as an effect of caffeine administration. For clinicians looking Supported by fellowships from National Council for Scientific and Technological Development (CNPq) and Research Fund Incentive Association (AFIP) (M.L.A. and S.T.).
Correspondence
for the best treatment for apnea of prematurity with the best health outcomes, as the authors state in the article, the results allay concerns about any adverse effects on sleep patterns. However, we believe that it would be useful to also consider electrophysiological markers that correlate brain maturation and sleep regulation to further investigate the possible effects of caffeine treatment. Caffeine acts on the sleep–wake cycle, increasing arousal and reducing sleep pressure, due to its action in the adenosinergic system. Adenosine is one of the main substances involved in the homeostatic modulation of sleep, a process defined by increased sleep pressure during wakefulness and the gradual reduction of this pressure during deep sleep. One marker of deep sleep and homeostasis response is the slow wave activity (SWA) during non–rapid eye movement sleep. SWA reflects the synchronized pattern of cortical neuronal activity (2), and some studies indicate that this electrophysiological marker can be used as a clinical tool to detect alterations in cortical maturation. In fact, there is an association between SWA and cortical maturation, in which slow waves undergo changes during development that correlate with changes in cortical maturation (3, 4). In rats, caffeine administration during a critical period for brain development delayed the physiological changes of SWA, indicating a possible impairment caused by the effects of caffeine on the regulatory response of sleep and brain maturation (5). Caffeine could interfere not only with the quantity of sleep and wakefulness, but also with the microstructure of sleep patterns. The investigation of electrophysiological markers that correlate with brain maturation and the development of sleep regulatory systems is a missing element in the Marcus study. Advances in medical conditions have increased survival rates of premature infants, but also elevated the need for better health support, due to their vulnerability to medical problems. Caffeine is the best treatment for apnea of prematurity, increasing survival and reducing morbidity. However, although lowering mortality is a significant aim in itself, we also need to ensure a good quality of life for the patient in the longer term. Given the importance of sleep for health and well being, this study (1) makes a valuable contribution to the fields of neonatology and sleep medicine. n Author disclosures are available with the text of this letter at www.atsjournals.org. Paula Araujo, Ph.D. Sergio Tufik, M.D., Ph.D. Monica Levy Andersen, Ph.D. Universidade Federal de São Paulo São Paulo, Brazil
References 1. Marcus CL, Meltzer LJ, Roberts RS, Traylor J, Dix J, D’ilario J, Asztalos E, Opie G, Doyle LW, Biggs SN, et al.; Caffeine for Apnea of Prematurity–Sleep Study. Long-term effects of caffeine therapy for apnea of prematurity on sleep at school age. Am J Respir Crit Care Med 2014;190:791–799. 2. Vyazovskiy VV, Olcese U, Lazimy YM, Faraguna U, Esser SK, Williams JC, Cirelli C, Tononi G. Cortical firing and sleep homeostasis. Neuron 2009;63:865–878.
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