Online Letters to the Editor
clinicians that targeting sleep architecture can make a clinically significant difference in outcomes in chronically ventilated patients. The authors have disclosed that they do not have any potential conflicts of interest. Antonio M. Esquinas, MD, PhD, FCCP, Intensive Care Unit, Hospital Morales Meseguer, Murcia, Spain; Peter J. Papadakos, MD, Department of Anesthesiology, University of Rochester, Rochester, NY; Alan R. Schwartz, MD, Sleep Disorders Center, Johns Hopkins School of Medicine, Baltimore, MD
REFERENCES
1. Parthasarathy S, Tobin MJ: Sleep in the intensive care unit. Intensive Care Med 2004; 30:197–206 2. Roche-Campo F, Thille AW, Drouot X, et al: Comparison of Sleep Quality With Mechanical Versus Spontaneous Ventilation During Weaning of Critically Ill Tracheostomized Patients. Crit Care Med 2013; 41:1637–1644 3. Cooper AB, Thornley KS, Young GB, et al: Sleep in critically ill patients requiring mechanical ventilation. Chest 2000; 117:809–818 4. Pandharipande P, Ely EW: Sedative and analgesic medications: Risk factors for delirium and sleep disturbances in the critically ill. Crit Care Clin 2006; 22:313–327 5. Jin K, Okabe S, Chida K, et al: Tracheostomy can fatally exacerbate sleep-disordered breathing in multiple system atrophy. Neurology 2007; 68:1618–1621 DOI: 10.1097/CCM.0b013e3182a84ccd
The authors reply:
W
e appreciate the interest shown by Esquinas et al in our work (1), and we welcome the opportunity to clarify their doubts. Below we address their comments point by point. First, regarding the crossover study design, our initial intention was to perform the study over two consecutive nights. However, we realized that patients able to tolerate spontaneous ventilation during the first night would have great difficulty in tolerating mechanical ventilation during the second night. For this reason, we decided to perform this crossover study in a single night. As explained in the Methods section (“Patients were randomized to receive either mechanical ventilation with pressure support ventilation or spontaneous ventilation during the first 5-hr period, after which patients were crossed over to the other ventilatory mode for the second 5-hr sleep period”) and as shown in Figure 1 in (2), the initial ventilatory mode was randomly selected and counterbalanced by the other ventilatory mode during the second part of the night. We believe that any effects that the first ventilatory mode might have had on sleep quality during the latter half of the night were minimized by randomization. Second, four patients presented asynchronies related to the mechanical ventilation. We believe that these asynchronies could have been minimized if the mechanical ventilation settings had been better adjusted. This is why we described ventilation in these four patients as “suboptimal.” This description of “suboptimal” ventilation comes, however, from our post hoc
Critical Care Medicine
analysis of the tracings, and it is possible that it would have been difficult to detect this issue clinically without spending an inordinate amount of time at the bedside. When we compared the two ventilatory modes in the 12 patients without ventilation-related asynchronies, the results did not differ significantly from those found in the sample as a whole. Finally, we agree that after 15 years of sleep studies in critical care patients—most of which have been descriptive—it is time to accelerate our progress. However, before we can do so, consensus needs to be reached on the methodological approach to be used. Fortunately, recent publications are moving in this direction (3, 4). Hopefully, new clinical research in this area will answer some of the questions posed by Esquinas et al (1). Dr. Brochard consulted for Draeger. His institution received grant support from Philips Respironics, Covidien, Vygon, Draeger, and General Electric. Dr. Roche-Campo disclosed that he does not have any potential conflicts of interest. Ferran Roche-Campo, MD, AP-HP, Medical Intensive Care Unit, Groupe Hospitalier Albert Chenevier-Henri Mondor, Créteil, France; Mondor Biomedical Research Center (INSERM U955), University of Paris EST, Créteil, France; and Intensive Care Unit, Hospital de Sant Pau, Barcelona, Spain; Laurent Brochard, MD, AP-HP, Medical Intensive Care Unit, Groupe Hospitalier Albert Chenevier–Henri Mondor, Créteil, France; Mondor Biomedical Research Center (INSERM U955), University of Paris EST, Créteil, France; and Medical Intensive Care Unit, University Hospital, University of Geneva, Geneva, Switzerland
REFERENCES
1. Esquinas AM, Papadakos PJ, Schwartz AR: Sleep Patterns During Long-Term Mechanical Ventilation in Tracheostomized Patients in the ICU. Do They Matter? Crit Care Med 2014; 42:e82–e83 2. Roche-Campo F, Thille AW, Drouot X, et al: Comparison of sleep quality with mechanical versus spontaneous ventilation during weaning of critically ill tracheostomized patients. Crit Care Med 2013; 41:1637–1644 3. Drouot X, Roche-Campo F, Thille AW, et al: A new classification for sleep analysis in critically ill patients. Sleep Med 2012; 13:7–14 4. Watson PL, Pandharipande P, Gehlbach BK, et al: Atypical sleep in ventilated patients: Empirical electroencephalography findings and the path toward revised ICU sleep scoring criteria. Crit Care Med 2013; 41:1958–1967 DOI: 10.1097CCM.0000000000000022
Evidence Base for the Use of Corticosteroids in Septic Shock in Children To the Editor:
W
e read with interest the recent publication by the Surviving Sepsis Campaign Guidelines Committee (1) in the issue of Critical Care Medicine, which provides clear evidence-based guidance for the management of severe sepsis that includes specific recommendations for children. However, we believe clarification is required in relation to the use of corticosteroids in children. In the abstract, the guideline recommends the “use of hydrocortisone only in children with suspected or proven ‘absolute’ www.ccmjournal.org
e83
Online Letters to the Editor
adrenal insufficiency” (graded as “2C”). It is therefore surprising to read in Table 9 in (1) that “timely hydrocortisone therapy in children with fluid refractory, catecholamine-resistant shock, and suspected or proven absolute (classic) adrenal insufficiency” is suggested (graded as “1A”). According to the GRADE system, which was used to evaluate evidence in this guideline, “1” would indicate “strong” and “A” would indicate that the recommendation is supported by high-quality randomized controlled trials. To our knowledge, only two randomized controlled trials that specifically investigated the efficacy of corticosteroids in children with septic shock have been published to date (2, 3). In addition, one small randomized trial has recently been presented in abstract form (4). The first trial, done in 1963 in children presumed to have “a life-threatening infection” at admission, showed no difference in mortality between the hydrocortisone and the placebo group (2). The second trial, based in two African hospitals where assisted ventilation was not available, included children who were “moderately or severely ill” and met the study criteria for sepsis syndrome or shock (3). Again, corticosteroids (dexamethasone) showed no benefit with regard to hemodynamic stability, duration of hospital stay, or survival. Importantly, both studies were done in populations without access to intensive care measures now considered standard in industrialized countries, including mechanical ventilation and circulatory support with inotropes. The recent Brazilian trial that included data from 42 children randomized to hydrocortisone or placebo also showed no statistically significant difference in mortality, use of vasoactive drugs, duration of mechanical ventilation, and length of PICU stay between both groups (4). Only a few large-scale retrospective studies investigating corticosteroids in children with septic shock have been done. This includes a retrospective analysis of data from the REsearching severe Sepsis and Organ dysfunction in children: a gLobal perspective (RESOLVE) study, the largest pediatric sepsis study to date, which is cited in the guideline as supporting evidence (5). However, Zimmerman and Williams (5) concluded that “outcomes were similar in children who did or did not receive corticosteroids as adjunctive therapy.” Importantly, the RESOLVE study included no specific protocol for the administration of corticosteroids and no randomization process, as previously highlighted (6). The definition of “absolute adrenal insufficiency” varies widely in the published literature (7). Absolute levels of cortisol at admission, response to adrenocorticotropic hormone, or a combination of the two are typically used to define this state. The guideline does not provide a clear definition, making it difficult for clinicians to base diagnostic and treatment decisions on this part of the guidance. Although many clinicians think that there may be a positive risk/benefit ratio for the use of corticosteroids in children with refractory septic shock, we believe that it is important to acknowledge the current lack of evidence in the pediatric setting. Due to the physiological differences between adults and children, one cannot simply extrapolate from adult data. Additional more robust pediatric data are therefore needed to enable evidence-based decisions in critically ill children. e84
www.ccmjournal.org
Dr. de Graaf is employed by the University Hospital Southampton and National Health Service Foundation Trust. Dr. Tebruegge is employed by the University of Southampton, is a named inventor on a provisional patent related to TB diagnostics (i.e., unrelated to manuscript) held by the University of Melbourne and Murdoch Children's Research Institute, and received funding from GlaxoSmithKline to attend one international conference. Dr. Faust is employed by the University of Southampton and has been a member of advisory boards for vaccine manufacturers and antimicrobial agents (attended an advisory board for Xoma regarding the antisepsis drug rBPI in 2007). He has lectured on behalf of vaccine manufacturers. His institution received grant support from the Meningitis Research Foundation, an Association of Medical Research Charities associated charity: Corticosteroids in Paediatric Sepsis—A Phase 2 Pilot Study grant to conduct a three-center pilot clinical trial of corticosteroids in pediatric sepsis, for which he serves as chief investigator. Hans de Graaf, MD, Marc Tebruegge, MD, MRCPCH, PhD, Saul N. Faust, MD, MRCPCH, PhD, United Kingdom National Institute for Health Research Wellcome Trust Clinical Research Facility, University Hospital Southampton NHS Foundation Trust, Southampton, UK, and Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine and Institute for Life Sciences, University of Southampton, Southampton, UK
REFERENCES
1. Dellinger RP, Levy MM, Rhodes A, et al; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup: Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2012. Crit Care Med 2013; 41:580–637 2. Group CS: The effectiveness of hydrocortisone in the management of severe infections. JAMA 1963; 183:462–465 3. Slusher T, Gbadero D, Howard C, et al: Randomized, placebo-controlled, double blinded trial of dexamethasone in African children with sepsis. Pediatr Infect Dis J 1996; 15:579–583 4. Amoretti C, Cabral F, Tonial C, et al: Corticosteroid replacement in children with septic shock: Randomized double blind placebo controlled trial. Abstr. Published in Abstracts from the 12th Brazilian Congress on Pediatric Critical Care Medicine/11th Congress of Latin-American Society of Pediatric Critical Care, São Paulo, 2012. Pediatr Crit Care Med 2012; 13:618 5. Zimmerman JJ, Williams MD: Adjunctive corticosteroid therapy in pediatric severe sepsis: Observations from the RESOLVE study. Pediatr Crit Care Med 2011; 12:2–8 6. Leclerc F, Botte A, Chêne G, et al: Adjunctive corticosteroid therapy in pediatric severe sepsis: Many unsolved questions. Pediatr Crit Care Med 2011; 12:101–102 7. Menon K, Lawson M: Identification of adrenal insufficiency in pediatric critical illness. Pediatr Crit Care Med 2007; 8:276–278 DOI: 10.1097/CCM.0b013e3182a5270c
The author replies:
W
e thank de Graaf et al (1) for pointing out the inconsistency of the pediatric steroid recommendation grading in the guidelines publication. The abstract grade is incorrect. It should be 1A in the abstract as it is graded 1A in the body of the text and in the table. We also now recognize that the use of the term “absolute (classic)” January 2014 • Volume 42 • Number 1
clinicians that targeting sleep architecture can make a clinically significant difference in outcomes in chronically ventilated patients. The authors have disclosed that they do not have any potential conflicts of interest. Antonio M. Esquinas, MD, PhD, FCCP, Intensive Care Unit, Hospital Morales Meseguer, Murcia, Spain; Peter J. Papadakos, MD, Department of Anesthesiology, University of Rochester, Rochester, NY; Alan R. Schwartz, MD, Sleep Disorders Center, Johns Hopkins School of Medicine, Baltimore, MD
REFERENCES
1. Parthasarathy S, Tobin MJ: Sleep in the intensive care unit. Intensive Care Med 2004; 30:197–206 2. Roche-Campo F, Thille AW, Drouot X, et al: Comparison of Sleep Quality With Mechanical Versus Spontaneous Ventilation During Weaning of Critically Ill Tracheostomized Patients. Crit Care Med 2013; 41:1637–1644 3. Cooper AB, Thornley KS, Young GB, et al: Sleep in critically ill patients requiring mechanical ventilation. Chest 2000; 117:809–818 4. Pandharipande P, Ely EW: Sedative and analgesic medications: Risk factors for delirium and sleep disturbances in the critically ill. Crit Care Clin 2006; 22:313–327 5. Jin K, Okabe S, Chida K, et al: Tracheostomy can fatally exacerbate sleep-disordered breathing in multiple system atrophy. Neurology 2007; 68:1618–1621 DOI: 10.1097/CCM.0b013e3182a84ccd
The authors reply:
W
e appreciate the interest shown by Esquinas et al in our work (1), and we welcome the opportunity to clarify their doubts. Below we address their comments point by point. First, regarding the crossover study design, our initial intention was to perform the study over two consecutive nights. However, we realized that patients able to tolerate spontaneous ventilation during the first night would have great difficulty in tolerating mechanical ventilation during the second night. For this reason, we decided to perform this crossover study in a single night. As explained in the Methods section (“Patients were randomized to receive either mechanical ventilation with pressure support ventilation or spontaneous ventilation during the first 5-hr period, after which patients were crossed over to the other ventilatory mode for the second 5-hr sleep period”) and as shown in Figure 1 in (2), the initial ventilatory mode was randomly selected and counterbalanced by the other ventilatory mode during the second part of the night. We believe that any effects that the first ventilatory mode might have had on sleep quality during the latter half of the night were minimized by randomization. Second, four patients presented asynchronies related to the mechanical ventilation. We believe that these asynchronies could have been minimized if the mechanical ventilation settings had been better adjusted. This is why we described ventilation in these four patients as “suboptimal.” This description of “suboptimal” ventilation comes, however, from our post hoc
Critical Care Medicine
analysis of the tracings, and it is possible that it would have been difficult to detect this issue clinically without spending an inordinate amount of time at the bedside. When we compared the two ventilatory modes in the 12 patients without ventilation-related asynchronies, the results did not differ significantly from those found in the sample as a whole. Finally, we agree that after 15 years of sleep studies in critical care patients—most of which have been descriptive—it is time to accelerate our progress. However, before we can do so, consensus needs to be reached on the methodological approach to be used. Fortunately, recent publications are moving in this direction (3, 4). Hopefully, new clinical research in this area will answer some of the questions posed by Esquinas et al (1). Dr. Brochard consulted for Draeger. His institution received grant support from Philips Respironics, Covidien, Vygon, Draeger, and General Electric. Dr. Roche-Campo disclosed that he does not have any potential conflicts of interest. Ferran Roche-Campo, MD, AP-HP, Medical Intensive Care Unit, Groupe Hospitalier Albert Chenevier-Henri Mondor, Créteil, France; Mondor Biomedical Research Center (INSERM U955), University of Paris EST, Créteil, France; and Intensive Care Unit, Hospital de Sant Pau, Barcelona, Spain; Laurent Brochard, MD, AP-HP, Medical Intensive Care Unit, Groupe Hospitalier Albert Chenevier–Henri Mondor, Créteil, France; Mondor Biomedical Research Center (INSERM U955), University of Paris EST, Créteil, France; and Medical Intensive Care Unit, University Hospital, University of Geneva, Geneva, Switzerland
REFERENCES
1. Esquinas AM, Papadakos PJ, Schwartz AR: Sleep Patterns During Long-Term Mechanical Ventilation in Tracheostomized Patients in the ICU. Do They Matter? Crit Care Med 2014; 42:e82–e83 2. Roche-Campo F, Thille AW, Drouot X, et al: Comparison of sleep quality with mechanical versus spontaneous ventilation during weaning of critically ill tracheostomized patients. Crit Care Med 2013; 41:1637–1644 3. Drouot X, Roche-Campo F, Thille AW, et al: A new classification for sleep analysis in critically ill patients. Sleep Med 2012; 13:7–14 4. Watson PL, Pandharipande P, Gehlbach BK, et al: Atypical sleep in ventilated patients: Empirical electroencephalography findings and the path toward revised ICU sleep scoring criteria. Crit Care Med 2013; 41:1958–1967 DOI: 10.1097CCM.0000000000000022
Evidence Base for the Use of Corticosteroids in Septic Shock in Children To the Editor:
W
e read with interest the recent publication by the Surviving Sepsis Campaign Guidelines Committee (1) in the issue of Critical Care Medicine, which provides clear evidence-based guidance for the management of severe sepsis that includes specific recommendations for children. However, we believe clarification is required in relation to the use of corticosteroids in children. In the abstract, the guideline recommends the “use of hydrocortisone only in children with suspected or proven ‘absolute’ www.ccmjournal.org
e83
Online Letters to the Editor
adrenal insufficiency” (graded as “2C”). It is therefore surprising to read in Table 9 in (1) that “timely hydrocortisone therapy in children with fluid refractory, catecholamine-resistant shock, and suspected or proven absolute (classic) adrenal insufficiency” is suggested (graded as “1A”). According to the GRADE system, which was used to evaluate evidence in this guideline, “1” would indicate “strong” and “A” would indicate that the recommendation is supported by high-quality randomized controlled trials. To our knowledge, only two randomized controlled trials that specifically investigated the efficacy of corticosteroids in children with septic shock have been published to date (2, 3). In addition, one small randomized trial has recently been presented in abstract form (4). The first trial, done in 1963 in children presumed to have “a life-threatening infection” at admission, showed no difference in mortality between the hydrocortisone and the placebo group (2). The second trial, based in two African hospitals where assisted ventilation was not available, included children who were “moderately or severely ill” and met the study criteria for sepsis syndrome or shock (3). Again, corticosteroids (dexamethasone) showed no benefit with regard to hemodynamic stability, duration of hospital stay, or survival. Importantly, both studies were done in populations without access to intensive care measures now considered standard in industrialized countries, including mechanical ventilation and circulatory support with inotropes. The recent Brazilian trial that included data from 42 children randomized to hydrocortisone or placebo also showed no statistically significant difference in mortality, use of vasoactive drugs, duration of mechanical ventilation, and length of PICU stay between both groups (4). Only a few large-scale retrospective studies investigating corticosteroids in children with septic shock have been done. This includes a retrospective analysis of data from the REsearching severe Sepsis and Organ dysfunction in children: a gLobal perspective (RESOLVE) study, the largest pediatric sepsis study to date, which is cited in the guideline as supporting evidence (5). However, Zimmerman and Williams (5) concluded that “outcomes were similar in children who did or did not receive corticosteroids as adjunctive therapy.” Importantly, the RESOLVE study included no specific protocol for the administration of corticosteroids and no randomization process, as previously highlighted (6). The definition of “absolute adrenal insufficiency” varies widely in the published literature (7). Absolute levels of cortisol at admission, response to adrenocorticotropic hormone, or a combination of the two are typically used to define this state. The guideline does not provide a clear definition, making it difficult for clinicians to base diagnostic and treatment decisions on this part of the guidance. Although many clinicians think that there may be a positive risk/benefit ratio for the use of corticosteroids in children with refractory septic shock, we believe that it is important to acknowledge the current lack of evidence in the pediatric setting. Due to the physiological differences between adults and children, one cannot simply extrapolate from adult data. Additional more robust pediatric data are therefore needed to enable evidence-based decisions in critically ill children. e84
www.ccmjournal.org
Dr. de Graaf is employed by the University Hospital Southampton and National Health Service Foundation Trust. Dr. Tebruegge is employed by the University of Southampton, is a named inventor on a provisional patent related to TB diagnostics (i.e., unrelated to manuscript) held by the University of Melbourne and Murdoch Children's Research Institute, and received funding from GlaxoSmithKline to attend one international conference. Dr. Faust is employed by the University of Southampton and has been a member of advisory boards for vaccine manufacturers and antimicrobial agents (attended an advisory board for Xoma regarding the antisepsis drug rBPI in 2007). He has lectured on behalf of vaccine manufacturers. His institution received grant support from the Meningitis Research Foundation, an Association of Medical Research Charities associated charity: Corticosteroids in Paediatric Sepsis—A Phase 2 Pilot Study grant to conduct a three-center pilot clinical trial of corticosteroids in pediatric sepsis, for which he serves as chief investigator. Hans de Graaf, MD, Marc Tebruegge, MD, MRCPCH, PhD, Saul N. Faust, MD, MRCPCH, PhD, United Kingdom National Institute for Health Research Wellcome Trust Clinical Research Facility, University Hospital Southampton NHS Foundation Trust, Southampton, UK, and Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine and Institute for Life Sciences, University of Southampton, Southampton, UK
REFERENCES
1. Dellinger RP, Levy MM, Rhodes A, et al; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup: Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2012. Crit Care Med 2013; 41:580–637 2. Group CS: The effectiveness of hydrocortisone in the management of severe infections. JAMA 1963; 183:462–465 3. Slusher T, Gbadero D, Howard C, et al: Randomized, placebo-controlled, double blinded trial of dexamethasone in African children with sepsis. Pediatr Infect Dis J 1996; 15:579–583 4. Amoretti C, Cabral F, Tonial C, et al: Corticosteroid replacement in children with septic shock: Randomized double blind placebo controlled trial. Abstr. Published in Abstracts from the 12th Brazilian Congress on Pediatric Critical Care Medicine/11th Congress of Latin-American Society of Pediatric Critical Care, São Paulo, 2012. Pediatr Crit Care Med 2012; 13:618 5. Zimmerman JJ, Williams MD: Adjunctive corticosteroid therapy in pediatric severe sepsis: Observations from the RESOLVE study. Pediatr Crit Care Med 2011; 12:2–8 6. Leclerc F, Botte A, Chêne G, et al: Adjunctive corticosteroid therapy in pediatric severe sepsis: Many unsolved questions. Pediatr Crit Care Med 2011; 12:101–102 7. Menon K, Lawson M: Identification of adrenal insufficiency in pediatric critical illness. Pediatr Crit Care Med 2007; 8:276–278 DOI: 10.1097/CCM.0b013e3182a5270c
The author replies:
W
e thank de Graaf et al (1) for pointing out the inconsistency of the pediatric steroid recommendation grading in the guidelines publication. The abstract grade is incorrect. It should be 1A in the abstract as it is graded 1A in the body of the text and in the table. We also now recognize that the use of the term “absolute (classic)” January 2014 • Volume 42 • Number 1
