Online Letters to the Editor
The authors reply:
W
e thank Salluh and Póvoa (1) for their interest in our study (2). The idea to propose C-reactive protein (CRP) as a marker to guide antibiotic therapy in patients with sepsis came from well-conducted studies, and most of them focused on community-acquired pneumonia (CAP) (3). These observational data coincided with our daily perception regarding CRP behavior in patients with sepsis. The nice Portuguese data (4), showing that the ratio of circulating CRP reduction associates with the outcome of ICU patients admitted with CAP, published in 2012, made our group even more confident of the potential benefit of this widely available and low-cost biomarker. However, there is a caveat: the predominant participation of medical patients in our study (87.2%) precludes anticipating if CRP would present that good usefulness among surgical or trauma ICU populations. We fully agree that in our study, a third arm with duration of antibiotic therapy guided by a clinical protocol supported by one evidence-based “best practice” (e.g., 7 d) would be relevant to better elucidate how helpful the biomarkers are, either CRP or procalcitonin. It is reasonable to conceive that a marker is superfluous when a predefined period of 7 days is set as length ceiling for the antibiotic therapy. However, in our opinion, this statement is quite disputable. Besides adding more conviction in the decision-making process, strong reductions of biomarkers levels along with an evident clinical improvement could allow clinicians to choose even shorter therapies, that is, stop antibiotics before the seventh day. As an example, this practice can be safe for patients with suspected ventilator-associated pneumonia with negative bronchoalveolar lavage cultures (5). It is worth mentioning that in our study, patients enrolled to the CRP groups had a median duration of 6 days of antibiotic therapy. On the other side, we must be careful to not unnecessarily prolong antibiotic therapy in patients doing clinically well, and with laboratory and microbiologic improvement, just because our target biomarker did not drop as expected. In our protocol, these kinds of patients had antibiotics stopped, but we acknowledge that this decision can be more complicated in the real world. We believe that in these situations, biomarkers must be wisely used, and instead of precluding interruption of antibiotic therapy, they might work as a warning sign for close surveillance. All told, we believe that biomarkers represent additional criteria to help us in the decision regarding antibiotic use and might compose the group of helping tools in the difficult but essential practice of antibiotic stewardship. These markers might aid in the interesting current trend of customizing the antibiotic therapy. Combination of biomarkers represents another exciting field of research. As suggested by Salluh and Póvoa (1), trials of biomarker-guided antimicrobial therapy for severe sepsis, including control groups treated according to the best care, could contribute to elucidate the above-mentioned questions. Large multicenter studies are very welcome to answer these relevant questions. The authors have disclosed that they do not have any potential conflicts of interest. Critical Care Medicine
Vandack Nobre, MD, PhD, Carolina Ferreira Oliveira, MD, PhD, Clara Rodrigues Alves de Oliveira, MD, PhD, Graduate Program in Infectious Diseases and Tropical Medicine, Universidade Federal de Minas Gerais, Minas Gerais, Brazil
REFERENCES
1. Salluh JIF, Póvoa P: Trials of Biomarker-Guided Antimicrobial Therapy in Sepsis: Improvements in Trial Design Require Better Control Groups. Crit Care Med 2014; 42:e172 2. Oliveira CF, Botoni FA, Oliveira CR, et al: Procalcitonin versus C-reactive protein for guiding antibiotic therapy in sepsis: A randomized trial. Crit Care Med 2013; 41:2336–2343 3. Chalmers JD, Singanayagam A, Hill AT: C-reactive protein is an independent predictor of severity in community-acquired pneumonia. Am J Med 2008; 121:219–225 4. Coelho LM, Salluh JI, Soares M, et al: Patterns of c-reactive protein RATIO response in severe community-acquired pneumonia: A cohort study. Crit Care 2012; 16:R53 5. Raman K, Nailor MD, Nicolau DP, et al: Early antibiotic discontinuation in patients with clinically suspected ventilator-associated pneumonia and negative quantitative bronchoscopy cultures. Crit Care Med 2013; 41:1656–1663 DOI: 10.1097/CCM.0000000000000069
Mistaking Complications of Critical Illness for Those of Critical Care To the Editor:
T
he recent publication in Critical Care Medicine by Bréchot et al (1) of a series of adult patients with refractory septic shock supported on extracorporeal membrane oxygenation (ECMO) was a welcome addition to the literature. In their accompanying editorial, Safi and Hollenberg (2) implicitly highlighted the importance of assessing both risks and benefits when evaluating new techniques or novel applications of existing technology. They drew attention to the apparently high complication rate of ECMO in the study and listed purpura fulminans, bleeding, and disseminated intravascular coagulation as adverse effects of ECMO. However, these problems not infrequently arise in patients with sepsis who do not receive ECMO (3, 4), and we are interested to learn on what basis they were able to attribute the hematological problems to the therapy rather than the disease. Furthermore, they did not discuss the potential risks of not placing these patients on ECMO, such as ventricular arrhythmias, progressive acidosis, and death. The editorialists commented on a similar prevalence of complications from ECMO in a series of patients infected with H1N1 influenza, but the study they cited (5) only had eight patients, four of whom received ECMO. These numbers seem insufficient to draw any proper conclusions. Prospective randomized trial data are required to accurately quantify the complications of ECMO. The only published study which has conclusively achieved this is the U.K. Collaborative Randomized Trial of Neonatal ECMO (6). When the survivors were assessed at 7 years of age, a range of neurodevelopmental problems were more frequently observed in those who had not www.ccmjournal.org
e173
Online Letters to the Editor
received ECMO, suggesting that the illness contributed more significantly to long-term problems than the therapy (7). ECMO is obviously associated with several complications, but it is very difficult to tease out what causes many of them in patients with this degree of critical illness. The study by Bréchot et al (1) shows that ECMO may be a useful last resort in managing critically ill adults with refractory sepsis-induced myocardial depression. Conclusions about the source and rate of complications in these patients should be deferred pending further study. Dr. Peek received a travel grant to attend Japanese Respiratory Intensive Care Society. Dr. Bartlett’s institution received grant support from the National Institutes of Health. The remaining authors have disclosed that they do not have any potential conflicts of interest. Graeme MacLaren, MBBS, FCCM, Cardiothoracic ICU, National University Hospital, Singapore, Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia, and Paediatric ICU, Royal Children’s Hospital, Melbourne, VIC, Australia; Warwick Butt, MBBS, FCICM, Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia, and Paediatric ICU, Royal Children’s Hospital, Melbourne, VIC, Australia; Giles Peek, MD, FFICM, Department of Cardiothoracic Surgery, Glenfield Hospital, Leicester, United Kingdom; William R. Lynch, MD, Robert H. Bartlett, MD, Department of Surgery, University of Michigan, Ann Arbor, MI
REFERENCES
1. Bréchot N, Luyt CE, Schmidt M, et al: Venoarterial Extracorporeal Membrane Oxygenation Support for Refractory Cardiovascular Dysfunction During Severe Bacterial Septic Shock. Crit Care Med 2013; 41:1616–1626 2. Safi L, Hollenberg SM: Extracorporeal membrane oxygenation to the rescue. Crit Care Med 2013; 41:1805–1806 3. Zeerleder S, Hack CE, Wuillemin WA: Disseminated intravascular coagulation in sepsis. Chest 2005; 128:2864–2875 4. Levi M, Schultz M, van der Poll T: Sepsis and thrombosis. Semin Thromb Hemost 2013; 39:559–566 5. Pabst D, Kuehn J, Schuler-Luettmann S, et al: Acute respiratory distress syndrome as a presenting manifestation in young patients infected with H1N1 influenza virus. Eur J Intern Med 2011; 22:e119–e124 6. UK Collaborative ECMO Trial Group: UK collaborative randomized trial of neonatal extracorporeal membrane oxygenation. Lancet 1996; 348:75–82 7. McNally H, Bennett CC, Elbourne D, et al: United Kingdom collaborative randomized trial of neonatal extracorporeal membrane oxygenation: Follow-up to age 7 years. Pediatrics 2006; 117:e845–e854 DOI: 10.1097/01.ccm.0000435671.37941.2e
The authors reply:
I
n their accompanying editorial (1) on our article of extracorporeal membrane oxygenation (ECMO) treatment to rescue refractory myocardial dysfunction associated with severe bacterial septic shock (2), Safi and Hollenberg (1) listed purpura fulminans and disseminated intravascular coagulation (DIC) as complications of ECMO. We agree with McLaren
e174
www.ccmjournal.org
et al (3) that these complications were more likely due to septic shock herein. Indeed, severe DIC and purpura fulminans are common features of septic shock (4) and 50% of our patients exhibited marked DIC before ECMO implantation, with a mean platelet count of 20 g/L (range, 23–48) and a mean prothrombin activity of 39% (10–52%). Half of our patients also had severe pneumococcal pneumonia, and purpura fulminans was due to bacteremic diffuse pneumococcal disease in the two patients (patients 7 and 13) who suffered severe distal ischemia. Alternatively, coagulation disorders and thrombopenia are frequently reported in ECMO patients (5, 6), which might aggravate DIC and increase the risk of bleeding in these critically ill patients. In the large French series of ECMO for severe influenza A (H1N1)-associated acute respiratory distress syndrome (7), 53% of the patients had at least one complication possibly related to ECMO, mainly hemorrhage, cannula site infection, and deep vein thrombosis. Obviously, these complications need to be balanced against delaying ECMO initiation in patients who frequently are dying of refractory cardiac and/or respiratory failure. Lastly, we strongly agree with Safi and Hollenberg (1) that the prevalence of such complications is related to both the experience and the expertise of medical-surgical teams caring for this very specific population of patients and that regionalization of this sort of intensive support modality is now warranted. Dr. Combes consulted for MAQUET. Dr. Bréchot disclosed that he does not have any potential conflicts of interest. Nicolas Bréchot, MD, PhD, Alain Combes, MD, PhD, Medical-Surgical Intensive Care Unit, iCAN, Institute of Cardiometabolism and Nutrition, Hôpital de la Pitié–Salpêtrière, Assistance Publique–Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France
REFERENCES
1. Safi L, Hollenberg SM: Extracorporeal membrane oxygenation to the rescue. Crit Care Med 2013; 41:1805–1806 2. Bréchot N, Luyt CE, Schmidt M, et al: Venoarterial extracorporeal membrane oxygenation support for refractory cardiovascular dysfunction during severe bacterial septic shock. Crit Care Med 2013; 41:1616–1626 3. MacLaren G, Butt W, Peek G, et al: Mistaking Complications of Critical Illness for Those of Critical Care. Crit Care Med 2014; 42: e173–e174 4. Zeerleder S, Hack CE, Wuillemin WA: Disseminated intravascular coagulation in sepsis. Chest 2005; 128:2864–2875 5. Arnold P, Jackson S, Wallis J, et al: Coagulation factor activity during neonatal extra-corporeal membrane oxygenation. Intensive Care Med 2001; 27:1395–1400 6. Heilmann C, Geisen U, Beyersdorf F, et al: Acquired von Willebrand syndrome in patients with extracorporeal life support (ECLS). Intensive Care Med 2012; 38:62–68 7. Pham T, Combes A, Rozé H, et al; REVA Research Network: Extracorporeal membrane oxygenation for pandemic influenza A(H1N1)-induced acute respiratory distress syndrome: A cohort study and propensity-matched analysis. Am J Respir Crit Care Med 2013; 187:276–285 DOI: 10.1097/CCM.0000000000000096
February 2014 • Volume 42 • Number 2
The authors reply:
W
e thank Salluh and Póvoa (1) for their interest in our study (2). The idea to propose C-reactive protein (CRP) as a marker to guide antibiotic therapy in patients with sepsis came from well-conducted studies, and most of them focused on community-acquired pneumonia (CAP) (3). These observational data coincided with our daily perception regarding CRP behavior in patients with sepsis. The nice Portuguese data (4), showing that the ratio of circulating CRP reduction associates with the outcome of ICU patients admitted with CAP, published in 2012, made our group even more confident of the potential benefit of this widely available and low-cost biomarker. However, there is a caveat: the predominant participation of medical patients in our study (87.2%) precludes anticipating if CRP would present that good usefulness among surgical or trauma ICU populations. We fully agree that in our study, a third arm with duration of antibiotic therapy guided by a clinical protocol supported by one evidence-based “best practice” (e.g., 7 d) would be relevant to better elucidate how helpful the biomarkers are, either CRP or procalcitonin. It is reasonable to conceive that a marker is superfluous when a predefined period of 7 days is set as length ceiling for the antibiotic therapy. However, in our opinion, this statement is quite disputable. Besides adding more conviction in the decision-making process, strong reductions of biomarkers levels along with an evident clinical improvement could allow clinicians to choose even shorter therapies, that is, stop antibiotics before the seventh day. As an example, this practice can be safe for patients with suspected ventilator-associated pneumonia with negative bronchoalveolar lavage cultures (5). It is worth mentioning that in our study, patients enrolled to the CRP groups had a median duration of 6 days of antibiotic therapy. On the other side, we must be careful to not unnecessarily prolong antibiotic therapy in patients doing clinically well, and with laboratory and microbiologic improvement, just because our target biomarker did not drop as expected. In our protocol, these kinds of patients had antibiotics stopped, but we acknowledge that this decision can be more complicated in the real world. We believe that in these situations, biomarkers must be wisely used, and instead of precluding interruption of antibiotic therapy, they might work as a warning sign for close surveillance. All told, we believe that biomarkers represent additional criteria to help us in the decision regarding antibiotic use and might compose the group of helping tools in the difficult but essential practice of antibiotic stewardship. These markers might aid in the interesting current trend of customizing the antibiotic therapy. Combination of biomarkers represents another exciting field of research. As suggested by Salluh and Póvoa (1), trials of biomarker-guided antimicrobial therapy for severe sepsis, including control groups treated according to the best care, could contribute to elucidate the above-mentioned questions. Large multicenter studies are very welcome to answer these relevant questions. The authors have disclosed that they do not have any potential conflicts of interest. Critical Care Medicine
Vandack Nobre, MD, PhD, Carolina Ferreira Oliveira, MD, PhD, Clara Rodrigues Alves de Oliveira, MD, PhD, Graduate Program in Infectious Diseases and Tropical Medicine, Universidade Federal de Minas Gerais, Minas Gerais, Brazil
REFERENCES
1. Salluh JIF, Póvoa P: Trials of Biomarker-Guided Antimicrobial Therapy in Sepsis: Improvements in Trial Design Require Better Control Groups. Crit Care Med 2014; 42:e172 2. Oliveira CF, Botoni FA, Oliveira CR, et al: Procalcitonin versus C-reactive protein for guiding antibiotic therapy in sepsis: A randomized trial. Crit Care Med 2013; 41:2336–2343 3. Chalmers JD, Singanayagam A, Hill AT: C-reactive protein is an independent predictor of severity in community-acquired pneumonia. Am J Med 2008; 121:219–225 4. Coelho LM, Salluh JI, Soares M, et al: Patterns of c-reactive protein RATIO response in severe community-acquired pneumonia: A cohort study. Crit Care 2012; 16:R53 5. Raman K, Nailor MD, Nicolau DP, et al: Early antibiotic discontinuation in patients with clinically suspected ventilator-associated pneumonia and negative quantitative bronchoscopy cultures. Crit Care Med 2013; 41:1656–1663 DOI: 10.1097/CCM.0000000000000069
Mistaking Complications of Critical Illness for Those of Critical Care To the Editor:
T
he recent publication in Critical Care Medicine by Bréchot et al (1) of a series of adult patients with refractory septic shock supported on extracorporeal membrane oxygenation (ECMO) was a welcome addition to the literature. In their accompanying editorial, Safi and Hollenberg (2) implicitly highlighted the importance of assessing both risks and benefits when evaluating new techniques or novel applications of existing technology. They drew attention to the apparently high complication rate of ECMO in the study and listed purpura fulminans, bleeding, and disseminated intravascular coagulation as adverse effects of ECMO. However, these problems not infrequently arise in patients with sepsis who do not receive ECMO (3, 4), and we are interested to learn on what basis they were able to attribute the hematological problems to the therapy rather than the disease. Furthermore, they did not discuss the potential risks of not placing these patients on ECMO, such as ventricular arrhythmias, progressive acidosis, and death. The editorialists commented on a similar prevalence of complications from ECMO in a series of patients infected with H1N1 influenza, but the study they cited (5) only had eight patients, four of whom received ECMO. These numbers seem insufficient to draw any proper conclusions. Prospective randomized trial data are required to accurately quantify the complications of ECMO. The only published study which has conclusively achieved this is the U.K. Collaborative Randomized Trial of Neonatal ECMO (6). When the survivors were assessed at 7 years of age, a range of neurodevelopmental problems were more frequently observed in those who had not www.ccmjournal.org
e173
Online Letters to the Editor
received ECMO, suggesting that the illness contributed more significantly to long-term problems than the therapy (7). ECMO is obviously associated with several complications, but it is very difficult to tease out what causes many of them in patients with this degree of critical illness. The study by Bréchot et al (1) shows that ECMO may be a useful last resort in managing critically ill adults with refractory sepsis-induced myocardial depression. Conclusions about the source and rate of complications in these patients should be deferred pending further study. Dr. Peek received a travel grant to attend Japanese Respiratory Intensive Care Society. Dr. Bartlett’s institution received grant support from the National Institutes of Health. The remaining authors have disclosed that they do not have any potential conflicts of interest. Graeme MacLaren, MBBS, FCCM, Cardiothoracic ICU, National University Hospital, Singapore, Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia, and Paediatric ICU, Royal Children’s Hospital, Melbourne, VIC, Australia; Warwick Butt, MBBS, FCICM, Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia, and Paediatric ICU, Royal Children’s Hospital, Melbourne, VIC, Australia; Giles Peek, MD, FFICM, Department of Cardiothoracic Surgery, Glenfield Hospital, Leicester, United Kingdom; William R. Lynch, MD, Robert H. Bartlett, MD, Department of Surgery, University of Michigan, Ann Arbor, MI
REFERENCES
1. Bréchot N, Luyt CE, Schmidt M, et al: Venoarterial Extracorporeal Membrane Oxygenation Support for Refractory Cardiovascular Dysfunction During Severe Bacterial Septic Shock. Crit Care Med 2013; 41:1616–1626 2. Safi L, Hollenberg SM: Extracorporeal membrane oxygenation to the rescue. Crit Care Med 2013; 41:1805–1806 3. Zeerleder S, Hack CE, Wuillemin WA: Disseminated intravascular coagulation in sepsis. Chest 2005; 128:2864–2875 4. Levi M, Schultz M, van der Poll T: Sepsis and thrombosis. Semin Thromb Hemost 2013; 39:559–566 5. Pabst D, Kuehn J, Schuler-Luettmann S, et al: Acute respiratory distress syndrome as a presenting manifestation in young patients infected with H1N1 influenza virus. Eur J Intern Med 2011; 22:e119–e124 6. UK Collaborative ECMO Trial Group: UK collaborative randomized trial of neonatal extracorporeal membrane oxygenation. Lancet 1996; 348:75–82 7. McNally H, Bennett CC, Elbourne D, et al: United Kingdom collaborative randomized trial of neonatal extracorporeal membrane oxygenation: Follow-up to age 7 years. Pediatrics 2006; 117:e845–e854 DOI: 10.1097/01.ccm.0000435671.37941.2e
The authors reply:
I
n their accompanying editorial (1) on our article of extracorporeal membrane oxygenation (ECMO) treatment to rescue refractory myocardial dysfunction associated with severe bacterial septic shock (2), Safi and Hollenberg (1) listed purpura fulminans and disseminated intravascular coagulation (DIC) as complications of ECMO. We agree with McLaren
e174
www.ccmjournal.org
et al (3) that these complications were more likely due to septic shock herein. Indeed, severe DIC and purpura fulminans are common features of septic shock (4) and 50% of our patients exhibited marked DIC before ECMO implantation, with a mean platelet count of 20 g/L (range, 23–48) and a mean prothrombin activity of 39% (10–52%). Half of our patients also had severe pneumococcal pneumonia, and purpura fulminans was due to bacteremic diffuse pneumococcal disease in the two patients (patients 7 and 13) who suffered severe distal ischemia. Alternatively, coagulation disorders and thrombopenia are frequently reported in ECMO patients (5, 6), which might aggravate DIC and increase the risk of bleeding in these critically ill patients. In the large French series of ECMO for severe influenza A (H1N1)-associated acute respiratory distress syndrome (7), 53% of the patients had at least one complication possibly related to ECMO, mainly hemorrhage, cannula site infection, and deep vein thrombosis. Obviously, these complications need to be balanced against delaying ECMO initiation in patients who frequently are dying of refractory cardiac and/or respiratory failure. Lastly, we strongly agree with Safi and Hollenberg (1) that the prevalence of such complications is related to both the experience and the expertise of medical-surgical teams caring for this very specific population of patients and that regionalization of this sort of intensive support modality is now warranted. Dr. Combes consulted for MAQUET. Dr. Bréchot disclosed that he does not have any potential conflicts of interest. Nicolas Bréchot, MD, PhD, Alain Combes, MD, PhD, Medical-Surgical Intensive Care Unit, iCAN, Institute of Cardiometabolism and Nutrition, Hôpital de la Pitié–Salpêtrière, Assistance Publique–Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France
REFERENCES
1. Safi L, Hollenberg SM: Extracorporeal membrane oxygenation to the rescue. Crit Care Med 2013; 41:1805–1806 2. Bréchot N, Luyt CE, Schmidt M, et al: Venoarterial extracorporeal membrane oxygenation support for refractory cardiovascular dysfunction during severe bacterial septic shock. Crit Care Med 2013; 41:1616–1626 3. MacLaren G, Butt W, Peek G, et al: Mistaking Complications of Critical Illness for Those of Critical Care. Crit Care Med 2014; 42: e173–e174 4. Zeerleder S, Hack CE, Wuillemin WA: Disseminated intravascular coagulation in sepsis. Chest 2005; 128:2864–2875 5. Arnold P, Jackson S, Wallis J, et al: Coagulation factor activity during neonatal extra-corporeal membrane oxygenation. Intensive Care Med 2001; 27:1395–1400 6. Heilmann C, Geisen U, Beyersdorf F, et al: Acquired von Willebrand syndrome in patients with extracorporeal life support (ECLS). Intensive Care Med 2012; 38:62–68 7. Pham T, Combes A, Rozé H, et al; REVA Research Network: Extracorporeal membrane oxygenation for pandemic influenza A(H1N1)-induced acute respiratory distress syndrome: A cohort study and propensity-matched analysis. Am J Respir Crit Care Med 2013; 187:276–285 DOI: 10.1097/CCM.0000000000000096
February 2014 • Volume 42 • Number 2
