Online Letters to the Editor
REFERENCES
1. Fuller BM, Wessman BT: Training Emergency Physicians to Meet the Critical Care Needs in the United States: A Consensus of Two. Crit Care Med 2014; 42:e677–e678 2. Critical Care Societies Collaborative Task Force: Training internists to meet critical care needs in the United States: A consensus statement from the Critical Care Societies Collaborative (CCSC). Crit Care Med 2014; 42:1272–1279 DOI: 10.1097/CCM.0000000000000531
Mortality in Pediatric Patients Receiving Centrifugal-Pump Extracorporeal Membrane Oxygenation: Time, Hemolysis, or Both To the Editor:
I
n a recent article by Lou et al (1), the well-known problem of hemolysis has been analyzed. Several variables such as age, weight, preexisting diagnosis, extracorporeal membrane oxygenation (ECMO) method, oxygenator type, and circuit pressures were assessed. The degree of hemolysis was defined as none when the plasma-free hemoglobin (PFH) level was less than or equal to 0.1 g/L, mild when the PFH was 0.1–0.5 g/L, moderate at 0.5–1.0 g/L, and severe when the PFH was greater than 1.0 g/L. Hemolysis is ubiquitous with implementation of ECMO treatment. Earlier studies showed that it often can be managed with circuit changes (2). The most prominent side effect of ECMO-enhanced hemolysis is renal toxicity and fluid balance derangements (3). However, treating hemoglobinuria nephropathy and renal failure can be complex, as the additional dialysis circuit can further hemolyze the red cells (4). The article by Lou et al (1) does not tie the hemolysis toxicity to renal changes. Free hemoglobin can be viewed as a contributing factor to a patient’s demise in many critical care syndromes (5). Hemoglobin-mediated nitric oxide scavenging is a plausible mechanism to explain a multisystem effect. It is indeed reasonable to hypothesize that some of the extensive spectrum of complications associated with ECMO is related to hemolysis/PFH. The authors informed us that the results confirm the hypothesis: after adjusting for age, weight, and pediatric index of mortality, “patients with severe hemolysis were more likely to die ... in hospital” (odds ratio, 6.34; 95% CI, 1.71–23.54). ECMO support can curtail an initial catastrophic course. If the underlying disease is reversible, then over time the patient will survive. However, catastrophic necrotizing myocarditis requires a heart transplant because ECMO is not per se curative. The time to act is limited, as ECMO increases the chances for a wide range of complications. Hemolysis/PFH is a time-dependent event, as shown in the literature and also from the data collection by Lou et al (1). The ECMO time reported for no hemolysis was 81 hours, 117 hours for mild hemolysis, 129 hours for moderate hemolysis, and 200 hours for severe hemolysis. Mortality and hemolysis increased with time. How much additional mortality is attributed to the level of hemolysis? The answer is not provided by the statistical Critical Care Medicine
structure of the model selected. Time and the degree of hemolysis are combined, and the conclusion is that mortality is higher for patients with severe hemolysis and longer periods of time on ECMO. A longitudinal time-based model might have been more informative. It could also provide us information about the role of circuit changes. There is enough evidence to suggest that iatrogenic hemolysis may be a contributor to critical care mortality, and hemolysis associated with ECMO is no exception. Every effort needs to be directed toward minimizing it. It is important to define the role of hemolysis in mortality over time. The combined analysis simply affirms a priori acceptance of the hypothesis. This work was performed at the University of Tennessee Health Science Center, Memphis, TN. Dr. Spentzas conceptualized, designed, drafted, and approved the final manuscript as submitted. The author has disclosed that he does not have any potential conflicts of interest. Thomas Spentzas, MD, MS, , Department of Pediatrics, University of Tennessee Health Science Center, Le Bonheur Children’s Hospital, Memphis, TN
REFERENCES
1. Lou S, MacLaren G, Best D, et al: Hemolysis in Pediatric Patients Receiving Centrifugal-Pump Extracorporeal Membrane Oxygenation: Prevalence, Risk Factors, and Outcomes. Crit Care Med 2014; 42:1213–1220 2. Steinhorn RH, Isham-Schopf B, Smith C, et al: Hemolysis during long-term extracorporeal membrane oxygenation. J Pediatr 1989; 115:625–630 3. Gbadegesin R, Zhao S, Charpie J, et al: Significance of hemolysis on extracorporeal life support after cardiac surgery in children. Pediatr Nephrol 2009; 24:589–595 4. Betrus C, Remenapp R, Charpie J, et al: Enhanced hemolysis in pediatric patients requiring extracorporeal membrane oxygenation and continuous renal replacement therapy. Ann Thorac Cardiovasc Surg 2007; 13:378–383 5. Rother RP, Bell L, Hillmen P, et al: The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: A novel mechanism of human disease. JAMA 2005; 293:1653–1662 DOI: 10.1097/CCM.0000000000000478
The authors reply:
W
e thank Dr. Spentzas (1) for the comments he made on our article. We demonstrated that hemolysis is common with extracorporeal membrane oxygenation (ECMO) (but not ubiquitous) and that severe hemolysis was associated with significant increases in ECMO duration, blood-product administration, and death (2). Spentzas has criticized the design of our study that it is unable to distinguish between the effects of hemolysis and ECMO duration on mortality. We agree completely. Does prolonged ECMO lead to more hemolysis, or does hemolysis cause organ damage that leads to longer ECMO runs? Are the multiple organ diseases for which ECMO is increasingly being used more likely to cause hemolysis or be associated with longer ECMO runs? These important questions are not www.ccmjournal.org
e679
Online Letters to the Editor
answered by our study. We confirmed an association but did not establish cause and effect. Our definition of hemolysis was based on the single highest level of plasma-free hemoglobin (PFH) at any point in the ECMO run. It would probably be more enlightening to look at PFH over time. The reason we did not adopt such a longitudinal time-based model is because this was a retrospective study with inconsistencies in the timing of PFH measurements. The model Spentzas recommends would be better served by a prospective study, one which we have already commenced. Although hemolysis from extracorporeal circuitry has been well studied, there is much that is not understood. We agree with Spentzas that more effort needs to be made in studying the mechanisms of hemolysis-induced organ failure and discovering how to minimize them. Our study (2) simply provides a starting point. The work was performed at the Royal Children’s Hospital, Melbourne, Australia. The authors have disclosed that they do not have any potential conflicts of interest. Graeme MacLaren, MBBS, FCCM, Paediatric Intensive Care Unit, Royal Children’s Hospital, Melbourne, Australia, Department of Paediatrics, University of Melbourne, Melbourne, Australia, and Cardiothoracic Intensive Care Unit, National University Health System, Singapore; Song Lou, MD, Paediatric Intensive Care Unit, Royal Children’s Hospital, Melbourne, Australia, and Department of Cardiopulmonary Bypass, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; Warwick Butt, MBBS, FRACP, FCICM, Paediatric Intensive Care Unit, Royal Children’s Hospital, Melbourne, Australia, and Department of Paediatrics, University of Melbourne, Melbourne, Australia
REFERENCES
1. Spentzas T: Mortality in Pediatric Patients Receiving CentrifugalPump Extracorporeal Membrane Oxygenation: Time, Hemolysis, or Both. Crit Care Med 2014; 42:e679 2. Lou S, MacLaren G, Best D, et al: Hemolysis in pediatric patients receiving centrifugal-pump extracorporeal membrane oxygenation: Prevalence, risk factors, and outcomes. Crit Care Med 2014; 42:1213–1220 DOI: 10.1097/CCM.0000000000000533
Evaluation of the Effectiveness and Safety of the Awakening and Breathing Coordination, Delirium Monitoring/Management, and Early Exercise/Mobility Bundle: Several Confounders to be Considered To the Editor:
I
n a recent with great Balas et al implementing e680
issue of Critical Care Medicine, we have read interest the prospective before-after study by (1) who investigated the benefit and harm of the Awakening and Breathing Coordination,
www.ccmjournal.org
Delirium monitoring/management, and Early exercise/mobility (ABCDE) bundle into everyday practice. In the study, the authors showed that in a diverse group of critically ill patients, implementation of the ABCDE bundle resulted in reduced time on the ventilator, less delirium, and more time spent out of bed compared with patients not treated with the bundle. Additionally, the study suggested that no significant differences were noted in self-extubation or reintubation rates pre- versus post-ABCDE bundle implementation. Consequently, the authors concluded that the ABCDE bundle appears to be a valuable tool in the management of critically ill patients. We acknowledge the authors for their effort to explore the effectiveness and safety of a multicomponent ICU management strategy in a critical care setting. The following key thoughts occurred to us after reviewing the study. As noted, patients in the postimplementation period were significantly younger than those in the preimplementation period (55.6 ± 14.9 vs 59.2 ± 16.1; p = 0.05). Given that older age is one of the most important predisposing factors for triggering delirium (2), the difference may supposedly influence the effect of evaluation on delirium monitoring/management. Similarly, the Acute Physiology and Chronic Health Evaluation (APACHE) II scores of patients in the postimplementation period differ considerably from those in the preimplementation period in spite of its negative statistical significance (21 [16–28] vs 23.5 [17–29]; p = 0.08). As we know, the APACHE II score is positively correlated with severity of illness, and the smaller APACHE II scores in the postimplementation period would lead us to form a feel that better outcomes of patients in the postimplementation period are owing to less severity of illness rather than the ABCDE bundle. Furthermore, we also noticed that the number of patients treated with benzodiazepine (51.3% vs 62.3%; p = 0.06) and the average daily dose of benzodiazepine (1.7 [0.4–7.8] vs 2.8 [1–12.7]; p = 0.09) in the postimplementation phase are less than those in the preimplementation phase, which may help patients experience less delirium (3–5). In a word, there are not a few possible confounders affecting the reliability of the conclusion. Thereby, the conclusion by Balas et al (1) should be taken cautiously. Apart from its relatively small sample size, we are amazed at the condition that 17 patients were excluded at the enrollment for non-English speaking, which, we believe, might not be a sufficient reason to exclude them. Finally, we would like to consult the authors on how they recognize and diagnose and deal with hypoactive delirium during the study period. In conclusion, we believe that before applying the ABCDE bundle to everyday practice on a large scale, prospective randomized controlled trials evaluating both the effectiveness and safety of this bundle are warranted. So, we with pleasure remind authors of this article to take that into consideration. The authors have disclosed that they do not have any potential conflicts of interest. Lei Yang, MM, Ligang Ye, MM, Zhongjun Zheng, MM, Mao Zhang, MD, PhD Department of Emergency Medicine, Second Affiliated Hospital, School of Medicine and Institute of Emergency Medicine, Zhejiang University, Hangzhou, China October 2014 • Volume 42 • Number 10
REFERENCES
1. Fuller BM, Wessman BT: Training Emergency Physicians to Meet the Critical Care Needs in the United States: A Consensus of Two. Crit Care Med 2014; 42:e677–e678 2. Critical Care Societies Collaborative Task Force: Training internists to meet critical care needs in the United States: A consensus statement from the Critical Care Societies Collaborative (CCSC). Crit Care Med 2014; 42:1272–1279 DOI: 10.1097/CCM.0000000000000531
Mortality in Pediatric Patients Receiving Centrifugal-Pump Extracorporeal Membrane Oxygenation: Time, Hemolysis, or Both To the Editor:
I
n a recent article by Lou et al (1), the well-known problem of hemolysis has been analyzed. Several variables such as age, weight, preexisting diagnosis, extracorporeal membrane oxygenation (ECMO) method, oxygenator type, and circuit pressures were assessed. The degree of hemolysis was defined as none when the plasma-free hemoglobin (PFH) level was less than or equal to 0.1 g/L, mild when the PFH was 0.1–0.5 g/L, moderate at 0.5–1.0 g/L, and severe when the PFH was greater than 1.0 g/L. Hemolysis is ubiquitous with implementation of ECMO treatment. Earlier studies showed that it often can be managed with circuit changes (2). The most prominent side effect of ECMO-enhanced hemolysis is renal toxicity and fluid balance derangements (3). However, treating hemoglobinuria nephropathy and renal failure can be complex, as the additional dialysis circuit can further hemolyze the red cells (4). The article by Lou et al (1) does not tie the hemolysis toxicity to renal changes. Free hemoglobin can be viewed as a contributing factor to a patient’s demise in many critical care syndromes (5). Hemoglobin-mediated nitric oxide scavenging is a plausible mechanism to explain a multisystem effect. It is indeed reasonable to hypothesize that some of the extensive spectrum of complications associated with ECMO is related to hemolysis/PFH. The authors informed us that the results confirm the hypothesis: after adjusting for age, weight, and pediatric index of mortality, “patients with severe hemolysis were more likely to die ... in hospital” (odds ratio, 6.34; 95% CI, 1.71–23.54). ECMO support can curtail an initial catastrophic course. If the underlying disease is reversible, then over time the patient will survive. However, catastrophic necrotizing myocarditis requires a heart transplant because ECMO is not per se curative. The time to act is limited, as ECMO increases the chances for a wide range of complications. Hemolysis/PFH is a time-dependent event, as shown in the literature and also from the data collection by Lou et al (1). The ECMO time reported for no hemolysis was 81 hours, 117 hours for mild hemolysis, 129 hours for moderate hemolysis, and 200 hours for severe hemolysis. Mortality and hemolysis increased with time. How much additional mortality is attributed to the level of hemolysis? The answer is not provided by the statistical Critical Care Medicine
structure of the model selected. Time and the degree of hemolysis are combined, and the conclusion is that mortality is higher for patients with severe hemolysis and longer periods of time on ECMO. A longitudinal time-based model might have been more informative. It could also provide us information about the role of circuit changes. There is enough evidence to suggest that iatrogenic hemolysis may be a contributor to critical care mortality, and hemolysis associated with ECMO is no exception. Every effort needs to be directed toward minimizing it. It is important to define the role of hemolysis in mortality over time. The combined analysis simply affirms a priori acceptance of the hypothesis. This work was performed at the University of Tennessee Health Science Center, Memphis, TN. Dr. Spentzas conceptualized, designed, drafted, and approved the final manuscript as submitted. The author has disclosed that he does not have any potential conflicts of interest. Thomas Spentzas, MD, MS, , Department of Pediatrics, University of Tennessee Health Science Center, Le Bonheur Children’s Hospital, Memphis, TN
REFERENCES
1. Lou S, MacLaren G, Best D, et al: Hemolysis in Pediatric Patients Receiving Centrifugal-Pump Extracorporeal Membrane Oxygenation: Prevalence, Risk Factors, and Outcomes. Crit Care Med 2014; 42:1213–1220 2. Steinhorn RH, Isham-Schopf B, Smith C, et al: Hemolysis during long-term extracorporeal membrane oxygenation. J Pediatr 1989; 115:625–630 3. Gbadegesin R, Zhao S, Charpie J, et al: Significance of hemolysis on extracorporeal life support after cardiac surgery in children. Pediatr Nephrol 2009; 24:589–595 4. Betrus C, Remenapp R, Charpie J, et al: Enhanced hemolysis in pediatric patients requiring extracorporeal membrane oxygenation and continuous renal replacement therapy. Ann Thorac Cardiovasc Surg 2007; 13:378–383 5. Rother RP, Bell L, Hillmen P, et al: The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: A novel mechanism of human disease. JAMA 2005; 293:1653–1662 DOI: 10.1097/CCM.0000000000000478
The authors reply:
W
e thank Dr. Spentzas (1) for the comments he made on our article. We demonstrated that hemolysis is common with extracorporeal membrane oxygenation (ECMO) (but not ubiquitous) and that severe hemolysis was associated with significant increases in ECMO duration, blood-product administration, and death (2). Spentzas has criticized the design of our study that it is unable to distinguish between the effects of hemolysis and ECMO duration on mortality. We agree completely. Does prolonged ECMO lead to more hemolysis, or does hemolysis cause organ damage that leads to longer ECMO runs? Are the multiple organ diseases for which ECMO is increasingly being used more likely to cause hemolysis or be associated with longer ECMO runs? These important questions are not www.ccmjournal.org
e679
Online Letters to the Editor
answered by our study. We confirmed an association but did not establish cause and effect. Our definition of hemolysis was based on the single highest level of plasma-free hemoglobin (PFH) at any point in the ECMO run. It would probably be more enlightening to look at PFH over time. The reason we did not adopt such a longitudinal time-based model is because this was a retrospective study with inconsistencies in the timing of PFH measurements. The model Spentzas recommends would be better served by a prospective study, one which we have already commenced. Although hemolysis from extracorporeal circuitry has been well studied, there is much that is not understood. We agree with Spentzas that more effort needs to be made in studying the mechanisms of hemolysis-induced organ failure and discovering how to minimize them. Our study (2) simply provides a starting point. The work was performed at the Royal Children’s Hospital, Melbourne, Australia. The authors have disclosed that they do not have any potential conflicts of interest. Graeme MacLaren, MBBS, FCCM, Paediatric Intensive Care Unit, Royal Children’s Hospital, Melbourne, Australia, Department of Paediatrics, University of Melbourne, Melbourne, Australia, and Cardiothoracic Intensive Care Unit, National University Health System, Singapore; Song Lou, MD, Paediatric Intensive Care Unit, Royal Children’s Hospital, Melbourne, Australia, and Department of Cardiopulmonary Bypass, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; Warwick Butt, MBBS, FRACP, FCICM, Paediatric Intensive Care Unit, Royal Children’s Hospital, Melbourne, Australia, and Department of Paediatrics, University of Melbourne, Melbourne, Australia
REFERENCES
1. Spentzas T: Mortality in Pediatric Patients Receiving CentrifugalPump Extracorporeal Membrane Oxygenation: Time, Hemolysis, or Both. Crit Care Med 2014; 42:e679 2. Lou S, MacLaren G, Best D, et al: Hemolysis in pediatric patients receiving centrifugal-pump extracorporeal membrane oxygenation: Prevalence, risk factors, and outcomes. Crit Care Med 2014; 42:1213–1220 DOI: 10.1097/CCM.0000000000000533
Evaluation of the Effectiveness and Safety of the Awakening and Breathing Coordination, Delirium Monitoring/Management, and Early Exercise/Mobility Bundle: Several Confounders to be Considered To the Editor:
I
n a recent with great Balas et al implementing e680
issue of Critical Care Medicine, we have read interest the prospective before-after study by (1) who investigated the benefit and harm of the Awakening and Breathing Coordination,
www.ccmjournal.org
Delirium monitoring/management, and Early exercise/mobility (ABCDE) bundle into everyday practice. In the study, the authors showed that in a diverse group of critically ill patients, implementation of the ABCDE bundle resulted in reduced time on the ventilator, less delirium, and more time spent out of bed compared with patients not treated with the bundle. Additionally, the study suggested that no significant differences were noted in self-extubation or reintubation rates pre- versus post-ABCDE bundle implementation. Consequently, the authors concluded that the ABCDE bundle appears to be a valuable tool in the management of critically ill patients. We acknowledge the authors for their effort to explore the effectiveness and safety of a multicomponent ICU management strategy in a critical care setting. The following key thoughts occurred to us after reviewing the study. As noted, patients in the postimplementation period were significantly younger than those in the preimplementation period (55.6 ± 14.9 vs 59.2 ± 16.1; p = 0.05). Given that older age is one of the most important predisposing factors for triggering delirium (2), the difference may supposedly influence the effect of evaluation on delirium monitoring/management. Similarly, the Acute Physiology and Chronic Health Evaluation (APACHE) II scores of patients in the postimplementation period differ considerably from those in the preimplementation period in spite of its negative statistical significance (21 [16–28] vs 23.5 [17–29]; p = 0.08). As we know, the APACHE II score is positively correlated with severity of illness, and the smaller APACHE II scores in the postimplementation period would lead us to form a feel that better outcomes of patients in the postimplementation period are owing to less severity of illness rather than the ABCDE bundle. Furthermore, we also noticed that the number of patients treated with benzodiazepine (51.3% vs 62.3%; p = 0.06) and the average daily dose of benzodiazepine (1.7 [0.4–7.8] vs 2.8 [1–12.7]; p = 0.09) in the postimplementation phase are less than those in the preimplementation phase, which may help patients experience less delirium (3–5). In a word, there are not a few possible confounders affecting the reliability of the conclusion. Thereby, the conclusion by Balas et al (1) should be taken cautiously. Apart from its relatively small sample size, we are amazed at the condition that 17 patients were excluded at the enrollment for non-English speaking, which, we believe, might not be a sufficient reason to exclude them. Finally, we would like to consult the authors on how they recognize and diagnose and deal with hypoactive delirium during the study period. In conclusion, we believe that before applying the ABCDE bundle to everyday practice on a large scale, prospective randomized controlled trials evaluating both the effectiveness and safety of this bundle are warranted. So, we with pleasure remind authors of this article to take that into consideration. The authors have disclosed that they do not have any potential conflicts of interest. Lei Yang, MM, Ligang Ye, MM, Zhongjun Zheng, MM, Mao Zhang, MD, PhD Department of Emergency Medicine, Second Affiliated Hospital, School of Medicine and Institute of Emergency Medicine, Zhejiang University, Hangzhou, China October 2014 • Volume 42 • Number 10
