Editorials 3. Henter JI, Samuelsson-Horne A, Aricò M, et al; Histocyte Society: Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. Blood 2002; 100:2367–2373 4. Castillo L, Carcillo J: Secondary hemophagocytic lymphohistiocytosis and severe sepsis/systemic inflammatory response syndrome/multiorgan dysfunction syndrome/macrophage activation syndrome share common intermediate phenotypes on a spectrum of inflammation. Pediatr Crit Care Med 2009; 10:387–392 5. Bryceson YT, Pende D, Maul-Pavicic A, et al: A prospective evaluation of degranulation assays in the rapid diagnosis of familial hemophagocytic syndromes. Blood 2012; 119:2754–2763 6. Halstead ES, Carcillo JA, Schilling B, et al: Reduced frequency of CD56 dim CD16 pos natural killer cells in pediatric systemic inflammatory response syndrome/sepsis patients. Pediatr Res 2013; 74:427–432 7. Demirkol D, Yildizdas D, Bayrakci B, et al; Turkish Secondary HLH/ MAS Critical Care Study Group: Hyperferritinemia in the critically ill child with secondary hemophagocytic lymphohistiocytosis/sepsis/ multiple organ dysfunction syndrome/macrophage activation syndrome: What is the treatment? Crit Care 2012; 16:R52 8. Kelly A, Ramanan AV: A case of macrophage activation syndrome successfully treated with anakinra. Nat Clin Pract Rheumatol 2008; 4:615–620 9. Bruck N, Suttorp M, Kabus M, et al: Rapid and sustained remission of systemic juvenile idiopathic arthritis-associated macrophage activation syndrome through treatment with anakinra and corticosteroids. J Clin Rheumatol 2011; 17:23–27 10. Loh NK, Lucas M, Fernandez S, et al: Successful treatment of macrophage activation syndrome complicating adult Still disease with anakinra. Intern Med J 2012; 42:1358–1362 11. Tayer-Shifman OE, Ben-Chetrit E: Refractory macrophage activation syndrome in a patient with SLE and APLA syndrome—Successful use of PET-CT and Anakinra in its diagnosis and treatment. Mod Rheumat 2013 Oct 21. [Epub ahead of print]
12. Rajasekaran S, Kruse K, Kovey K, et al: Therapeutic Role of Anakinra, an Interleukin-1 Receptor Antagonist, in the Management of Secondary Hemophagocytic Lymphohistiocytosis/Sepsis/ Multiple Organ Dysfunction/Macrophage Activating Syndrome in Critically Ill Children. Pediatr Crit Care Med 2014; 15: 401–408 13. Teachey DT, Rheingold SR, Maude SL, et al: Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy. Blood 2013; 121:5154–5157 14. Estlin EJ, Palmer RD, Windebank KP, et al: Successful treatment of non-familial haemophagocytic lymphohistiocytosis with interferon and gammaglobulin. Arch Dis Child 1996; 75:432–435 15. Shakoory B, Carcillo J, Zhao H, et al: IL-1 receptor antagonist improves mortality in severe sepsis subset with hemophagocytic syndrome. Abstr. Crit Care Med 2013; 41:A1105 16. Behrens EM, Canna SW, Slade K, et al: Repeated TLR9 stimulation results in macrophage activation syndrome-like disease in mice. J Clin Invest 2011; 121:2264–2277 17. Tsujimoto H, Ono S, Matsumoto A, et al: A critical role of CpG motifs in a murine peritonitis model by their binding to highly expressed toll-like receptor-9 on liver NKT cells. J Hepatol 2006; 45: 836–843 18. Petrasek J, Dolganiuc A, Csak T, et al: Type I interferons protect from Toll-like receptor 9-associated liver injury and regulate IL-1 receptor antagonist in mice. Gastroenterology 2011; 140:697–708.e4 19. Ruddell RG, Hoang-Le D, Barwood JM, et al: Ferritin functions as a proinflammatory cytokine via iron-independent protein kinase C zeta/ nuclear factor kappaB-regulated signaling in rat hepatic stellate cells. Hepatology 2009; 49:887–900 20. Rosário C, Zandman-Goddard G, Meyron-Holtz EG, et al: The hyperferritinemic syndrome: Macrophage activation syndrome, Still’s disease, septic shock and catastrophic antiphospholipid syndrome. BMC Med 2013; 11:185
Transfusion Practices in Evolution, Not Revolution* Scot T. Bateman, MD Department of Pediatrics University of Massachusetts Medical School Worcester, MA
R
BC transfusion practices in the PICU and adult ICUs are undergoing an evolution. Slowly, practice is changing, as more and more of those in our field appreciate the risks inherent in transfusions for our ICU patients. There are many researchers and clinicians who might have expected a revolution of practice with the mounting evidence against a liberal transfusion practice, particularly in hemodynamically stable, nonbleeding ICU patients (1, 2). The results are clear and convincing in favor *See also p. 409. Key Words: packed red blood cell; transfusion threshold The author has disclosed that he does not have any potential conflicts of interest. Copyright © 2014 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10.1097/PCC.0000000000000136
488
www.pccmjournal.org
of restricting blood transfusions in these patients, but translating that into clinical practice remains a process of change. The Transfusion Requirement in PICU (TRIPICU) study published in 2007 remains a seminal article for our field, yet to focus on the date of publication as a focal point does not factor in the depth of beliefs of the powers of blood to improve outcomes. If the evidence presented was related to a drug we had used, there more than likely would have been a faster adoption of restricting its use. Blood, as a therapy, has a long and intriguing history of serious highs (saving combat injured soldiers) and lows (HIV-tainted blood in the 1980s) but remains captivating as a therapy. The book by Starr (3) is a fascinating review of how blood has entered our psyche. He states, “Blood is one of the world’s most vital medical commodities: The liquid and its derivatives save millions of lives each year. Yet blood is a complex resource not completely understood, easily contaminated, and bearing more than its share of cultural baggage. Indeed, the mythic and moral symbolism of blood, which has been with us since ancient times, subtly endures” (3). That blood saves lives and improves the well-being of our patients was something that most of us who have practiced for 10 years or more learned in our training. It was ingrained into our practice. In fact, in the mid 2000s some centers actively declined June 2014 • Volume 15 • Number 5
Editorials
participation in the TRIPICU study, essentially because of the belief that our transfusion thresholds were appropriate and the fear that the restrictive approach would place our patients at risk. I was at one of those centers and vividly remember the data being presented about the TRIPICU study design, justifying equipoise for the two arms of the project, and having a vote go against joining the study. Clearly at that point in our evolution of blood product use, despite the infectious scandals of the 1980s, packed RBC transfusions were considered a safe and a necessary treatment. It is not surprising to see that incorporating the mounting evidence against liberal transfusion in the ICU has required time and ongoing efforts to prove that the results from a trial like TRIPICU were in fact valid and worthy enough to change practice. The results over time have been promising, though not revolutionary. In this issue of Pediatric Critical Care Medicine, Du Pont-Thibodeau et al (4) report the results of a survey of pediatric intensivist’s opinion, initially conducted in 1997 and then repeated in 2010, about transfusion thresholds in various clinical scenarios with stable but critically ill children. Their hypothesis was that in those intervening years, most clinicians should be aware of the recommendations for lower transfusion triggers. The drop in reported threshold, though comparing a largely European physician cohort in 1997 to a more North American cohort in 2010, does support the idea that clinicians are beginning to incorporate this evidence into their practice. They are still not to a level supported by the evidence, but the trend continues to improve. The number of clinicians who chose a restrictive approach as defined by the TRIPICU study has significantly increased. Physician’s hypothetical responses to a survey question have been corroborated by actual transfusion data. Dallman et al (5) reported a decrease in transfusions in a PICU over a 10-year period and a change in pretransfusion hemoglobin from 10.5 to only 9.3. A similar study done by Valentine et al (6) showed that the average hemoglobin thresholds have significantly dropped (8.0–7.5 g/dL) in stable PICU patients, but over two thirds of children were still receiving transfusions for a hemoglobin level of greater than 7.0 g/dL. Looking at their data more closely, however, there was a trend toward a restrictive practice over time because the number of transfusions given for a hemoglobin greater than 7 g/dL decreased from 75% in 2009 to 64% in 2010. The TRIPICU results published in 2007 did cause most in our field to pause and ponder. It was an evolutionary mutation in the mindset of our field that affected a few at first and has started spreading. Starting with the safest patients, those who are hemodynamically stable, we have been learning through experience and ongoing research that holding on transfusions is okay for a wide variety of PICU patients. The key is helping sustain that shift in practice. Substantial evidence suggests that changing behavior is possible, but this change generally requires comprehensive approaches at different levels (doctor, team practice, hospital, and wider environment), tailored to specific settings and target groups (7). With blood and its unique place in the mindset of clinicians, those efforts need to continue. The multipronged efforts to make our blood transfusion thresholds more accountable continue to help move us along.
Pediatric Critical Care Medicine
Computerized order entry with transfusion algorithms has shown promise in this field (8). Behavioral scientists have been evaluating systems to help clinicians understand their beliefs related to transfusions (9, 10). Patient education as well has begun in earnest. The Choosing Wisely Campaign started by the American Board of Internal Medicine has created a forum to educate physicians and patients about key clinical topics. The Critical Care Societies Collaborative-Critical Care with endorsement from the major critical care societies has recently created a list of five things that all critical care physicians and patients should know (11). Number 2 on the list is, “Don’t transfuse red blood cells in hemodynamically stable, non-bleeding ICU patients with a hemoglobin concentration greater than 7 g/dL.” This is primarily based on adult data, but there is enough pediatric data to endorse the same statement for children. Our field has smart, caring, and cautious people whose opinions matter when it comes to the safety of our critically ill children and the therapies we choose. Articles, such as the one by Du Pont-Thibodeau et al (4), show that these opinions are changeable and educable (even among the older professors in the survey). We are becoming a more enlightened group about the careful use of transfusions, and with time, our patients will get fewer and fewer unnecessary transfusions.
REFERENCES
1. Lacroix J, Hébert PC, Hutchison JS, et al; TRIPICU Investigators; Canadian Critical Care Trials Group; Pediatric Acute Lung Injury and Sepsis Investigators Network: Transfusion strategies for patients in pediatric intensive care units. N Engl J Med 2007; 356:1609–1619 2. Carson JL, Carless PA, Hebert PC: Transfusion thresholds and other strategies for guiding allogenic red blood cell transfusions. Cochrane Database Syst Rev 2012; 4:CD002042 3. Starr D: Blood: An Epic History of Medicine and Commerce. New York, NY, Alfred A. Knopf, 2002, p. xii 4. Du Pont-Thibodeau G, Tucci M, Ducruet T, et al: Survey on Stated Transfusion Practices in PICUs. Pediatr Crit Care Med 2014; 15:409–416 5. Dallman MD, Liu X, Harris AD, et al: Changes in transfusion practice over time in the PICU. Pediatr Crit Care Med 2013; 14:843–850 6. Valentine SL, Lightdale JR, Tran CM, et al: Assessment of hemoglobin threshold for packed RBC transfusion in a medical-surgical PICU. Pediatr Crit Care Med 2014; 15:e89–e94 7. Grol R, Grimshaw J: From best evidence to best practice: Effective implementation of change in patients’ care. Lancet 2003; 362:1225–1230 8. Adams ES, Longhurst CA, Pageler N, et al: Computerized physician order entry with decision support decreases blood transfusions in children. Pediatrics 2011; 127:e1112–e1119 9. Tinmouth A, Macdougall L, Fergusson D, et al: Reducing the amount of blood transfused: A systematic review of behavioral interventions to change physicians’ transfusion practices. Arch Intern Med 2005; 165:845–852 10. Islam R, Tinmouth AT, Francis JJ, et al: A cross-country comparison of intensive care physicians’ beliefs about their transfusion behaviour: A qualitative study using the Theoretical Domains Framework. Implement Sci 2012; 7:93 11. Halpern SD, Becker D, Curtis JR, et al; on behalf of the Critical Care Societies Collaborative-Critical Care (American Association of Critical Care Nurses, American College of Physicians, American Thoracic Society, and Society of Critical Care Medicine): Choosing Wisely: Five things physicians and patients should question. Available at: http://www.choosingwisely.org. Accessed January 27, 2014
www.pccmjournal.org
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12. Rajasekaran S, Kruse K, Kovey K, et al: Therapeutic Role of Anakinra, an Interleukin-1 Receptor Antagonist, in the Management of Secondary Hemophagocytic Lymphohistiocytosis/Sepsis/ Multiple Organ Dysfunction/Macrophage Activating Syndrome in Critically Ill Children. Pediatr Crit Care Med 2014; 15: 401–408 13. Teachey DT, Rheingold SR, Maude SL, et al: Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy. Blood 2013; 121:5154–5157 14. Estlin EJ, Palmer RD, Windebank KP, et al: Successful treatment of non-familial haemophagocytic lymphohistiocytosis with interferon and gammaglobulin. Arch Dis Child 1996; 75:432–435 15. Shakoory B, Carcillo J, Zhao H, et al: IL-1 receptor antagonist improves mortality in severe sepsis subset with hemophagocytic syndrome. Abstr. Crit Care Med 2013; 41:A1105 16. Behrens EM, Canna SW, Slade K, et al: Repeated TLR9 stimulation results in macrophage activation syndrome-like disease in mice. J Clin Invest 2011; 121:2264–2277 17. Tsujimoto H, Ono S, Matsumoto A, et al: A critical role of CpG motifs in a murine peritonitis model by their binding to highly expressed toll-like receptor-9 on liver NKT cells. J Hepatol 2006; 45: 836–843 18. Petrasek J, Dolganiuc A, Csak T, et al: Type I interferons protect from Toll-like receptor 9-associated liver injury and regulate IL-1 receptor antagonist in mice. Gastroenterology 2011; 140:697–708.e4 19. Ruddell RG, Hoang-Le D, Barwood JM, et al: Ferritin functions as a proinflammatory cytokine via iron-independent protein kinase C zeta/ nuclear factor kappaB-regulated signaling in rat hepatic stellate cells. Hepatology 2009; 49:887–900 20. Rosário C, Zandman-Goddard G, Meyron-Holtz EG, et al: The hyperferritinemic syndrome: Macrophage activation syndrome, Still’s disease, septic shock and catastrophic antiphospholipid syndrome. BMC Med 2013; 11:185
Transfusion Practices in Evolution, Not Revolution* Scot T. Bateman, MD Department of Pediatrics University of Massachusetts Medical School Worcester, MA
R
BC transfusion practices in the PICU and adult ICUs are undergoing an evolution. Slowly, practice is changing, as more and more of those in our field appreciate the risks inherent in transfusions for our ICU patients. There are many researchers and clinicians who might have expected a revolution of practice with the mounting evidence against a liberal transfusion practice, particularly in hemodynamically stable, nonbleeding ICU patients (1, 2). The results are clear and convincing in favor *See also p. 409. Key Words: packed red blood cell; transfusion threshold The author has disclosed that he does not have any potential conflicts of interest. Copyright © 2014 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10.1097/PCC.0000000000000136
488
www.pccmjournal.org
of restricting blood transfusions in these patients, but translating that into clinical practice remains a process of change. The Transfusion Requirement in PICU (TRIPICU) study published in 2007 remains a seminal article for our field, yet to focus on the date of publication as a focal point does not factor in the depth of beliefs of the powers of blood to improve outcomes. If the evidence presented was related to a drug we had used, there more than likely would have been a faster adoption of restricting its use. Blood, as a therapy, has a long and intriguing history of serious highs (saving combat injured soldiers) and lows (HIV-tainted blood in the 1980s) but remains captivating as a therapy. The book by Starr (3) is a fascinating review of how blood has entered our psyche. He states, “Blood is one of the world’s most vital medical commodities: The liquid and its derivatives save millions of lives each year. Yet blood is a complex resource not completely understood, easily contaminated, and bearing more than its share of cultural baggage. Indeed, the mythic and moral symbolism of blood, which has been with us since ancient times, subtly endures” (3). That blood saves lives and improves the well-being of our patients was something that most of us who have practiced for 10 years or more learned in our training. It was ingrained into our practice. In fact, in the mid 2000s some centers actively declined June 2014 • Volume 15 • Number 5
Editorials
participation in the TRIPICU study, essentially because of the belief that our transfusion thresholds were appropriate and the fear that the restrictive approach would place our patients at risk. I was at one of those centers and vividly remember the data being presented about the TRIPICU study design, justifying equipoise for the two arms of the project, and having a vote go against joining the study. Clearly at that point in our evolution of blood product use, despite the infectious scandals of the 1980s, packed RBC transfusions were considered a safe and a necessary treatment. It is not surprising to see that incorporating the mounting evidence against liberal transfusion in the ICU has required time and ongoing efforts to prove that the results from a trial like TRIPICU were in fact valid and worthy enough to change practice. The results over time have been promising, though not revolutionary. In this issue of Pediatric Critical Care Medicine, Du Pont-Thibodeau et al (4) report the results of a survey of pediatric intensivist’s opinion, initially conducted in 1997 and then repeated in 2010, about transfusion thresholds in various clinical scenarios with stable but critically ill children. Their hypothesis was that in those intervening years, most clinicians should be aware of the recommendations for lower transfusion triggers. The drop in reported threshold, though comparing a largely European physician cohort in 1997 to a more North American cohort in 2010, does support the idea that clinicians are beginning to incorporate this evidence into their practice. They are still not to a level supported by the evidence, but the trend continues to improve. The number of clinicians who chose a restrictive approach as defined by the TRIPICU study has significantly increased. Physician’s hypothetical responses to a survey question have been corroborated by actual transfusion data. Dallman et al (5) reported a decrease in transfusions in a PICU over a 10-year period and a change in pretransfusion hemoglobin from 10.5 to only 9.3. A similar study done by Valentine et al (6) showed that the average hemoglobin thresholds have significantly dropped (8.0–7.5 g/dL) in stable PICU patients, but over two thirds of children were still receiving transfusions for a hemoglobin level of greater than 7.0 g/dL. Looking at their data more closely, however, there was a trend toward a restrictive practice over time because the number of transfusions given for a hemoglobin greater than 7 g/dL decreased from 75% in 2009 to 64% in 2010. The TRIPICU results published in 2007 did cause most in our field to pause and ponder. It was an evolutionary mutation in the mindset of our field that affected a few at first and has started spreading. Starting with the safest patients, those who are hemodynamically stable, we have been learning through experience and ongoing research that holding on transfusions is okay for a wide variety of PICU patients. The key is helping sustain that shift in practice. Substantial evidence suggests that changing behavior is possible, but this change generally requires comprehensive approaches at different levels (doctor, team practice, hospital, and wider environment), tailored to specific settings and target groups (7). With blood and its unique place in the mindset of clinicians, those efforts need to continue. The multipronged efforts to make our blood transfusion thresholds more accountable continue to help move us along.
Pediatric Critical Care Medicine
Computerized order entry with transfusion algorithms has shown promise in this field (8). Behavioral scientists have been evaluating systems to help clinicians understand their beliefs related to transfusions (9, 10). Patient education as well has begun in earnest. The Choosing Wisely Campaign started by the American Board of Internal Medicine has created a forum to educate physicians and patients about key clinical topics. The Critical Care Societies Collaborative-Critical Care with endorsement from the major critical care societies has recently created a list of five things that all critical care physicians and patients should know (11). Number 2 on the list is, “Don’t transfuse red blood cells in hemodynamically stable, non-bleeding ICU patients with a hemoglobin concentration greater than 7 g/dL.” This is primarily based on adult data, but there is enough pediatric data to endorse the same statement for children. Our field has smart, caring, and cautious people whose opinions matter when it comes to the safety of our critically ill children and the therapies we choose. Articles, such as the one by Du Pont-Thibodeau et al (4), show that these opinions are changeable and educable (even among the older professors in the survey). We are becoming a more enlightened group about the careful use of transfusions, and with time, our patients will get fewer and fewer unnecessary transfusions.
REFERENCES
1. Lacroix J, Hébert PC, Hutchison JS, et al; TRIPICU Investigators; Canadian Critical Care Trials Group; Pediatric Acute Lung Injury and Sepsis Investigators Network: Transfusion strategies for patients in pediatric intensive care units. N Engl J Med 2007; 356:1609–1619 2. Carson JL, Carless PA, Hebert PC: Transfusion thresholds and other strategies for guiding allogenic red blood cell transfusions. Cochrane Database Syst Rev 2012; 4:CD002042 3. Starr D: Blood: An Epic History of Medicine and Commerce. New York, NY, Alfred A. Knopf, 2002, p. xii 4. Du Pont-Thibodeau G, Tucci M, Ducruet T, et al: Survey on Stated Transfusion Practices in PICUs. Pediatr Crit Care Med 2014; 15:409–416 5. Dallman MD, Liu X, Harris AD, et al: Changes in transfusion practice over time in the PICU. Pediatr Crit Care Med 2013; 14:843–850 6. Valentine SL, Lightdale JR, Tran CM, et al: Assessment of hemoglobin threshold for packed RBC transfusion in a medical-surgical PICU. Pediatr Crit Care Med 2014; 15:e89–e94 7. Grol R, Grimshaw J: From best evidence to best practice: Effective implementation of change in patients’ care. Lancet 2003; 362:1225–1230 8. Adams ES, Longhurst CA, Pageler N, et al: Computerized physician order entry with decision support decreases blood transfusions in children. Pediatrics 2011; 127:e1112–e1119 9. Tinmouth A, Macdougall L, Fergusson D, et al: Reducing the amount of blood transfused: A systematic review of behavioral interventions to change physicians’ transfusion practices. Arch Intern Med 2005; 165:845–852 10. Islam R, Tinmouth AT, Francis JJ, et al: A cross-country comparison of intensive care physicians’ beliefs about their transfusion behaviour: A qualitative study using the Theoretical Domains Framework. Implement Sci 2012; 7:93 11. Halpern SD, Becker D, Curtis JR, et al; on behalf of the Critical Care Societies Collaborative-Critical Care (American Association of Critical Care Nurses, American College of Physicians, American Thoracic Society, and Society of Critical Care Medicine): Choosing Wisely: Five things physicians and patients should question. Available at: http://www.choosingwisely.org. Accessed January 27, 2014
www.pccmjournal.org
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