Editorials 9. Azoulay E, Pochard F, Chevret S, et al; French FAMIREA Group: Meeting the needs of intensive care unit patient families: A multicenter study. Am J Respir Crit Care Med 2001; 163:135–139 10. Meert KL, Templin TN: Validity of family satisfaction measures: An ongoing process. Pediatr Crit Care Med 2013; 14:826–827 11. Lanken PN, Terry PB, Delisser HM, et al; ATS End-of-Life Care Task Force: An official American Thoracic Society clinical policy statement: Palliative care for patients with respiratory diseases and critical illnesses. Am J Respir Crit Care Med 2008; 177:912–927 12. Feudtner C, Nathanson PG: Pediatric palliative care and pediatric medical ethics: Effects opportunities and challenges. Pediatrics 2014; 133(Suppl 1):S1–S7 13. Nelson LP, Gold JI: Posttraumatic stress disorder in children and their parents following admission to the pediatric intensive care unit: A review. Pediatr Crit Care Med 2012; 13:338–347 14. Davidson JP: Family response to critical illness: Post intensive care syndrome-family. Crit Care Med 2012; 40:618–624
15. Yuen JK, Mehta SS, Roberts JE, et al: A brief educational intervention to teach residents shared decision making in the intensive care unit. J Palliat Med 2013; 16:531–536 16. Curtis JR, Back AL, Ford DW, et al: Effect of communication skills training for residents and nurse practitioners on quality of communication with patients with serious illness: A randomized trial. JAMA 2013; 310:2271–2281 17. Kamel G, Paniagua M, Uppalapati A: Palliative care in the intensive care unit: Are residents well trained to provide optimal care to critically ill patients? Am J Hosp Palliat Care 2014 May 30. [Epub ahead of print] 18. Schiffman JD, Chamberlain LJ, Palmer L, et al: Introduction of a pediatric palliative care curriculum for pediatric residents. J Palliat Med 2008; 11:164–170 19. Danis M, Federman D, Fins JJ, et al: Incorporating palliative care into critical care education: Principles, challenges, and opportunities. Crit Care Med 1999; 27:2005–2013
How We Measure Anticoagulation Is Just As Important (Maybe More Important) As How We Anticoagulate* Robert I. Parker, MD Department of Pediatrics Stony Brook Children’s Hospital State University of New York at Stony Brook School of Medicine Stony Brook, NY
U
p until recently, the continuous infusion of unfractionated heparin (UFH) has been the “gold standard” for acute anticoagulation therapy for both children and adults (1, 2). Historically, dose monitoring of patients receiving UFH has been with the activated partial thromboplastin time (aPTT), commonly referred to as the “PTT.” The therapeutic range for the aPTT was set at 1.5–2.5 times the patient’s pretherapy baseline and rigorously validated in a clinical study by Hirsh and colleagues (3). Subsequently, this range for aPTT values was shown to correspond to a plasma heparin concentration of 0.2–0.4 U/mL and later to an anti-Xa activity of 0.3–0.7 U/mL (1). Although the aPTT has historically been the preferred monitoring test for assessment of UFH dosing, the aPTT demonstrates a high degree of intra- and interpatient variability, which often results in the need for increased blood tests for monitoring and multiple dose modifications.
*See also p. e340. Key Words: anti-Xa; anticoagulation monitoring; antithrombin III concentrates; unfractionated heparin 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.0000000000000189
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Factors that contribute to this variability include patient age, body habitus, levels of other plasma proteins (e.g., factor VIII and fibrinogen), and plasma anti-thrombin-III (antithrombin) level (2, 4–8). This test variability and subsequent need for additional blood sampling is particularly problematic in pediatric patients owing to the desire to limit the volume of blood taken for tests and restrictions on venous access (9, 10). Consequently, many clinical laboratories and clinicians have substituted the anti-Xa assay for UFH monitoring. Although the anti-Xa assay has been shown to reduce test variability and result in fewer monitoring blood tests (11), the anti-Xa assay does not measure the antithrombin-mediated thrombin (activated factor II [FIIa]) inhibition produced by UFH and may thereby give an incomplete (potentially misleading) assessment of anticoagulation (8, 12, 13). In this issue of Pediatric Critical Care Medicine, Ryerson et al (14) report on the effect of commercially available antithrombin concentrate infusions in achieving and maintaining aPTT and/or anti-Xa values in the desired target range during therapeutic anticoagulation of children with UFH. The authors found that administration of antithrombin concentrates (ATCs) to children with antithrombin plasma levels less than 0.5 U/mL who were receiving UFH for therapeutic anticoagulation resulted in a statistically significant reduction in the dose of UFH required to achieve a target anti-Xa level. Of interest, however, was the observation that the benefit of ATC infusion was strongest in the younger patients (i.e., 3 mo old) patients. In children less than 12 months old, ATC infusion resulted in an increase in anti-Xa levels from 0.21 to 0.47 U/mL (p < 0.001), whereas October 2014 • Volume 15 • Number 8
Editorials
aPTT increase following ATC infusion did not reach statistical significance (110–136 s; p = 0.11) in this age group. In the older children (> 12 mo old), increase in anti-Xa levels was similar to that noted in the younger patients, but did not reach statistical significance (0.24–0.31 U/mL; p = 0.07), whereas aPTT demonstrated no significant change (66–63 s; p = 0.51). If the anti-Xa and aPTT measurements are equivalent in assessing anticoagulant intensity, one might expect that there would have been a consistent increase in aPTT values similar to those noted in anti-Xa levels following ATC infusions. Given the retrospective nature of the data collection in this study, the authors were not able to present any data that would address this apparent inconsistency. UFH exerts its anticoagulant effect through the antithrombin-III (antithrombin)-mediated inhibition of thrombin (FIIa) and activated factor X (FXa) (1, 15). In contrast to low-molecular-weight heparin (LMWH) where the anticoagulant effect is almost exclusively through inhibition of FXa, inhibition of FIIa represents a substantial anticoagulant mechanism for UFH (12, 16–18). This difference is due to the shorter polymer length and consequent reduction in sulfate groups of LMWH preparations. Although both UFH and LMWH possess the specific pentasaccharide sequence required for binding to antithrombin, only the longer heparin polymers present in UFH preparations are able to support the binding of both antithrombin and thrombin (factor IIa) in a manner that allows for neutralization of thrombin by antithrombin (12, 18). As the aPTT is highly sensitive to the presence of UFH, but much less so to LMWH, this difference likely contributes to the lack of concordance between aPTT and anti-Xa assays noted by Ryerson et al and other investigators (8, 19–21). An additional factor possibly contributing to the greater effect of ATC infusions in the younger patients noted by Ryerson et al may be the previously described differences in pro- and anticoagulant factors noted in infants when compared with older children (22). As a consequence of the lower antithrombin levels documented in infants, the major process by which thrombin is neutralized is through interaction with α2-macroglobulin, a process that is not as efficient as neutralization by antithrombin. It may be that the greater effect of ATC in young children noted by Ryerson et al may, in part, be related to this difference in physiology. Again, due to the retrospective nature of their study, no data addressing this possibility are available. Not surprisingly, because of the limitations of the aPTT and anti-Xa assays, other (better) tests to monitor and guide anticoagulant therapy have been investigated. Among the candidates are old tests (such as the activated clotting time), modifications of old tests (e.g., prothrombinase-induced clotting time), and newer tests including Ecarin clotting time, measurements of thrombin generation (e.g., endogenous thrombin potential), and more global measurements of hemostasis (e.g., thromboelastogram) (23–26). Each of these tests has “pluses” and each has their own “minuses”; to date, there is no consensus on which may represent an improvement over the aPTT and/ or anti-Xa assays. Indeed, in recent issues of Pediatric Critical Pediatric Critical Care Medicine
Care Medicine, several studies published have purported to show that the aPTT is the preferred test for monitoring anticoagulation in extracorporeal membrane oxygenation (ECMO) or that the anti-Xa assay is better in this same patient population (27–29). When considering the issue of therapeutic anticoagulation, it may be beneficial to realize that we are actually trying to affect hemostasis (i.e., the balance between clotting and NOT clotting) rather than merely produce anticoagulation (no clot formation). Indeed, a commentary by Nguyen et al (30) that accompanied the publication of one of these recent studies describes the individualized, multidisciplinary process that they use at Texas Children’s Hospital to manage their patients on ECMO support. Although the aPTT may not be the “ideal” test to monitor UFH therapy, it may be the best we have. However, there is no consensus. With the development and anticipated use of newer anticoagulant medications (i.e., direct thrombin inhibitors and anti-Xa agents) that are poorly measured by traditional tests such as the prothrombin time, aPTT, or anti-Xa assay, there exists a need for better tests to assess and monitor anticoagulant therapy. To date, much of the data used to form pediatric recommendations on drug choice, dose, monitoring, and adjustment come from extrapolation of adult patient-derived data and too often are in the form of “expert opinion.” This is neither desirable nor optimal. Ryerson et al should be commended for generating pediatric-specific data that provide important insights as to how we may improve the effectiveness of UFH therapy in children.
REFERENCES
1. Hirsh J, Raschke R: Heparin and low-molecular-weight heparin: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126:188S–203S 2. Smythe MA, Koerber JM, Westley SJ, et al: Use of the activated partial thromboplastin time for heparin monitoring. Am J Clin Pathol 2001; 115:148–155 3. Basu D, Gallus A, Hirsh J, et al: A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time. N Engl J Med 1972; 287:324–327 4. Kim JS, Lee HJ, Sung JD, et al: Monitoring of unfractionated heparin using activated partial thromboplastin time: An assessment of the current normogram and analysis according to age. Clin Appl Thromb Hemost 2013 Apr 24. [E-pub ahead of print] 5. Aarab R, van Es J, de Pont AC, et al: Monitoring of unfractionated heparin in critically ill patients. Neth J Med 2013; 71:466–471 6. Olson JD, Arkin CF, Brandt JT, et al: College of American Pathologists Conference XXXI on laboratory monitoring of anticoagulant therapy: Laboratory monitoring of unfractionated heparin therapy. Arch Pathol Lab Med 1998; 122:782–798 7. Zehnder J, Price E, Jin J: Controversies in heparin monitoring. Am J Hematol 2012; 87(Suppl 1):S137–S140 8. Takemoto CM, Streiff MB, Shermock KM, et al: Activated partial thromboplastin time and anti-xa measurements in heparin monitoring: Biochemical basis for discordance. Am J Clin Pathol 2013; 139:450–456 9. Payne JH: Aspects of anticoagulation in children. Br J Haematol 2010; 150:259–277 10. Ronghe MD, Halsey C, Goulden NJ: Anticoagulation therapy in children. Paediatr Drugs 2003; 5:803–820 11. Rosborough TK: Monitoring unfractionated heparin therapy with antifactor Xa activity results in fewer monitoring tests and dosage changes than monitoring with the activated partial thromboplastin time. Pharmacotherapy 1999; 19:760–766 www.pccmjournal.org
787
Editorials 12. Amar J, Caranobe C, Sie P, et al: Antithrombotic potencies of heparins in relation to their antifactor Xa and antithrombin activities: An experimental study in two models of thrombosis in the rabbit. Br J Haematol 1990; 76:94–100 13. Rosenberg AF, Zumberg M, Taylor L, et al: The use of anti-Xa assay to monitor intravenous unfractionated heparin therapy. J Pharm Pract 2010; 23:210–216 14. Ryerson LM, Bauman ME, Kuhle S, et al: Antithrombin Concentrate in Pediatric Patients Requiring Unfractionated Heparin Anticoagulation: A Retrospective Cohort Study. Pediatr Crit Care Med 2014; 15:e340–e346 15. Bussey H, Francis JL, Heparin Consensus Group: Heparin overview and issues. Pharmacotherapy 2004; 24(8, Part 2):103S–107S 16. Ockelford PA, Carter CJ, Mitchell L, et al: Discordance between the anti-Xa activity and the antithrombotic activity in an ultra-low molecular weight heparin fraction. Thromb Res 1982; 28:401–409 17. Ofosu FA, Blajchman MA, Modi GJ, et al: The importance of thrombin inhibition for the expression of the anticoagulant activities of heparin, dermatan sulphate, low molecular weight heparin and pentosan polysulphate. Br J Haematol 1985; 60:695–704 18. Barrowcliffe TW, Mulloy B, Johnson EA, et al: The anticoagulant activity of heparin: Measurement and relationship to chemical structure. J Pharm Biomed Anal 1989; 7:217–226 19. ten Cate H, Lamping RJ, Henny CP, et al: Automated amidolytic method for determining heparin, a heparinoid, and a low-Mr heparin fragment, based on their anti-Xa activity. Clin Chem 1984; 30:860–864 20. Bara L, Mardiguian J, Samama M: In vitro effect on Heptest of low molecular weight heparin fractions and preparations with various antiIIa and anti-Xa activities. Thromb Res 1990; 57:585–592 21. Price EA, Jin J, Nguyen HM, et al: Discordant aPTT and anti-Xa values and outcomes in hospitalized patients treated with intravenous unfractionated heparin. Ann Pharmacother 2013; 47:151–158
22. Andrew M, Paes B, Johnston M: Development of the hemostatic system in the neonate and young infant. Am J Pediatr Hematol Oncol 1990; 12:95–104 23. Kher A, Al Dieri R, Hemker HC, et al: Laboratory assessment of antithrombotic therapy: What tests and if so why? Haemostasis 1997; 27:211–218 24. Spinler SA, Wittkowsky AK, Nutescu EA, et al: Anticoagulation monitoring part 2: Unfractionated heparin and low-molecular-weight heparin. Ann Pharmacother 2005; 39:1275–1285 25. Korte W, Jovic R, Hollenstein M, et al: The uncalibrated prothrombinase-induced clotting time test. Equally convenient but more precise than the aPTT for monitoring of unfractionated heparin. Hamostaseologie 2010; 30:212–216 26. Lind SE, Boyle ME, Fisher S, et al: Comparison of the aPTT with alternative tests for monitoring direct thrombin inhibitors in patient samples. Am J Clin Pathol 2014; 141:665–674 27. Maul TM, Wolff EL, Kuch BA, et al: Activated partial thromboplastin time is a better trending tool in pediatric extracorporeal membrane oxygenation. Pediatr Crit Care Med 2012; 13:e363–e371 28. Liveris A, Bello RA, Friedmann P, et al: Anti-factor Xa assay is a superior correlate of heparin dose than activated partial thromboplastin time or activated clotting time in pediatric extracorporeal membrane oxygenation. Pediatr Crit Care Med 2014; 15:e72–e79 29. Irby K, Swearingen C, Byrnes J, et al: Unfractionated heparin activity measured by anti-factor xa levels is associated with the need for extracorporeal membrane oxygenation circuit/membrane oxygenator change: A retrospective pediatric study. Pediatr Crit Care Med 2014; 15:e175–e182 30. Nguyen T, Musick M, Teruya J: Anticoagulation monitoring during extracorporeal membrane oxygenation: Is anti-factor Xa assay (heparin level) a better test? Pediatr Crit Care Med 2014; 15:178–179
Do You Smell Something Burning? Could It Be You?* Alan I. Fields, MD, MCCM Clinical Resource Management Children’s National Washington, DC
B
urnout is a state of chronic psychological stress with long-term exhaustion and diminished interest in work. Burnout may interfere with personal and job satisfaction and is associated with decreased job performance and dysfunctional professional relationships. For physicians, this may involve performance issues such as medical errors and relationships with patients and families (1, 2). Since the first publication on burnout in pediatric intensivists almost 2 decades ago (3), there has been a growing literature on physician burnout. *See also p. e347. Key Words: burnout; family conflict; pediatric intensivists; pediatricians; risk of burnout Dr. Fields consulted for The Coordinating Center, Millersville, MD (Medical Director), and Anchor Healthcare Services, Merrifield, VA (consultant). Copyright © 2014 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10.1097/PCC.0000000000000241
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Since both work and lifestyle factors are associated with burnout, the risk for burnout differs for different specialties and work environments. Although factors associated with burnout have been investigated for many specialties, there have been few investigations of burnout in pediatric intensivists beyond the prevalence and basic demographic descriptors (4, 5). The components of burnout are incorporated into the domains of the Maslach Burnout Inventory (MBI) Scale, the methodology most commonly used in the evaluation of burnout (6). The MBI assesses the three basic domains of psychological functioning associated with burnout: emotional exhaustion (i.e., “I feel used up at the end of the workday”), depersonalization (i.e., “I feel I treat some patients as if they were impersonal objects”), and personal accomplishments (i.e., “I have accomplished many worthwhile things in this job”). Burnout represents a spectrum of severity of negative feelings in any of these domains and in the composite. In this issue of Pediatric Critical Care Medicine, Garcia et al (7) compared the prevalence of burnout and factors associated with burnout between intensivists and general pediatricians. The study population came from PICUs and outpatient departments in two regional hospitals in Brazil. Using the MBI Scale, burnout was much more frequent among pediatric intensivists October 2014 • Volume 15 • Number 8
15. Yuen JK, Mehta SS, Roberts JE, et al: A brief educational intervention to teach residents shared decision making in the intensive care unit. J Palliat Med 2013; 16:531–536 16. Curtis JR, Back AL, Ford DW, et al: Effect of communication skills training for residents and nurse practitioners on quality of communication with patients with serious illness: A randomized trial. JAMA 2013; 310:2271–2281 17. Kamel G, Paniagua M, Uppalapati A: Palliative care in the intensive care unit: Are residents well trained to provide optimal care to critically ill patients? Am J Hosp Palliat Care 2014 May 30. [Epub ahead of print] 18. Schiffman JD, Chamberlain LJ, Palmer L, et al: Introduction of a pediatric palliative care curriculum for pediatric residents. J Palliat Med 2008; 11:164–170 19. Danis M, Federman D, Fins JJ, et al: Incorporating palliative care into critical care education: Principles, challenges, and opportunities. Crit Care Med 1999; 27:2005–2013
How We Measure Anticoagulation Is Just As Important (Maybe More Important) As How We Anticoagulate* Robert I. Parker, MD Department of Pediatrics Stony Brook Children’s Hospital State University of New York at Stony Brook School of Medicine Stony Brook, NY
U
p until recently, the continuous infusion of unfractionated heparin (UFH) has been the “gold standard” for acute anticoagulation therapy for both children and adults (1, 2). Historically, dose monitoring of patients receiving UFH has been with the activated partial thromboplastin time (aPTT), commonly referred to as the “PTT.” The therapeutic range for the aPTT was set at 1.5–2.5 times the patient’s pretherapy baseline and rigorously validated in a clinical study by Hirsh and colleagues (3). Subsequently, this range for aPTT values was shown to correspond to a plasma heparin concentration of 0.2–0.4 U/mL and later to an anti-Xa activity of 0.3–0.7 U/mL (1). Although the aPTT has historically been the preferred monitoring test for assessment of UFH dosing, the aPTT demonstrates a high degree of intra- and interpatient variability, which often results in the need for increased blood tests for monitoring and multiple dose modifications.
*See also p. e340. Key Words: anti-Xa; anticoagulation monitoring; antithrombin III concentrates; unfractionated heparin 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.0000000000000189
786
www.pccmjournal.org
Factors that contribute to this variability include patient age, body habitus, levels of other plasma proteins (e.g., factor VIII and fibrinogen), and plasma anti-thrombin-III (antithrombin) level (2, 4–8). This test variability and subsequent need for additional blood sampling is particularly problematic in pediatric patients owing to the desire to limit the volume of blood taken for tests and restrictions on venous access (9, 10). Consequently, many clinical laboratories and clinicians have substituted the anti-Xa assay for UFH monitoring. Although the anti-Xa assay has been shown to reduce test variability and result in fewer monitoring blood tests (11), the anti-Xa assay does not measure the antithrombin-mediated thrombin (activated factor II [FIIa]) inhibition produced by UFH and may thereby give an incomplete (potentially misleading) assessment of anticoagulation (8, 12, 13). In this issue of Pediatric Critical Care Medicine, Ryerson et al (14) report on the effect of commercially available antithrombin concentrate infusions in achieving and maintaining aPTT and/or anti-Xa values in the desired target range during therapeutic anticoagulation of children with UFH. The authors found that administration of antithrombin concentrates (ATCs) to children with antithrombin plasma levels less than 0.5 U/mL who were receiving UFH for therapeutic anticoagulation resulted in a statistically significant reduction in the dose of UFH required to achieve a target anti-Xa level. Of interest, however, was the observation that the benefit of ATC infusion was strongest in the younger patients (i.e., 3 mo old) patients. In children less than 12 months old, ATC infusion resulted in an increase in anti-Xa levels from 0.21 to 0.47 U/mL (p < 0.001), whereas October 2014 • Volume 15 • Number 8
Editorials
aPTT increase following ATC infusion did not reach statistical significance (110–136 s; p = 0.11) in this age group. In the older children (> 12 mo old), increase in anti-Xa levels was similar to that noted in the younger patients, but did not reach statistical significance (0.24–0.31 U/mL; p = 0.07), whereas aPTT demonstrated no significant change (66–63 s; p = 0.51). If the anti-Xa and aPTT measurements are equivalent in assessing anticoagulant intensity, one might expect that there would have been a consistent increase in aPTT values similar to those noted in anti-Xa levels following ATC infusions. Given the retrospective nature of the data collection in this study, the authors were not able to present any data that would address this apparent inconsistency. UFH exerts its anticoagulant effect through the antithrombin-III (antithrombin)-mediated inhibition of thrombin (FIIa) and activated factor X (FXa) (1, 15). In contrast to low-molecular-weight heparin (LMWH) where the anticoagulant effect is almost exclusively through inhibition of FXa, inhibition of FIIa represents a substantial anticoagulant mechanism for UFH (12, 16–18). This difference is due to the shorter polymer length and consequent reduction in sulfate groups of LMWH preparations. Although both UFH and LMWH possess the specific pentasaccharide sequence required for binding to antithrombin, only the longer heparin polymers present in UFH preparations are able to support the binding of both antithrombin and thrombin (factor IIa) in a manner that allows for neutralization of thrombin by antithrombin (12, 18). As the aPTT is highly sensitive to the presence of UFH, but much less so to LMWH, this difference likely contributes to the lack of concordance between aPTT and anti-Xa assays noted by Ryerson et al and other investigators (8, 19–21). An additional factor possibly contributing to the greater effect of ATC infusions in the younger patients noted by Ryerson et al may be the previously described differences in pro- and anticoagulant factors noted in infants when compared with older children (22). As a consequence of the lower antithrombin levels documented in infants, the major process by which thrombin is neutralized is through interaction with α2-macroglobulin, a process that is not as efficient as neutralization by antithrombin. It may be that the greater effect of ATC in young children noted by Ryerson et al may, in part, be related to this difference in physiology. Again, due to the retrospective nature of their study, no data addressing this possibility are available. Not surprisingly, because of the limitations of the aPTT and anti-Xa assays, other (better) tests to monitor and guide anticoagulant therapy have been investigated. Among the candidates are old tests (such as the activated clotting time), modifications of old tests (e.g., prothrombinase-induced clotting time), and newer tests including Ecarin clotting time, measurements of thrombin generation (e.g., endogenous thrombin potential), and more global measurements of hemostasis (e.g., thromboelastogram) (23–26). Each of these tests has “pluses” and each has their own “minuses”; to date, there is no consensus on which may represent an improvement over the aPTT and/ or anti-Xa assays. Indeed, in recent issues of Pediatric Critical Pediatric Critical Care Medicine
Care Medicine, several studies published have purported to show that the aPTT is the preferred test for monitoring anticoagulation in extracorporeal membrane oxygenation (ECMO) or that the anti-Xa assay is better in this same patient population (27–29). When considering the issue of therapeutic anticoagulation, it may be beneficial to realize that we are actually trying to affect hemostasis (i.e., the balance between clotting and NOT clotting) rather than merely produce anticoagulation (no clot formation). Indeed, a commentary by Nguyen et al (30) that accompanied the publication of one of these recent studies describes the individualized, multidisciplinary process that they use at Texas Children’s Hospital to manage their patients on ECMO support. Although the aPTT may not be the “ideal” test to monitor UFH therapy, it may be the best we have. However, there is no consensus. With the development and anticipated use of newer anticoagulant medications (i.e., direct thrombin inhibitors and anti-Xa agents) that are poorly measured by traditional tests such as the prothrombin time, aPTT, or anti-Xa assay, there exists a need for better tests to assess and monitor anticoagulant therapy. To date, much of the data used to form pediatric recommendations on drug choice, dose, monitoring, and adjustment come from extrapolation of adult patient-derived data and too often are in the form of “expert opinion.” This is neither desirable nor optimal. Ryerson et al should be commended for generating pediatric-specific data that provide important insights as to how we may improve the effectiveness of UFH therapy in children.
REFERENCES
1. Hirsh J, Raschke R: Heparin and low-molecular-weight heparin: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126:188S–203S 2. Smythe MA, Koerber JM, Westley SJ, et al: Use of the activated partial thromboplastin time for heparin monitoring. Am J Clin Pathol 2001; 115:148–155 3. Basu D, Gallus A, Hirsh J, et al: A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time. N Engl J Med 1972; 287:324–327 4. Kim JS, Lee HJ, Sung JD, et al: Monitoring of unfractionated heparin using activated partial thromboplastin time: An assessment of the current normogram and analysis according to age. Clin Appl Thromb Hemost 2013 Apr 24. [E-pub ahead of print] 5. Aarab R, van Es J, de Pont AC, et al: Monitoring of unfractionated heparin in critically ill patients. Neth J Med 2013; 71:466–471 6. Olson JD, Arkin CF, Brandt JT, et al: College of American Pathologists Conference XXXI on laboratory monitoring of anticoagulant therapy: Laboratory monitoring of unfractionated heparin therapy. Arch Pathol Lab Med 1998; 122:782–798 7. Zehnder J, Price E, Jin J: Controversies in heparin monitoring. Am J Hematol 2012; 87(Suppl 1):S137–S140 8. Takemoto CM, Streiff MB, Shermock KM, et al: Activated partial thromboplastin time and anti-xa measurements in heparin monitoring: Biochemical basis for discordance. Am J Clin Pathol 2013; 139:450–456 9. Payne JH: Aspects of anticoagulation in children. Br J Haematol 2010; 150:259–277 10. Ronghe MD, Halsey C, Goulden NJ: Anticoagulation therapy in children. Paediatr Drugs 2003; 5:803–820 11. Rosborough TK: Monitoring unfractionated heparin therapy with antifactor Xa activity results in fewer monitoring tests and dosage changes than monitoring with the activated partial thromboplastin time. Pharmacotherapy 1999; 19:760–766 www.pccmjournal.org
787
Editorials 12. Amar J, Caranobe C, Sie P, et al: Antithrombotic potencies of heparins in relation to their antifactor Xa and antithrombin activities: An experimental study in two models of thrombosis in the rabbit. Br J Haematol 1990; 76:94–100 13. Rosenberg AF, Zumberg M, Taylor L, et al: The use of anti-Xa assay to monitor intravenous unfractionated heparin therapy. J Pharm Pract 2010; 23:210–216 14. Ryerson LM, Bauman ME, Kuhle S, et al: Antithrombin Concentrate in Pediatric Patients Requiring Unfractionated Heparin Anticoagulation: A Retrospective Cohort Study. Pediatr Crit Care Med 2014; 15:e340–e346 15. Bussey H, Francis JL, Heparin Consensus Group: Heparin overview and issues. Pharmacotherapy 2004; 24(8, Part 2):103S–107S 16. Ockelford PA, Carter CJ, Mitchell L, et al: Discordance between the anti-Xa activity and the antithrombotic activity in an ultra-low molecular weight heparin fraction. Thromb Res 1982; 28:401–409 17. Ofosu FA, Blajchman MA, Modi GJ, et al: The importance of thrombin inhibition for the expression of the anticoagulant activities of heparin, dermatan sulphate, low molecular weight heparin and pentosan polysulphate. Br J Haematol 1985; 60:695–704 18. Barrowcliffe TW, Mulloy B, Johnson EA, et al: The anticoagulant activity of heparin: Measurement and relationship to chemical structure. J Pharm Biomed Anal 1989; 7:217–226 19. ten Cate H, Lamping RJ, Henny CP, et al: Automated amidolytic method for determining heparin, a heparinoid, and a low-Mr heparin fragment, based on their anti-Xa activity. Clin Chem 1984; 30:860–864 20. Bara L, Mardiguian J, Samama M: In vitro effect on Heptest of low molecular weight heparin fractions and preparations with various antiIIa and anti-Xa activities. Thromb Res 1990; 57:585–592 21. Price EA, Jin J, Nguyen HM, et al: Discordant aPTT and anti-Xa values and outcomes in hospitalized patients treated with intravenous unfractionated heparin. Ann Pharmacother 2013; 47:151–158
22. Andrew M, Paes B, Johnston M: Development of the hemostatic system in the neonate and young infant. Am J Pediatr Hematol Oncol 1990; 12:95–104 23. Kher A, Al Dieri R, Hemker HC, et al: Laboratory assessment of antithrombotic therapy: What tests and if so why? Haemostasis 1997; 27:211–218 24. Spinler SA, Wittkowsky AK, Nutescu EA, et al: Anticoagulation monitoring part 2: Unfractionated heparin and low-molecular-weight heparin. Ann Pharmacother 2005; 39:1275–1285 25. Korte W, Jovic R, Hollenstein M, et al: The uncalibrated prothrombinase-induced clotting time test. Equally convenient but more precise than the aPTT for monitoring of unfractionated heparin. Hamostaseologie 2010; 30:212–216 26. Lind SE, Boyle ME, Fisher S, et al: Comparison of the aPTT with alternative tests for monitoring direct thrombin inhibitors in patient samples. Am J Clin Pathol 2014; 141:665–674 27. Maul TM, Wolff EL, Kuch BA, et al: Activated partial thromboplastin time is a better trending tool in pediatric extracorporeal membrane oxygenation. Pediatr Crit Care Med 2012; 13:e363–e371 28. Liveris A, Bello RA, Friedmann P, et al: Anti-factor Xa assay is a superior correlate of heparin dose than activated partial thromboplastin time or activated clotting time in pediatric extracorporeal membrane oxygenation. Pediatr Crit Care Med 2014; 15:e72–e79 29. Irby K, Swearingen C, Byrnes J, et al: Unfractionated heparin activity measured by anti-factor xa levels is associated with the need for extracorporeal membrane oxygenation circuit/membrane oxygenator change: A retrospective pediatric study. Pediatr Crit Care Med 2014; 15:e175–e182 30. Nguyen T, Musick M, Teruya J: Anticoagulation monitoring during extracorporeal membrane oxygenation: Is anti-factor Xa assay (heparin level) a better test? Pediatr Crit Care Med 2014; 15:178–179
Do You Smell Something Burning? Could It Be You?* Alan I. Fields, MD, MCCM Clinical Resource Management Children’s National Washington, DC
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urnout is a state of chronic psychological stress with long-term exhaustion and diminished interest in work. Burnout may interfere with personal and job satisfaction and is associated with decreased job performance and dysfunctional professional relationships. For physicians, this may involve performance issues such as medical errors and relationships with patients and families (1, 2). Since the first publication on burnout in pediatric intensivists almost 2 decades ago (3), there has been a growing literature on physician burnout. *See also p. e347. Key Words: burnout; family conflict; pediatric intensivists; pediatricians; risk of burnout Dr. Fields consulted for The Coordinating Center, Millersville, MD (Medical Director), and Anchor Healthcare Services, Merrifield, VA (consultant). Copyright © 2014 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10.1097/PCC.0000000000000241
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Since both work and lifestyle factors are associated with burnout, the risk for burnout differs for different specialties and work environments. Although factors associated with burnout have been investigated for many specialties, there have been few investigations of burnout in pediatric intensivists beyond the prevalence and basic demographic descriptors (4, 5). The components of burnout are incorporated into the domains of the Maslach Burnout Inventory (MBI) Scale, the methodology most commonly used in the evaluation of burnout (6). The MBI assesses the three basic domains of psychological functioning associated with burnout: emotional exhaustion (i.e., “I feel used up at the end of the workday”), depersonalization (i.e., “I feel I treat some patients as if they were impersonal objects”), and personal accomplishments (i.e., “I have accomplished many worthwhile things in this job”). Burnout represents a spectrum of severity of negative feelings in any of these domains and in the composite. In this issue of Pediatric Critical Care Medicine, Garcia et al (7) compared the prevalence of burnout and factors associated with burnout between intensivists and general pediatricians. The study population came from PICUs and outpatient departments in two regional hospitals in Brazil. Using the MBI Scale, burnout was much more frequent among pediatric intensivists October 2014 • Volume 15 • Number 8
