Biomarkers to Detect Sepsis: A “Burning” Issue But Still a Long Way to Go* Patrick M. Honore, MD, PhD Rita Jacobs, MD Elisabeth De Waele, MD Herbert D. Spapen, MD, PhD, FCCM ICU Department Universitair Ziekenhuis Brussel Vrije Universiteit Brussel Brussels, Belgium
epsis is a common cause of death in hospitalized patients worldwide. Early detection of sepsis remains challenging, as a delayed diagnosis substantially undermines treat ment efforts and increases the mortality risk. In recent years, there has been a move away from the rather vague and nonspe cific signs used to diagnose sepsis toward a possible adjunctive role of biomarkers. However, currently proposed biomarkers lack specificity, do not correlate with severity or mortality of sepsis, incompletely determine the correct timing and appro priateness of antimicrobial therapy, and are poorly investigated in specific critically ill populations (1). In this issue of Critical Care Medicine, Paratz et al (2) present a provocative biomarker study in burn patients. Diagnosing sepsis in these patients is extremely difficult due to the often outspoken or lingering inflammatory state that accompanies burn injury. Among other biomarkers, procalcitonin (PCT) is traditionally considered to be the best marker for detecting infection in burn patients (3). Daily consecutive PCT, but not C-reactive protein (CRP), measurement was found to be valuable for monitoring the effectiveness of antibiotic therapy in these patients (4). Inter estingly, the article by Paratz et al (2) seriously challenges the role of PCT as a reliable diagnostic and prognostic biomarker in severe burn patients. The authors demonstrated that daily sam pling of the N-terminal fragment of the prohormone brain-type natriuretic peptide (NT-proBNP) largely outperformed PCT as an early indicator of sepsis (2). B-type natriuretic peptide (BNP) is a 32-amino acid polypeptide that plays a vital role in fluid vol ume homeostasis (5). BNP is synthesized as pre-proBNP in the ventricular cardiomyocyte. In response to ventricular stretch, pre-proBNP is cleaved to proBNP which in turn forms biologi cally active (BNP) and inactive (NT-proBNP) cleavage products.
S
‘ See also p. 2029. Key Words: biomarkers; B-type natriuretic peptide; burns; continuous renal replacement therapy; C-reactive protein; monomeric C-reactive protein; N-terminal fragment of the prohormone brain-type natriuretic peptide; procalcitonin; sepsis The authors have disclosed that they do not have any potential conflicts of interest. Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.0000000000000456
Critical Care Medicine
From a practical viewpoint, dosing of NT-proBNP is preferred to BNP because its plasma levels are higher and less fluctuat ing (5). Serum BNP measurement essentially offered important diagnostic and prognostic information in congestive heart fail ure (5). Recently, BNP was identified as a potential biomarker in sepsis. BNP was increased in patients with severe sepsis and septic shock and high levels were associated with poor out come (6). Initially, increased NT-proBNP was related to sepsisinduced myocardial depression. Current insight, however, linked augmented NT-proBNP levels to impaired enzymatic clearance (7) and correlated them with the degree of inflammation rather than with ventricular dysfunction (8). Some minor limitations of the study must be highlighted. The observational and monocentric design, including young patients with few comorbidities and unspecified organ fail ure, prohibits generalization of study results to a broader burn population. Also, it is unclear whether the observed hemody namic changes in the septic group are related to increasing BNP levels (as suggested by the authors) or merely represent unreported vasoactive interventions affecting cardiac output, blood pressure, or heart rate, An important question raised by this study is whether NTproBNP could supplant CRP and/or PCT to detect infection in other than burn patients. The “classic” biomarkers are indeed less performing in cirrhotic (9) or transplant patients (10, 11). To date, the systematic use of NT-proBNP as an infection detector in these patients has not been thoroughly investigated (8) . Biomarker assessment is also problematic in critically ill patients undergoing continuous renal replacement therapy (CRRT). This population is dramatically increasing over the years. Native pentameric CRP with a molecular weight of around 120 kDa is made of 5 subunits. Bounding between these subunits is very fragile and most of the circulating CRP is monomeric. Monomeric CRP (mCRP), which circulates in the blood as a 18-22 kDa monomer, is cleared by filtration since its molecular weight lies below the 35 kDa cutoff of com monly used CRRT membranes as opposed to the pentameric CRP native form (12). In addition, a certain amount of mCRP is removed by adsorption on the filtration membrane (13). The increasing use of highly adsorptive filter membranes (12, 14) in many ICUs may accentuate mCRP removal even more. PCT is also eliminated during CRRT, albeit to a greater extent than mCRP and mainly by adsorption (14, 15). As a result, plasma levels of these biomarkers may become falsely low dur ing CRRT and thus incorrectly reflect presence or evolution of infection. Because of its low molecular weight (8.5 kDa), NT-proBNP is likely to be effectively cleared by both high- and low-flux membranes (16). Thus, its potential to detect sepsis in CRRT-treated patients may be significantly flawed. By demonstrating a clear superiority of NT-proBNP above the proclaimed “gold standard” PCT for early detection of w w w .c c m jo u r n a l.o r g
2137
Editorials
sepsis in patients with severe b urn injury, Paratz et al (2) highly contribute to the field of biom arker research in the crit ically ill. This prelim inary observation needs confirm ation by a large m ulticenter trial. W hether NT-proBNP acts as a better sepsis biom arker than CRP or PCT in specific patient groups in whom early diagnosis of sepsis is of vital im portance (e.g., liver failure, transplant, and CRRT patients) remains highly topical.
REFERENCES 1. Ventetuolo CE, Levy MM: Biomarkers: Diagnosis and risk assessment in sepsis. Clin Chest M ed 2008; 2 9 :5 9 1 -6 0 3 , vii
8. Pirracchio R, Salem R, Mebazaa A: Use of B-type natriuretic peptide in critically ill patients. Biomark M ed 2009; 3:541 -5 4 7 9. Su DH, Zhuo C, Liao K, et al: Value of serum procalcitonin levels in predicting spontaneous bacterial peritonitis. Hepatogastroenterology 2013; 6 0 :6 4 1 -6 4 6 10. Grammatikopoulos T, Dhawan A, Bansal S, et al: Baseline evaluation of serum markers of inflammation and their utility in clinical practice in paediatric liver transplant recipients. Clin Res Hepatol Gastroenterol 2 0 1 2 ;3 6 :3 6 5 -3 7 0 11. Komoda T, Hetzer R, Knosalla C, et al: Increase in N-terminal fragment of the prohormone brain-type natriuretic peptide as a measure for pre dicting outcome after urgent heart transplantation. Eur J Cardiothorac Surg 2010; 3 7 :8 6 4 -8 6 9
2. Paratz JD, Lipman J, Boots RJ, et al: A New Marker of Sepsis Post Burn Injury? Crit Care Med 2014; 4 2 :2 0 2 9 -2 0 3 6
12. Honore PM, Jacobs R, Joannes-Boyau O, et al: Newly designed CRRT membranes for sepsis and S IR S -A pragmatic approach for bedside intensivists summarizing the more recent advances: A sys tematic structured review. ASAIO J 2013; 5 9 :9 9 -1 0 6
3. Barati M, Alinejad F, Bahar MA, et al: Comparison of W B C , ESR, CRP and PCT serum levels in septic and non-septic burn cases. Burns 2008; 34:770-774
13. Grandi F, Bolasco P, Palladino G, et al Adsoprtion in extracorporeal blood purification: How to enhance solutes removal beyond diffusion and convection. Intech 2013; 1:3 8 1 -4 0 8
4. Lavrentieva A, Papadopoulou S, Kioumis J, et al: PCT as a diagnostic and prognostic tool in burn patients. Whether time course has a role in monitoring sepsis treatment. Burns 2012; 3 8 :3 5 6 -3 6 3
14. Dahaba AA, Elawady GA, Rehak PH, et al: Procalcitonin and proinflammatory cytokine clearance during continuous venovenous haemofiltration in septic patients. Anaesth Intensive Care 2002; 3 0 :2 6 9 -2 7 4
5. Akashi YJ, Springer J, Lainscak M, et al: Atrial natriuretic peptide and related peptides. Clin Chem Lab Med 2007; 4 5 :1 2 5 9 -1 2 6 7 6. Omar AS, Ur Rahman M, Dhatt GS, et al: Dynamics of brain natri uretic peptide in critically ill patients with severe sepsis and septic shock. Saudi J Anaesth 2013; 7 :2 70 -2 7 6
15. Level C, Chauveau P, Guisset O, et al: Mass transfer, clearance and plasma concentration of procalcitonin during continuous venovenous hemofiltration in patients with septic shock and acute oliguric renal failure. C rit Care 2003; 6 :1 6 0 -1 6 6
7. Pirracchio R, Deye N, Lukaszewicz AC, et al: Impaired plasma B-type natriuretic peptide clearance in human septic shock. Crit Care Med 2008; 3 6 :2 5 4 2 -2 5 4 6
16. Wahl HG, Graf S, Renz H, et al: Elimination of the cardiac natriuretic peptides B-type natriuretic peptide (BNP) and N-terminal proBNP by hemodialysis. Clin Chem 2004; 5 0 :1 0 7 1 -1 0 7 4
Why Do-Not-Resuscitate Orders Matter in Comparative Effectiveness Research* Brian H. Nathanson, PhD OptiStatim, LLC Longmeadow, MA f this editorial was a text message it would say something like “OMG! FYI, U Need 2 DTRT W / DNR & NALOPKT” which translates roughly into “Oh my gosh, for your information you need to do the right thing with do-not-resuscitate (DNR) orders and not a lot of people know this.” Talking about DNR orders in today’s “textese” is not entirely off the wall, as DNR orders them selves have only been formally implemented since 1976 (1).
I
*See also p. 2042. Key Words: activated protein c; do-not-resuscitate; outcomes research; sepsis Dr. Nathanson disclosed that his company, OptiStatim, LLC, does data analysis for the healthcare industry. One current client is the Cerner Cor poration, which owns the Acute Physiology and Chronic Health Evaluation and Mortality Prediction Model models. Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/C C M .0000000000000450 2138
w w w .c c m jo u rn a l.o rg
In this issue of Critical Care Medicine, Bradford et al (2) present a fascinating study on how not taking a patient’s DNR status on hospital admission into account can produce misleading results in observational studies (2). To recap, the authors examined the effect of activated protein C (APC; Xigris) within 48 hours of hospital admission in patients with septic shock. Using regression with inhospital mortality as the outcome, they calculated the odds ratio with and without the DNR status variable. For sensitivity analyses, they re-ran the model after excluding patients with an early DNR order, after excluding patients who died on day 1 (i.e., patients likely to die regardless of treatment) or who had cardiopulmonary resuscitation (CPR) in the presence of an early DNR order (i.e., likely the DNR order was recorded incorrectly), and after DNR was included with additional interventions such as early mechanical ventilation and dialysis. Without taking DNR status into account, the authors found a protective effect associated with APC (odds ratio, 0.78; 95% Cl, 0.62-0.99; P = 0.04), a finding similar to other observational studies (3,4). However, APC became nonsignificant when DNR status was included in the model (odds ratio, 0.85; 95% Cl, 0.67-1.08; P = 0.18) and when DNR patients were excluded (0.82; 95% Cl, 0.64-1.05) or when DNR was modeled with addi tional interventions (0.82; 95% Cl, 0.65-1.04). September 2014 • Volume 42 • Number 9
Copyright of Critical Care Medicine is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
epsis is a common cause of death in hospitalized patients worldwide. Early detection of sepsis remains challenging, as a delayed diagnosis substantially undermines treat ment efforts and increases the mortality risk. In recent years, there has been a move away from the rather vague and nonspe cific signs used to diagnose sepsis toward a possible adjunctive role of biomarkers. However, currently proposed biomarkers lack specificity, do not correlate with severity or mortality of sepsis, incompletely determine the correct timing and appro priateness of antimicrobial therapy, and are poorly investigated in specific critically ill populations (1). In this issue of Critical Care Medicine, Paratz et al (2) present a provocative biomarker study in burn patients. Diagnosing sepsis in these patients is extremely difficult due to the often outspoken or lingering inflammatory state that accompanies burn injury. Among other biomarkers, procalcitonin (PCT) is traditionally considered to be the best marker for detecting infection in burn patients (3). Daily consecutive PCT, but not C-reactive protein (CRP), measurement was found to be valuable for monitoring the effectiveness of antibiotic therapy in these patients (4). Inter estingly, the article by Paratz et al (2) seriously challenges the role of PCT as a reliable diagnostic and prognostic biomarker in severe burn patients. The authors demonstrated that daily sam pling of the N-terminal fragment of the prohormone brain-type natriuretic peptide (NT-proBNP) largely outperformed PCT as an early indicator of sepsis (2). B-type natriuretic peptide (BNP) is a 32-amino acid polypeptide that plays a vital role in fluid vol ume homeostasis (5). BNP is synthesized as pre-proBNP in the ventricular cardiomyocyte. In response to ventricular stretch, pre-proBNP is cleaved to proBNP which in turn forms biologi cally active (BNP) and inactive (NT-proBNP) cleavage products.
S
‘ See also p. 2029. Key Words: biomarkers; B-type natriuretic peptide; burns; continuous renal replacement therapy; C-reactive protein; monomeric C-reactive protein; N-terminal fragment of the prohormone brain-type natriuretic peptide; procalcitonin; sepsis The authors have disclosed that they do not have any potential conflicts of interest. Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.0000000000000456
Critical Care Medicine
From a practical viewpoint, dosing of NT-proBNP is preferred to BNP because its plasma levels are higher and less fluctuat ing (5). Serum BNP measurement essentially offered important diagnostic and prognostic information in congestive heart fail ure (5). Recently, BNP was identified as a potential biomarker in sepsis. BNP was increased in patients with severe sepsis and septic shock and high levels were associated with poor out come (6). Initially, increased NT-proBNP was related to sepsisinduced myocardial depression. Current insight, however, linked augmented NT-proBNP levels to impaired enzymatic clearance (7) and correlated them with the degree of inflammation rather than with ventricular dysfunction (8). Some minor limitations of the study must be highlighted. The observational and monocentric design, including young patients with few comorbidities and unspecified organ fail ure, prohibits generalization of study results to a broader burn population. Also, it is unclear whether the observed hemody namic changes in the septic group are related to increasing BNP levels (as suggested by the authors) or merely represent unreported vasoactive interventions affecting cardiac output, blood pressure, or heart rate, An important question raised by this study is whether NTproBNP could supplant CRP and/or PCT to detect infection in other than burn patients. The “classic” biomarkers are indeed less performing in cirrhotic (9) or transplant patients (10, 11). To date, the systematic use of NT-proBNP as an infection detector in these patients has not been thoroughly investigated (8) . Biomarker assessment is also problematic in critically ill patients undergoing continuous renal replacement therapy (CRRT). This population is dramatically increasing over the years. Native pentameric CRP with a molecular weight of around 120 kDa is made of 5 subunits. Bounding between these subunits is very fragile and most of the circulating CRP is monomeric. Monomeric CRP (mCRP), which circulates in the blood as a 18-22 kDa monomer, is cleared by filtration since its molecular weight lies below the 35 kDa cutoff of com monly used CRRT membranes as opposed to the pentameric CRP native form (12). In addition, a certain amount of mCRP is removed by adsorption on the filtration membrane (13). The increasing use of highly adsorptive filter membranes (12, 14) in many ICUs may accentuate mCRP removal even more. PCT is also eliminated during CRRT, albeit to a greater extent than mCRP and mainly by adsorption (14, 15). As a result, plasma levels of these biomarkers may become falsely low dur ing CRRT and thus incorrectly reflect presence or evolution of infection. Because of its low molecular weight (8.5 kDa), NT-proBNP is likely to be effectively cleared by both high- and low-flux membranes (16). Thus, its potential to detect sepsis in CRRT-treated patients may be significantly flawed. By demonstrating a clear superiority of NT-proBNP above the proclaimed “gold standard” PCT for early detection of w w w .c c m jo u r n a l.o r g
2137
Editorials
sepsis in patients with severe b urn injury, Paratz et al (2) highly contribute to the field of biom arker research in the crit ically ill. This prelim inary observation needs confirm ation by a large m ulticenter trial. W hether NT-proBNP acts as a better sepsis biom arker than CRP or PCT in specific patient groups in whom early diagnosis of sepsis is of vital im portance (e.g., liver failure, transplant, and CRRT patients) remains highly topical.
REFERENCES 1. Ventetuolo CE, Levy MM: Biomarkers: Diagnosis and risk assessment in sepsis. Clin Chest M ed 2008; 2 9 :5 9 1 -6 0 3 , vii
8. Pirracchio R, Salem R, Mebazaa A: Use of B-type natriuretic peptide in critically ill patients. Biomark M ed 2009; 3:541 -5 4 7 9. Su DH, Zhuo C, Liao K, et al: Value of serum procalcitonin levels in predicting spontaneous bacterial peritonitis. Hepatogastroenterology 2013; 6 0 :6 4 1 -6 4 6 10. Grammatikopoulos T, Dhawan A, Bansal S, et al: Baseline evaluation of serum markers of inflammation and their utility in clinical practice in paediatric liver transplant recipients. Clin Res Hepatol Gastroenterol 2 0 1 2 ;3 6 :3 6 5 -3 7 0 11. Komoda T, Hetzer R, Knosalla C, et al: Increase in N-terminal fragment of the prohormone brain-type natriuretic peptide as a measure for pre dicting outcome after urgent heart transplantation. Eur J Cardiothorac Surg 2010; 3 7 :8 6 4 -8 6 9
2. Paratz JD, Lipman J, Boots RJ, et al: A New Marker of Sepsis Post Burn Injury? Crit Care Med 2014; 4 2 :2 0 2 9 -2 0 3 6
12. Honore PM, Jacobs R, Joannes-Boyau O, et al: Newly designed CRRT membranes for sepsis and S IR S -A pragmatic approach for bedside intensivists summarizing the more recent advances: A sys tematic structured review. ASAIO J 2013; 5 9 :9 9 -1 0 6
3. Barati M, Alinejad F, Bahar MA, et al: Comparison of W B C , ESR, CRP and PCT serum levels in septic and non-septic burn cases. Burns 2008; 34:770-774
13. Grandi F, Bolasco P, Palladino G, et al Adsoprtion in extracorporeal blood purification: How to enhance solutes removal beyond diffusion and convection. Intech 2013; 1:3 8 1 -4 0 8
4. Lavrentieva A, Papadopoulou S, Kioumis J, et al: PCT as a diagnostic and prognostic tool in burn patients. Whether time course has a role in monitoring sepsis treatment. Burns 2012; 3 8 :3 5 6 -3 6 3
14. Dahaba AA, Elawady GA, Rehak PH, et al: Procalcitonin and proinflammatory cytokine clearance during continuous venovenous haemofiltration in septic patients. Anaesth Intensive Care 2002; 3 0 :2 6 9 -2 7 4
5. Akashi YJ, Springer J, Lainscak M, et al: Atrial natriuretic peptide and related peptides. Clin Chem Lab Med 2007; 4 5 :1 2 5 9 -1 2 6 7 6. Omar AS, Ur Rahman M, Dhatt GS, et al: Dynamics of brain natri uretic peptide in critically ill patients with severe sepsis and septic shock. Saudi J Anaesth 2013; 7 :2 70 -2 7 6
15. Level C, Chauveau P, Guisset O, et al: Mass transfer, clearance and plasma concentration of procalcitonin during continuous venovenous hemofiltration in patients with septic shock and acute oliguric renal failure. C rit Care 2003; 6 :1 6 0 -1 6 6
7. Pirracchio R, Deye N, Lukaszewicz AC, et al: Impaired plasma B-type natriuretic peptide clearance in human septic shock. Crit Care Med 2008; 3 6 :2 5 4 2 -2 5 4 6
16. Wahl HG, Graf S, Renz H, et al: Elimination of the cardiac natriuretic peptides B-type natriuretic peptide (BNP) and N-terminal proBNP by hemodialysis. Clin Chem 2004; 5 0 :1 0 7 1 -1 0 7 4
Why Do-Not-Resuscitate Orders Matter in Comparative Effectiveness Research* Brian H. Nathanson, PhD OptiStatim, LLC Longmeadow, MA f this editorial was a text message it would say something like “OMG! FYI, U Need 2 DTRT W / DNR & NALOPKT” which translates roughly into “Oh my gosh, for your information you need to do the right thing with do-not-resuscitate (DNR) orders and not a lot of people know this.” Talking about DNR orders in today’s “textese” is not entirely off the wall, as DNR orders them selves have only been formally implemented since 1976 (1).
I
*See also p. 2042. Key Words: activated protein c; do-not-resuscitate; outcomes research; sepsis Dr. Nathanson disclosed that his company, OptiStatim, LLC, does data analysis for the healthcare industry. One current client is the Cerner Cor poration, which owns the Acute Physiology and Chronic Health Evaluation and Mortality Prediction Model models. Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/C C M .0000000000000450 2138
w w w .c c m jo u rn a l.o rg
In this issue of Critical Care Medicine, Bradford et al (2) present a fascinating study on how not taking a patient’s DNR status on hospital admission into account can produce misleading results in observational studies (2). To recap, the authors examined the effect of activated protein C (APC; Xigris) within 48 hours of hospital admission in patients with septic shock. Using regression with inhospital mortality as the outcome, they calculated the odds ratio with and without the DNR status variable. For sensitivity analyses, they re-ran the model after excluding patients with an early DNR order, after excluding patients who died on day 1 (i.e., patients likely to die regardless of treatment) or who had cardiopulmonary resuscitation (CPR) in the presence of an early DNR order (i.e., likely the DNR order was recorded incorrectly), and after DNR was included with additional interventions such as early mechanical ventilation and dialysis. Without taking DNR status into account, the authors found a protective effect associated with APC (odds ratio, 0.78; 95% Cl, 0.62-0.99; P = 0.04), a finding similar to other observational studies (3,4). However, APC became nonsignificant when DNR status was included in the model (odds ratio, 0.85; 95% Cl, 0.67-1.08; P = 0.18) and when DNR patients were excluded (0.82; 95% Cl, 0.64-1.05) or when DNR was modeled with addi tional interventions (0.82; 95% Cl, 0.65-1.04). September 2014 • Volume 42 • Number 9
Copyright of Critical Care Medicine is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
