Could biomarkers direct therapy for the septic patient?

Journal of Pharmacology and Experimental Therapeutics

Volumn 357, Issue 2, 2016, Pages 228-239

  Sims, Clark R ^a   Nguyen, Trung C ^b   Mayeux, Philip R ^a  

^a UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES   (United States)

^b TEXAS CHILDREN S HOSPITAL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACTIVATED PROTEIN C; ANGIOPOIETIN 1; ANGIOPOIETIN 2; ANGIOPOIETIN RECEPTOR; ANTITHROMBIN III; BIOLOGICAL MARKER; C REACTIVE PROTEIN; CXCL3 CHEMOKINE; CYTOKINE; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; HEAT SHOCK PROTEIN 70; HEPARIN; INTERLEUKIN 1; INTERLEUKIN 27; INTERLEUKIN 6; INTERLEUKIN 7; INTERLEUKIN 8; LACTIC ACID; NEUTROPHIL COLLAGENASE; PADGEM PROTEIN; PROCALCITONIN; SPHINGOSINE 1 PHOSPHATE; THROMBOMODULIN; THROMBOPLASTIN; TUMOR NECROSIS FACTOR ALPHA; VON WILLEBRAND FACTOR; VON WILLEBRAND FACTOR CLEAVING PROTEINASE;

ANTICOAGULANT THERAPY; BLOOD CLOTTING; BLOOD CLOTTING TIME; BLOOD VESSEL PERMEABILITY; CECAL LIGATION AND PUNCTURE-INDUCED SEPSIS; CLINICAL EFFECTIVENESS; DISEASE SEVERITY; DOPPLER FLOWMETRY; ECHOCARDIOGRAPHY; ENDOTHELIUM CELL; HEMOSTASIS; HUMAN; IMMUNOMODULATION; INFLAMMATION; LACTATE BLOOD LEVEL; MICROVASCULATURE; NONHUMAN; PATHOPHYSIOLOGY; PATIENT CODING; PERSONALIZED MEDICINE; PRIORITY JOURNAL; PROGNOSIS; PULMONARY ARTERY CATHETERIZATION; QUALITY OF LIFE; REVIEW; SEPSIS; SURVIVAL; SYSTEMIC INFLAMMATORY RESPONSE SYNDROME; ANIMAL; DISEASE MODEL; INTENSIVE CARE;

ANIMALS; BIOMARKERS; CRITICAL CARE; DISEASE MODELS, ANIMAL; HUMANS; PRECISION MEDICINE; SEPSIS;

EID: 84963815086     PISSN: 00223565     EISSN: 15210103     Source Type: Journal    
DOI: 10.1124/jpet.115.230797     Document Type: Review

References (195)

1. Abraham E, Reinhart K, Opal S, Demeyer I, Doig C, Rodriguez AL, Beale R, Svoboda P, Laterre PF, and Simon S, et al.; OPTIMIST Trial Study Group (2003) Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA 290:238-247.
2. Adam N, Kandelman S, Mantz J, Chrétien F, and Sharshar T (2013) Sepsis-induced brain dysfunction. Expert Rev Anti Infect Ther 11:211-221.
3. Adkins B, Leclerc C, and Marshall-Clarke S (2004) Neonatal adaptive immunity comes of age. Nat Rev Immunol 4:553-564.
4. Agrawal A, Matthay MA, Kangelaris KN, Stein J, Chu JC, Imp BM, Cortez A, Abbott J, Liu KD, and Calfee CS (2013) Plasma angiopoietin-2 predicts the onset of acute lung injury in critically ill patients. Am J Respir Crit Care Med 187:736-742.
5. Alhamdi Y, Abrams ST, Cheng Z, Jing S, Su D, Liu Z, Lane S, Welters I, Wang G, and Toh CH (2015) Circulating histones are major mediators of cardiac injury in patients with sepsis. Crit Care Med 43:2094-2103.
6. Andonegui G, Goring K, Liu D, McCafferty DM, and Winston BW (2009) Characterization of S. pneumoniae pneumonia-induced multiple organ dysfunction syndrome: an experimental mouse model of gram-positive sepsis. Shock 31:423-428.
7. Aneja R and Carcillo J (2011) Differences between adult and pediatric septic shock. Minerva Anestesiol 77:986-992.
8. Asano S, Manne ND, Nandyala G, Ma B, Selvaraj V, Arvapalli R, Rice KM, and Blough ER (2015) Cecal inoculum peritonitis: an alternative model for sepsis vascular dysfunction study. Life Sci 141:108-118.
9. Azabou E, Magalhaes E, Braconnier A, Yahiaoui L, Moneger G, Heming N, Annane D, Mantz J, Chrétien F, and Durand MC, et al.; Groupe d'Explorations Neurologiques en Réanimation (GENER) (2015) Early standard electroencephalogram abnormalities predict mortality in septic intensive care unit patients. PLoS One 10:e0139969.
10. Basu RK, Standage SW, Cvijanovich NZ, Allen GL, Thomas NJ, Freishtat RJ, Anas N, Meyer K, Checchia PA, and Lin R, et al. (2011) Identification of candidate serum biomarkers for severe septic shock-associated kidney injury via microarray. Crit Care 15:R273.
11. Benes J, Chvojka J, Sykora R, Radej J, Krouzecky A, Novak I, and Matejovic M (2011) Searching for mechanisms that matter in early septic acute kidney injury: an experimental study. Crit Care 15:R256.
12. Bersani I, Auriti C, Ronchetti MP, Prencipe G, Gazzolo D, and Dotta A (2015) Use of early biomarkers in neonatal brain damage and sepsis: state of the art and future perspectives. BioMed Res Int 2015:253520.
13. Bhatti MM, Boonlayangoor S, Beavis KG, and Tesic V (2014a) Evaluation of FilmArray and Verigene systems for rapid identification of positive blood cultures. J Clin Microbiol 52:3433-3436.
14. Bhatti MM, Boonlayangoor S, Beavis KG, and Tesic V (2014b) Rapid identification of positive blood cultures by matrix-assisted laser desorption ionization-time of flight mass spectrometry using prewarmed agar plates. J Clin Microbiol 52:4334-4338.
15. Biomarkers Definitions Working Group. (2001) Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 69:89-95.
16. Biron BM, Ayala A, and Lomas-Neira JL (2015) Biomarkers for sepsis: What is and what might be? Biomark Insights 10(Suppl 4):7-17.
17. Bockmeyer CL, Claus RA, Budde U, Kentouche K, Schneppenheim R, Lösche W, Reinhart K, and Brunkhorst FM (2008) Inflammation-associated ADAMTS13 deficiency promotes formation of ultra-large von Willebrand factor. Haematologica 93:137-140.
18. Bone RC (1996) Sir Isaac Newton, sepsis, SIRS, and CARS. Crit Care Med 24:1125-1128.
19. Boomer JS, Green JM, and Hotchkiss RS (2014) The changing immune system in sepsis: is individualized immuno-modulatory therapy the answer? Virulence 5:45-56.
20. Boss GR and Seegmiller JE (1981) Age-related physiological changes and their clinical significance. West J Med 135:434-440.
21. Cao Z and Robinson RA (2014) The role of proteomics in understanding biological mechanisms of sepsis. Proteomics Clin Appl 8:35-52.
22. Cao Z, Yende S, Kellum JA, Angus DC, and Robinson RA (2014) Proteomics reveals age-related differences in the host immune response to sepsis. J Proteome Res 13:422-432.
23. Carcillo J, Han YY, Doughty L, Hall M, Nguyen T, and Aneja R (2011) Inflammation and immunity: systemic inflammatory response syndrome, sepsis, acute lung injury, and multiple organ failure, in Pediatric Critical Care. 4th ed (Fuhrman BP, Zimmerman JJ, ed) pp 1430-1438, Mosby, Philadelphia.
24. Casserly B, Phillips GS, Schorr C, Dellinger RP, Townsend SR, Osborn TM, Reinhart K, Selvakumar N, and Levy MM (2015) Lactate measurements in sepsis-induced tissue hypoperfusion: results from the Surviving Sepsis Campaign database. Crit Care Med 43:567-573.
25. Chang DW, Tseng CH, and Shapiro MF (2015) Rehospitalizations following sepsis: common and costly. Crit Care Med 43:2085-2093.
26. Charchaflieh J, Rushbrook J, Worah S, and Zhang M (2015) Activated complement factors as disease markers for sepsis. Dis Markers 2015:382463.
27. Chavan SS, Huerta PT, Robbiati S, Valdes-Ferrer SI, Ochani M, Dancho M, Frankfurt M, Volpe BT, Tracey KJ, and Diamond B (2012) HMGB1 mediates cognitive impairment in sepsis survivors. Mol Med 18:930-937.
28. Chertoff J, Chisum M, Garcia B, and Lascano J (2015) Lactate kinetics in sepsis and septic shock: a review of the literature and rationale for further research. J Intensive Care 3:39.
29. Christaki E and Giamarellos-Bourboulis EJ (2014) The beginning of personalized medicine in sepsis: small steps to a bright future. Clin Genet 86:56-61.
30. Cohen J, Vincent JL, Adhikari NK, Machado FR, Angus DC, Calandra T, Jaton K, Giulieri S, Delaloye J, and Opal S, et al. (2015) Sepsis: a roadmap for future research. Lancet Infect Dis 15:581-614.
31. Coldewey SM, Rogazzo M, Collino M, Patel NS, and Thiemermann C (2013) Inhibition of IκB kinase reduces the multiple organ dysfunction caused by sepsis in the mouse. Dis Model Mech 6:1031-1042.
32. Comim CM, Bussmann RM, Simão SR, Ventura L, Freiberger V, Patrício JJ, Palmas D, Mendonça BP, Cassol-Jr OJ, and Quevedo J (2015) Experimental neonatal sepsis causes long-term cognitive impairment. Mol Neurobiol, in press.
33. Conference NAC (1992) American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 20:864-874.
34. Corrêa TD, Vuda M, Blaser AR, Takala J, Djafarzadeh S, Dünser MW, Silva E, Lensch M, Wilkens L, and Jakob SM (2012) Effect of treatment delay on disease severity and need for resuscitation in porcine fecal peritonitis. Crit Care Med 40:2841-2849.
35. Darwish I and Liles WC (2013) Emerging therapeutic strategies to prevent infectionrelated microvascular endothelial activation and dysfunction. Virulence 4:572-582.
36. Daviaud F, Grimaldi D, Dechartres A, Charpentier J, Geri G, Marin N, Chiche JD, Cariou A, Mira JP, and Pène F (2015) Timing and causes of death in septic shock. Ann Intensive Care 5:58.
37. De Backer D, Donadello K, and Cortes DO (2012) Monitoring the microcirculation. J Clin Monit Comput 26:361-366.
38. De Backer D, Donadello K, Sakr Y, Ospina-Tascon G, Salgado D, Scolletta S, and Vincent JL (2013) Microcirculatory alterations in patients with severe sepsis: impact of time of assessment and relationship with outcome. Crit Care Med 41:791-799.
39. De Backer D, Orbegozo Cortes D, Donadello K, and Vincent JL (2014) Pathophysiology of microcirculatory dysfunction and the pathogenesis of septic shock. Virulence 5:73-79.
40. Dear JW, Kobayashi H, Jo SK, Holly MK, Hu X, Yuen PS, Brechbiel MW, and Star RA (2005) Dendrimer-enhanced MRI as a diagnostic and prognostic biomarker of sepsis-induced acute renal failure in aged mice. Kidney Int 67:2159-2167.
41. Dear JW, Yasuda H, Hu X, Hieny S, Yuen PS, Hewitt SM, Sher A, and Star RA (2006) Sepsis-induced organ failure is mediated by different pathways in the kidney and liver: acute renal failure is dependent on MyD88 but not renal cell apoptosis. Kidney Int 69:832-836.
42. DeCoux A, Tian Y, DeLeon-Pennell KY, Nguyen NT, de Castro Brás LE, Flynn ER, Cannon PL, Griswold ME, Jin YF, and Puskarich MA, et al. (2015) Plasma glycoproteomics reveals sepsis outcomes linked to distinct proteins in common pathways. Crit Care Med 43:2049-2058.
43. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, and Jaeschke R, et al.; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup (2013) Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 41:580-637.
44. Doi K, Leelahavanichkul A, Hu X, Sidransky KL, Zhou H, Qin Y, Eisner C, Schnermann J, Yuen PS, and Star RA (2008) Pre-existing renal disease promotes sepsis-induced acute kidney injury and worsens outcome. Kidney Int 74:1017-1025.
45. Drewry AM and Hotchkiss RS (2015) Sepsis: revising definitions of sepsis. Nat Rev Nephrol 11:326-328.
46. Dupuy AM, Philippart F, Péan Y, Lasocki S, Charles PE, Chalumeau M, Claessens YE, Quenot JP, Guen CG, and Ruiz S, et al.; Maurice Rapin Institute Biomarkers Group (2013) Role of biomarkers in the management of antibiotic therapy: an expert panel review: I-currently available biomarkers for clinical use in acute infections. Ann Intensive Care 3:22.
47. Duran-Bedolla J, Montes de Oca-Sandoval MA, Saldaña-Navor V, Villalobos-Silva JA, Rodriguez MC, and Rivas-Arancibia S (2014) Sepsis, mitochondrial failure and multiple organ dysfunction. Clin Invest Med 37:E58-E69.
48. Dyson A and Singer M (2009) Animal models of sepsis: why does preclinical efficacy fail to translate to the clinical setting? Crit Care Med 37:S30-S37.
49. Efron PA, Mohr AM, Moore FA, and Moldawer LL (2015) The future of murine sepsis and trauma research models. J Leukoc Biol 98:945-952.
50. Elseviers MM, Lins RL, Van der Niepen P, Hoste E, Malbrain ML, Damas P, and Devriendt J; SHARF investigators (2010) Renal replacement therapy is an independent risk factor for mortality in critically ill patients with acute kidney injury. Crit Care 14:R221.
51. Fang Y, Li C, Shao R, Yu H, Zhang Q, and Zhao L (2015) Prognostic significance of the angiopoietin-2/angiopoietin-1 and angiopoietin-1/Tie-2 ratios for early sepsis in an emergency department. Crit Care 19:367.
52. Filgueiras LR, Jr, Martins JO, Serezani CH, Capelozzi VL, Montes MB, and Jancar S (2012) Sepsis-induced acute lung injury (ALI) is milder in diabetic rats and correlates with impaired NFkB activation. PLoS One 7:e44987.
53. Fink MP (2014) Animal models of sepsis. Virulence 5:143-153.
54. Fink MP (2015) Cytopathic hypoxia and sepsis: is mitochondrial dysfunction pathophysiologically important or just an epiphenomenon. Pediatr Crit Care Med 16:89-91.
55. Fink MP and Warren HS (2014) Strategies to improve drug development for sepsis. Nat Rev Drug Discov 13:741-758.
56. Fink T, Heymann P, Taha-Melitz S, Taha A, Wolf B, Rensing H, Volk T, and Mathes AM (2013) Dobutamine pretreatment improves survival, liver function, and hepatic microcirculation after polymicrobial sepsis in rat. Shock 40:129-135.
57. Fiusa MM, Carvalho-Filho MA, Annichino-Bizzacchi JM, and De Paula EV (2015) Causes and consequences of coagulation activation in sepsis: an evolutionary medicine perspective. BMC Med 13:105.
58. Fortenberry JD, Knezevic A, and Nguyen TC (2012) 520: Outcome in children on ECMO with TAMOF receiving plasma exchange: results from the Prospective Pediatric TAMOF Network Study. Crit Care Med 40:A520.
59. Gaieski DF, Edwards JM, Kallan MJ, and Carr BG (2013) Benchmarking the incidence and mortality of severe sepsis in the United States. Crit Care Med 41:1167-1174.
60. Gao R, Kan MQ, Wang SG, Yang RH, and Zhang SG (2015) Disrupted tryptophan metabolism induced cognitive impairment in a mouse model of sepsis-associated encephalopathy. Inflammation, in press.
61. García-Septien J, Lorente JA, Delgado MA, de Paula M, Nin N, Moscoso A, Sánchez-Ferrer A, Perez-Vizcaino F, and Esteban A (2010) Levosimendan increases portal blood flow and attenuates intestinal intramucosal acidosis in experimental septic shock. Shock 34:275-280.
62. Ghosh CC, Thamm K, Berghelli AV, Schrimpf C, Maski MR, Abid T, Milam KE, Rajakumar A, Santel A, and Kielstein JT, et al. (2015) Drug repurposing screen identifies Foxo1-dependent angiopoietin-2 regulation in sepsis. Crit Care Med 43:e230-e240.
63. Gibot S, Béné MC, Noel R, Massin F, Guy J, Cravoisy A, Barraud D, De Carvalho Bittencourt M, Quenot JP, and Bollaert PE, et al. (2012) Combination biomarkers to diagnose sepsis in the critically ill patient. Am J Respir Crit Care Med 186:65-71.
64. Ginde AA, Blatchford PJ, Trzeciak S, Hollander JE, Birkhahn R, Otero R, Osborn TM, Moretti E, Nguyen HB, and Gunnerson KJ, et al. (2014) Age-related differences in biomarkers of acute inflammation during hospitalization for sepsis. Shock 42:99-107.
65. Goto T, Hussein MH, Kato S, Daoud GA, Kato T, Kakita H, Mizuno H, Imai M, Ito T, and Kato I, et al. (2010) Endothelin receptor antagonist attenuates inflammatory response and prolongs the survival time in a neonatal sepsis model. Intensive Care Med 36:2132-2139.
66. Gustot T (2011) Multiple organ failure in sepsis: prognosis and role of systemic inflammatory response. Curr Opin Crit Care 17:153-159.
67. Han JH, Nachamkin I, Coffin SE, Gerber JS, Fuchs B, Garrigan C, Han X, Bilker WB, Wise J, and Tolomeo P, et al.; Prevention Epicenters Program of the Centers for Disease Control and Prevention (2015) Use of a combination biomarker algorithm to identify medical intensive care unit patients with suspected sepsis at very low likelihood of bacterial infection. Antimicrob Agents Chemother 59:6494-6500.
68. Hartman ME, Linde-Zwirble WT, Angus DC, and Watson RS (2013) Trends in the epidemiology of pediatric severe sepsis. Pediatr Crit Care Med 14:686-693.
69. He X, Su F, Velissaris D, Salgado DR, de Souza Barros D, Lorent S, Taccone FS, Vincent JL, and De Backer D (2012) Administration of tetrahydrobiopterin improves the microcirculation and outcome in an ovine model of septic shock. Crit Care Med 40:2833-2840.
70. Heron M (2015) Deaths: leading causes for 2011. Natl Vital Stat Rep 64:1-96.
71. Holthoff JH, Wang Z, Patil NK, Gokden N, and Mayeux PR (2013) Rolipram improves renal perfusion and function during sepsis in the mouse. J Pharmacol Exp Ther 347:357-364.
72. Holthoff JH, Wang Z, Seely KA, Gokden N, and Mayeux PR (2012) Resveratrol improves renal microcirculation, protects the tubular epithelium, and prolongs survival in a mouse model of sepsis-induced acute kidney injury. Kidney Int 81:370-378.
73. Hotchkiss RS, Monneret G, and Payen D (2013a) Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. Lancet Infect Dis 13:260-268.
74. Hotchkiss RS, Monneret G, and Payen D (2013b) Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol 13:862-874.
75. Hotchkiss RS and Sherwood ER (2015) Immunology. Getting sepsis therapy right. Science 347:1201-1202.
76. Hutchins NA, Unsinger J, Hotchkiss RS, and Ayala A (2014) The new normal: immunomodulatory agents against sepsis immune suppression. Trends Mol Med 20:224-233.
77. Ishikawa K, Bellomo R, and May CN (2011) The impact of intrarenal nitric oxide synthase inhibition on renal blood flow and function in mild and severe hyperdynamic sepsis. Crit Care Med 39:770-776.
78. Iskander KN, Osuchowski MF, Stearns-Kurosawa DJ, Kurosawa S, Stepien D, Valentine C, and Remick DG (2013) Sepsis: multiple abnormalities, heterogeneous responses, and evolving understanding. Physiol Rev 93:1247-1288.
79. Iwashyna TJ, Cooke CR, Wunsch H, and Kahn JM (2012) Population burden of longterm survivorship after severe sepsis in older Americans. J Am Geriatr Soc 60:1070-1077.
80. Iwashyna TJ, Ely EW, Smith DM, and Langa KM (2010) Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA 304:1787-1794.
81. Jacob A, Steinberg ML, Yang J, Dong W, Ji Y, and Wang P (2008) Sepsis-induced inflammation is exacerbated in an animal model of type 2 diabetes. Int J Clin Exp Med 1:22-31.
82. Jaimes F, De La Rosa G, Morales C, Fortich F, Arango C, Aguirre D, and Muñoz A (2009) Unfractioned heparin for treatment of sepsis: A randomized clinical trial (The HETRASE Study). Crit Care Med 37:1185-1196.
83. Jeger V, Djafarzadeh S, Jakob SM, and Takala J (2013) Mitochondrial function in sepsis. Eur J Clin Invest 43:532-542.
84. Ji MH, Qiu LL, Tang H, Ju LS, Sun XR, Zhang H, Jia M, Zuo ZY, Shen JC, and Yang JJ (2015) Sepsis-induced selective parvalbumin interneuron phenotype loss and cognitive impairments may be mediated by NADPH oxidase 2 activation in mice. J Neuroinflammation 12:182.
85. Kalbitz M, Grailer JJ, Fattahi F, Jajou L, Herron TJ, Campbell KF, Zetoune FS, Bosmann M, Sarma JV, and Huber-Lang M, et al. (2015) Role of extracellular histones in the cardiomyopathy of sepsis. FASEB J 29:2185-2193.
86. Kaplan JM and Wong HR (2011) Biomarker discovery and development in pediatric critical care medicine. Pediatr Crit Care Med 12:165-173.
87. Kapoor A, Shintani Y, Collino M, Osuchowski MF, Busch D, Patel NS, Sepodes B, Castiglia S, Fantozzi R, and Bishop-Bailey D, et al. (2010) Protective role of peroxisome proliferator-activated receptor-β/δ in septic shock. Am J Respir Crit Care Med 182:1506-1515.
88. Kaukonen KM, Bailey M, Pilcher D, Cooper DJ, and Bellomo R (2015) Systemic inflammatory response syndrome criteria in defining severe sepsis. N Engl J Med 372:1629-1638.
89. Kawai T, Adachi O, Ogawa T, Takeda K, and Akira S (1999) Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 11:115-122.
90. Kissoon N, Carcillo JA, Espinosa V, Argent A, Devictor D, Madden M, Singhi S, van der Voort E, and Latour J; Global Sepsis Initiative Vanguard Center Contributors (2011) World Federation of Pediatric Intensive Care and Critical Care Societies: Global Sepsis Initiative. Pediatr Crit Care Med 12:494-503.
91. Kojic D, Siegler BH, Uhle F, Lichtenstern C, Nawroth PP, Weigand MA, Hofer S, and Brenner T (2015) Are there new approaches for diagnosis, therapy guidance and outcome prediction of sepsis? World J Exp Med 5:50-63.
92. Lapeyraque AL, Malina M, Fremeaux-Bacchi V, Boppel T, Kirschfink M, Oualha M, Proulx F, Clermont MJ, Le Deist F, and Niaudet P, et al. (2011) Eculizumab in severe Shiga-toxin-associated HUS. N Engl J Med 364:2561-2563.
93. László I, Trásy D, Molnár Z, and Fazakas J (2015) Sepsis: from pathophysiology to individualized patient care. J Immunol Res 2015:510436.
94. Lee MJ, Thangada S, Claffey KP, Ancellin N, Liu CH, Kluk M, Volpi M, Sha'afi RI, and Hla T (1999) Vascular endothelial cell adherens junction assembly and morphogenesis induced by sphingosine-1-phosphate. Cell 99:301-312.
95. Leelahavanichkul A, Huang Y, Hu X, Zhou H, Tsuji T, Chen R, Kopp JB, Schnermann J, Yuen PS, and Star RA (2011) Chronic kidney disease worsens sepsis and sepsisinduced acute kidney injury by releasing high mobility group box protein-1. Kidney Int 80:1198-1211.
96. Levi M and van der Poll T (2013) Disseminated intravascular coagulation: a review for the internist. Intern Emerg Med 8:23-32.
97. Liangos O, Perianayagam MC, Vaidya VS, Han WK, Wald R, Tighiouart H, MacKinnon RW, Li L, Balakrishnan VS, and Pereira BJ, et al. (2007) Urinary N-acetyl-b-(D) - glucosaminidase activity and kidney injury molecule-1 level are associated with adverse outcomes in acute renal failure. J Am Soc Nephrol 18:904-912.
98. Liu X, Ren H, and Peng D (2014) Sepsis biomarkers: an omics perspective. Front Med 8:58-67.
99. Lorente JA and Marshall JC (2005) Neutralization of tumor necrosis factor in preclinical models of sepsis. Shock 24(Suppl 1):107-119.
100. Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, Compton D, McClain J, Aldrich TH, and Papadopoulos N, et al. (1997) Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277:55-60.
101. Marshall JC (2014) Why have clinical trials in sepsis failed? Trends Mol Med 20:195-203.
102. Marshall JC and Reinhart K; International Sepsis Forum (2009) Biomarkers of sepsis. Crit Care Med 37:2290-2298.
103. Martin GS (2012) Sepsis, severe sepsis and septic shock: changes in incidence, pathogens and outcomes. Expert Rev Anti Infect Ther 10:701-706.
104. Martin GS, Mannino DM, and Moss M (2006) The effect of age on the development and outcome of adult sepsis. Crit Care Med 34:15-21.
105. Martin K, Borgel D, Lerolle N, Feys HB, Trinquart L, Vanhoorelbeke K, Deckmyn H, Legendre P, Diehl JL, and Baruch D (2007) Decreased ADAMTS-13 (A disintegrinlike and metalloprotease with thrombospondin type 1 repeats) is associated with a poor prognosis in sepsis-induced organ failure. Crit Care Med 35:2375-2382.
106. Matejovic M, Ince C, Chawla LS, Blantz R, Molitoris BA, Rosner MH, Okusa MD, Kellum JA, and Ronco C; ADQI XIII Work Group (2016) Renal hemodynamics in AKI: in search of new treatment targets. J Am Soc Nephrol 27:49-58.
107. Mathias B, Szpila BE, Moore FA, Efron PA, and Moldawer LL (2015) A review of GM-CSF therapy in sepsis. Medicine (Baltimore) 94:e2044.
108. Mayeux PR and MacMillan-Crow LA (2012) Pharmacological targets in the renal peritubular microenvironment: implications for therapy for sepsis-induced acute kidney injury. Pharmacol Ther 134:139-155.
109. Mera S, Tatulescu D, Cismaru C, Bondor C, Slavcovici A, Zanc V, Carstina D, and Oltean M (2011) Multiplex cytokine profiling in patients with sepsis. APMIS 119:155-163.
110. Mikkelsen ME, Shah CV, Meyer NJ, Gaieski DF, Lyon S, Miltiades AN, Goyal M, Fuchs BD, Bellamy SL, and Christie JD (2013) The epidemiology of acute respiratory distress syndrome in patients presenting to the emergency department with severe sepsis. Shock 40:375-381.
111. Miyaji T, Hu X, Yuen PS, Muramatsu Y, Iyer S, Hewitt SM, and Star RA (2003) Ethyl pyruvate decreases sepsis-induced acute renal failure and multiple organ damage in aged mice. Kidney Int 64:1620-1631.
112. Nadel S, Goldstein B, Williams MD, Dalton H, Peters M, Macias WL, Abd-Allah SA, Levy H, Angle R, and Wang D, et al.; Researching Severe Sepsis and Organ Dysfunction in Children: A Global Perspective (RESOLVE) Study Group (2007) Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial. Lancet 369:836-843.
113. Nguyen TC, Han YY, Kiss JE, Hall MW, Hassett AC, Jaffe R, Orr RA, Janosky J, and Carcillo JA (2008) Intensive plasma exchange increases a disintegrin and metalloprotease with thrombospondin motifs-13 activity and reverses organ dysfunction in children with thrombocytopenia-associated multiple organ failure. Crit Care Med 36:2878-2887.
114. Nguyen TC, Han Y, Fortenberry J, Zhou Z, Cruz MA, and Carcillo JA (2014) Thrombocytopenia-Associated Multiple Organ Failure Syndrome, in Pediatric Critical Care Medicine 2nd ed (Wheeler DS, Wong HR and Shanley TP ed) pp 481-492, Springer-Verlag, London.
115. Noris M, Mescia F, and Remuzzi G (2012) STEC-HUS, atypical HUS and TTP are all diseases of complement activation. Nat Rev Nephrol 8:622-633.
116. Orde SR, Pulido JN, Masaki M, Gillespie S, Spoon JN, Kane GC, and Oh JK (2014) Outcome prediction in sepsis: speckle tracking echocardiography based assessment of myocardial function. Crit Care 18:R149.
117. Ostrowski SR, Haase N, Müller RB, Møller MH, Pott FC, Perner A, and Johansson PI (2015) Association between biomarkers of endothelial injury and hypocoagulability in patients with severe sepsis: a prospective study. Crit Care 19:191.
118. Osuchowski MF, Craciun FL, Schuller E, Sima C, Gyurko R, and Remick DG (2010) Untreated type 1 diabetes increases sepsis-induced mortality without inducing a prelethal cytokine response. Shock 34:369-376.
119. Osuchowski MF, Remick DG, Lederer JA, Lang CH, Aasen AO, Aibiki M, Azevedo LC, Bahrami S, Boros M, and Cooney R, et al. (2014) Abandon the mouse research ship? Not just yet! Shock 41:463-475.
120. Pålsson-McDermott EM and O'Neill LA (2004) Signal transduction by the lipopolysaccharide receptor, Toll-like receptor-4. Immunology 113:153-162.
121. Patil NK, Parajuli N, MacMillan-Crow LA, and Mayeux PR (2014) Inactivation of renal mitochondrial respiratory complexes and manganese superoxide dismutase during sepsis: mitochondria-targeted antioxidant mitigates injury. Am J Physiol Renal Physiol 306:F734-F743.
122. Pierrakos C and Vincent JL (2010) Sepsis biomarkers: a review. Crit Care 14:R15.
123. Portella VG, Silva-Filho JL, Landgraf SS, de Rico TB, Vieira MA, Takiya CM, Souza MC, Henriques MG, Canetti C, and Pinheiro AA, et al. (2013) Sepsis-surviving mice are more susceptible to a secondary kidney insult. Crit Care Med 41:1056-1068.
124. Prescott HC, Langa KM, Liu V, Escobar GJ, and Iwashyna TJ (2014) Increased 1-year healthcare use in survivors of severe sepsis. Am J Respir Crit Care Med 190:62-69.
125. Prowle JR and Davenport A (2015) Does early-start renal replacement therapy improve outcomes for patients with acute kidney injury? Kidney Int 88:670-673.
126. Prowle JR, Molan MP, Hornsey E, and Bellomo R (2012) Measurement of renal blood flow by phase-contrast magnetic resonance imaging during septic acute kidney injury: a pilot investigation. Crit Care Med 40:1768-1776.
127. Ramchandra R, Wan L, Hood SG, Frithiof R, Bellomo R, and May CN (2009) Septic shock induces distinct changes in sympathetic nerve activity to the heart and kidney in conscious sheep. Am J Physiol Regul Integr Comp Physiol 297:R1247-R1253.
128. Ranieri VM, Thompson BT, Barie PS, Dhainaut JF, Douglas IS, Finfer S, Gårdlund B, Marshall JC, Rhodes A, and Artigas A, et al.; PROWESS-SHOCK Study Group (2012) Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med 366:2055-2064.
129. Rautanen A, Mills TC, Gordon AC, Hutton P, Steffens M, Nuamah R, Chiche JD, Parks T, Chapman SJ, and Davenport EE, et al.; ESICM/ECCRN GenOSept Investigators (2015) Genome-wide association study of survival from sepsis due to pneumonia: an observational cohort study. Lancet Respir Med 3:53-60.
130. Remick DG, Newcomb DE, Bolgos GL, and Call DR (2000) Comparison of the mortality and inflammatory response of two models of sepsis: lipopolysaccharide vs. cecal ligation and puncture. Shock 13:110-116.
131. Rittirsch D, Hoesel LM, and Ward PA (2007) The disconnect between animal models of sepsis and human sepsis. J Leukoc Biol 81:137-143.
132. Rittirsch D, Huber-Lang MS, Flierl MA, and Ward PA (2009) Immunodesign of experimental sepsis by cecal ligation and puncture. Nat Protoc 4:31-36.
133. Romanovsky A, Morgan C, and Bagshaw SM (2014) Pathophysiology and management of septic acute kidney injury. Pediatr Nephrol 29:1-12.
134. Rule JA, Hynan LS, Attar N, Sanders C, Korzun WJ, and Lee WM; Acute Liver Failure Study Group (2015) Procalcitonin identifies cell injury, not bacterial infection, in acute liver failure. PLoS One 10:e0138566.
135. Ruth A, McCracken CE, Fortenberry JD, Hall M, Simon HK, and Hebbar KB (2014) Pediatric severe sepsis: current trends and outcomes from the Pediatric Health Information Systems database. Pediatr Crit Care Med 15:828-838.
136. Saito H, Maruyama I, Shimazaki S, Yamamoto Y, Aikawa N, Ohno R, Hirayama A, Matsuda T, Asakura H, and Nakashima M, et al. (2007) Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: results of a phase III, randomized, double-blind clinical trial. J Thromb Haemost 5:31-41.
137. Sandquist M and Wong HR (2014) Biomarkers of sepsis and their potential value in diagnosis, prognosis and treatment. Expert Rev Clin Immunol 10:1349-1356.
138. Schmidt EP, Yang Y, Janssen WJ, Gandjeva A, Perez MJ, Barthel L, Zemans RL, Bowman JC, Koyanagi DE, and Yunt ZX, et al. (2012) The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis. Nat Med 18:1217-1223.
139. Schneider AG, Goodwin MD, and Bellomo R (2013) Measurement of kidney perfusion in critically ill patients. Crit Care 17:220.
140. Seely KA, Holthoff JH, Burns ST, Wang Z, Thakali KM, Gokden N, Rhee SW, and Mayeux PR (2011) Hemodynamic changes in the kidney in a pediatric rat model of sepsis-induced acute kidney injury. Am J Physiol Renal Physiol 301:F209-F217.
141. Seok J, Warren HS, Cuenca AG, Mindrinos MN, Baker HV, Xu W, Richards DR, McDonald-Smith GP, Gao H, and Hennessy L, et al.; Inflammation and Host Response to Injury, Large Scale Collaborative Research Program (2013) Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci USA 110:3507-3512.
142. Shah BA and Padbury JF (2014) Neonatal sepsis: an old problem with new insights. Virulence 5:170-178.
143. Shahul S, Gulati G, Hacker MR, Mahmood F, Canelli R, Nizamuddin J, Mahmood B, Mueller A, Simon BA, and Novack V, et al. (2015) Detection of myocardial dysfunction in septic shock: a speckle-tracking echocardiography study. Anesth Analg 121:1547-1554.
144. Sims CR, MacMillan-Crow LA, and Mayeux PR (2014) Targeting mitochondrial oxidants may facilitate recovery of renal function during infant sepsis. Clin Pharmacol Ther 96:662-664.
145. Soerensen KE, Nielsen OL, Birck MM, Soerensen DB, Leifsson PS, Jensen HE, Aalbaek B, Kristensen AT, Wiinberg B, and Kjelgaard-Hansen M, et al. (2012) The use of sequential organ failure assessment parameters in an awake porcine model of severe Staphylococcus aureus sepsis. APMIS 120:909-921.
146. Souza AC, Yuen PS, and Star RA (2015) Microparticles: markers and mediators of sepsis-induced microvascular dysfunction, immunosuppression, and AKI. Kidney Int 87:1100-1108.
147. Srinivasan L, Kirpalani H, and Cotten CM (2015) Elucidating the role of genomics in neonatal sepsis. Semin Perinatol 39:611-616.
148. Starr ME, Steele AM, Saito M, Hacker BJ, Evers BM, and Saito H (2014) A new cecal slurry preparation protocol with improved long-term reproducibility for animal models of sepsis. PLoS One 9:e115705.
149. Starr ME, Takahashi H, Okamura D, Zwischenberger BA, Mrazek AA, Ueda J, Stromberg AJ, Evers BM, Esmon CT, and Saito H (2015) Increased coagulation and suppressed generation of activated protein C in aged mice during intraabdominal sepsis. Am J Physiol Heart Circ Physiol 308:H83-H91.
150. Stearns-Kurosawa DJ, Osuchowski MF, Valentine C, Kurosawa S, and Remick DG (2011) The pathogenesis of sepsis. Annu Rev Pathol 6:19-48.
151. Stevenson EK, Rubenstein AR, Radin GT, Wiener RS, and Walkey AJ (2014) Two decades of mortality trends among patients with severe sepsis: a comparative meta-analysis. Crit Care Med 42:625-631.
152. Stubbs DJ, Yamamoto AK, and Menon DK (2013) Imaging in sepsis-associated encephalopathy-insights and opportunities. Nat Rev Neurol 9:551-561.
153. Suetrong B and Walley KR (2016) Lactic acidosis in sepsis: it's not all anaerobic: implications for diagnosis and management. Chest 149:252-261.
154. Sun Z, Ye H, Shen X, Chao H, Wu X, and Yang J (2014) Continuous venovenous hemofiltration versus extended daily hemofiltration in patients with septic acute kidney injury: a retrospective cohort study. Crit Care 18:R70.
155. Supinski GS, Murphy MP, and Callahan LA (2009) MitoQ administration prevents endotoxin-induced cardiac dysfunction. Am J Physiol Regul Integr Comp Physiol 297:R1095-R1102.
156. Taccone FS, Su F, De Deyne C, Abdellhai A, Pierrakos C, He X, Donadello K, Dewitte O, Vincent JL, and De Backer D (2014) Sepsis is associated with altered cerebral microcirculation and tissue hypoxia in experimental peritonitis. Crit Care Med 42:e114-e122.
157. Talan DA (2015) Procalcitonin is not a useful biomarker of sepsis. Ann Emerg Med 66:320-321.
158. Taylor FB, Jr, Kinasewitz GT, and Lupu F (2012) Pathophysiology, staging and therapy of severe sepsis in baboon models. J Cell Mol Med 16:672-682.
159. Torio CM and Andrews RM (2013) National inpatient hospital costs: the most expensive conditions by payer, 2011. Statistical Brief 60, Agency for Healthcare Research and Quality, Rockville, MD.
160. Tsalik EL, Willig LK, Rice BJ, van Velkinburgh JC, Mohney RP, McDunn JE, Dinwiddie DL, Miller NA, Mayer ES, and Glickman SW, et al. (2015) Renal systems biology of patients with systemic inflammatory response syndrome. Kidney Int 88:804-814.
161. Turnbull IR, Clark AT, Stromberg PE, Dixon DJ, Woolsey CA, Davis CG, Hotchkiss RS, Buchman TG, and Coopersmith CM (2009) Effects of aging on the immunopathologic response to sepsis. Crit Care Med 37:1018-1023.
162. Unsinger J, McGlynn M, Kasten KR, Hoekzema AS, Watanabe E, Muenzer JT, McDonough JS, Tschoep J, Ferguson TA, and McDunn JE, et al. (2010) IL-7 promotes T cell viability, trafficking, and functionality and improves survival in sepsis. J Immunol 184:3768-3779.
163. Vincent JL, Opal SM, Marshall JC, and Tracey KJ (2013) Sepsis definitions: time for change. Lancet 381:774-775.
164. Wacker C, Prkno A, Brunkhorst FM, and Schlattmann P (2013) Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis. Lancet Infect Dis 13:426-435.
165. Wada H, Thachil J, Di Nisio M, Mathew P, Kurosawa S, Gando S, Kim HK, Nielsen JD, Dempfle CE, and Levi M, et al.; The Scientific Standardization Committee on DIC of the International Society on Thrombosis Haemostasis (2013) Guidance for diagnosis and treatment of DIC from harmonization of the recommendations from three guidelines. J Thromb Haemost 11:761-767.
166. Wald R, Adhikari NK, Smith OM, Weir MA, Pope K, Cohen A, Thorpe K, McIntyre L, Lamontagne F, and Soth M, et al.; Canadian Critical Care Trials Group (2015) Comparison of standard and accelerated initiation of renal replacement therapy in acute kidney injury. Kidney Int 88:897-904.
167. Wang B, Chen G, Zhang J, Xue J, Cao Y, and Wu Y (2015a) Increased neutrophil gelatinase-associated lipocalin is associated with mortality and multiple organ dysfunction syndrome in severe sepsis and septic shock. Shock 44:234-238.
168. Wang H and Ma S (2008) The cytokine storm and factors determining the sequence and severity of organ dysfunction in multiple organ dysfunction syndrome. Am J Emerg Med 26:711-715.
169. Wang K, Bhandari V, Giuliano JS, Jr, O'Hern CS, Shattuck MD, and Kirby M (2014) Angiopoietin-1, angiopoietin-2 and bicarbonate as diagnostic biomarkers in children with severe sepsis. PLoS One 9:e108461.
170. Wang L and Dudek SM (2009) Regulation of vascular permeability by sphingosine 1-phosphate. Microvasc Res 77:39-45.
171. Wang Z, Sims CR, Patil NK, Gokden N, and Mayeux PR (2015b) Pharmacologic targeting of sphingosine-1-phosphate receptor 1 improves the renal microcirculation during sepsis in the mouse. J Pharmacol Exp Ther 352:61-66.
172. Ward NS, Casserly B, and Ayala A (2008) The compensatory anti-inflammatory response syndrome (CARS) in critically ill patients. Clin Chest Med 29:617-625, viii.
173. Ward PA (2012) New approaches to the study of sepsis. EMBO Mol Med 4:1234-1243.
174. Warren BL, Eid A, Singer P, Pillay SS, Carl P, Novak I, Chalupa P, Atherstone A, Pénzes I, and Kübler A, et al.; KyberSept Trial Study Group (2001) Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 286:1869-1878.
175. Weiss SL, Fitzgerald JC, Pappachan J, Wheeler D, Jaramillo-Bustamante JC, Salloo A, Singhi SC, Erickson S, Roy JA, and Bush JL, et al.; Sepsis Prevalence, Outcomes, and Therapies (SPROUT) Study Investigators and Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network (2015) Global epidemiology of pediatric severe sepsis: the sepsis prevalence, outcomes, and therapies study. Am J Respir Crit Care Med 191:1147-1157.
176. Wepler M, Hafner S, Scheuerle A, Reize M, Gröger M, Wagner F, Simon F, Matallo J, Gottschalch F, and Seifritz A, et al. (2013) Effects of the PPAR-b/d agonist GW0742 during resuscitated porcine septic shock. Intensive Care Med Exp 1:28.
177. Wheeler DS, Wong HR, and Zingarelli B (2011) Pediatric sepsis-Part I: "Children are not small adults!" Open Inflamm J 4:4-15.
178. Winkler MS, Nierhaus A, Holzmann M, Mudersbach E, Bauer A, Robbe L, Zahrte C, Geffken M, Peine S, and Schwedhelm E, et al. (2015) Decreased serum concentrations of sphingosine-1-phosphate in sepsis. Crit Care 19:372.
179. Wong HR, Cvijanovich NZ, Anas N, Allen GL, Thomas NJ, Bigham MT, Weiss SL, Fitzgerald J, Checchia PA, and Meyer K, et al. (2015a) A multibiomarker-based model for estimating the risk of septic acute kidney injury. Crit Care Med 43:1646-1653.
180. Wong HR, Cvijanovich NZ, Anas N, Allen GL, Thomas NJ, Bigham MT, Weiss SL, Fitzgerald J, Checchia PA, and Meyer K, et al. (2015b) Developing a clinically feasible personalized medicine approach to pediatric septic shock. Am J Respir Crit Care Med 191:309-315.
181. Wong HR, Weiss SL, Giuliano JS, Jr, Wainwright MS, Cvijanovich NZ, Thomas NJ, Allen GL, Anas N, Bigham MT, and Hall M, et al. (2014) Testing the prognostic accuracy of the updated pediatric sepsis biomarker risk model. PLoS One 9:e86242.
182. Wood M, Song A, Maslove D, Ferri C, Howes D, Muscedere J, and Boyd JG (2016) Brain tissue oxygenation in patients with septic shock: a feasibility study. Can J Neurol Sci 43:65-73.
183. Wu L, Gokden N, and Mayeux PR (2007) Evidence for the role of reactive nitrogen species in polymicrobial sepsis-induced renal peritubular capillary dysfunction and tubular injury. J Am Soc Nephrol 18:1807-1815.
184. Wynn JL, Scumpia PO, Delano MJ, O'Malley KA, Ungaro R, Abouhamze A, and Moldawer LL (2007) Increased mortality and altered immunity in neonatal sepsis produced by generalized peritonitis. Shock 28:675-683.
185. Wynn JL, Scumpia PO, Winfield RD, Delano MJ, Kelly-Scumpia K, Barker T, Ungaro R, Levy O, and Moldawer LL (2008) Defective innate immunity predisposes murine neonates to poor sepsis outcome but is reversed by TLR agonists. Blood 112:1750-1758.
186. Xiao Z, Wilson C, Robertson HL, Roberts DJ, Ball CG, Jenne CN, and Kirkpatrick AW (2015) Inflammatory mediators in intra-abdominal sepsis or injury-a scoping review. Crit Care 19:373.
187. Yao X, Carlson D, Sun Y, Ma L, Wolf SE, Minei JP, and Zang QS (2015) Mitochondrial ROS induces cardiac inflammation via a pathway through mtDNA damage in a pneumonia-related sepsis model. PLoS One 10:e0139416.
188. Yini S, Heng Z, Xin A, and Xiaochun M (2015) Effect of unfractionated heparin on endothelial glycocalyx in a septic shock model. Acta Anaesthesiol Scand 59:160-169.
189. Zang QS, Sadek H, Maass DL, Martinez B, Ma L, Kilgore JA, Williams NS, Frantz DE, Wigginton JG, and Nwariaku FE, et al. (2012) Specific inhibition of mitochondrial oxidative stress suppresses inflammation and improves cardiac function in a rat pneumonia-related sepsis model. Am J Physiol Heart Circ Physiol 302:H1847-H1859.
190. Zanotti-Cavazzoni SL and Goldfarb RD (2009) Animal models of sepsis. Crit Care Clin 25:703-719.
191. Zeng Y, Adamson RH, Curry FR, and Tarbell JM (2014) Sphingosine-1-phosphate protects endothelial glycocalyx by inhibiting syndecan-1 shedding. Am J Physiol Heart Circ Physiol 306:H363-H372.
192. Zhao X, Chen YX, and Li CS (2015) Predictive value of the complement system for sepsis-induced disseminated intravascular coagulation in septic patients in emergency department. J Crit Care 30:290-295.
193. Ziaja M (2013) Septic encephalopathy. Curr Neurol Neurosci Rep 13:383.
194. Ziegler T, Horstkotte J, Schwab C, Pfetsch V, Weinmann K, Dietzel S, Rohwedder I, Hinkel R, Gross L, and Lee S, et al. (2013) Angiopoietin 2 mediates microvascular and hemodynamic alterations in sepsis. J Clin Invest 123:3436-3445.
195. Zonneveld R, Martinelli R, Shapiro NI, Kuijpers TW, Plötz FB, and Carman CV (2014) Soluble adhesion molecules as markers for sepsis and the potential pathophysiological discrepancy in neonates, children and adults. Crit Care 18:204.