Skip to main navigation menu Skip to main content Skip to site footer

Review article: Biomedical intelligence

Vol. 145 No. 0708 (2015)

Biomarker-guided personalised emergency medicine for all – hope for another hype?

  • Philipp Schuetz
  • Drahomir Aujesky
  • Christian Müller
  • Beat Müller
DOI
https://doi.org/10.4414/smw.2015.14079
Cite this as:
Swiss Med Wkly. 2015;145:w14079
Published
08.02.2015

Abstract

Polymorbid patients, diverse diagnostic and therapeutic options, more complex hospital structures, financial incentives, benchmarking, as well as perceptional and societal changes put pressure on medical doctors, specifically if medical errors surface. This is particularly true for the emergency department setting, where patients face delayed or erroneous initial diagnostic or therapeutic measures and costly hospital stays due to sub-optimal triage.

A “biomarker” is any laboratory tool with the potential better to detect and characterise diseases, to simplify complex clinical algorithms and to improve clinical problem solving in routine care. They must be embedded in clinical algorithms to complement and not replace basic medical skills. Unselected ordering of laboratory tests and shortcomings in test performance and interpretation contribute to diagnostic errors. Test results may be ambiguous with false positive or false negative results and generate unnecessary harm and costs. Laboratory tests should only be ordered, if results have clinical consequences. In studies, we must move beyond the observational reporting and meta-analysing of diagnostic accuracies for biomarkers. Instead, specific cut-off ranges should be proposed and intervention studies conducted to prove outcome relevant impacts on patient care.

The focus of this review is to exemplify the appropriate use of selected laboratory tests in the emergency setting for which randomised-controlled intervention studies have proven clinical benefit. Herein, we focus on initial patient triage and allocation of treatment opportunities in patients with cardiorespiratory diseases in the emergency department. The following five biomarkers will be discussed: proadrenomedullin for prognostic triage assessment and site-of-care decisions, cardiac troponin for acute myocardial infarction, natriuretic peptides for acute heart failure, D-dimers for venous thromboembolism, C-reactive protein as a marker of inflammation, and procalcitonin for antibiotic stewardship in infections of the respiratory tract and sepsis. For these markers we provide an overview on physiopathology, historical evolution of evidence, strengths and limitations for a rational implementation into clinical algorithms. We critically discuss results from key intervention trials that led to their use in clinical routine and potential future indications.

The rational for the use of all these biomarkers, is to tackle, first, diagnostic ambiguity and consecutive defensive medicine, second, delayed and sub-optimal therapeutic decisions, and third, prognostic uncertainty with misguided triage and site-of-care decisions all contributing to the waste of our limited health care resources. A multifaceted approach for a more targeted management of medical patients from emergency admission to discharge including biomarkers, will translate into better resource use, shorter length of hospital stay, reduced overall costs, improved patients satisfaction and outcomes in terms of mortality and re-hospitalisation. Hopefully, the concepts outlined in this review will help the reader to improve their diagnostic skills and become more parsimonious laboratory test requesters.

References

  1. Enderli SK, S. Lorber, C. Sandmeier, H. Gesundheitswesen Schweiz Ausgabe 2014. Basel: Interpharma, 2014.
  2. Williams RM. The costs of visits to emergency departments. N Engl J Med. 1996;334(10):642–6.
  3. Graber ML. The incidence of diagnostic error in medicine. BMJ quality & safety. 2013;22(Suppl 2):ii21–ii7.
  4. Albrich WC, Dusemund F, Bucher B, Meyer S, Thomann R, Kuhn F, et al. Effectiveness and safety of procalcitonin-guided antibiotic therapy in lower respiratory tract infections in “real life”: an international, multicenter poststudy survey (ProREAL). Arch Intern Med. 2012;172(9):715–22.
  5. Schuetz P, Mueller B. Biomarker-guided de-escalation of empirical therapy is associated with lower risk for adverse outcomes. Intensive Care Med. 2014;40(1):141.
  6. Lipinski MJ, Escarcega RO, D’Ascenzo F, Magalhaes MA, Baker NC, Torguson R, et al. A Systematic Review and Collaborative Meta-Analysis to Determine the Incremental Value of Copeptin for Rapid Rule-Out of Acute Myocardial Infarction. Am J Cardiol. 2014;113(9):1581–91.
  7. Raskovalova T, Twerenbold R, Collinson PO, Keller T, Bouvaist H, Folli C, et al. Diagnostic accuracy of combined cardiac troponin and copeptin assessment for early rule-out of myocardial infarction: a systematic review and meta-analysis. Eur Heart J Acute Cardiovasc Care. 2014;3(1):18–27.
  8. Torbicki A, Perrier A, Konstantinides S, Agnelli G, Galie N, Pruszczyk P, et al. Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Eur Heart J. 2008;29(18):2276–315.
  9. Aujesky D, Hayoz D, Yersin B, Perrier A, Barghouth G, Schnyder P, et al. Exclusion of pulmonary embolism using C-reactive protein and D-dimer. A prospective comparison. Thromb Haemost. 2003;90(6):1198–203.
  10. Blendon RJ, DesRoches CM, Brodie M, Benson JM, Rosen AB, Schneider E, et al. Views of practicing physicians and the public on medical errors. N Engl J Med. 2002;347(24):1933–40.
  11. Kaliniak C. Misdiagnosis is an overlooked and growing patient safety issue and core mission of isabel healthcare. Accessed May 18th.
  12. Mangalmurti SS, Harold JG, Parikh PD, Flannery FT, Oetgen WJ. Characteristics of Medical Professional Liability Claims Against Internists. JAMA internal medicine. 2014.
  13. Garber AM, Tunis SR. Does comparative-effectiveness research threaten personalized medicine? N Engl J Med. 2009;360(19):1925–7.
  14. Paynter NP, Chasman DI, Buring JE, Shiffman D, Cook NR, Ridker PM. Cardiovascular disease risk prediction with and without knowledge of genetic variation at chromosome 9p21.3. Ann Intern Med. 2009;150(2):65–72.
  15. Johnson EG, Horne BD, Carlquist JF, Anderson JL. Genotype-based dosing algorithms for warfarin therapy: data review and recommendations. Molecular diagnosis & therapy. 2011;15(5):255–64.
  16. Mueller C, Scholer A, Laule-Kilian K, Martina B, Schindler C, Buser P, et al. Use of B-type natriuretic peptide in the evaluation and management of acute dyspnea. N Engl J Med. 2004;350(7):647–54.
  17. Wallgren UM, Castren M, Svensson AE, Kurland L. Identification of adult septic patients in the prehospital setting: a comparison of two screening tools and clinical judgment. European journal of emergency medicine: official journal of the European Society for Emergency Medicine. 2013.
  18. Heuer JF, Gruschka D, Crozier TA, Bleckmann A, Plock E, Moerer O, et al. Accuracy of prehospital diagnoses by emergency physicians: comparison with discharge diagnosis. European journal of emergency medicine: official journal of the European Society for Emergency Medicine. 2012;19(5):292–6.
  19. Misch F, Messmer AS, Nickel CH, Gujan M, Graber A, Blume K, et al. Impact of observation on disposition of elderly patients presenting to emergency departments with non-specific complaints. PLoS One. 2014;9(5):e98097.
  20. Nemec M, Koller MT, Nickel CH, Maile S, Winterhalder C, Karrer C, et al. Patients presenting to the emergency department with non-specific complaints: the Basel Non-specific Complaints (BANC) study. Acad Emerg Med. 2010;17(3):284–92.
  21. Baehni C, Meier S, Spreiter P, Schild U, Regez K, Bossart R, et al. Which patients with lower respiratory tract infections need inpatient treatment? Perceptions of physicians, nurses, patients and relatives. BMC pulmonary medicine. 2010;10:12.
  22. Graber ML, Franklin N, Gordon R. Diagnostic error in internal medicine. Arch Intern Med. 2005;165(13):1493–9.
  23. Platt R. Manchester University Medical School gazette. 1947;27:139–45.
  24. Kirch W, Schafii C. Misdiagnosis at a university hospital in 4 medical eras. Medicine (Baltimore). 1996;75(1):29–40.
  25. Leuppi JD, Dieterle T, Koch G, Martina B, Tamm M, Perruchoud AP, et al. Diagnostic value of lung auscultation in an emergency room setting. Swiss Med Wkly. 2005;135(35–36):520–4.
  26. Feddock CA. The lost art of clinical skills. Am J Med. 2007;120(4):374–8.
  27. Kevat DA, Cameron PA, Davies AR, Landrigan CP, Rajaratnam SW. Safer hours for doctors and improved safety for patients. Med J Aust. 2014;200(7):396–8.
  28. Muller B, Harbarth S, Stolz D, Bingisser R, Mueller C, Leuppi J, et al. Diagnostic and prognostic accuracy of clinical and laboratory parameters in community-acquired pneumonia. BMC infectious diseases. 2007;7:10.
  29. Spiteri MA, Cook DG, Clarke SW. Reliability of eliciting physical signs in examination of the chest. Lancet. 1988;1(8590):873–5.
  30. Samaras N, Chevalley T, Samaras D, Gold G. Older patients in the emergency department: a review. Ann Emerg Med. 2010;56(3):261–9.
  31. Metlay JP, Kapoor WN, Fine MJ. Does this patient have community-acquired pneumonia? Diagnosing pneumonia by history and physical examination. Jama. 1997;278(17):1440–5.
  32. Koran LM. The reliability of clinical methods, data and judgments (first of two parts). N Engl J Med. 1975 293(13):642–6.
  33. Koran LM. The reliability of clinical methods, data and judgments (second of two parts). N Engl J Med. 1975;293(14):695–701.
  34. Mueller C, Frana B, Rodriguez D, Laule-Kilian K, Perruchoud AP. Emergency diagnosis of congestive heart failure: impact of signs and symptoms. Can J Cardiol. 2005;21(11):921–4.
  35. Stolz D, Christ-Crain M, Gencay MM, Bingisser R, Huber PR, Muller B, et al. Diagnostic value of signs, symptoms and laboratory values in lower respiratory tract infection. Swiss Med Wkly. 2006;136(27–28):434–40.
  36. Stolz D, Tamm M. Discriminate use of antibiotics for exacerbation of COPD. Current Opinion in Pulmonary Medicine. 2009;15(2):126–32.
  37. Renaud B, Schuetz P, Claessens YE, Labarere J, Albrich W, Mueller B. Proadrenomedullin improves Risk of Early Admission to ICU score for predicting early severe community-acquired pneumonia. Chest. 2012;142(6):1447–54.
  38. Bettencourt P, Azevedo A, Pimenta J, Frioes F, Ferreira S, Ferreira A. N-terminal-pro-brain natriuretic peptide predicts outcome after hospital discharge in heart failure patients. Circulation. 2004;110(15):2168–74.
  39. Schuetz P, Litke A, Albrich WC, Mueller B. Blood biomarkers for personalized treatment and patient management decisions in community-acquired pneumonia. Curr Opin Infect Dis. 2013;26(2):159–67.
  40. Albrich WC, Ruegger K, Dusemund F, Schuetz P, Arici B, Litke A, et al. Biomarker-enhanced triage in respiratory infections: a proof-of-concept feasibility trial. Eur Respir J. 2013;42(4):1064–75.
  41. Epner PL, Gans JE, Graber ML. When diagnostic testing leads to harm: a new outcomes-based approach for laboratory medicine. BMJ quality & safety. 2013;22(Suppl 2):ii6–ii10.
  42. Wahner-Roedler DL, Chaliki SS, Bauer BA, Bundrick JB, Bergstrom LR, Lee MC, et al. Who makes the diagnosis? The role of clinical skills and diagnostic test results. J Eval Clin Pract. 2007;13(3):321–5.
  43. Hauser RG, Shirts BH. Do We Now Know What Inappropriate Laboratory Utilization Is? An Expanded Systematic Review of Laboratory Clinical Audits. Am J Clin Pathol. 2014;141(6):774–83.
  44. Singh H, Arora HS, Vij MS, Rao R, Khan MM, Petersen LA. Communication outcomes of critical imaging results in a computerized notification system. J Am Med Inform Assoc. 2007;14(4):459–66.
  45. Nylen E, Muller B, Becker KL, Snider R. The future diagnostic role of procalcitonin levels: the need for improved sensitivity. Clin Infect Dis. 2003;36(6):823–4; author reply 6–7.
  46. Muller B, Christ-Crain M, Nylen ES, Snider R, Becker KL. Limits to the use of the procalcitonin level as a diagnostic marker. Clin Infect Dis. 2004;39(12):1867–8.
  47. van Walraven C, Naylor CD. Do we know what inappropriate laboratory utilization is? A systematic review of laboratory clinical audits. JAMA. 1998;280(6):550–8.
  48. Salisbury AC, Reid KJ, Alexander KP, Masoudi FA, Lai SM, Chan PS, et al. Diagnostic blood loss from phlebotomy and hospital-acquired anemia during acute myocardial infarction. Arch Intern Med. 2011;171(18):1646–53.
  49. Detsky AS, Krumholz HM. Reducing the Trauma of Hospitalization. JAMA. 2014.
  50. Cassel CK, Guest JA. Choosing wisely: helping physicians and patients make smart decisions about their care. JAMA. 2012;307(17):1801–2.
  51. Attali M, Barel Y, Somin M, Beilinson N, Shankman M, Ackerman A, et al. A cost-effective method for reducing the volume of laboratory tests in a university-associated teaching hospital. The Mount Sinai journal of medicine, New York. 2006;73(5):787–94.
  52. May TA, Clancy M, Critchfield J, Ebeling F, Enriquez A, Gallagher C, et al. Reducing unnecessary inpatient laboratory testing in a teaching hospital. Am J Clin Pathol. 2006;126(2):200–6.
  53. Burt CW, McCaig LF, Rechtsteiner EA. Ambulatory medical care utilization estimates for 2005. Adv Data. 2007;388:1–15.
  54. McCaig LF, Burt CW. National Hospital Ambulatory Medical Care Survey: 2002 emergency department summary. Adv Data. 2004;340:1–34.
  55. Cantor WJ, Fitchett D, Borgundvaag B, Ducas J, Heffernan M, Cohen EA, et al. Routine early angioplasty after fibrinolysis for acute myocardial infarction. N Engl J Med. 2009;360(26):2705–18.
  56. Adams HP, Jr., Effron MB, Torner J, Davalos A, Frayne J, Teal P, et al. Emergency administration of abciximab for treatment of patients with acute ischemic stroke: results of an international phase III trial: Abciximab in Emergency Treatment of Stroke Trial (AbESTT-II). Stroke. 2008;39(1):87–99.
  57. Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34(6):1589–96.
  58. Puskarich MA, Trzeciak S, Shapiro NI, Heffner AC, Kline JA, Jones AE, et al. Outcomes of patients undergoing early sepsis resuscitation for cryptic shock compared with overt shock. Resuscitation. 2011;82(10):1289–93.
  59. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345(19):1368–77.
  60. Kumar A, Haery C, Paladugu B, Kumar A, Symeoneides S, Taiberg L, et al. The duration of hypotension before the initiation of antibiotic treatment is a critical determinant of survival in a murine model of Escherichia coli septic shock: association with serum lactate and inflammatory cytokine levels. J Infect Dis. 2006;193(2):251–8.
  61. Puskarich MA, Trzeciak S, Shapiro NI, Arnold RC, Horton JM, Studnek JR, et al. Association between timing of antibiotic administration and mortality from septic shock in patients treated with a quantitative resuscitation protocol. Crit Care Med. 2011;39(9):2066–71.
  62. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013;39(2):165–228.
  63. Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N, et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008;358(2):125–39.
  64. Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008;358(2):111–24.
  65. Fried BJ, Topping S, Morrissey JP, Ellis AR, Stroup S, Blank M. Comparing provider perceptions of access and utilization management in full-risk and no-risk Medicaid programs for adults with serious mental illness. The journal of behavioral health services & research. 2000;27(1):29–46.
  66. Aliyu ZY, Aliyu MH, McCormick K. Determinants for hospitalization in “low-risk” community acquired pneumonia. BMC Infect Dis. 2003;3:11.
  67. Labarere J, Stone RA, Scott Obrosky D, Yealy DM, Meehan TP, Auble TE, et al. Factors associated with the hospitalization of low-risk patients with community-acquired pneumonia in a cluster-randomized trial. J Gen Intern Med. 2006;21(7):745–52.
  68. Menendez R, Cremades MJ, Martinez-Moragon E, Soler JJ, Reyes S, Perpina M. Duration of length of stay in pneumonia: influence of clinical factors and hospital type. Eur Respir J. 2003;22(4):643–8.
  69. McGregor MJ, Fitzgerald JM, Reid RJ, Levy AR, Schulzer M, Jung D, et al. Determinants of hospital length of stay among patients with pneumonia admitted to a large Canadian hospital from 1991 to 2001. Can Respir J. 2005;12(7):365–70.
  70. Self WH, Grijalva CG, Zhu Y, McNaughton CD, Barrett TW, Collins SP, et al. Rates of emergency department visits due to pneumonia in the United States, July 2006–June 2009. Acad Emerg Med. 2013;20(9):957–60.
  71. Dixon RE. Economic costs of respiratory tract infections in the United States. Am J Med. 1985;78(6B):45–51.
  72. Niederman MS, Mandell LA, Anzueto A, Bass JB, Broughton WA, Campbell GD, et al. Guidelines for the management of adults with community-acquired pneumonia. Diagnosis, assessment of severity, antimicrobial therapy, and prevention. Am J Respir Crit Care Med. 2001;163(7):1730–54.
  73. Chalmers JD, Al-Khairalla M, Short PM, Fardon TC, Winter JH. Proposed changes to management of lower respiratory tract infections in response to the Clostridium difficile epidemic. J Antimicrob Chemother. 2010;65(4):608–18.
  74. Schuetz P, Christ-Crain M, Thomann R, Falconnier C, Wolbers M, Widmer I, et al. Effect of procalcitonin-based guidelines vs standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. JAMA. 2009;302(10):1059–66.
  75. Yealy DM, Auble TE, Stone RA, Lave JR, Meehan TP, Graff LG, et al. Effect of increasing the intensity of implementing pneumonia guidelines: a randomized, controlled trial. Ann Intern Med. 2005;143(12):881–94.
  76. Marrie TJ. Deaths in risk classes I–III: a measure of quality of care in patients hospitalised with CAP? Eur Respir J. 2004;23(1):103–5.
  77. Hedlund JU, Ortqvist AB, Kalin ME, Granath F. Factors of importance for the long term prognosis after hospital treated pneumonia. Thorax. 1993;48(8):785–9.
  78. Jasti H, Mortensen EM, Obrosky DS, Kapoor WN, Fine MJ. Causes and risk factors for rehospitalization of patients hospitalized with community-acquired pneumonia. Clin Infect Dis. 2008;46(4):550–6.
  79. Kitamura K, Kangawa K, Kawamoto M, Ichiki Y, Nakamura S, Matsuo H, et al. Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. BiochemBiophysResCommun. 1993;192(2):553–60.
  80. Kitamura K, Sakata J, Kangawa K, Kojima M, Matsuo H, Eto T. Cloning and characterization of cDNA encoding a precursor for human adrenomedullin. Biochem Biophys Res Commun. 1993;194(2):720–5.
  81. Linscheid P, Seboek D, Zulewski H, Keller U, Muller B. Autocrine/paracrine role of inflammation-mediated calcitonin gene-related peptide and adrenomedullin expression in human adipose tissue. Endocrinology. 2005;146(6):2699–708.
  82. Schuetz P, Christ-Crain M, Muller B. Biomarkers to improve diagnostic and prognostic accuracy in systemic infections. Curr Opin Crit Care. 2007;13(5):578–85.
  83. Christ-Crain M, Muller B. Calcitonin peptides – the mediators in sepsis or just another fairy tale? Crit Care Med. 2008;36(5):1684–7.
  84. Schuetz P, Christ-Crain M, Muller B. Procalcitonin and other biomarkers to improve assessment and antibiotic stewardship in infections--hope for hype? Swiss Med Wkly. 2009;139(23–24):318–26.
  85. Becker KL, Nylen ES, White JC, Muller B, Snider RH, Jr. Clinical review 167: Procalcitonin and the calcitonin gene family of peptides in inflammation, infection, and sepsis: a journey from calcitonin back to its precursors. J Clin Endocrinol Metab. 2004;89(4):1512–25.
  86. Becker KL, Snider R, Nylen ES. Procalcitonin assay in systemic inflammation, infection, and sepsis: clinical utility and limitations. Crit Care Med. 2008;36(3):941–52.
  87. Muller B, Becker KL, Schachinger H, Rickenbacher PR, Huber PR, Zimmerli W, et al. Calcitonin precursors are reliable markers of sepsis in a medical intensive care unit. Crit Care Med. 2000;28(4):977–83.
  88. Sexton PM, Christopoulos G, Christopoulos A, Nylen ES, Snider RH, Jr., Becker KL. Procalcitonin has bioactivity at calcitonin receptor family complexes: potential mediator implications in sepsis. Crit Care Med. 2008;36(5):1637–40.
  89. McLatchie LM, Fraser NJ, Main MJ, Wise A, Brown J, Thompson N, et al. RAMPs regulate the transport and ligand specificity of the calcitonin- receptor-like receptor. Nature. 1998;393(6683):333–9.
  90. Becker KL, Nylen ES, White JC, Muller B, Snider RH, Jr. Procalcitonin and the calcitonin gene family of peptides in inflammation, infection, and sepsis: a journey from calcitonin back to its precursors. J Clin Endocrinol Metab. 2004;89(4):1512–25.
  91. Elsasser TH, Kahl S. Adrenomedullin has multiple roles in disease stress: development and remission of the inflammatory response. Microsc Res Tech. 2002;57(2):120–9.
  92. Xue Y, Taub P, Iqbal N, Fard A, Clopton P, Maisel A. Mid-region pro-adrenomedullin adds predictive value to clinical predictors and Framingham risk score for long-term mortality in stable outpatients with heart failure. Eur J Heart Fail. 2013;15(12):1343–9.
  93. Schuetz P, Christ-Crain M, Morgenthaler NG, Struck J, Bergmann A, Muller B. Circulating precursor levels of endothelin-1 and adrenomedullin, two endothelium-derived, counteracting substances, in sepsis. Endothelium: journal of endothelial cell research. 2007;14(6):345–51.
  94. Hoeboer SH, Alberts E, van den Hul I, Tacx AN, Debets-Ossenkopp YJ, Groeneveld AB. Old and new biomarkers for predicting high and low risk microbial infection in critically ill patients with new onset fever: a case for procalcitonin. J Infect. 2012;64(5):484–93.
  95. Allaker RP, Grosvenor PW, McAnerney DC, Sheehan BE, Srikanta BH, Pell K, et al. Mechanisms of adrenomedullin antimicrobial action. Peptides. 2006;27(4):661–6.
  96. Matsui H, Shimosawa T, Itakura K, Guanqun X, Ando K, Fujita T. Adrenomedullin can protect against pulmonary vascular remodeling induced by hypoxia. Circulation. 2004;109(18):2246–51.
  97. Smith JG, Newton-Cheh C, Hedblad B, Struck J, Morgenthaler NG, Bergmann A, et al. Distribution and correlates of midregional proadrenomedullin in the general population. Clinical chemistry. 2009;55(8):1593–5.
  98. Temmesfeld-Wollbruck B, Hocke AC, Suttorp N, Hippenstiel S. Adrenomedullin and endothelial barrier function. Thromb Haemost. 2007;98(5):944–51.
  99. Stolz D, Kostikas K, Blasi F, Boersma W, Milenkovic B, Lacoma A, et al. Adrenomedullin refines mortality prediction by the BODE index in COPD: the “BODE-A” index. Eur Respir J. 2014;43(2):397–408.
  100. Morgenthaler NG, Struck J, Alonso C, Bergmann A. Measurement of midregional proadrenomedullin in plasma with an immunoluminometric assay. Clinical chemistry. 2005;51(10):1823–9.
  101. Lewis LK, Smith MW, Yandle TG, Richards AM, Nicholls MG. Adrenomedullin(1–52) measured in human plasma by radioimmunoassay: plasma concentration, adsorption, and storage. Clinical chemistry. 1998;44(3):571–7.
  102. Struck J, Tao C, Morgenthaler NG, Bergmann A. Identification of an Adrenomedullin precursor fragment in plasma of sepsis patients. Peptides. 2004;25(8):1369–72.
  103. Goode KM, Nicholls R, Pellicori P, Clark AL, Cleland JG. The in vitro stability of novel cardiovascular and sepsis biomarkers at ambient temperature. Clin Chem Lab Med. 2014;52(6):911–8.
  104. Christ-Crain M, Morgenthaler NG, Struck J, Harbarth S, Bergmann A, Muller B. Mid-regional pro-adrenomedullin as a prognostic marker in sepsis: an observational study. Crit Care. 2005;9(6):R816–24.
  105. Christ-Crain M, Morgenthaler NG, Stolz D, Muller C, Bingisser R, Harbarth S, et al. Pro-adrenomedullin to predict severity and outcome in community-acquired pneumonia [ISRCTN04176397]. Crit Care. 2006;10(3):R96.
  106. Chalmers JD, Al-Khairalla M, Short PM, Fardon TC, Winter JH. Proposed changes to management of lower respiratory tract infections in response to the Clostridium difficile epidemic. J Antimicrob Chemother. 2010.
  107. Holm A, Pedersen SS, Nexoe J, Obel N, Nielsen LP, Koldkjaer O, et al. Procalcitonin versus C-reactive protein for predicting pneumonia in adults with lower respiratory tract infection in primary care. Br J Gen Pract. 2007;57(540):555–60.
  108. Kruger S, Ewig S, Marre R, Papassotiriou J, Richter K, von Baum H, et al. Procalcitonin predicts patients at low risk of death from community-acquired pneumonia across all CRB-65 classes. Eur Respir J. 2008;31(2):349–55.
  109. Menendez R, Martinez R, Reyes S, Mensa J, Filella X, Marcos MA, et al. Biomarkers improve mortality prediction by prognostic scales in community-acquired pneumonia. Thorax. 2009;64(7):587–91.
  110. Huang DT, Angus DC, Kellum JA, Pugh NA, Weissfeld LA, Struck J, et al. Midregional proadrenomedullin as a prognostic tool in community-acquired pneumonia. Chest. 2009;136(3):823–31.
  111. Schuetz P, Wolbers M, Christ-Crain M, Thomann R, Falconnier C, Widmer I, et al. Prohormones for prediction of adverse medical outcome in community-acquired pneumonia and lower respiratory tract infections. Crit Care. 2010;14(3) R106.
  112. Stolz D, Christ-Crain M, Morgenthaler NG, Miedinger D, Leuppi J, Muller C, et al. Plasma pro-adrenomedullin but not plasma pro-endothelin predicts survival in exacerbations of COPD. Chest. 2008;134(2):263–72.
  113. Christ-Crain M, Breidthardt T, Stolz D, Zobrist K, Bingisser R, Miedinger D, et al. Use of B-type natriuretic peptide in the risk stratification of community-acquired pneumonia. J Intern Med. 2008;264(2):166–76.
  114. Christ-Crain M, Schuetz P, Müller B. Biomarkers in the management of pneumonia. Expert Rev Respir Med. 2008;2(5):565–72.
  115. Christ-Crain M, Stolz D, Jutla S, Couppis O, Muller C, Bingisser R, et al. Free and total cortisol levels as predictors of severity and outcome in community-acquired pneumonia. Am J Respir Crit Care Med. 2007;176(9):913–20.
  116. Muller B, Morgenthaler N, Stolz D, Schuetz P, Muller C, Bingisser R, et al. Circulating levels of copeptin, a novel biomarker, in lower respiratory tract infections. Eur J Clin Invest. 2007;37(2):145–52.
  117. Muller B, Suess E, Schuetz P, Muller C, Bingisser R, Bergmann A, et al. Circulating levels of pro-atrial natriuretic peptide in lower respiratory tract infections. J Intern Med. 2006;260(6):568–76.
  118. Schuetz P, Muller B, Nusbaumer C, Wieland M, Christ-Crain M. Circulating levels of GH predict mortality and complement prognostic scores in critically ill medical patients. Eur J Endocrinol. 2009;160(2):157–63.
  119. Schuetz P, Stolz D, Mueller B, Morgenthaler NG, Struck J, Mueller C, et al. Endothelin-1 precursor peptides correlate with severity of disease and outcome in patients with community acquired pneumonia. BMC infectious diseases. 2008;8:22.
  120. Chalmers JD, Singanayagam A, Scally C, Hill AT. Admission D-dimer can identify low-risk patients with community-acquired pneumonia. Ann Emerg Med. 2009;53(5):633–8.
  121. Albrich WC, Dusemund F, Ruegger K, Christ-Crain M, Zimmerli W, Bregenzer T, et al. Enhancement of CURB65 score with proadrenomedullin (CURB65–A) for outcome prediction in lower respiratory tract infections: derivation of a clinical algorithm. BMC infectious diseases. 2011;11:112.
  122. Alpert JS, Thygesen K, Antman E, Bassand JP. Myocardial infarction redefined--a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol. 2000;36(3):959–69.
  123. Bertrand ME, Simoons ML, Fox KA, Wallentin LC, Hamm CW, McFadden E, et al. Management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J. 2002;23(23):1809–40.
  124. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, et al. Third universal definition of myocardial infarction. Eur Heart J. 2012;33(20):2551–67.
  125. Martina B, Bucheli B, Stotz M, Battegay E, Gyr N. First clinical judgment by primary care physicians distinguishes well between nonorganic and organic causes of abdominal or chest pain. J Gen Intern Med. 1997;12(8):459–65.
  126. Hamm CW, Goldmann BU, Heeschen C, Kreymann G, Berger J, Meinertz T. Emergency room triage of patients with acute chest pain by means of rapid testing for cardiac troponin T or troponin I. N Engl J Med. 1997;337(23):1648–53.
  127. Mueller C, Neumann FJ, Perruchoud AP, Zeller T, Buettner HJ. Prognostic value of quantitative troponin T measurements in unstable angina/non-ST-segment elevation acute myocardial infarction treated early and predominantly with percutaneous coronary intervention. Am J Med. 2004;117(12):897–902.
  128. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, et al. Third universal definition of myocardial infarction. J Am Coll Cardiol. 2012;60(16):1581–98.
  129. Reichlin T, Schindler C, Drexler B, Twerenbold R, Reiter M, Zellweger C, et al. One-hour rule-out and rule-in of acute myocardial infarction using high-sensitivity cardiac troponin T. Arch Intern Med. 2012;172(16):1211–8.
  130. Mockel M, Searle J, Hamm C, Slagman A, Blankenberg S, Huber K, et al. Early discharge using single cardiac troponin and copeptin testing in patients with suspected acute coronary syndrome (ACS): a randomized, controlled clinical process study. Eur Heart J. 2014.
  131. Wang CS, FitzGerald JM, Schulzer M, Mak E, Ayas NT. Does this dyspneic patient in the emergency department have congestive heart failure? JAMA. 2005;294(15):1944–56.
  132. Davis M, Espiner E, Richards G, Billings J, Town I, Neill A, et al. Plasma brain natriuretic peptide in assessment of acute dyspnoea. Lancet. 1994;343(8895):440–4.
  133. Maisel AS, Krishnaswamy P, Nowak RM, McCord J, Hollander JE, Duc P, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med. 2002;347(3):161–7.
  134. Silver MA, Maisel A, Yancy CW, McCullough PA, Burnett JC, Jr., Francis GS, et al. BNP Consensus Panel 2004: A clinical approach for the diagnostic, prognostic, screening, treatment monitoring, and therapeutic roles of natriuretic peptides in cardiovascular diseases. Congest Heart Fail. 2004;10(5 Suppl 3):1–30.
  135. Januzzi JL, van Kimmenade R, Lainchbury J, Bayes-Genis A, Ordonez-Llanos J, Santalo-Bel M, et al. NT-proBNP testing for diagnosis and short-term prognosis in acute destabilized heart failure: an international pooled analysis of 1256 patients: the International Collaborative of NT-proBNP Study. Eur Heart J. 2006;27(3):330–7.
  136. Mueller C, Breidthardt T, Laule-Kilian K, Christ M, Perruchoud AP. The integration of BNP and NT-proBNP into clinical medicine. Swiss Med Wkly. 2007;137(1–2):4–12.
  137. Ritter M, Laule-Kilian K, Klima T, Christ A, Christ M, Perruchoud A, et al. Gender differences in acute congestive heart failure. Swiss Med Wkly. 2006;136(19–20):311–7.
  138. Moe GW, Howlett J, Januzzi JL, Zowall H, Canadian Multicenter Improved Management of Patients With Congestive Heart Failure Study I. N-terminal pro-B-type natriuretic peptide testing improves the management of patients with suspected acute heart failure: primary results of the Canadian prospective randomized multicenter IMPROVE-CHF study. Circulation. 2007;115(24):3103–10.
  139. Christ M, Laule-Kilian K, Hochholzer W, Klima T, Breidthardt T, Perruchoud AP, et al. Gender-specific risk stratification with B-type natriuretic peptide levels in patients with acute dyspnea: insights from the B-type natriuretic peptide for acute shortness of breath evaluation study. J Am Coll Cardiol. 2006;48(9):1808–12.
  140. Logeart D, Thabut G, Jourdain P, Chavelas C, Beyne P, Beauvais F, et al. Predischarge B-type natriuretic peptide assay for identifying patients at high risk of re-admission after decompensated heart failure. J Am Coll Cardiol. 2004;43(4):635–41.
  141. Troughton RW, Frampton CM, Yandle TG, Espiner EA, Nicholls MG, Richards AM. Treatment of heart failure guided by plasma aminoterminal brain natriuretic peptide (N-BNP) concentrations. Lancet. 2000;355(9210):1126–30.
  142. Jourdain P, Jondeau G, Funck F, Gueffet P, Le Helloco A, Donal E, et al. Plasma brain natriuretic peptide-guided therapy to improve outcome in heart failure: the STARS-BNP Multicenter Study. J Am Coll Cardiol. 2007;49(16):1733–9.
  143. Richards AM, Doughty R, Nicholls MG, MacMahon S, Sharpe N, Murphy J, et al. Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin: prognostic utility and prediction of benefit from carvedilol in chronic ischemic left ventricular dysfunction. Australia-New Zealand Heart Failure Group. J Am Coll Cardiol. 2001;37(7):1781–7.
  144. Investigators P. Value of the ventilation/perfusion scan in acute pulmonary embolism. Results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). JAMA: the journal of the American Medical Association. 1990;263(20):2753–9.
  145. Cogo A, Lensing AW, Prandoni P, Hirsh J. Distribution of thrombosis in patients with symptomatic deep vein thrombosis. Implications for simplifying the diagnostic process with compression ultrasound. Arch Intern Med. 1993;153(24):2777–80.
  146. Bates SM. D-dimer assays in diagnosis and management of thrombotic and bleeding disorders. Semin Thromb Hemost. 2012;38(7):673–82.
  147. Rowbotham BJ, Carroll P, Whitaker AN, Bunce IH, Cobcroft RG, Elms MJ, et al. Measurement of crosslinked fibrin derivatives – use in the diagnosis of venous thrombosis. Thromb Haemost. 1987;57(1):59–61.
  148. Bounameaux H, Cirafici P, de Moerloose P, Schneider PA, Slosman D, Reber G, et al. Measurement of D-dimer in plasma as diagnostic aid in suspected pulmonary embolism. Lancet. 1991;337(8735):196–200.
  149. Stein PD, Hull RD, Patel KC, Olson RE, Ghali WA, Brant R, et al. D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a systematic review. Ann Intern Med. 2004;140(8):589–602.
  150. Di Nisio M, Squizzato A, Rutjes AW, Buller HR, Zwinderman AH, Bossuyt PM. Diagnostic accuracy of D-dimer test for exclusion of venous thromboembolism: a systematic review. Journal of thrombosis and haemostasis: JTH. 2007;5(2):296–304.
  151. Fancher TL, White RH, Kravitz RL. Combined use of rapid D-dimer testing and estimation of clinical probability in the diagnosis of deep vein thrombosis: systematic review. BMJ. 2004;329(7470):821.
  152. Carrier M, Righini M, Djurabi RK, Huisman MV, Perrier A, Wells PS, et al. VIDAS D-dimer in combination with clinical pre-test probability to rule out pulmonary embolism. A systematic review of management outcome studies. Thromb Haemost. 2009;101(5):886–92.
  153. Kruip MJ, Leclercq MG, van der Heul C, Prins MH, Buller HR. Diagnostic strategies for excluding pulmonary embolism in clinical outcome studies. A systematic review. Ann Intern Med. 2003;138(12):941–51.
  154. Ten Cate-Hoek AJ, Prins MH. Management studies using a combination of D-dimer test result and clinical probability to rule out venous thromboembolism: a systematic review. Journal of thrombosis and haemostasis: JTH. 2005;3(11):2465–70.
  155. Geersing GJ, Zuithoff NP, Kearon C, Anderson DR, Ten Cate-Hoek AJ, Elf JL, et al. Exclusion of deep vein thrombosis using the Wells rule in clinically important subgroups: individual patient data meta-analysis. BMJ. 2014;348:g1340.
  156. Wells PS, Anderson DR, Rodger M, Forgie M, Kearon C, Dreyer J, et al. Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med. 2003;349(13):1227–35.
  157. Kearon C, Ginsberg JS, Douketis J, Turpie AG, Bates SM, Lee AY, et al. An evaluation of D-dimer in the diagnosis of pulmonary embolism: a randomized trial. Ann Intern Med. 2006;144(11):812–21.
  158. Bates SM, Jaeschke R, Stevens SM, Goodacre S, Wells PS, Stevenson MD, et al. Diagnosis of DVT: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e351S-418S.
  159. Schuur JD, Carney DP, Lyn ET, Raja AS, Michael JA, Ross NG, et al. A top-five list for emergency medicine: a pilot project to improve the value of emergency care. JAMA internal medicine. 2014;174(4):509–15.
  160. Righini M, Goehring C, Bounameaux H, Perrier A. Effects of age on the performance of common diagnostic tests for pulmonary embolism. Am J Med. 2000;109(5):357–61.
  161. Righini M, Le Gal G, De Lucia S, Roy PM, Meyer G, Aujesky D, et al. Clinical usefulness of D-dimer testing in cancer patients with suspected pulmonary embolism. Thromb Haemost. 2006;95(4):715–9.
  162. Miron MJ, Perrier A, Bounameaux H, de Moerloose P, Slosman DO, Didier D, et al. Contribution of noninvasive evaluation to the diagnosis of pulmonary embolism in hospitalized patients. Eur Respir J. 1999;13(6):1365–70.
  163. Segard T, Macdonald WB. Changing trends in venous thromboembolism-related imaging in Western Australian teaching hospitals, 2002–2010. Med J Aust. 2013;198(2):100–3.
  164. Ingber S, Selby R, Lee J, Geerts W, Brnjac E. Combination pretest probability assessment and D-dimer did not reduce outpatient imaging for venous thromboembolism in a tertiary care hospital emergency department. Cjem. 2014;16(1):53–62.
  165. Singh B, Mommer SK, Erwin PJ, Mascarenhas SS, Parsaik AK. Pulmonary embolism rule-out criteria (PERC) in pulmonary embolism--revisited: a systematic review and meta-analysis. Emergency medicine journal: EMJ. 2013;30(9):701–6.
  166. Le Gal G, Bounameaux H. Diagnosing pulmonary embolism: running after the decreasing prevalence of cases among suspected patients. Journal of thrombosis and haemostasis: JTH. 2004;2(8):1244–6.
  167. Righini M, Van Es J, Den Exter PL, Roy PM, Verschuren F, Ghuysen A, et al. Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism: the ADJUST-PE study. JAMA. 2014;311(11):1117–24.
  168. Sackett DL. The rational clinical examination. A primer on the precision and accuracy of the clinical examination. JAMA. 1992;267(19):2638–44.
  169. Coburn B, Morris AM, Tomlinson G, Detsky AS. Does this adult patient with suspected bacteremia require blood cultures? JAMA. 2012;308(5):502–11.
  170. Bates DW, Cook EF, Goldman L, Lee TH. Predicting bacteremia in hospitalized patients. A prospectively validated model. Ann Intern Med. 1990;113(7):495–500.
  171. Muller F, Christ-Crain M, Bregenzer T, Krause M, Zimmerli W, Mueller B, et al. Procalcitonin levels predict bacteremia in patients with community-acquired pneumonia: a prospective cohort trial. Chest. 2010;138(1):121–9.
  172. Bates DW, Goldman L, Lee TH. Contaminant blood cultures and resource utilization. The true consequences of false-positive results. JAMA. 1991;265(3):365–9.
  173. Schuetz P, Mueller B, Trampuz A. Serum procalcitonin for discrimination of blood contamination from bloodstream infection due to coagulase-negative staphylococci. Infection. 2007;35(5):352–5.
  174. Muller B, Schuetz P, Trampuz A. Circulating biomarkers as surrogates for bloodstream infections. Int J Antimicrob Agents. 2007;30(Suppl 1):S16–23.
  175. Bullowa JGM, Wilcox C. Incidence of bacteremia in the pneumonias and its relation to mortality. Arch Intern Med. 1935;55:558–73.
  176. Schuetz P, Albrich W, Mueller B. Procalcitonin for diagnosis of infection and guide to antibiotic decisions: past, present and future. BMC medicine. 2011;9(1):107.
  177. Schuetz P, Briel M, Mueller B. Clinical outcomes associated with procalcitonin algorithms to guide antibiotic therapy in respiratory tract infections. JAMA. 2013;309(7):717–8.
  178. Haubitz S, Mueller B, Schuetz P. Streamlining antibiotic therapy with procalcitonin protocols: consensus and controversies. Expert Rev Respir Med. 2013;7(2):145–57.
  179. Vincent JL. Dear SIRS, I’m sorry to say that I don’t like you.. 1997;25(2):372–4.
  180. Simon L, Gauvin F, Amre DK, Saint-Louis P, Lacroix J. Serum procalcitonin and C-reactive protein levels as markers of bacterial infection: a systematic review and meta-analysis. Clin Infect Dis. 2004;39(2):206–17.
  181. Tang BM, Eslick GD, Craig JC, McLean AS. Accuracy of procalcitonin for sepsis diagnosis in critically ill patients: systematic review and meta-analysis. Lancet Infect Dis. 2007;7(3):210–7.
  182. Tang H, Huang T, Jing J, Shen H, Cui W. Effect of procalcitonin-guided treatment in patients with infections: a systematic review and meta-analysis. Infection. 2009;37(6):497–507.
  183. Harbarth S, Holeckova K, Froidevaux C, Pittet D, Ricou B, Grau GE, et al. Diagnostic value of procalcitonin, interleukin-6, and interleukin-8 in critically ill patients admitted with suspected sepsis. Am J Respir Crit Care Med. 2001;164(3):396–402.
  184. Muller B, Peri G, Doni A, Perruchoud AP, Landmann R, Pasqualini F, et al. High circulating levels of the IL-1 type II decoy receptor in critically ill patients with sepsis: association of high decoy receptor levels with glucocorticoid administration. J Leukoc Biol. 2002;72(4):643–9.
  185. Howell MD, Talmor D, Schuetz P, Hunziker S, Jones AE, Shapiro NI. Proof of principle: the predisposition, infection, response, organ failure sepsis staging system. Crit Care Med. 2011;39(2):322–7.
  186. Rhodes B, Furnrohr BG, Vyse TJ. C-reactive protein in rheumatology: biology and genetics. Nat Rev Rheumatol. 2011;7(5):282–9.
  187. Henriquez-Camacho C, Losa J. Biomarkers for sepsis. BioMed research international. 2014;2014:547818.
  188. Libby P, Ridker PM. Inflammation and atherosclerosis: role of C-reactive protein in risk assessment. Am J Med. 2004;116(Suppl 6A):9S–16S.
  189. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000;342(12):836–43.
  190. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002;347(20):1557–65.
  191. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM, Jr., Kastelein JJ, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195–207.
  192. Barnett ML, Linder JA. Antibiotic prescribing to adults with sore throat in the United States, 1997–2010. JAMA internal medicine. 2014;174(1):138–40.
  193. Samore MH, Bateman K, Alder SC, Hannah E, Donnelly S, Stoddard GJ, et al. Clinical decision support and appropriateness of antimicrobial prescribing: a randomized trial. JAMA. 2005;294(18):2305–14.
  194. Cals JW, Butler CC, Hopstaken RM, Hood K, Dinant GJ. Effect of point of care testing for C reactive protein and training in communication skills on antibiotic use in lower respiratory tract infections: cluster randomised trial. BMJ. 2009;338:b1374.
  195. Cals JW, Schot MJ, de Jong SA, Dinant GJ, Hopstaken RM. Point-of-care C-reactive protein testing and antibiotic prescribing for respiratory tract infections: a randomized controlled trial. Ann Fam Med. 2010;8(2):124–33.
  196. Gonzales R, Aagaard EM, Camargo CA, Jr., Ma OJ, Plautz M, Maselli JH, et al. C-reactive protein testing does not decrease antibiotic use for acute cough illness when compared to a clinical algorithm. J Emerg Med. 2011;41(1):1–7.
  197. Christ-Crain M, Muller B. Procalcitonin in bacterial infections – hype, hope, more or less? Swiss Med Wkly. 2005;135(31–32):451–60.
  198. Stolz D, Christ-Crain M, Morgenthaler NG, Leuppi J, Miedinger D, Bingisser R, et al. Copeptin, C-reactive protein, and procalcitonin as prognostic biomarkers in acute exacerbation of COPD. Chest. 2007;131(4):1058–67.
  199. Muller B, White JC, Nylen ES, Snider RH, Becker KL, Habener JF. Ubiquitous expression of the calcitonin-i gene in multiple tissues in response to sepsis. J Clin Endocrinol Metab. 2001;86(1):396–404.
  200. Linscheid P, Seboek D, Nylen ES, Langer I, Schlatter M, Becker KL, et al. In vitro and in vivo calcitonin I gene expression in parenchymal cells: a novel product of human adipose tissue. Endocrinology. 2003;144(12):5578–84.
  201. Linscheid P, Seboek D, Schaer DJ, Zulewski H, Keller U, Muller B. Expression and secretion of procalcitonin and calcitonin gene-related peptide by adherent monocytes and by macrophage-activated adipocytes. Crit Care Med. 2004;32(8):1715–21.
  202. Dandona P, Nix D, Wilson MF, Aljada A, Love J, Assicot M, et al. Procalcitonin increase after endotoxin injection in normal subjects. J Clin Endocrinol Metab. 1994;79(6):1605–8.
  203. de Werra I, Jaccard C, Corradin SB, Chiolero R, Yersin B, Gallati H, et al. Cytokines, nitrite/nitrate, soluble tumor necrosis factor receptors, and procalcitonin concentrations: comparisons in patients with septic shock, cardiogenic shock, and bacterial pneumonia. Crit Care Med. 1997;25(4):607–13.
  204. Brunkhorst FM, Clark AL, Forycki ZF, Anker SD. Pyrexia, procalcitonin, immune activation and survival in cardiogenic shock: the potential importance of bacterial translocation. Int J Cardiol. 1999;72(1):3–10.
  205. Becker KL, Snider R, Nylen ES. Procalcitonin in sepsis and systemic inflammation: a harmful biomarker and a therapeutic target. Br J Pharmacol. 2010;159(2):253–64.
  206. Muller B, Becker KL, Kranzlin M, Schachinger H, Huber PR, Nylen ES, et al. Disordered calcium homeostasis of sepsis: association with calcitonin precursors. Eur J Clin Invest. 2000;30(9):823–31.
  207. Habener JF, Schiller AL. Pathogenesis of renal osteodystrophy – a role for calcitonin? 1977;296(19):1112–4.
  208. Zudaire E, Portal-Nunez S, Cuttitta F. The central role of adrenomedullin in host defense. J Leukoc Biol. 2006;80(2):237–44.
  209. Nylen ES, Whang KT, Snider RH, Jr., Steinwald PM, White JC, Becker KL. Mortality is increased by procalcitonin and decreased by an antiserum reactive to procalcitonin in experimental sepsis. Crit Care Med. 1998;26(6):1001–6.
  210. Tavares E, Minano FJ. Immunoneutralization of the aminoprocalcitonin peptide of procalcitonin protects rats from lethal endotoxaemia: neuroendocrine and systemic studies. Clin Sci (Lond). 2010;119(12):519–34.
  211. Martinez JM, Wagner KE, Snider RH, Nylen ES, Muller B, Sarani B, et al. Late immunoneutralization of procalcitonin arrests the progression of lethal porcine sepsis. Surgical Inf. 2002;2:193–201.
  212. Wagner KE, Martinez JM, Vath SD, Snider RH, Nylen ES, Becker KL, et al. Early immunoneutralization of calcitonin precursors attenuates the adverse physiologic response to sepsis in pigs. Crit Care Med. 2002;30(10):2313–21.
  213. Canale DD, Donabedian RK. Hypercalcitoninemia in acute pancreatitis. J Clin Endocrinol Metab. 1975;40(4):738–41.
  214. Chesney RW, McCarron DM, Haddad JG, Hawker CD, DiBella FP, Chesney PJ, et al. Pathogenic mechanisms of the hypocalcemia of the staphylococcal toxic- shock syndrome. J Lab Clin Med. 1983;101(4):576–85.
  215. Becker K, Silva O, Snider R, Moore C, Geelhood G, Nash D, et al. The pathophysiology of pulmonary calcitonin. In: Becker K, Gazdar A. The Endocrine Lung in Health and Disease. Philadelphia, PA: WB Saunders Co., 1984:277–9.
  216. Nylen ES, O'Neill W, Jordan MH, Snider RH, Moore CF, Lewis M, et al. Serum procalcitonin as an index of inhalation injury in burns. Horm Metab Res. 1992;24(9):439–43.
  217. Assicot M, Gendrel D, Carsin H, Raymond J, Guilbaud J, Bohuon C. High serum procalcitonin concentrations in patients with sepsis and infection. Lancet. 1993;341(8844):515–8.
  218. Gendrel D, Raymond J, Assicot M, Moulin F, Iniguez JL, Lebon P, et al. Measurement of procalcitonin levels in children with bacterial or viral meningitis. ClinInfectDis. 1997;24(6):1240–2.
  219. Gendrel D, Assicot M, Raymond J, Moulin F, Francoual C, Badoual J, et al. Procalcitonin as a marker for the early diagnosis of neonatal infection. JPediatr. 1996;128(4):570–3.
  220. Karzai W, Oberhoffer M, Meier-Hellmann A, Reinhart K. Procalcitonin – a new indicator of the systemic response to severe infections. 1997;25(6):329–34.
  221. Ugarte H, Silva E, Mercan D, De Mendonca A, Vincent JL. Procalcitonin used as a marker of infection in the intensive care unit. Crit Care Med. 1999;27(3):498–504.
  222. Vincent JL. Procalcitonin: THE marker of sepsis? Crit Care Med. 2000;28(4):1226–8.
  223. Ruokonen E, Ilkka L, Niskanen M, Takala J. Procalcitonin and neopterin as indicators of infection in critically ill patients. Acta Anaesthesiol Scand. 2002;46(4):398–404.
  224. Brunkhorst FM, Heinz U, Forycki ZF. Kinetics of procalcitonin in iatrogenic sepsis. Intensive Care Med. 1998;24(8):888–9.
  225. van Nieuwkoop C, Bonten TN, van’t Wout JW, Kuijper EJ, Groeneveld GH, Becker MJ, et al. Procalcitonin reflects bacteremia and bacterial load in urosepsis syndrome: a prospective observational study. Crit Care. 2010;14(6):R206.
  226. Schuetz P, Suter-Widmer I, Chaudri A, Christ-Crain M, Zimmerli W, Mueller B, et al. Prognostic value of procalcitonin in community-acquired pneumonia. Eur Respir J. 2011;37(2):384–92.
  227. Haeuptle J, Zaborsky R, Fiumefreddo R, Trampuz A, Steffen I, Frei R, et al. Prognostic value of procalcitonin in Legionella pneumonia. Eur J Clin Microbiol Infect Dis. 2009;28(1):55–60.
  228. Schuetz P, Amin DN, Greenwald JL. Role of procalcitonin in managing adult patients with respiratory tract infections. Chest. 2012;141(4):1063–73.
  229. Huang D, Weissfeld L, Kellum J, Yealy D, Kong L, Martino M, et al. Risk Prediction With Procalcitonin and Clinical Rules in Community-Acquired Pneumonia. Ann Emerg Med. 2008;52(1):48–58.e2.
  230. Jensen JU, Heslet L, Jensen TH, Espersen K, Steffensen P, Tvede M. Procalcitonin increase in early identification of critically ill patients at high risk of mortality. Crit Care Med. 2006;34(10):2596–602.
  231. Jensen JU, Hein L, Lundgren B, Bestle MH, Mohr TT, Andersen MH, et al. Procalcitonin-guided interventions against infections to increase early appropriate antibiotics and improve survival in the intensive care unit: a randomized trial. Crit Care Med. 2011;39(9):2048–58.
  232. Johansen ME, Jensen JU, Lundgren JD. Antibiotics in intensive care: too little or too much? Crit Care Med. 2011;39(7):1849–51.
  233. Bouadma L, Luyt CE, Tubach F, Cracco C, Alvarez A, Schwebel C, et al. Use of procalcitonin to reduce patients’ exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial. Lancet. 2010;375(9713):463–74.
  234. Schuetz P, Chiappa V, Briel M, Greenwald JL. Procalcitonin algorithms for antibiotic therapy decisions: a systematic review of randomized controlled trials and recommendations for clinical algorithms. Arch Intern Med. 2011;171(15):1322–31.
  235. Schuetz P, Muller B, Christ-Crain M, Stolz D, Tamm M, Bouadma L, et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst Rev. 2012; 9: CD007498.
  236. Gencay M, Roth M, Christ-Crain M, Mueller B, Tamm M, Stolz D. Single and multiple viral infections in lower respiratory tract infection. Respiration. 2010;80(6):560–7.
  237. Cuquemelle E, Soulis F, Villers D, Roche-Campo F, Ara Somohano C, Fartoukh M, et al. Can procalcitonin help identify associated bacterial infection in patients with severe influenza pneumonia? A multicentre study. Intensive Care Med. 2011;37(5):796–800.
  238. Ingram PR, Inglis T, Moxon D, Speers D. Procalcitonin and C-reactive protein in severe 2009 H1N1 influenza infection. Intensive Care Med. 2010;36(3):528–32.
  239. Piacentini E, Sanchez B, Arauzo V, Calbo E, Cuchi E, Nava JM. Procalcitonin levels are lower in intensive care unit patients with H1N1 influenza A virus pneumonia than in those with community-acquired bacterial pneumonia. A pilot study. J Crit Care. 2011;26(2):201–5.
  240. Christ-Crain M, Jaccard-Stolz D, Bingisser R, Gencay MM, Huber PR, Tamm M, et al. Effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomised, single-blinded intervention trial. Lancet. 2004;363(9409):600–7.
  241. Stolz D, Christ-Crain M, Bingisser R, Leuppi J, Miedinger D, Muller C, et al. Antibiotic treatment of exacerbations of COPD: a randomized, controlled trial comparing procalcitonin-guidance with standard therapy. Chest. 2007;131(1):9–19.
  242. Stolz D, Smyrnios N, Eggimann P, Pargger H, Thakkar N, Siegemund M, et al. Procalcitonin for reduced antibiotic exposure in Ventilator Associated Pneumonia – a randomized study. Eur Respir J. 2009.
  243. Carlet J, Cohen J, Calandra T, Opal SM, Masur H. Sepsis: time to reconsider the concept. Crit Care Med. 2008;36(3):964–6.
  244. Christ-Crain M, Muller B. Procalictonin – you only find what you look for, and you only look for what you know. J Am Geriatr Soc. 2006;54(3):546; author reply 7–8.
  245. Baer G, Baumann P, Buettcher M, Heininger U, Berthet G, Schafer J, et al. Procalcitonin guidance to reduce antibiotic treatment of lower respiratory tract infection in children and adolescents (ProPAED): a randomized controlled trial. PLoS One. 2013;8(8):e68419.
  246. Korppi M, Remes S, Heiskanen-Kosma T. Serum procalcitonin concentrations in bacterial pneumonia in children: a negative result in primary healthcare settings. Pediatr Pulmonol. 2003;35(1):56–61.
  247. Sachse C, Dressler F, Henkel E. Increased serum procalcitonin in newborn infants without infection. 1998;44(6 Pt 1):1343–4.
  248. Assumma M, Signore F, Pacifico L, Rossi N, Osborn JF, Chiesa C. Serum procalcitonin concentrations in term delivering mothers and their healthy offspring: A longitudinal study. Clinical chemistry. 2000;46(10):1583–7.
  249. Chiesa C, Panero A, Rossi N, Stegagno M, De Giusti M, Osborn JF, et al. Reliability of procalcitonin concentrations for the diagnosis of sepsis in critically ill neonates. 1998;26(3):664–72.
  250. Marc E, Menager C, Moulin F, Stos B, Chalumeau M, Guerin S, et al. Procalcitonin and viral meningitis: reduction of unnecessary antibiotics by measurement during an outbreak. Arch Pediatr. 2002;9(4):358–64.
  251. Benador N, Siegrist CA, Gendrel D, Greder C, Benador D, Assicot M, et al. Procalcitonin is a marker of severity of renal lesions in pyelonephritis. Pediatrics. 1998;102(6):1422–5.
  252. Drozdov D, Thomer A, Meili M, Schwarz S, Kouegbe RB, Regez K, et al. Procalcitonin, pyuria and proadrenomedullin in the management of urinary tract infections – “triple p in uti”: study protocol for a randomized controlled trial. Trials. 2013;14:84.
  253. Ottiger C, Schaer G, Huber AR. Time-course of quantitative urinary leukocytes and bacteria counts during antibiotic therapy in women with symptoms of urinary tract infection. Clinica chimica acta; international journal of clinical chemistry. 2007;379(1–2):36–41.
  254. Drozdov D, Schwarz S, Kutz A, Grolimund E, Rast AC, Regez K, et al. A Procalcitonin and Pyuria-based algorithm reduces antibiotic use in urinary tract infections in a randomized controlled trial. In: Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Washington, D.C., USA, 2014.
  255. Muller B, Prat C. Markers of acute inflammation in assessing and managing lower respiratory tract infections: focus on procalcitonin. Clin Microbiol Infect. 2006;12(Suppl 9):8–16.
  256. Shapiro NI, Wolfe RE, Wright SB, Moore R, Bates DW. Who needs a blood culture? A prospectively derived and validated prediction rule. J Emerg Med. 2008;35(3):255–64.
  257. Woodhead M, Blasi F, Ewig S, Garau J, Huchon M, Leven M, et al. Guidelines for the management of adult lower respiratory tract infections. Clin Microbiol Infect. 2011;17(Suppl. 6):E1–E59.
  258. Allen RB. Medical Education and the Changing Order. The Commonwealth Fund, 1946.
  259. Engel GL. Editorial: Are Medical Schools neglecting clinical skills? JAMA. 1976;236(7):861–3.
  260. van Zanten AR, Brinkman S, Arbous MS, Abu-Hanna A, Levy MM, de Keizer NF, et al. Guideline bundles adherence and mortality in severe sepsis and septic shock. Crit Care Med. 2014;42(8):1890–8.
  261. Schuetz P, Hausfater P, Amin D, Haubitz S, Fassler L, Grolimund E, et al. Optimizing triage and hospitalization in adult general medical emergency patients: the triage project. BMC emergency medicine. 2013;13(1):12.
  262. Courtais C, Kuster N, Dupuy AM, Folschveiller M, Jreige R, Bargnoux AS, et al. Proadrenomedullin, a useful tool for risk stratification in high Pneumonia Severity Index score community acquired pneumonia. Am J Emerg Med. 2013;31(1):215–21.
  263. Rast AC, Mueller B, Schuetz P. Clinical scores and blood biomarkers for early risk assessment of patients presenting to the emergency department – Critical review. OA Emergency Medicine. 2014;2:1–9.
  264. Righini M, Perrier A, De Moerloose P, Bounameaux H. D-Dimer for venous thromboembolism diagnosis: 20 years later. J Thromb Haemost. 2008;6(7):1059–71.
  265. Twerenbold R, Reichlin T, Mueller C. Clinical application of sensitive cardiac troponin assays: potential and limitations. Biomark Med. 2010;4(3):395–401.
  266. Reichlin T, Hochholzer W, Bassetti S, Steuer S, Stelzig C, Hartwiger S, et al. Early diagnosis of myocardial infarction with sensitive cardiac troponin assays. N Engl J Med. 2009;361(9):858–67.
  267. Salazar J, Martinez MS, Chavez M, Toledo A, Anez R, Torres Y, et al. C-reactive protein: clinical and epidemiological perspectives. Cardiology research and practice. 2014;2014:605810.
  268. Ridker PM. C-reactive protein and the prediction of cardiovascular events among those at intermediate risk: moving an inflammatory hypothesis toward consensus. J Am Coll Cardiol. 2007;49(21):2129–38.
  269. Blum CA, Nigro N, Briel M, Schuetz P, Ullmer E, Suter-Widmer I, et al. Adjunct prednisone therapy for patients with community-acquired pneumonia – a randomized, double-blind, placebo-controlled multicenter trial. The Lancet 2015; (in press).

Most read articles by the same author(s)

1 2 3 4 > >>