Skip to main content
Top
Published in: Intensive Care Medicine 5/2015

01-05-2015 | Original

Phenotypic clusters within sepsis-associated multiple organ dysfunction syndrome

Authors: Daniel B. Knox, Michael J. Lanspa, Kathryn G. Kuttler, Simon C. Brewer, Samuel M. Brown

Published in: Intensive Care Medicine | Issue 5/2015

Login to get access

Abstract

Introduction

Sepsis is a devastating condition that is generally treated as a single disease. Identification of meaningfully distinct clusters may improve research, treatment and prognostication among septic patients. We therefore sought to identify clusters among patients with severe sepsis or septic shock.

Methods

We retrospectively studied all patients with severe sepsis or septic shock admitted directly from the emergency department to the intensive care units (ICUs) of three hospitals, 2006–2013. Using age and Sequential Organ Failure Assessment (SOFA) subscores, we defined clusters utilizing self-organizing maps, a method for representing multidimensional data in intuitive two-dimensional grids to facilitate cluster identification.

Results

We identified 2533 patients with severe sepsis or septic shock. Overall mortality was 17 %, with a mean APACHE II score of 24, mean SOFA score of 8 and a mean ICU stay of 5.4 days. Four distinct clusters were identified; (1) shock with elevated creatinine, (2) minimal multi-organ dysfunction syndrome (MODS), (3) shock with hypoxemia and altered mental status, and (4) hepatic disease. Mortality (95 % confidence intervals) for these clusters was 11 (8–14), 12 (11–14), 28 (25-32), and 21 (16–26) %, respectively (p < 0.0001). Regression modeling demonstrated that the clusters differed in the association between clinical outcomes and predictors, including APACHE II score.

Conclusions

We identified four distinct clusters of MODS among patients with severe sepsis or septic shock. These clusters may reflect underlying pathophysiological differences and could potentially facilitate tailored treatments or directed research.
Appendix
Available only for authorised users
Literature
1.
go back to reference Zimmerman JE, Kramer AA, Knaus WA (2013) Changes in hospital mortality for United States intensive care unit admissions from 1988 to 2012. Crit Care 17:R81CrossRefPubMedCentralPubMed Zimmerman JE, Kramer AA, Knaus WA (2013) Changes in hospital mortality for United States intensive care unit admissions from 1988 to 2012. Crit Care 17:R81CrossRefPubMedCentralPubMed
2.
go back to reference Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, Reinhart CK, Suter PM, Thijs LG (1996) The SOFA (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. On behalf of the Working group on sepsis-related problems of the European society of intensive care medicine. Intensive Care Med 22:707–710CrossRefPubMed Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, Reinhart CK, Suter PM, Thijs LG (1996) The SOFA (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. On behalf of the Working group on sepsis-related problems of the European society of intensive care medicine. Intensive Care Med 22:707–710CrossRefPubMed
3.
go back to reference Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, Gerlach H, Moreno R, Carlet J, Le Gall JR, Payen D (2006) Sepsis occurrence in acutely Ill patients I, sepsis in European intensive care units: results of the SOAP study. Crit Care Med 34:344–353CrossRefPubMed Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, Gerlach H, Moreno R, Carlet J, Le Gall JR, Payen D (2006) Sepsis occurrence in acutely Ill patients I, sepsis in European intensive care units: results of the SOAP study. Crit Care Med 34:344–353CrossRefPubMed
4.
go back to reference Leligdowicz A, Dodek PM, Norena M, Wong H, Kumar A, Kumar A, Co-operative antimicrobial therapy of septic shock database research G, (2014) Association between source of infection and hospital mortality in patients who have septic shock. Am J Respir Crit Care Med 189:1204–1213CrossRefPubMed Leligdowicz A, Dodek PM, Norena M, Wong H, Kumar A, Kumar A, Co-operative antimicrobial therapy of septic shock database research G, (2014) Association between source of infection and hospital mortality in patients who have septic shock. Am J Respir Crit Care Med 189:1204–1213CrossRefPubMed
5.
go back to reference Howell MD, Talmor D, Schuetz P, Hunziker S, Jones AE, Shapiro NI (2011) Proof of principle: the predisposition, infection, response, organ failure sepsis staging system. Crit Care Med 39:322–327CrossRefPubMed Howell MD, Talmor D, Schuetz P, Hunziker S, Jones AE, Shapiro NI (2011) Proof of principle: the predisposition, infection, response, organ failure sepsis staging system. Crit Care Med 39:322–327CrossRefPubMed
6.
go back to reference Namas R, Zamora R, Namas R, An G, Doyle J, Dick TE, Jacono FJ, Androulakis IP, Nieman GF, Chang S, Billiar TR, Kellum JA, Angus DC, Vodovotz Y (2012) Sepsis: something old, something new, and a systems view. J Crit Care 27(314):e311–e312 Namas R, Zamora R, Namas R, An G, Doyle J, Dick TE, Jacono FJ, Androulakis IP, Nieman GF, Chang S, Billiar TR, Kellum JA, Angus DC, Vodovotz Y (2012) Sepsis: something old, something new, and a systems view. J Crit Care 27(314):e311–e312
7.
go back to reference Fuhrmann V, Kneidinger N, Herkner H, Heinz G, Nikfardjam M, Bojic A, Schellongowski P, Angermayr B, Schoniger-Hekele M, Madl C, Schenk P (2011) Impact of hypoxic hepatitis on mortality in the intensive care unit. Intensive Care Med 37:1302–1310CrossRefPubMed Fuhrmann V, Kneidinger N, Herkner H, Heinz G, Nikfardjam M, Bojic A, Schellongowski P, Angermayr B, Schoniger-Hekele M, Madl C, Schenk P (2011) Impact of hypoxic hepatitis on mortality in the intensive care unit. Intensive Care Med 37:1302–1310CrossRefPubMed
8.
go back to reference Mehta RL, Bouchard J, Soroko SB, Ikizler TA, Paganini EP, Chertow GM, Himmelfarb J (2011) Sepsis as a cause and consequence of acute kidney injury: program to improve care in acute renal disease. Intensive Care Med 37:241–248CrossRefPubMedCentralPubMed Mehta RL, Bouchard J, Soroko SB, Ikizler TA, Paganini EP, Chertow GM, Himmelfarb J (2011) Sepsis as a cause and consequence of acute kidney injury: program to improve care in acute renal disease. Intensive Care Med 37:241–248CrossRefPubMedCentralPubMed
9.
go back to reference Brown SM, Pittman JE, Hirshberg EL, Jones JP, Lanspa MJ, Kuttler KG, Litwin SE, Grissom CK (2012) Diastolic dysfunction and mortality in early severe sepsis and septic shock: a prospective, observational echocardiography study. Crit Ultrasound J 4:8CrossRefPubMedCentralPubMed Brown SM, Pittman JE, Hirshberg EL, Jones JP, Lanspa MJ, Kuttler KG, Litwin SE, Grissom CK (2012) Diastolic dysfunction and mortality in early severe sepsis and septic shock: a prospective, observational echocardiography study. Crit Ultrasound J 4:8CrossRefPubMedCentralPubMed
10.
go back to reference Encode Project Consortium, Bernstein BE, Birney E, Dunham I, Green ED, Gunter C, Snyder M (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489:57–74CrossRef Encode Project Consortium, Bernstein BE, Birney E, Dunham I, Green ED, Gunter C, Snyder M (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489:57–74CrossRef
11.
go back to reference Presson AP, Yoon NK, Bagryanova L, Mah V, Alavi M, Maresh EL, Rajasekaran AK, Goodglick L, Chia D, Horvath S (2011) Protein expression based multimarker analysis of breast cancer samples. BMC Cancer 11:230CrossRefPubMedCentralPubMed Presson AP, Yoon NK, Bagryanova L, Mah V, Alavi M, Maresh EL, Rajasekaran AK, Goodglick L, Chia D, Horvath S (2011) Protein expression based multimarker analysis of breast cancer samples. BMC Cancer 11:230CrossRefPubMedCentralPubMed
12.
go back to reference Gattinoni L, Ranieri VM, Pesenti A (2015) Sepsis: needs for defining severity. Intensive Care Med 41:551–552CrossRefPubMed Gattinoni L, Ranieri VM, Pesenti A (2015) Sepsis: needs for defining severity. Intensive Care Med 41:551–552CrossRefPubMed
14.
go back to reference Boudier A, Curjuric I, Basagana X, Hazgui H, Anto JM, Bousquet J, Bridevaux PO, Dupuis-Lozeron E, Garcia-Aymerich J, Heinrich J, Janson C, Kunzli N, Leynaert B, de Marco R, Rochat T, Schindler C, Varraso R, Pin I, Probst-Hensch N, Sunyer J, Kauffmann F, Siroux V (2013) Ten-Year follow-up of cluster-based asthma phenotypes in adults. a pooled analysis of three cohorts. Am J Respir Crit Care Med 188:550–560CrossRefPubMed Boudier A, Curjuric I, Basagana X, Hazgui H, Anto JM, Bousquet J, Bridevaux PO, Dupuis-Lozeron E, Garcia-Aymerich J, Heinrich J, Janson C, Kunzli N, Leynaert B, de Marco R, Rochat T, Schindler C, Varraso R, Pin I, Probst-Hensch N, Sunyer J, Kauffmann F, Siroux V (2013) Ten-Year follow-up of cluster-based asthma phenotypes in adults. a pooled analysis of three cohorts. Am J Respir Crit Care Med 188:550–560CrossRefPubMed
15.
go back to reference Vanfleteren LE, Spruit MA, Groenen M, Gaffron S, van Empel VP, Bruijnzeel PL, Rutten EP, Op ‘t Roodt J, Wouters EF, Franssen FM (2013) Clusters of comorbidities based on validated objective measurements and systemic inflammation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 187:728–735CrossRefPubMed Vanfleteren LE, Spruit MA, Groenen M, Gaffron S, van Empel VP, Bruijnzeel PL, Rutten EP, Op ‘t Roodt J, Wouters EF, Franssen FM (2013) Clusters of comorbidities based on validated objective measurements and systemic inflammation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 187:728–735CrossRefPubMed
16.
go back to reference Lotsch J, Ultsch A (2013) A machine-learned knowledge discovery method for associating complex phenotypes with complex genotypes. Application to pain. J Biomed Inform 46:921–928CrossRefPubMed Lotsch J, Ultsch A (2013) A machine-learned knowledge discovery method for associating complex phenotypes with complex genotypes. Application to pain. J Biomed Inform 46:921–928CrossRefPubMed
17.
go back to reference Knox DB, Lanspa MJ, Kuttler K, Brewer S, Brown SM (2014) Phenotyping septic shock: use of kohonen self-organizing maps to identify patterns of organ dysfunction. Am J Respir Crit Care Med 189:A3791 Knox DB, Lanspa MJ, Kuttler K, Brewer S, Brown SM (2014) Phenotyping septic shock: use of kohonen self-organizing maps to identify patterns of organ dysfunction. Am J Respir Crit Care Med 189:A3791
18.
go back to reference Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb SA, Beale RJ, Vincent JL, Moreno R, Surviving Sepsis Campaign GuidelinesCommitteeincluding the Pediatric S (2013) Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 41:580–637CrossRefPubMed Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb SA, Beale RJ, Vincent JL, Moreno R, Surviving Sepsis Campaign GuidelinesCommitteeincluding the Pediatric S (2013) Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 41:580–637CrossRefPubMed
19.
go back to reference Miller RR 3rd, Dong L, Nelson NC, Brown SM, Kuttler KG, Probst DR, Allen TL, Clemmer TP, Intermountain healthcare intensive medicine clinical P (2013) Multicenter implementation of a severe sepsis and septic shock treatment bundle. Am J Respir Crit Care Med 188:77–82CrossRefPubMedCentralPubMed Miller RR 3rd, Dong L, Nelson NC, Brown SM, Kuttler KG, Probst DR, Allen TL, Clemmer TP, Intermountain healthcare intensive medicine clinical P (2013) Multicenter implementation of a severe sepsis and septic shock treatment bundle. Am J Respir Crit Care Med 188:77–82CrossRefPubMedCentralPubMed
20.
go back to reference Knaus WA, Draper EA, Wagner DP, Zimmerman JE (1985) APACHE II: a severity of disease classification system. Crit Care Med 13:818–829CrossRefPubMed Knaus WA, Draper EA, Wagner DP, Zimmerman JE (1985) APACHE II: a severity of disease classification system. Crit Care Med 13:818–829CrossRefPubMed
21.
go back to reference Elixhauser A, Steiner C, Harris DR, Coffey RM (1998) Comorbidity measures for use with administrative data. Med Care 36:8–27CrossRefPubMed Elixhauser A, Steiner C, Harris DR, Coffey RM (1998) Comorbidity measures for use with administrative data. Med Care 36:8–27CrossRefPubMed
22.
go back to reference Grissom CK, Brown SM, Kuttler KG, Boltax JP, Jones J, Jephson AR, Orme JF Jr (2010) A modified sequential organ failure assessment score for critical care triage. Disaster Med Public Health Preparedness 4:277–284CrossRef Grissom CK, Brown SM, Kuttler KG, Boltax JP, Jones J, Jephson AR, Orme JF Jr (2010) A modified sequential organ failure assessment score for critical care triage. Disaster Med Public Health Preparedness 4:277–284CrossRef
23.
go back to reference Knox DB, Lanspa MJ, Pratt CM, Kuttler KG, Jones JP, Brown SM (2014) Glasgow coma scale score dominates the association between admission sequential organ failure assessment score and 30 day mortality in a mixed intensive care unit population. J Crit Care 29:780–785CrossRefPubMed Knox DB, Lanspa MJ, Pratt CM, Kuttler KG, Jones JP, Brown SM (2014) Glasgow coma scale score dominates the association between admission sequential organ failure assessment score and 30 day mortality in a mixed intensive care unit population. J Crit Care 29:780–785CrossRefPubMed
24.
go back to reference Teasdale G, Jennett B (1974) Assessment of coma and impaired consciousness. A practical scale. Lancet 2:81–84CrossRefPubMed Teasdale G, Jennett B (1974) Assessment of coma and impaired consciousness. A practical scale. Lancet 2:81–84CrossRefPubMed
25.
go back to reference Ellis RK (1989) Determination of PO2 from saturation. J Appl Physiol 67:902PubMed Ellis RK (1989) Determination of PO2 from saturation. J Appl Physiol 67:902PubMed
26.
go back to reference Severinghaus JW (1979) Simple, accurate equations for human blood O2 dissociation computations. J Appl Physiol Respir Environ Exerc Physiol 46:599–602PubMed Severinghaus JW (1979) Simple, accurate equations for human blood O2 dissociation computations. J Appl Physiol Respir Environ Exerc Physiol 46:599–602PubMed
27.
go back to reference Dean NC, Jones JP, Aronsky D, Brown S, Vines CG, Jones BE, Allen T (2012) Hospital admission decision for patients with community-acquired pneumonia: variability among physicians in an emergency department. Ann Emerg Med 59:35–41CrossRefPubMed Dean NC, Jones JP, Aronsky D, Brown S, Vines CG, Jones BE, Allen T (2012) Hospital admission decision for patients with community-acquired pneumonia: variability among physicians in an emergency department. Ann Emerg Med 59:35–41CrossRefPubMed
28.
go back to reference Hartigan JA (1975) Clustering algorithms. Wiley, New York Hartigan JA (1975) Clustering algorithms. Wiley, New York
30.
go back to reference Friedman JH, Roosen CB (1995) An introduction to multivariate adaptive regression splines. Stat Methods Med Res 4:197–217CrossRefPubMed Friedman JH, Roosen CB (1995) An introduction to multivariate adaptive regression splines. Stat Methods Med Res 4:197–217CrossRefPubMed
31.
go back to reference Poukkanen M, Wilkman E, Vaara ST, Pettila V, Kaukonen KM, Korhonen AM, Uusaro A, Hovilehto S, Inkinen O, Laru-Sompa R, Hautamaki R, Kuitunen A, Karlsson S, Group FS (2013) Hemodynamic variables and progression of acute kidney injury in critically ill patients with severe sepsis: data from the prospective observational FINNAKI study. Crit Care 17:R295CrossRefPubMedCentralPubMed Poukkanen M, Wilkman E, Vaara ST, Pettila V, Kaukonen KM, Korhonen AM, Uusaro A, Hovilehto S, Inkinen O, Laru-Sompa R, Hautamaki R, Kuitunen A, Karlsson S, Group FS (2013) Hemodynamic variables and progression of acute kidney injury in critically ill patients with severe sepsis: data from the prospective observational FINNAKI study. Crit Care 17:R295CrossRefPubMedCentralPubMed
32.
go back to reference Tafelski S, Nachtigall I, Stengel S, Wernecke K, Spies CD, (2014) Comparison of three models for sepsis patient discrimination according to PIRO: predisposition, infection, response and organ dysfunction. Minerva Anestesiol (in press) Tafelski S, Nachtigall I, Stengel S, Wernecke K, Spies CD, (2014) Comparison of three models for sepsis patient discrimination according to PIRO: predisposition, infection, response and organ dysfunction. Minerva Anestesiol (in press)
33.
go back to reference Joannidis M, Metnitz PG (2005) Epidemiology and natural history of acute renal failure in the ICU. Crit Care Clin 21:239–249CrossRefPubMed Joannidis M, Metnitz PG (2005) Epidemiology and natural history of acute renal failure in the ICU. Crit Care Clin 21:239–249CrossRefPubMed
34.
go back to reference Fitzpatrick AM, Teague WG, Meyers DA, Peters SP, Li X, Li H, Wenzel SE, Aujla S, Castro M, Bacharier LB, Gaston BM, Bleecker ER, Moore WC, NationalInstitutesof Health, National Heart L, Blood Institute Severe Asthma Research P (2011) Heterogeneity of severe asthma in childhood: confirmation by cluster analysis of children in the national institutes of health/national heart, lung, and blood institute severe asthma research program. J Allergy Clin Immunol 127(382–389):e381–381 Fitzpatrick AM, Teague WG, Meyers DA, Peters SP, Li X, Li H, Wenzel SE, Aujla S, Castro M, Bacharier LB, Gaston BM, Bleecker ER, Moore WC, NationalInstitutesof Health, National Heart L, Blood Institute Severe Asthma Research P (2011) Heterogeneity of severe asthma in childhood: confirmation by cluster analysis of children in the national institutes of health/national heart, lung, and blood institute severe asthma research program. J Allergy Clin Immunol 127(382–389):e381–381
35.
go back to reference Mangiameli P, Chen SK, West D (1996) A comparison of SOM neural network and hierarchical clustering methods. Eur J Oper Res 93:402–417CrossRef Mangiameli P, Chen SK, West D (1996) A comparison of SOM neural network and hierarchical clustering methods. Eur J Oper Res 93:402–417CrossRef
36.
go back to reference Barnay-Verdier S, Fattoum L, Borde C, Kaveri S, Gibot S, Marechal V (2011) Emergence of autoantibodies to HMGB1 is associated with survival in patients with septic shock. Intensive Care Med 37:957–962CrossRefPubMed Barnay-Verdier S, Fattoum L, Borde C, Kaveri S, Gibot S, Marechal V (2011) Emergence of autoantibodies to HMGB1 is associated with survival in patients with septic shock. Intensive Care Med 37:957–962CrossRefPubMed
37.
go back to reference Dombrovskiy VY, Martin AA, Sunderram J, Paz HL (2007) Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: a trend analysis from 1993 to 2003. Crit Care Med 35:1244–1250CrossRefPubMed Dombrovskiy VY, Martin AA, Sunderram J, Paz HL (2007) Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: a trend analysis from 1993 to 2003. Crit Care Med 35:1244–1250CrossRefPubMed
38.
go back to reference Investigators ProCess, Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA, Pike F, Terndrup T, Wang HE, Hou PC, LoVecchio F, Filbin MR, Shapiro NI, Angus DC (2014) A randomized trial of protocol-based care for early septic shock. N Engl J Med 370:1683–1693CrossRef Investigators ProCess, Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA, Pike F, Terndrup T, Wang HE, Hou PC, LoVecchio F, Filbin MR, Shapiro NI, Angus DC (2014) A randomized trial of protocol-based care for early septic shock. N Engl J Med 370:1683–1693CrossRef
39.
go back to reference Kaukonen KM, Bailey M, Suzuki S, Pilcher D, Bellomo R (2014) Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000–2012. JAMA 311:1308–1316CrossRefPubMed Kaukonen KM, Bailey M, Suzuki S, Pilcher D, Bellomo R (2014) Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000–2012. JAMA 311:1308–1316CrossRefPubMed
40.
go back to reference Brown SM, Lanspa MJ, Jones JP, Kuttler KG, Li Y, Carlson R, Miller RR, Hirshberg EL, Grissom CK, Morris AH (2013) Survival after shock requiring high-dose vasopressor therapy. Chest 143:664–671PubMedCentralPubMed Brown SM, Lanspa MJ, Jones JP, Kuttler KG, Li Y, Carlson R, Miller RR, Hirshberg EL, Grissom CK, Morris AH (2013) Survival after shock requiring high-dose vasopressor therapy. Chest 143:664–671PubMedCentralPubMed
Metadata
Title
Phenotypic clusters within sepsis-associated multiple organ dysfunction syndrome
Authors
Daniel B. Knox
Michael J. Lanspa
Kathryn G. Kuttler
Simon C. Brewer
Samuel M. Brown
Publication date
01-05-2015
Publisher
Springer Berlin Heidelberg
Published in
Intensive Care Medicine / Issue 5/2015
Print ISSN: 0342-4642
Electronic ISSN: 1432-1238
DOI
https://doi.org/10.1007/s00134-015-3764-7

Other articles of this Issue 5/2015

Intensive Care Medicine 5/2015 Go to the issue