New or Progressive Multiple Organ Dysfunction Syndrome in Pediatric Severe Sepsis: A Sepsis Phenotype With Higher Morbidity and Mortality

doi:10.1097/PCC.0000000000000978

Observational Study

. 2017 Jan;18(1):8-16.

doi: 10.1097/PCC.0000000000000978.

New or Progressive Multiple Organ Dysfunction Syndrome in Pediatric Severe Sepsis: A Sepsis Phenotype With Higher Morbidity and Mortality

John C Lin¹, Philip C Spinella, Julie C Fitzgerald, Marisa Tucci, Jenny L Bush, Vinay M Nadkarni, Neal J Thomas, Scott L Weiss; Sepsis Prevalence, Outcomes, and Therapy Study Investigators

Collaborators, Affiliations

Collaborators

Sepsis Prevalence, Outcomes, and Therapy Study Investigators:
P Fontela, M Tucci, M Dumistrascu, P Skippen, G Krahn, E Bezares, G Puig, A Puig-Ramos, R Garcia, M Villar, M Bigham, T Polanski, S Latifi, D Giebner, H Anthony, J Hume, A Galster, L Linnerud, R Sanders, G Hefley, K Madden, A Thompson, S Shein, S Gertz, Y Han, T Williams, A Hughes-Schalk, H Chandler, A Orioles, E Zielinski, A Doucette, C Zebuhr, T Wilson, C Dimitriades, J Ascani, S Layburn, S Valley, B Markowitz, J Terry, R Morzov, A Mcinnes, J McArthur, K Woods, K Murkowski, M Spaeder, M Sharron, D Wheeler, E Beckman, E Frank, K Howard, C Carroll, S Nett, D Jarvis, V Patel, R Higgerson, L Christie, K Typpo, J Deschenes, A Kirby, T Uhl, K Rehder, I Cheifetz, S Wrenn, K Kypuros, K Ackerman, F Maffei, G Bloomquist, N Rizkalla, D Kimura, S Shah, C Tigges, F Su, C Barlow, K Michelson, K Wolfe, D Goodman, L Campbell, L Sorce, K Bysani, T Monjure, M Evans, Totapally, M Chegondi, C Rodriguez, J Frazier, L Steele, S Viteri, A Costarino, N Thomas, D Spear, E Hirshberg, J Lilley, C Rowan, C Rider, J Kane, J Zimmerman, C Greeley, J Lin, R Jacobs, M Parker, K Culver, L Loftis, N Jaimon, M Goldsworthy, J Fitzgerald, S Weiss, V Nadkarni, J Bush, M Diliberto, C Alen, M Gessouroun, A Sapru, T Lang, M Alkhouli, S Kamath, D Friel, J Daufeldt, D Hsing, C Carlo, S Pon, J Scimeme, A Shaheen, A Hassinger, H Qiao, J Giuliano, J Tala, D Vinciguerra, A Fernandez, R Carrero, P Hoyos, J Jaramillo, A Posada, L Izquiierdo, B E Piñeres Olave, J Donado, R Dalmazzo, S Rendich, L Palma, M Lapadula, C Acuna, P Cruces, S Clement De Clety, M Dujardin, C Berghe, S Renard, J Zurek, H Steinherr, K Mougkou, E Critselis, K Mougkou, M Di Nardo, S Picardo, F Tortora, E Rossetti, T Fragasso, P Cogo, R Netto, A Dagys, V Gurskis, R Kevalas, C Neeleman, J Lemson, C Luijten, K Wojciech, I Pagowska-Klimek, M Szczepanska, J Karpe, P Nunes, H Almeida, J Rios, M Vieira, J P Garcia Iniguez, P Revilla, J Urbano, J Lopez-Herce, A Bustinza, A Cuesta, S Hofheinz, A Rodriguez-Nunez, S Sanagustin, E Gonzalez, M Riaza, R Piaya, P Soler, E Esteban, J Laraudogoitia, C Monge, V Herrera, J Granados, C Gonzalez, T Koroglu, E Ozcelik, P Baines, A Plunkett, P Davis, S George, S Tibby, J Harris, R Agbeko, R Lampitt, J Brierley, M Peters, A Jones, T Dominguez, T Thiruchelvam, A Deep, L Ridley, W Bowen, R Levin, I Macleod, M Gray, N Hemat, J Alexander, S Ali, J Pappachan, J McCorkell, P Fortune, M MacDonald, P Hudnott, Q Suyun, S Singhi, K Nallasamy, R Lodha, N Shime, Y Tabata, O Saito, T Ikeyama, T Kawasaki, L Lum, A Abidin, S Kee, S Tang, R Jalil, Y Guan, L Yao, K Lin, J Ong, A Salloo, L Doedens, L Mathivha, G Reubenson, S Moaisi, A Pentz, R Green, A Schibler, A Fernandez, S Erickson, J McEneiry, D Long, T Dorofaeff, M Coulthard, J Millar, C Delzoppo, G Williams, M Morritt, N Watts, M Morritt, J Beca, C Sherring, T Bushell

Affiliation

¹ 1Division of Critical Care Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO.2Department of Anesthesiology and Critical Care, The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.3Division of Critical Care Medicine, Department of Pediatrics, University of Montreal, Montreal, QC, Canada.4Pediatric Critical Care Medicine, Departments of Pediatrics and Public Health Sciences, Penn State University College of Medicine, Hershey, PA.

PMID: 28060151
PMCID: PMC7261134
DOI: 10.1097/PCC.0000000000000978

Observational Study

New or Progressive Multiple Organ Dysfunction Syndrome in Pediatric Severe Sepsis: A Sepsis Phenotype With Higher Morbidity and Mortality

John C Lin et al. Pediatr Crit Care Med. 2017 Jan.

. 2017 Jan;18(1):8-16.

doi: 10.1097/PCC.0000000000000978.

Authors

John C Lin¹, Philip C Spinella, Julie C Fitzgerald, Marisa Tucci, Jenny L Bush, Vinay M Nadkarni, Neal J Thomas, Scott L Weiss; Sepsis Prevalence, Outcomes, and Therapy Study Investigators

Collaborators

Sepsis Prevalence, Outcomes, and Therapy Study Investigators:
P Fontela, M Tucci, M Dumistrascu, P Skippen, G Krahn, E Bezares, G Puig, A Puig-Ramos, R Garcia, M Villar, M Bigham, T Polanski, S Latifi, D Giebner, H Anthony, J Hume, A Galster, L Linnerud, R Sanders, G Hefley, K Madden, A Thompson, S Shein, S Gertz, Y Han, T Williams, A Hughes-Schalk, H Chandler, A Orioles, E Zielinski, A Doucette, C Zebuhr, T Wilson, C Dimitriades, J Ascani, S Layburn, S Valley, B Markowitz, J Terry, R Morzov, A Mcinnes, J McArthur, K Woods, K Murkowski, M Spaeder, M Sharron, D Wheeler, E Beckman, E Frank, K Howard, C Carroll, S Nett, D Jarvis, V Patel, R Higgerson, L Christie, K Typpo, J Deschenes, A Kirby, T Uhl, K Rehder, I Cheifetz, S Wrenn, K Kypuros, K Ackerman, F Maffei, G Bloomquist, N Rizkalla, D Kimura, S Shah, C Tigges, F Su, C Barlow, K Michelson, K Wolfe, D Goodman, L Campbell, L Sorce, K Bysani, T Monjure, M Evans, Totapally, M Chegondi, C Rodriguez, J Frazier, L Steele, S Viteri, A Costarino, N Thomas, D Spear, E Hirshberg, J Lilley, C Rowan, C Rider, J Kane, J Zimmerman, C Greeley, J Lin, R Jacobs, M Parker, K Culver, L Loftis, N Jaimon, M Goldsworthy, J Fitzgerald, S Weiss, V Nadkarni, J Bush, M Diliberto, C Alen, M Gessouroun, A Sapru, T Lang, M Alkhouli, S Kamath, D Friel, J Daufeldt, D Hsing, C Carlo, S Pon, J Scimeme, A Shaheen, A Hassinger, H Qiao, J Giuliano, J Tala, D Vinciguerra, A Fernandez, R Carrero, P Hoyos, J Jaramillo, A Posada, L Izquiierdo, B E Piñeres Olave, J Donado, R Dalmazzo, S Rendich, L Palma, M Lapadula, C Acuna, P Cruces, S Clement De Clety, M Dujardin, C Berghe, S Renard, J Zurek, H Steinherr, K Mougkou, E Critselis, K Mougkou, M Di Nardo, S Picardo, F Tortora, E Rossetti, T Fragasso, P Cogo, R Netto, A Dagys, V Gurskis, R Kevalas, C Neeleman, J Lemson, C Luijten, K Wojciech, I Pagowska-Klimek, M Szczepanska, J Karpe, P Nunes, H Almeida, J Rios, M Vieira, J P Garcia Iniguez, P Revilla, J Urbano, J Lopez-Herce, A Bustinza, A Cuesta, S Hofheinz, A Rodriguez-Nunez, S Sanagustin, E Gonzalez, M Riaza, R Piaya, P Soler, E Esteban, J Laraudogoitia, C Monge, V Herrera, J Granados, C Gonzalez, T Koroglu, E Ozcelik, P Baines, A Plunkett, P Davis, S George, S Tibby, J Harris, R Agbeko, R Lampitt, J Brierley, M Peters, A Jones, T Dominguez, T Thiruchelvam, A Deep, L Ridley, W Bowen, R Levin, I Macleod, M Gray, N Hemat, J Alexander, S Ali, J Pappachan, J McCorkell, P Fortune, M MacDonald, P Hudnott, Q Suyun, S Singhi, K Nallasamy, R Lodha, N Shime, Y Tabata, O Saito, T Ikeyama, T Kawasaki, L Lum, A Abidin, S Kee, S Tang, R Jalil, Y Guan, L Yao, K Lin, J Ong, A Salloo, L Doedens, L Mathivha, G Reubenson, S Moaisi, A Pentz, R Green, A Schibler, A Fernandez, S Erickson, J McEneiry, D Long, T Dorofaeff, M Coulthard, J Millar, C Delzoppo, G Williams, M Morritt, N Watts, M Morritt, J Beca, C Sherring, T Bushell

Affiliation

¹ 1Division of Critical Care Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO.2Department of Anesthesiology and Critical Care, The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.3Division of Critical Care Medicine, Department of Pediatrics, University of Montreal, Montreal, QC, Canada.4Pediatric Critical Care Medicine, Departments of Pediatrics and Public Health Sciences, Penn State University College of Medicine, Hershey, PA.

PMID: 28060151
PMCID: PMC7261134
DOI: 10.1097/PCC.0000000000000978

Abstract

Objectives: To describe the epidemiology, morbidity, and mortality of new or progressive multiple organ dysfunction syndrome in children with severe sepsis.

Design: Secondary analysis of a prospective, cross-sectional, point prevalence study.

Setting: International, multicenter PICUs.

Patients: Pediatric patients with severe sepsis identified on five separate days over a 1-year period.

Interventions: None.

Measurements and main results: Of 567 patients from 128 PICUs in 26 countries enrolled, 384 (68%) developed multiple organ dysfunction syndrome within 7 days of severe sepsis recognition. Three hundred twenty-seven had multiple organ dysfunction syndrome on the day of sepsis recognition. Ninety-one of these patients developed progressive multiple organ dysfunction syndrome, whereas an additional 57 patients subsequently developed new multiple organ dysfunction syndrome, yielding a total proportion with severe sepsis-associated new or progressive multiple organ dysfunction syndrome of 26%. Hospital mortality in patients with progressive multiple organ dysfunction syndrome was 51% compared with patients with new multiple organ dysfunction syndrome (28%) and those with single-organ dysfunction without multiple organ dysfunction syndrome (10%) (p < 0.001). Survivors of new or progressive multiple organ dysfunction syndrome also had a higher frequency of moderate to severe disability defined as a Pediatric Overall Performance Category score of greater than or equal to 3 and an increase of greater than or equal to 1 from baseline: 22% versus 29% versus 11% for progressive, new, and no multiple organ dysfunction syndrome, respectively (p < 0.001).

Conclusions: Development of new or progressive multiple organ dysfunction syndrome is common (26%) in severe sepsis and is associated with a higher risk of morbidity and mortality than severe sepsis without new or progressive multiple organ dysfunction syndrome. Our data support the use of new or progressive multiple organ dysfunction syndrome as an important outcome in trials of pediatric severe sepsis although efforts are needed to validate whether reducing new or progressive multiple organ dysfunction syndrome leads to improvements in more definitive morbidity and mortality endpoints.

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Figures

**Figure 1.**
Flow diagram of severe sepsis patients presenting with or without MODS and subsequently developing NPMODS or having no progression of MODS.

**Figure 2.**
Timing of MODS onset within the first seven days following severe sepsis recognition. Day 1 is the day of sepsis recognition.

**Figure 3.**
Hospital mortality and total number of patients by maximum number of concurrent organ system dysfunctions.

See this image and copyright information in PMC

Comment in

Searching for a Pediatric Severe Sepsis Phenotype: Are We There Yet?
Workman JK, Larsen GY. Workman JK, et al. Pediatr Crit Care Med. 2017 Jan;18(1):82-83. doi: 10.1097/PCC.0000000000001003. Pediatr Crit Care Med. 2017. PMID: 28060154 No abstract available.
New or Progressive Multiple Organ Dysfunction Syndrome as Surrogate Outcome for Mortality in Pediatric Severe Sepsis Trials.
Baldanzi G, Delgado AF. Baldanzi G, et al. Pediatr Crit Care Med. 2017 May;18(5):500-501. doi: 10.1097/PCC.0000000000001148. Pediatr Crit Care Med. 2017. PMID: 28475542 No abstract available.
The authors reply.
Lin JC, Spinella PC, Fitzgerald JC, Tucci M, Bush JL, Nadkarni VM, Thomas NJ, Weiss SL. Lin JC, et al. Pediatr Crit Care Med. 2017 May;18(5):501-502. doi: 10.1097/PCC.0000000000001158. Pediatr Crit Care Med. 2017. PMID: 28475543 Free PMC article. No abstract available.

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Diagnostic significance of microRNAs in sepsis.
Zheng X, Zhang Y, Lin S, Li Y, Hua Y, Zhou K. Zheng X, et al. PLoS One. 2023 Feb 22;18(2):e0279726. doi: 10.1371/journal.pone.0279726. eCollection 2023. PLoS One. 2023. PMID: 36812225 Free PMC article.
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Hsu HE, Abanyie F, Agus MSD, Balamuth F, Brady PW, Brilli RJ, Carcillo JA, Dantes R, Epstein L, Fiore AE, Gerber JS, Gokhale RH, Joyner BL Jr, Kissoon N, Klompas M, Lee GM, Macias CG, Puopolo KM, Sulton CD, Weiss SL, Rhee C. Hsu HE, et al. Pediatrics. 2019 Dec;144(6):e20191790. doi: 10.1542/peds.2019-1790. Pediatrics. 2019. PMID: 31776196 Free PMC article.
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References

1. Hartman ME, Linde-Zwirble WT, Angus DC, Watson RS. Trends in the epidemiology of pediatric severe sepsis*. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies 2013;14:686–93. - PubMed
1. Jaramillo-Bustamante JC, Marin-Agudelo A, Fernandez-Laverde M, Bareno-Silva J. Epidemiology of sepsis in pediatric intensive care units: first Colombian multicenter study. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies 2012;13:501–8. - PubMed
1. Wolfler A, Silvani P, Musicco M, Antonelli M, Salvo I, Italian Pediatric Sepsis Study g. Incidence of and mortality due to sepsis, severe sepsis and septic shock in Italian Pediatric Intensive Care Units: a prospective national survey. Intensive care medicine 2008;34:1690–7. - PubMed
1. Ruth A, McCracken CE, Fortenberry JD, Hall M, Simon HK, Hebbar KB. Pediatric severe sepsis: current trends and outcomes from the Pediatric Health Information Systems database. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies 2014;15:828–38. - PubMed
1. Nadel S, Goldstein B, Williams MD, et al. Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial. Lancet 2007;369:836–43. - PubMed

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[1] Hartman ME, Linde-Zwirble WT, Angus DC, Watson RS. Trends in the epidemiology of pediatric severe sepsis*. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies 2013;14:686–93. - PubMed

[2] Hartman ME, Linde-Zwirble WT, Angus DC, Watson RS. Trends in the epidemiology of pediatric severe sepsis*. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies 2013;14:686–93. - PubMed

[3] Jaramillo-Bustamante JC, Marin-Agudelo A, Fernandez-Laverde M, Bareno-Silva J. Epidemiology of sepsis in pediatric intensive care units: first Colombian multicenter study. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies 2012;13:501–8. - PubMed

[4] Jaramillo-Bustamante JC, Marin-Agudelo A, Fernandez-Laverde M, Bareno-Silva J. Epidemiology of sepsis in pediatric intensive care units: first Colombian multicenter study. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies 2012;13:501–8. - PubMed

[5] Wolfler A, Silvani P, Musicco M, Antonelli M, Salvo I, Italian Pediatric Sepsis Study g. Incidence of and mortality due to sepsis, severe sepsis and septic shock in Italian Pediatric Intensive Care Units: a prospective national survey. Intensive care medicine 2008;34:1690–7. - PubMed

[6] Wolfler A, Silvani P, Musicco M, Antonelli M, Salvo I, Italian Pediatric Sepsis Study g. Incidence of and mortality due to sepsis, severe sepsis and septic shock in Italian Pediatric Intensive Care Units: a prospective national survey. Intensive care medicine 2008;34:1690–7. - PubMed

[7] Ruth A, McCracken CE, Fortenberry JD, Hall M, Simon HK, Hebbar KB. Pediatric severe sepsis: current trends and outcomes from the Pediatric Health Information Systems database. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies 2014;15:828–38. - PubMed

[8] Ruth A, McCracken CE, Fortenberry JD, Hall M, Simon HK, Hebbar KB. Pediatric severe sepsis: current trends and outcomes from the Pediatric Health Information Systems database. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies 2014;15:828–38. - PubMed

[9] Nadel S, Goldstein B, Williams MD, et al. Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial. Lancet 2007;369:836–43. - PubMed

[10] Nadel S, Goldstein B, Williams MD, et al. Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial. Lancet 2007;369:836–43. - PubMed

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New or Progressive Multiple Organ Dysfunction Syndrome in Pediatric Severe Sepsis: A Sepsis Phenotype With Higher Morbidity and Mortality

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New or Progressive Multiple Organ Dysfunction Syndrome in Pediatric Severe Sepsis: A Sepsis Phenotype With Higher Morbidity and Mortality

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