Pathophysiology of pediatric multiple organ dysfunction syndrome

Joseph A. Carcillo*, Bradley Podd, Rajesh Aneja, Scott L. Weiss, Mark W. Hall, Timothy T. Cornell, Thomas P. Shanley, Lesley A. Doughty, Trung C. Nguyen

*Corresponding author for this work

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Objective: To describe the pathophysiology associated with multiple organ dysfunction syndrome in children. Data Sources: Literature review, research data, and expert opinion. Study Selection: Not applicable. Data Extraction: Moderated by an experienced expert from the field, pathophysiologic processes associated with multiple organ dysfunction syndrome in children were described, discussed, and debated with a focus on identifying knowledge gaps and research priorities. Data Synthesis: Summary of presentations and discussion supported and supplemented by relevant literature. Conclusions: Experiment modeling suggests that persistent macrophage activation may be a pathophysiologic basis for multiple organ dysfunction syndrome. Children with multiple organ dysfunction syndrome have 1) reduced cytochrome P450 metabolism inversely proportional to inflammation; 2) increased circulating damage-associated molecular pattern molecules from injured tissues; 3) increased circulating pathogen-associated molecular pattern molecules from infection or endogenous microbiome; and 4) cytokine-driven epithelial, endothelial, mitochondrial, and immune cell dysfunction. Cytochrome P450s metabolize endogenous compounds and xenobiotics, many of which ameliorate inflammation, whereas damageassociated molecular pattern molecules and pathogen-associated molecular pattern molecules alone and together amplify the cytokine production leading to the inflammatory multiple organ dysfunction syndrome response. Genetic and environmental factors can impede inflammation resolution in children with a spectrum of multiple organ dysfunction syndrome pathobiology phenotypes. Thrombocytopenia-associated multiple organ dysfunction syndrome patients have extensive endothelial activation and thrombotic microangiopathy with associated oligogenic deficiencies in inhibitory complement and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13. Sequential multiple organ dysfunction syndrome patients have soluble Fas ligand-Fas-mediated hepatic failure with associated oligogenic deficiencies in perforin and granzyme signaling. Immunoparalysis-associated multiple organ dysfunction syndrome patients have impaired ability to resolve infection and have associated environmental causes of lymphocyte apoptosis. These inflammation phenotypes can lead to macrophage activation syndrome. Resolution of multiple organ dysfunction syndrome requires elimination of the source of inflammation. Full recovery of organ functions is noted 6-18 weeks later when epithelial, endothelial, mitochondrial, and immune cell regeneration and reprogramming is completed.

Original languageEnglish (US)
Pages (from-to)S32-S45
JournalPediatric Critical Care Medicine
Volume18
Issue number3
DOIs
StatePublished - Jan 1 2017

Fingerprint

Multiple Organ Failure
Pediatrics
Inflammation
Macrophage Activation Syndrome
Thrombotic Microangiopathies
Cytokines
Thrombospondin 1
Disintegrins
Phenotype
Granzymes
Perforin
Fas Ligand Protein
Macrophage Activation
Information Storage and Retrieval
Microbiota
Recovery of Function
Liver Failure
Expert Testimony
Metalloproteases
Xenobiotics

Keywords

  • Cytochrome P450 metabolism
  • Immunoparalysis
  • Macrophage activation syndrome
  • Sequential multiple organ failure
  • Thrombocytopenia-associated multiple organ failure

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Critical Care and Intensive Care Medicine

Cite this

Carcillo, J. A., Podd, B., Aneja, R., Weiss, S. L., Hall, M. W., Cornell, T. T., ... Nguyen, T. C. (2017). Pathophysiology of pediatric multiple organ dysfunction syndrome. Pediatric Critical Care Medicine, 18(3), S32-S45. https://doi.org/10.1097/PCC.0000000000001052
Carcillo, Joseph A. ; Podd, Bradley ; Aneja, Rajesh ; Weiss, Scott L. ; Hall, Mark W. ; Cornell, Timothy T. ; Shanley, Thomas P. ; Doughty, Lesley A. ; Nguyen, Trung C. / Pathophysiology of pediatric multiple organ dysfunction syndrome. In: Pediatric Critical Care Medicine. 2017 ; Vol. 18, No. 3. pp. S32-S45.
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Carcillo, JA, Podd, B, Aneja, R, Weiss, SL, Hall, MW, Cornell, TT, Shanley, TP, Doughty, LA & Nguyen, TC 2017, 'Pathophysiology of pediatric multiple organ dysfunction syndrome', Pediatric Critical Care Medicine, vol. 18, no. 3, pp. S32-S45. https://doi.org/10.1097/PCC.0000000000001052

Pathophysiology of pediatric multiple organ dysfunction syndrome. / Carcillo, Joseph A.; Podd, Bradley; Aneja, Rajesh; Weiss, Scott L.; Hall, Mark W.; Cornell, Timothy T.; Shanley, Thomas P.; Doughty, Lesley A.; Nguyen, Trung C.

In: Pediatric Critical Care Medicine, Vol. 18, No. 3, 01.01.2017, p. S32-S45.

Research output: Contribution to journalArticle

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Carcillo JA, Podd B, Aneja R, Weiss SL, Hall MW, Cornell TT et al. Pathophysiology of pediatric multiple organ dysfunction syndrome. Pediatric Critical Care Medicine. 2017 Jan 1;18(3):S32-S45. https://doi.org/10.1097/PCC.0000000000001052