title: Mitochondrial dysfunction in peripheral blood mononuclear cells in pediatric septic shock.
abstract: OBJECTIVE
  Mitochondrial dysfunction in peripheral blood mononuclear cells has been linked to immune dysregulation and organ failure in adult sepsis, but pediatric data are limited. We hypothesized that pediatric septic shock patients exhibit mitochondrial dysfunction within peripheral blood mononuclear cells which in turn correlates with global organ injury.
  
  
  METHODS
  Prospective observational study.
  
  
  METHODS
  Academic PICU.
  
  
  METHODS
  Thirteen pediatric patients with septic shock and greater than or equal to two organ failures and 11 PICU controls without sepsis or organ failure.
  
  
  METHODS
  Ex vivo measurements of mitochondrial oxygen consumption and membrane potential (ΔΨm) were performed in intact peripheral blood mononuclear cells on day 1-2 and day 5-7 of septic illness and in controls. The Pediatric Logistic Organ Dysfunction score, inotrope score, and organ failure-free days were determined from medical records.
  
  
  RESULTS
  Spare respiratory capacity, an index of bioenergetic reserve, was lower in septic peripheral blood mononuclear cells on day 1-2 (median, 1.81; interquartile range, 0.52-2.09 pmol O2/s/10 cells) compared with controls (5.55; 2.80-7.21; p = 0.03). Spare respiratory capacity normalized by day 5-7. Patients with sepsis on day 1-2 exhibited a higher ratio of LEAK to maximal respiration than controls (17% vs < 1%; p = 0.047) with normalization by day 5-7 (1%; p = 0.008), suggesting mitochondrial uncoupling early in sepsis. However, septic peripheral blood mononuclear cells exhibited no differences in basal or adenosine triphosphate-linked oxygen consumption or ΔΨm. Oxygen consumption did not correlate with Pediatric Logistic Organ Dysfunction score, inotrope score, or organ failure-free days (all p > 0.05). Although there was a weak overall association between ΔΨm on day 1-2 and organ failure-free days (Spearman ρ = 0.56, p = 0.06), patients with sepsis with normal organ function by day 7 exhibited higher ΔΨm on day 1-2 compared with patients with organ failure for more than 7 days (p = 0.04).
  
  
  CONCLUSIONS
  Mitochondrial dysfunction was present in peripheral blood mononuclear cells in pediatric sepsis, evidenced by decreased bioenergetic reserve and increased uncoupling. Mitochondrial membrane potential, but not respiration, was associated with duration of organ injury.
authors.affiliation: 1Division of Critical Care Medicine, Department of Anesthesia and Critical Care, The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. 2Department of Emergency Medicine, Center for Resuscitation Science, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. 3Flow Cytometry Research Core, The Children's Hospital of Philadelphia Research Institute, Philadelphia, PA. 4Department of Anesthesiology and Critical Care, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. 5Department of Emergency Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Weiss
authors.forename: Mary A
authors.initials: MA
authors.lastname: Selak
authors.forename: Florin
authors.initials: F
authors.lastname: Tuluc
authors.forename: Jose
authors.initials: J
authors.lastname: Perales Villarroel
authors.forename: Vinay M
authors.initials: VM
authors.lastname: Nadkarni
authors.forename: Clifford S
authors.initials: CS
authors.lastname: Deutschman
authors.forename: Lance B
authors.initials: LB
authors.lastname: Becker
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004734:Energy Metabolism; D005260:Female; D006801:Humans; D015278:Intensive Care Units, Pediatric; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials; D008928:Mitochondria / Q000378:metabolism*; D028361:Mitochondrial Diseases / Q000097:blood* / Q000378:metabolism; D063305:Organ Dysfunction Scores; D010101:Oxygen Consumption; D011446:Prospective Studies; D012772:Shock, Septic / Q000097:blood* / Q000503:physiopathology