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Persistent Mitochondrial Dysfunction Linked to Prolonged Organ Dysfunction in Pediatric Sepsis

Weiss, Scott L. MD, MSCE1–3; Zhang, Donglan BS1,3; Bush, Jenny RNC1; Graham, Kathryn BS1; Starr, Jonathan BS1,3; Tuluc, Florin MD, PhD4; Henrickson, Sarah MD, PhD5,6; Kilbaugh, Todd MD1,3; Deutschman, Clifford S. MD, MS7; Murdock, Deborah PhD3; McGowan, Francis X. Jr MD1,3; Becker, Lance MD8; Wallace, Douglas C. PhD3

doi: 10.1097/CCM.0000000000003931
Pediatric Critical Care
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Objectives: Limited data exist about the timing and significance of mitochondrial alterations in children with sepsis. We therefore sought to determine if alterations in mitochondrial respiration and content within circulating peripheral blood mononuclear cells were associated with organ dysfunction in pediatric sepsis.

Design: Prospective observational study

Setting: Single academic PICU.

Patients: One-hundred sixty-seven children with sepsis/septic shock and 19 PICU controls without sepsis, infection, or organ dysfunction.

Interventions: None.

Measurements and Main Results: Mitochondrial respiration and content were measured in peripheral blood mononuclear cells on days 1–2, 3–5, and 8–14 after sepsis recognition or once for controls. Severity and duration of organ dysfunction were determined using the Pediatric Logistic Organ Dysfunction score and organ failure-free days through day 28. Day 1–2 maximal uncoupled respiration (9.7 ± 7.7 vs 13.7 ± 4.1 pmol O2/s/106 cells; p = 0.02) and spare respiratory capacity (an index of bioenergetic reserve: 6.2 ± 4.3 vs 9.6 ± 3.1; p = 0.005) were lower in sepsis than controls. Mitochondrial content, measured by mitochondrial DNA/nuclear DNA, was higher in sepsis on day 1–2 than controls (p = 0.04) and increased in sepsis patients who had improving spare respiratory capacity over time (p = 0.005). Mitochondrial respiration and content were not associated with day 1–2 Pediatric Logistic Organ Dysfunction score, but low spare respiratory capacity was associated with higher Pediatric Logistic Organ Dysfunction score on day 3–5. Persistently low spare respiratory capacity was predictive of residual organ dysfunction on day 14 (area under the receiver operating characteristic, 0.72; 95% CI, 0.61–0.84) and trended toward fewer organ failure-free days although day 28 (β coefficient, –0.64; 95% CI, –1.35 to 0.06; p = 0.08).

Conclusions: Mitochondrial respiration was acutely decreased in peripheral blood mononuclear cells in pediatric sepsis despite an increase in mitochondrial content. Over time, a rise in mitochondrial DNA tracked with improved respiration. Although initial mitochondrial alterations in peripheral blood mononuclear cells were unrelated to organ dysfunction, persistently low respiration was associated with slower recovery from organ dysfunction.

1Department of Anesthesiology and Critical Care, Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.

2Pediatric Sepsis Program at the Children’s Hospital of Philadelphia, Philadelphia, PA.

3Center for Mitochondrial and Epigenomic Medicine at the Children’s Hospital of Philadelphia, Philadelphia, PA.

4Flow Cytometry Research Core, Children’s Hospital of Philadelphia, Philadelphia, PA.

5Department of Pediatrics, Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.

6Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.

7Feinstein Institute for Medical Research at Hofstra-Northwell School of Medicine, Hempstead, NY.

8Department of Emergency Medicine at Hofstra-Northwell School of Medicine, Hempstead, NY.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

Dr. Weiss’ institution received funding from Eunice Kennedy Shriver National Institute of Child Health and Human Development K12HD047349, National Institute of General Medical Sciences K23GM110496, Society of Critical Care Medicine (SCCM) Weil Research Grant; he disclosed that the study was also supported by the Center for Mitochondrial and Epigenomic Medicine (although grants awarded to Dr. Wallace including National Institutes of Health (NIH) NS021328, MH108592, OD010944 and U.S. Department of Defense grant W81XWH-16-1-0401) and Department of Anesthesiology and Critical Care at the Children’s Hospital of Philadelphia; and he received funding from Bristol-Myers Squibb (Advisory Panel Member). Drs. Weiss, Zhang, Starr, Henrickson, and Kilbaugh received support for article research from the NIH. Dr. Deutschman received funding from SCCM (Scientific Editor for Critical Care Medicine); Department of Anesthesiology, NYU; St. Johns University; Western Ireland Critical Care Society; and International Society of Thrombosis and Hemostasis. Dr. McGowan’s institution received funding from Merck and the NIH. Dr. Becker’s institution received funding from Nihon Kohden, the NIH, and United Therapeutics, and he received other funding from Northwell Health, Philips, and Zoll. The remaining authors have disclosed that they do not have any potential conflicts of interest.

This study was performed at the Children’s Hospital of Philadelphia.

For information regarding this article, E-mail: WeissS@email.chop.edu

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