Pediatric Critical Care

Delayed Antimicrobial Therapy Increases Mortality and Organ Dysfunction Duration in Pediatric Sepsis*

Weiss, Scott L. MD; Fitzgerald, Julie C. MD, PhD; Balamuth, Fran MD, PhD; Alpern, Elizabeth R. MD, MSCE; Lavelle, Jane MD; Chilutti, Marianne MS; Grundmeier, Robert MD; Nadkarni, Vinay M. MD, MS; Thomas, Neal J. MD, MSc

Author Information

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.

²Division of Emergency Medicine, Department of Pediatrics, The Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.

³Division of Emergency Medicine, Department of Pediatrics, Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL.

⁴The Children's Hospital of Philadelphia Research Institute, Philadelphia, PA.

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

⁶Division of Pediatric Critical Care Medicine, Penn State Hershey Children’s Hospital, Penn State University College of Medicine, Hershey, PA.

* See also p. 2455.

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

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).

Supported, in part, by the Endowed Chair, Department of Anesthesia and Critical Care, Division of Emergency Medicine, and the Office of the Chief Medical Office at The Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine.

Dr. Weiss is employed by The Children’s Hospital of Philadelphia (CHOP) and received royalties from Up-To-Date. Dr. Weiss and his institution received grant support from Pediatric Critical Care and Scientist Development Program K12. His institution received grant support from the CHOP Center for Pediatric Clinical Effectiveness. Dr. Balamuth received support for travel (divisional funds used to reimburse for conference attendance: American Academy of Pediatrics, Pediatric Academic Societies, and Society for Academic Emergency Medicine), received support from divisional funds from Emergency medicine and critical care to CHOP center for biomedical informatics for development of sepsis registry, is employed by the University of Pennsylvania Perelman School of Medicine, and received support for article research from the National Institutes of Health (NIH) (National Heart, Lung, and Blood Institute [NHLBI] K12 HL109009). Her institution received grant support from the NIH-NHLBI (Dr. Balamuth received salary support from the NHLBI K12 grant HL109009) and an Internal McCabe grant through the Perelman School of Medicine University of Pennsylvania. Dr. Alpern received royalties from Lippincott Williams and Wilkins. Her institution received grant support from Agency for Healthcare Research and Quality and Emergency Medical Services for Children. Dr. Lavelle received support from divisional funds. Dr. Thomas served as an advisory board member for Discovery Labs and received grant support from the U.S. Food and Drug Administration (R01 grant). The remaining authors have disclosed that they do not have any potential conflicts of interest.

Address requests for reprints to: Scott L. Weiss, MD, Department of Anesthesia and Critical Care, The Children’s Hospital of Philadelphia, 34th Street and Civic Center Boulevard, 7 South Tower, Rm 7C04, Philadelphia, PA 19104. E-mail: [email protected]

Critical Care Medicine 42(11):p 2409-2417, November 2014. | DOI: 10.1097/CCM.0000000000000509

Abstract

Objectives:

Delayed antimicrobials are associated with poor outcomes in adult sepsis, but data relating antimicrobial timing to mortality and organ dysfunction in pediatric sepsis are limited. We sought to determine the impact of antimicrobial timing on mortality and organ dysfunction in pediatric patients with severe sepsis or septic shock.

Design:

Retrospective observational study.

Setting:

PICU at an academic medical center.

Patients:

One hundred thirty patients treated for severe sepsis or septic shock.

Interventions:

None.

Measurements and Main Results:

We determined if hourly delays from sepsis recognition to initial and first appropriate antimicrobial administration were associated with PICU mortality (primary outcome); ventilator-free, vasoactive-free, and organ failure–free days; and length of stay. Median time from sepsis recognition to initial antimicrobial administration was 140 minutes (interquartile range, 74–277 min) and to first appropriate antimicrobial was 177 minutes (90–550 min). An escalating risk of mortality was observed with each hour delay from sepsis recognition to antimicrobial administration, although this did not achieve significance until 3 hours. For patients with more than 3-hour delay to initial and first appropriate antimicrobials, the odds ratio for PICU mortality was 3.92 (95% CI, 1.27–12.06) and 3.59 (95% CI, 1.09–11.76), respectively. These associations persisted after adjustment for individual confounders and a propensity score analysis. After controlling for severity of illness, the odds ratio for PICU mortality increased to 4.84 (95% CI, 1.45–16.2) and 4.92 (95% CI, 1.30–18.58) for more than 3-hour delay to initial and first appropriate antimicrobials, respectively. Initial antimicrobial administration more than 3 hours was also associated with fewer organ failure–free days (16 [interquartile range, 1–23] vs 20 [interquartile range, 6–26]; p = 0.04).