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Prompt Administration of Antibiotics and Fluids in the Treatment of Sepsis: A Murine Trial*

Lewis, Anthony J. MD, MSc1; Griepentrog, John E. MD1; Zhang, Xianghong PhD1; Angus, Derek C. MD, MPH2,3; Seymour, Christopher W. MD, MSc2,3; Rosengart, Matthew R. MD, MPH1,2,3

doi: 10.1097/CCM.0000000000003004
Online Laboratory Investigations

Objectives: Sepsis, the acute organ dysfunction caused by a dysregulated host response to infection, poses a serious public health burden. Current management includes early detection, initiation of antibiotics and fluids, and source control as necessary. Although observational data suggest that delays of even a few hours in the initiation of antibiotics or IV fluids is associated with survival, these findings are controversial. There are no randomized data in humans, and prior animal studies studied time from experimental manipulation, not from the onset of clinical features of sepsis. Using a recently developed murine cecal ligation and puncture model that precisely monitors physiologic deterioration, we hypothesize that incremental hourly delays in the first dose of antibiotics, in the first bolus of fluid resuscitation, or a combination of the two at a clinically relevant point of physiologic deterioration during polymicrobial sepsis will shorten survival.

Design: Randomized laboratory animal experimental trial.

Setting: University basic science laboratory.

Subjects: Male C57BL/6J, female C57BL/6J, aged (40–50 wk old) male C57BL/6J, and BALB/C mice.

Interventions: Mice (n = 200) underwent biotelemetry-enhanced cecal ligation and puncture and were randomized after meeting validated criteria for acute physiologic deterioration. Treatment groups consisted of a single dose of imipenem/cilastatin, a single bolus of 30 mL/kg fluid resuscitation, or a combination of the two. Mice were allocated to receive treatment at the time of meeting deterioration criteria, after a 2-hour delay or after a 4-hour delay.

Measurements and Main Results: Hourly delays in the initiation of antibiotic therapy led to progressively shortened survival in our model (p < 0.001). The addition of fluid resuscitation was unable to rescue animals, which received treatment 4 hours after meeting enrollment criteria. Systemic inflammation was increased, and host physiology was increasingly deranged with hourly delays to antibiotics.

Conclusions: We conclude that antibiotic therapy is highly time sensitive, and efforts should be made to deliver this critical therapy as early as possible in sepsis, perhaps extending into the first point of medical contact outside the hospital.

1Department of Surgery, University of Pittsburgh, Pittsburgh, PA.

2Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA.

3Clinical Research, Investigation, and Systems Modeling of Acute Illness Center (CRISMA), Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA.

*See also p. 835.

This work was performed at the University of Pittsburgh.

Data and materials availability: Material availability is noted within the article.

Drs. Seymour and Rosengart share senior coauthorship for this article.

Dr. Lewis designed and performed experiments, analyzed and interpreted data, and drafted the article. Drs. Griepentrog and Zhang performed experiments and participated in drafting the article. Drs. Angus and Seymour designed experiments, participating in drafting the article, and approved the final version of the article. Dr. Rosengart designed experiments, analyzed and interpreted data, drafted the article, and approved of the final version of the article.

Supported, in part, by a Basic/Translational Research Training Fellowship Grant awarded by the Surgical Infection Society (to Dr. Rosengart), R01 GM082852 (to Dr. Rosengart), R01 GM116929 (to Dr. Rosengart), T32GM008516 (to Dr. Lewis), and R35GM119519 (to Dr. Seymour) from the National Institutes of Health.

Drs. Lewis, Griepentrog, Zhang, Seymour, and Rosengart received support for article research from the National Institutes of Health (NIH). Dr. Seymour’s institution received funding from NIH National Institute of General Medical Sciences, and he received funding from Beckman Coulter and Edwards. Dr. Angus has disclosed that he does not have any potential conflicts of interest.

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