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Effect of treatment delay on disease severity and need for resuscitation in porcine fecal peritonitis

Corrêa, Thiago D. MD; Vuda, Madhusudanarao MSc; Blaser, Annika Reintam MD, PhD; Takala, Jukka MD, PhD; Djafarzadeh, Siamak PhD; Dünser, Martin W. MD; Silva, Eliézer MD, PhD; Lensch, Michael RN; Wilkens, Ludwig MD, PhD; Jakob, Stephan M. MD, PhD

doi: 10.1097/CCM.0b013e31825b916b
Laboratory Investigations

Objective: Early treatment in sepsis may improve outcome. The aim of this study was to evaluate how the delay in starting resuscitation influences the severity of sepsis and the treatment needed to achieve hemodynamic stability.

Design: Prospective, randomized, controlled experimental study.

Setting: Experimental laboratory in a university hospital.

Subjects: Thirty-two anesthetized and mechanically ventilated pigs.

Interventions: Pigs were randomly assigned (n = 8 per group) to a nonseptic control group or one of three groups in which fecal peritonitis (peritoneal instillation of 2 g/kg autologous feces) was induced, and a 48-hr period of protocolized resuscitation started 6 (ΔT-6 hrs), 12 (ΔT-12 hrs), or 24 (ΔT-24 hrs) hrs later. The aim of this study was to evaluate the impact of delays in resuscitation on disease severity, need for resuscitation, and the development of sepsis-associated organ and mitochondrial dysfunction.

Measurements and Main Results: Any delay in starting resuscitation was associated with progressive signs of hypovolemia and increased plasma levels of interleukin-6 and tumor necrosis factor-α prior to resuscitation. Delaying resuscitation increased cumulative net fluid balances (2.1 ± 0.5 mL/kg/hr, 2.8 ± 0.7 mL/kg/hr, and 3.2 ± 1.5 mL/kg/hr, respectively, for groups ΔT-6 hrs, ΔT-12 hrs, and ΔT-24 hrs; p < .01) and norepinephrine requirements during the 48-hr resuscitation protocol (0.02 ± 0.04 μg/kg/min, 0.06 ± 0.09 μg/kg/min, and 0.13 ± 0.15 µg/kg/min; p = .059), decreased maximal brain mitochondrial complex II respiration (p = .048), and tended to increase mortality (p = .08). Muscle tissue adenosine triphosphate decreased in all groups (p < .01), with lowest values at the end in groups ΔT-12 hrs and ΔT-24 hrs.

Conclusions: Increasing the delay between sepsis initiation and resuscitation increases disease severity, need for resuscitation, and sepsis-associated brain mitochondrial dysfunction. Our results support the concept of a critical window of opportunity in sepsis resuscitation.

Supplemental Digital Content is available in the text.

From the Department of Intensive Care Medicine (TDC, MV, ARB, JT, SD, MWD, ML, SMJ), Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland; Intensive Care Unit (ES), Hospital Israelita Albert Einstein, São Paulo, Brazil; Institute of Pathology (LW), Klinikum Nordstadt, Hannover, Germany.

Current address for Dr. Corrêa: Department of Anesthesiology, University of São Paulo, São Paulo, Brazil.

Drs. Corrêa and Vuda contributed equally.

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 Web site (

The work was performed in the Experimental Surgery Unit of the University of Bern.

This work was supported by the Swiss National Science Foundation (Grant no 32003B-127619) and the Stiftung für die Forschung in Anästhesiologie und Intensivmedizin, Bern, awarded to SD and SMJ.

The authors have not disclosed any potential conflicts of interest.

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© 2012 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins