• Thiago D Corrêa, Madhusudanarao Vuda, Annika Reintam Blaser, Jukka Takala, Siamak Djafarzadeh, Martin W Dünser, Eliézer Silva, Michael Lensch, Ludwig Wilkens, and Stephan M Jakob.
• Department of Intensive Care Medicine, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland.
• Crit. Care Med.. 2012 Oct 1;40(10):2841-9.

ObjectiveEarly 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.DesignProspective, randomized, controlled experimental study.SettingExperimental laboratory in a university hospital.SubjectsThirty-two anesthetized and mechanically ventilated pigs.InterventionsPigs 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 ResultsAny 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.ConclusionsIncreasing 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.

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