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


METHODS
Prospective, randomized, controlled experimental study.


METHODS
Experimental laboratory in a university hospital.


METHODS
Thirty-two anesthetized and mechanically ventilated pigs.


METHODS
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.


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.
Department of Intensive Care Medicine, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland.
Thiago D
TD
Corrêa
Madhusudanarao
M
Vuda
Annika Reintam
AR
Blaser
Jukka
J
Takala
Siamak
S
Djafarzadeh
Martin W
MW
Dünser
Eliézer
E
Silva
Michael
M
Lensch
Ludwig
L
Wilkens
Stephan M
SM
Jakob
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005440:Fluid Therapy; D006439:Hemodynamics; D008297:Male; D010538:Peritonitis / Q000401:mortality / Q000503:physiopathology / Q000628:therapy; D011446:Prospective Studies; D011897:Random Allocation; D012151:Resuscitation / Q000379:methods*; D018805:Sepsis / Q000401:mortality / Q000503:physiopathology* / Q000628:therapy*; D012720:Severity of Illness Index; D013552:Swine; D013997:Time Factors
D016207:Cytokines