Granulocyte colony-stimulating factor prophylaxis improves survival and inflammation in a two-hit model of hemorrhage and sepsis.
OBJECTIVE
We evaluated the effects of a granulocyte-colony stimulating factor (G-CSF) prophylaxis in two clinically relevant situations, hemorrhage on the day before infection (e.g., trauma) and acute hemorrhage followed subsequently by infection (e.g., operative complication). A two-hit model of hemorrhage and polymicrobial peritoneal contamination and infection (PCI) was used to assess the influence of G-CSF on the outcome, bacterial clearance, and cytokine pattern.


METHODS
Clinic modeling randomized laboratory trial.


METHODS
University laboratory.


METHODS
One hundred thirty-two male rats.


METHODS
In trial 1 we compared a) preoperative PCI only; b) preoperative hemorrhage plus PCI; and c) hemorrhage plus PCI plus G-CSF prophylaxis (n=18 rats/group). In trial 2, intraoperative hemorrhage was assessed with the same trial design. Primary end point was survival at 120 hrs. In trial 2 additionally, six rats per group and six naive control rats were used for secondary end point analysis.


RESULTS
Primary end point was mortality at 120 hrs. Secondary end points were granulocyte counts, bacterial clearance, and local cytokine levels. In trial 1 survival rate was 56% after PCI only, 17% after hemorrhage plus PCI, and 61% after hemorrhage plus PCI plus G-CSF (p<.01). In trial 2 survival rate was 33% after PCI only, 17% after hemorrhage plus PCI, and 50% after hemorrhage plus PCI plus G-CSF (p<.05). In trial 2, neutrophil counts were doubled to 66% 1 hr after hemorrhage (p<.05), colony-forming units of microbes in the lung and liver were halved to 166+/-56 and 134+/-28 colony-forming units (p<.05 for liver), and the macrophage inflammatory protein-2 expression in the lung was halved to 0.88+/-0.06 pg of complementary DNA (p<.05) by G-CSF prophylaxis compared with hemorrhage and PCI.


CONCLUSIONS
Hemorrhage (first hit) sensitized the host for a second hit of polymicrobial PCI independent of the timing. G-CSF prophylaxis improved survival and clearance of microbes and reduced the proinflammatory chemokine macrophage inflammatory protein-2 in the lung.
Bauhofer
Artur
A
Institute of Theoretical Surgery, Philipps-University Marburg, Germany.
Lorenz
Wilfried
W
Kohlert
Frank
F
Torossian
Alexander
A
D000818:Animals; D015169:Colony Count, Microbial; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology / Q000627:therapeutic use*; D006470:Hemorrhage / Q000150:complications / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality; D007249:Inflammation / Q000503:physiopathology; D008297:Male; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins; D018805:Sepsis / Q000150:complications / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality; D016019:Survival Analysis
D016207:Cytokines; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor