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Association between apoptosis and mortality in severe septic patients


The apoptotic process, in which cells are actively eliminated by a programmed pathway, is increased in sepsis. Extrinsic and intrinsic apoptotic death cell pathways activate caspase-3, which leads to cell apoptosis. Cytokeratin 18 (CK-18), a protein present in most epithelial and parenchymal cells, is cleaved by the action of caspases and released into the blood as caspase-cleaved CK (CCCK)-18 during apoptotic death. The novel objectives of this study were to determine whether there are associations between serum caspase-3 levels, serum CK-18 levels and mortality in septic patients.


A prospective, multicenter, observational study in six Spanish ICUs, including 216 patients with severe sepsis. We collected blood samples at the severe sepsis diagnosis moment to determine serum levels of caspase-3 (to assess the main executor of apoptosis) and CCCK18 (to assess the apoptosis level). The endpoint was 30-day mortality.


We found that nonsurvivor (n = 76) in comparison with survivor (n = 140) septic patients showed higher serum levels of caspase-3 (0.41 ng/ml (0.14 to 0.52) vs. 0.11 ng/ml (0.10 to 0.25); P < 0.001) and CCCK18 (448 (310 to 723) vs. 319 (236 to 445); P < 0.001). Multiple logistic regression showed that serum caspase-3 levels >0.25 ng/ml were associated with mortality at 30 days (odds ratio = 6.51; 95% confidence interval = 3.32 to 12.77; P < 0.001), controlling for SOFA score and age. Kaplan-Meier survival analysis showed a higher risk of death in septic patients with serum caspase-3 levels >0.25 ng/ml than in patients with lower levels (hazard ratio = 3.80; 95% CI = 2.35 to 6.15; P < 0.001). We found a positive association between serum levels of caspase-3 and CCCK-18 (ρ = 0.32; P < 0.001).


The novel findings of our study were that there is an association between serum caspase-3 levels, serum CK-18 levels and mortality in septic patients. There has been reported decreased apoptosis and increased survival in septic rats with the administration of caspase inhibitors; thus, it may be interesting to explore those agents in septic patients.


Funded by Grant FIS-PI-14-00220 from Instituto de Salud Carlos III (Madrid, Spain) and co-financed by Fondo Europeo de Desarrollo Regional (FEDER).

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Correspondence to L Lorente.

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Lorente, L., Martín, M., González-Rivero, A. et al. Association between apoptosis and mortality in severe septic patients. Crit Care 19, P53 (2015).

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  • Severe Sepsis
  • Septic Patient
  • Apoptotic Death
  • Death Cell Pathway
  • Sofa Score