Abstract
IntroductionPlasma levels of cell-free hemoglobin are associated with mortality in patients with sepsis; however descriptions of independent associations with free hemoglobin and free heme scavengers, haptoglobin and hemopexin, are lacking beyond their description as acute phase reactants. We sought to determine the association of plasma levels of endogenous free hemoglobin and haptoglobin and hemopexin with in-hospital mortality in adults with sepsis.MethodsWe conducted a retrospective observational study of a total of 387 critically ill patients with sepsis in multiple intensive care units in an academic tertiary care hospital. Measurements of plasma haptoglobin and hemopexin were made on blood drawn within 24 hours of intensive care unit admission. The primary outcome was the association between plasma haptoglobin and hemopexin with in-hospital mortality.ResultsSurvivors had significantly higher plasma haptoglobin concentrations (median 1234 μg/ml, interquartile range (IQR) 569 to 3037) and hemopexin concentrations (616 μg/ml, IQR 397 to 934) measured on enrollment compared to non-survivors (haptoglobin 750 μg/ml, IQR 404 to 2421, P = 0.008; hemopexin 470 μg/ml, IQR 303 to 891, P = 0.012). After controlling for potential confounders including cell-free hemoglobin concentration, patients with higher haptoglobin concentrations were significantly less likely to die in the hospital (odds ratio (OR) 0.653, 95% CI 0.433 to 0.984, P = 0.042), while the same association was not seen with hemopexin (OR 0.53, 95% CI 0.199 to 1.416, P = 0.206). In a subgroup analysis, the association between increased haptoglobin and hemopexin and decreased risk of mortality was no longer significant when analyzing patients with no detectable cell-free hemoglobin (P = 0.737 and P = 0.584, respectively).ConclusionIn critically ill patients with sepsis, elevated plasma levels of haptoglobin were associated with a decreased risk of in-hospital mortality and this association was independent of confounders. Increased haptoglobin may play a protective role in sepsis patients who have elevated levels of circulating cell-free hemoglobin beyond its previous description as an acute phase reactant.
Highlights
Plasma levels of cell-free hemoglobin are associated with mortality in patients with sepsis; descriptions of independent associations with free hemoglobin and free heme scavengers, haptoglobin and hemopexin, are lacking beyond their description as acute phase reactants
We developed multivariable logistic regression models to analyze the risks of in-hospital mortality using known risk factors for poor outcomes and reduced haptoglobin and hemopexin levels, including measured levels of cell-free hemoglobin
Survivors were significantly younger, had lower severity of illness scores measured by Acute Physiology and Chronic Health Evaluation (APACHE II), were less likely to have chronic liver disease, and had lower cell-free hemoglobin levels
Summary
Plasma levels of cell-free hemoglobin are associated with mortality in patients with sepsis; descriptions of independent associations with free hemoglobin and free heme scavengers, haptoglobin and hemopexin, are lacking beyond their description as acute phase reactants. We sought to determine the association of plasma levels of endogenous free hemoglobin and haptoglobin and hemopexin with in-hospital mortality in adults with sepsis. Haptoglobin and hemopexin are proteins produced by the liver that function, respectively, to scavenge cell-free hemoglobin and its byproduct, cell-free heme. To this end, both haptoglobin and hemopexin have been shown to have significant antioxidant properties in both animals and humans [20,21]. In an animal model of red blood-cell transfusion with increased levels of cell-free hemoglobin, supplementation with haptoglobin attenuated the development of vasoconstriction, endothelial damage, and kidney injury [15]. In animal models of sepsis, supplementation with haptoglobin or hemopexin decreases biomarkers of inflammation [22], reduces the incidence of acute lung injury [23], improves organ function, and decreases mortality [24]
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