Mortality prediction in patients with severe septic shock: a pilot study using a target metabolomics approach

Manuela Ferrario, Alice Cambiaghi, Laura Brunelli, Silvia Giordano, Pietro Caironi, Luca Guatteri, Ferdinando Raimondi, Luciano Gattinoni, Roberto Latini, Serge Masson, Giuseppe Ristagno, Roberta Pastorelli, Manuela Ferrario, Alice Cambiaghi, Laura Brunelli, Silvia Giordano, Pietro Caironi, Luca Guatteri, Ferdinando Raimondi, Luciano Gattinoni, Roberto Latini, Serge Masson, Giuseppe Ristagno, Roberta Pastorelli

Abstract

Septic shock remains a major problem in Intensive Care Unit, with high lethality and high-risk second lines treatments. In this preliminary retrospective investigation we examined plasma metabolome and clinical features in a subset of 20 patients with severe septic shock (SOFA score >8), enrolled in the multicenter Albumin Italian Outcome Sepsis study (ALBIOS, NCT00707122). Our purpose was to evaluate the changes of circulating metabolites in relation to mortality as a pilot study to be extended in a larger cohort. Patients were analyzed according to their 28-days and 90-days mortality. Metabolites were measured using a targeted mass spectrometry-based quantitative metabolomic approach that included acylcarnitines, aminoacids, biogenic amines, glycerophospholipids, sphingolipids, and sugars. Data-mining techniques were applied to evaluate the association of metabolites with mortality. Low unsaturated long-chain phosphatidylcholines and lysophosphatidylcholines species were associated with long-term survival (90-days) together with circulating kynurenine. Moreover, a decrease of these glycerophospholipids was associated to the event at 28-days and 90-days in combination with clinical variables such as cardiovascular SOFA score (28-day mortality model) or renal replacement therapy (90-day mortality model). Early changes in the plasma levels of both lipid species and kynurenine associated with mortality have potential implications for early intervention and discovering new target therapy.

Figures

Figure 1. Flow chart, which displays the…
Figure 1. Flow chart, which displays the progress of patient selection from the ALBIOS biobank according to our inclusion/exclusion criteria.
Figure 2
Figure 2
Heat maps of the metabolites (mean Log 2 μM) whose concentrations changed significantly from day 1 (D1) to day 7 (D7) in survivors (S) (a) and non-survivors (NS) (b) both considering mortality at 28 days and 90 days (Wilcoxon test p < 0.05, FDR < 0.15).
Figure 3
Figure 3
Comparison of the absolute differences in metabolite concentrations (μM) from day 1 to day 7 (Delta = D7–D1) in survivors (S) and non-survivors (NS) at 28 days (a) or 90 days (b). Distribution of differences is shown as box-plots, where the central mark is the median concentration, the edges of the box are the 25th and 75th percentiles, the outliers are defined as 1.5 times of interquartile range and highlighted by stars. Each plot represents a different metabolite. (Wilcoxon test p < 0.05, FDR < 0.15).
Figure 4
Figure 4
Elastic Net coefficients built on metabolites concentration at day 1 (a) and day 7 (b) for 28-day and 90 days mortality (c). The MSE computed for the models are 0.21 for (a), 0.26 for (b) and 0.27 for (c).
Figure 5
Figure 5
Elastic Net coefficients built on metabolites concentration and clinical parameters collected at day 7 for 28-day (a) and 90 days mortality (b). The MSE computed for the models are 0.23 for the 28-day one (a) and 0.24 for the 90-day (b). SOFA CARD: cardiovascular SOFA score; SOFA TOT: total SOFA score; MAP: mean arterial pressure; pHv: venous pH; diuresis (ml/die) collected at day 7; RRT: renal replacement therapy administered during the first 7 days of treatment.

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