EMF-116 Platelet Mitochondrial Function in Early Severe Sepsis

Abstract

The prognostic value of lactate in sepsis is well established, but evolving literature suggests that lactate elevation does not result solely from tissue hypoperfusion, but can also arise following sepsis-induced changes in aerobic metabolism, sometimes referred to as cytopathic hypoxia. Recent advances allow for the measurement of mitochondrial function in peripherally available cells such as platelets, and the degree of mitochondrial dysfunction from multiple cell lines is associated with mortality in sepsis. However, it remains unclear if these changes are present on emergency department (ED) presentation, and if the degree of dysfunction is associated with metabolic changes. We sought to determine the association between platelet mitochondrial function as measured by high resolution respirometry and 1) lactate and pyruvate levels and 2) severity of illness as measured by the Sequential Organ Failure Assessment (SOFA) score. Prospective observational cohort of ED patients presenting to a single, urban, tertiary care ED from November 2013 to present. Abbreviated inclusion criteria were age >17, 2 or more SIRS criteria, hypotension despite fluid resuscitation, and confirmed or suspected infection; exclusion criteria include established do not resuscitate order, transfer with resuscitation in progress, and inability to obtain informed consent. Blood was drawn and immediately processed to yield a platelet rich plasma which was placed in an O2k Oxygraph (Oroboros Instruments, Austria). Routine respiration rate was determined by measuring the rate of oxygen consumption in a chamber with a fixed volume of oxygen. Leak and oxidative phosphorylation (oxphos) rates were determined following serial additions of oligomycin and FCCP. Residual non-mitrochondrial oxygen consumption following the addition of rotenone and antimycin A was subtracted from these values, and all values were normalized to cell count. SOFA score, lactate and pyruvate were measured at enrollment. L/P ratio was calculated as the quotient of lactate/pyruvate. Descriptive statistics and simple linear regression were used to determine the association between mitochondrial measurements and lactate and pyruvate measurements, as well as SOFA score. All tests were two-sided and P values of <.05 were considered significant. Eight patients were enrolled to date. Median SOFA score was 7 (IQR 3.5, 9.5). Initial median lactate and pyruvate levels were 1.6 mmol/L (IQR 0.7, 3.2) and 0.09 mmol/L (IQR 0.04, 0.10); while median L/P ratio was 23 (IQR 16, 39). There were significant associations between routine and leak respiration and lactate value (P=.006 and .01), and a trend towards a linear association between routine, leak, and oxphos rates and SOFA score (P=.1, .36, and .12). Similar trends were not observed with pyruvate or L/P ratios. In the first study of platelet mitochondrial function in ED patients with sepsis to date, there is a suggestion of associations between several measures of mitochondrial function and both severity of illness and lactate levels, supportive of the hypothesis that elevated lactate may be partially due to changes in mitochondrial function. If validated in an ongoing study of a larger cohort of patients, these data suggest that novel therapeutics targeting mitochondrial function deserve further clinical investigation.