Pyruvate Dehydrogenase Activity Is Decreased in the Peripheral Blood Mononuclear Cells of Patients with Sepsis. A Prospective Observational Trial

Abstract

Rationale: Rodent studies have shown that pyruvate dehydrogenase (PDH) levels are low in sepsis. This may cause cells to shift to anaerobic metabolism, resulting in increased lactate production. Alterations in PDH during sepsis have never been studied in humans.

Objectives: The objective of this pilot study was to measure PDH activity and quantity in patients with severe sepsis.

Methods: We conducted a pilot case-control study at a single urban tertiary care center. We compared PDH activity and quantity between patients with severe sepsis admitted to the intensive care unit and healthy control subjects. PDH activity and quantity were measured in isolated peripheral blood mononuclear cells. We measured PDH activity and quantity in control subjects at baseline and in patients with sepsis at 0 (baseline), 24, 48, and 72 hours.

Measurements and main results: We enrolled 56 patients with sepsis and 20 control subjects with at least one blood sample being drawn from each patient. PDH activity and quantity in the sepsis group were significantly lower than the control group (P < 0.001). In multivariable linear regression adjusting for age, race, sex, and assay plate, the difference remained significant. Patients with sepsis who died had significantly lower PDH activity compared with those who survived (P = 0.03).

Conclusions: PDH activity and quantity is decreased in peripheral blood mononuclear cells of humans with severe sepsis when compared with healthy control subjects, and may be associated with mortality. Whether decreased PDH activity plays a role in lactate metabolism or whether pharmacologic modification of PDH activity may improve outcomes remains unknown.

Keywords: aerobic; lactate; metabolism; mitochondria; mortality.

Figure 1.

Pyruvate dehydrogenase (PDH) values in patients with sepsis and control subjects. PDH activity (A), quantity (B), and specific activity (C) in control subjects and patients with sepsis at enrollment (0 hours) and 24, 48, and 72 hours thereafter. Compared with baseline values in the septic cohort, control subjects had significantly higher activity, quantity, and specific activity.

Figure 2.

Pyruvate dehydrogenase (PDH) activity in survivors and nonsurvivors. PDH activity in the septic cohort stratified by survival status. Patients who survived had significantly higher PDH activity over time as compared with those not surviving (P = 0.02).