Platelet Bioenergetics and Associations With Delirium and Coma in Patients With Sepsis: A Prospective Cohort Study

Abstract

Background: Acute brain dysfunction during sepsis, which manifests as delirium or coma, is common and is associated with multiple adverse outcomes, including longer periods of mechanical ventilation, prolonged hospital stays, and increased mortality. Delirium and coma during sepsis may be manifestations of alteration in systemic metabolism. Because access to brain mitochondria is a limiting factor, measurement of peripheral platelet bioenergetics offers a potential opportunity to understand metabolic changes associated with acute brain dysfunction during sepsis.

Research question: Are altered platelet mitochondrial bioenergetics associated with acute brain dysfunction during sepsis?

Study design and methods: We assessed participants with critical illness in the ICU for the presence of delirium or coma via validated assessment measures. Blood samples were collected and processed to isolate and measure platelet mitochondrial oxygen consumption. We used Seahorse extracellular flux to measure directly baseline, proton leak, maximal oxygen consumption rate, and extracellular acidification rate. We calculated adenosine triphosphate-linked, spare respiratory capacity, and nonmitochondrial oxygen consumption rate from the measured values.

Results: Maximum oxygen consumption was highest in patients with coma, as was spare respiratory capacity and extracellular acidification rate in unadjusted analysis. After adjusting for age, sedation, modified Sequential Organ Failure Assessment score without the neurologic component, and preexisting cognitive function, increased spare respiratory capacity remained associated with coma. Delirium was not associated with any platelet mitochondrial bioenergetics.

Interpretation: In this single-center exploratory prospective cohort study, we found that increased platelet mitochondrial spare respiratory capacity was associated with coma in patients with sepsis. Future studies powered to determine any relationship between delirium and mitochondrial respiration bioenergetics are needed.

Keywords: acute brain dysfunction; bioenergetics; coma; delirium; platelet mitochondria; sepsis.

Figure 1 -

Screening and recuirtment flowchart.

Figure 2 -

A-E, Graphs showing unadjusted comparisons of platelet mitochondrial OCR by delirium, coma, and normal mental status. A, Maximum OCR was significantly different between the coma (n = 19) and normal (n = 34) groups and between the coma and delirium (n = 10) groups. Delirium was not significantly different from normal. B, After removing baseline effect, spare respiratory capacity revealed similar differences among the mental status groups. C, Proton leak was not different among mental status groups. D, Nonmitochondrial OCR was significantly different between those with coma and normal mental status and between those with coma and delirium. No significant difference was found between those with delirium and normal mental status. E, Extracellular acidification rate was significantly different among those with coma and normal mental status as well as among those with coma and delirium. The delirium group did not show significantly different findings than the normal mental status group. The bar and whisker plots depict median and interquartile range. OCR = oxygen consumption rate.

Figure 3 -

A-D, Graphs showing platelet bioenergetic measures according to RASS score. After adjusting for age, sedation, modified Sequential Organ Failure Assessment score, and preexisting cognitive function, increased maximum OCR (A) and spare respiratory capacity (B) were associated with lower RASS scores, whereas proton leak (C) and nonmitochondrial OCR (D) were not associated with RASS scores. OCR = oxygen consumption rate; RASS = Richmond Agitation-Sedation Scale.