Evolution of mitochondrial dysfunction and hypermetabolic inflammatory status in septic Intensive Care Unit patients

Sepsis is a major cause of admission to the intensive care unit (ICU) and may
result in hospital death rates up to 40-60% of septic shock cases.
Mitochondrial dysfunction has been demonstrated in a variety of cells in septic
ICU patients, including peripheral blood mononuclear cells (PBMCs). To avoid
more invasive sample methods we selected the PBMCs to be used in our present
research project. Multiple studies have found a relation between the amount of
nutrients (e.g. glucose) in the blood and severity of mitochondrial dysfunction
in PBMCs and clinical outcomes. Based on these findings, in sepsis there seems
to be interplay between the hypermetabolic inflammatory state (e.g.
hyperglycaemia), mitochondrial function/dynamics and clinical outcome. However,
this interplay remains vague due to lack of research which includes all of
these factors simultaneously. More knowledge on this interplay will
undisputedly contribute to better treatment strategies, which is to some extent
still subject of controversy, such as insulin therapy or the timing of
parenteral nutrition. With respect to the latter, the observed negative effects
of early versus late parenteral nutrition on clinical outcome suggest a
time-dependent progression of the processes involved in the pathogenesis of
sepsis. However, the course of the above mentioned factors over time has never
been measured. Mapping the progression of the hypermetabolic inflammatory
state, mitochondrial function/dynamics and clinical outcome in septic ICU
patients would create a better understanding on how mitochondrial dysfunction
emerges, and how this is related to the hypermetabolic inflammatory state and
clinical outcome. Creating more knowledge on the this interplay is a promising
way to establish better (nutritional) therapy in septic ICU patients.

The main objective is to investigate how mitochondrial function progresses over
time in septic ICU patients. The secondary objective of the study is (a) to
investigate how mitochondrial dynamics progress over time and how this is
associated with mitochondrial function in septic ICU patients, (b) to
investigate if and how parameters of the hypermetabolic inflammatory state are
related to the progression of mitochondrial function in septic ICU patients and
(c) to investigate if and how the progression of mitochondrial function is
related to physical performance and clinical outcomes in septic ICU patients.

Prospective cohort study with matched controls.

Among the septic ICU patients three blood samples will be drawn and physical
tests will be performed. As the septic ICU patients have vascular access, no
extra punctures are necessary. The donation of blood samples can lead to a
decrease in hemoglobin concentration in the blood, a decreased circulating
volume or a decreased fluid level. These risks are closely monitored within the
ICU. If any disturbance is measured, this will be restored by means of
administration of physiological saline fluid or a blood transfusion. The
control patients will give one blood sample, which has a small risk of
complications (such as bruising), and will preferably be combined with blood
sampling of other clinical reasons.

Moreover, two physical tests will be performed: The MRC sum score and the
Chelsea Critical Care Physical Assessment Tool. The septic ICU patients will
perform these tests twice, namely at discharge from the ICU and at discharge
from the hospital.

Mitochondrial dysfunction in PBMCs of septic ICU patients has been linked to
severity of sepsis and clinical outcomes. New knowledge on mitochondrial
dysfunction may contribute to a better understanding of the pathophysiology of
this important biological process among septic ICU patients and may potentially
lead to information to prevent mitochondrial dysfunction with specific
nutrients or medications.