Mark Wefers Bettink

Chapter 7 128 INTRODUCTION Sepsis remains a life-threatening disease with mortality rates ranging between 20-40%. (1, 2) The exact role of mitochondrial function in sepsis is unclear, but mitochondrial dysfunctionmay play a central role in its pathophysiology.(3–6) Mitochondrial dysfunction or elevated mitochondrial damage proteins in serum are linked to mortality in sepsis patients on the ICU. (7–9) Translating these insights from animal experiments to human studies or clinical practice has been hampered by technical difficulties and limitations. Measuring the mitochondrial function with ex vivo techniques, in isolated mitochondria or in small tissue biopsies, may not reflect the in vivo situation correctly. (10) Thus, showing feasibility of a non-invasive in vivo measurement technique to monitor mitochondrial (dys)function in critical illness would be of considerable value. The recent development of the COMET monitor, a clinical monitor for assessment of Cellular Oxygen METabolism, allows cutaneous mitochondrial oxygen tension (mitoPO 2 ) and mitochondrial oxygen consumption (mitoVO 2 ) measurement in humans. COMET measures mitoPO 2 by means of the Protoporphyrin IX-Triplet State Lifetime Technique (PpIX-TSLT). The background of this technique was first published in 2006 by Mik et al. (11) Broadly, COMET measures mitoPO 2 levels through lifetime measurement of oxygen- dependent endogenous Protoporphyrin IX (PpIX). By stopping microvascular flow, oxygen transport to the mitochondria is disrupted and by tracking mitoPO 2 over time, mitoVO 2 can be determined. Cutaneous application of 5-aminolevulinic acid (ALA) is a necessary step to induce sufficient mitochondrial PpIX for detection of the weak delayed fluorescence signal. (11, 12) Since the first publication of this technique, extensive research has been done to develop an instrument for clinical use. (13) The technique has been tested and calibrated for use in isolated organs and in vivo in experimental animals, and positive results of a feasibility test in healthy volunteers have been published. (14) COMET was able to detect meaningful changes in mitoPO 2 and mitoVO 2 concentrations in vivo in sepsis-like conditions in a rat model. (15, 16) The aim of this study was to replicate data of the experimental setup in patients, to validate the hypothesis that patients with sepsis will suffer from a decline of mitoVO 2 as compared to a control group. Recent validation of the COMET technique in healthy volunteers, combined with its low risk profile for determining in vivo mitochondrial function, paves the way for an observational study on the intensive care ward. However, an important outstanding question for use of the COMET technique on the ICU ward remains its reliability in patients with sepsis, since mitochondrial function is a prerequisite for the conversion of ALA to PpIX.