Mark Wefers Bettink

General discussion 11 191 of mitochondrial function in sepsis is notoriously difficult. Bedside monitoring was not available and ex vivo determination of mitochondrial function is difficult and laborious to perform. Moreover, ex vivo measurements are disruptive and alter the cellular environment. In critically ill patients an increase, decrease, or stable oxygen consumption by the mitochondria have been described. Recent work showed that the effects of the medium used in ex vivo tests play a major role in these tests [4,5]. Our findings in chapter 5 underline this phenomenon in which in vivo mitochondrial dysfunction is measured but ex vivo tests with a lab-based medium failed to measure mitochondrial dysfunction. These observations could point to a possible reversal of mitochondrial dysfunction in this stage of change in our endotoxemia model. LPS was also used in a human volunteer model to study the initiation phase of sepsis. In collaboration with the Radboud UMC we measured the effect of LPS on mitoPO 2 and mitoVO 2 in healthy volunteers ( chapter 6 ). Most interestingly, we measured a direct decline of mitoPO 2 1.45 hours after LPS administration, whereas no decline was observed in the control group. In the LPS group mitoVO 2 increased significantly over time versus no observed change in the control group. Measuring a change in mitoPO 2 but not in mitoVO 2 show these are distinct parameters which can change independently. Measuring a decrease of mitochondrial function in our rat model but an increase of mitochondrial function in our healthy volunteer model is an example of the difficulty in determining the role of mitochondrial dysfunction in the pathophysiology of sepsis. The PpIX-TSLT technique is robust in the preclinical phase, given that mitochondrial function is required to produce the PpIX signal. However, measurement of mitochondrial parameters with the COMET monitor in patients with sepsis was not a certainty. Although we did not reach the first target number of occlusion in our ICU study, we were able to successfully use the COMET monitor on the ICU and complete various measurements ( chapter 7 ). Recently, Coldewey et al. showed usability of COMET measurements in septic patients [6]. In part three we showed the ability to measure mitochondrial oxygenation during neurosurgery in the intraoperative setting in a challenging environment, with strong interference of the surgery lights on our signal ( chapter 8 ). Measuring stable mitoPO 2 values over time when the clinical status is also stable shows a reliability of the monitoring technique under anesthesia. The COMET monitor also proved viable during neonatal surgery, as we presented in chapter 9. When the mitoPO 2 values change in patients with hemodynamic challenges during an operation, as shown in both chapters,