Mark Wefers Bettink

Mind the mitochondria! 2 27 e.g. ototoxicity, are known from bactericidal antibiotics and are linked to mitochondrial dysfunction (41). Chemotherapy-induced cardiotoxicity (42) and myopathy (43) are linked to the oxidative stress on mitochondria caused by these therapies. Although most recognized mitochondria-linked side effects by medication are severe, they are not limited to a single medication group and seem to be widespread. It is unknown if and how medication-induced mitochondrial dysfunction might contribute to the complex pathophysiology seen in ICU patients. Small alterations that in the general population are likely to remain subclinical might add to e.g. sepsis-induced metabolic dysregulation and become an important factor in the progression to multi-organ failure. In translational research on sepsis, several endotoxemia models in rat and pigs lead to the description of the development of mitochondrial dysfunction over time (44-46). Infectious and inflammatory driven changes in mitochondrial function in humans are not a new phenomenon either (3,47). Because of invasiveness, muscle biopsies, needed for the classical measurement of mitochondrial function in isolated mitochondria, are rarely performed in the ICU. However, differences in development of mitochondrial dysfunction in different muscle types have been shown (48). Also a correlation between mortality, severity of organ dysfunction and mitochondrial dysfunction has been demonstrated in several studies (3,49-51). Although a link has been shown between mitochondrial dysfunction and sepsis, a proof of causality is missing and some argue mitochondrial dysfunction in sepsis might be an epiphenomenon (50). Alternatively, mitochondrial dysfunction and a reduced mitochondrial respiration and ATP production have been suggested to mimic hypoxia, so-called “cytopatic hypoxia” (52). Cytopathic Hypoxia In intensive care, a primary goal of the intensivist is to preserve organ function or replace it. Corner stones of sepsis treatment on the intensive care are supportive care, safe- guarding a sufficient macrohemodynamic organ perfusion (sufficient mean arterial pressure, lowering of lactate), replacement of organ function (e.g. ventilator support, renal replacement or extracorporal membrane oxygenation), and early antimicrobial therapy. The measurement of microcirculatory function, let alone mitochondrial function, is not part of standard care on the ward and is, as far as we are aware, only performed in research settings. Although lactate is an important factor indicating anaerobicmetabolism and therefore tissue hypo-perfusion in sepsis (53), the level of lactate is a crude measure and is known to have pitfalls (54). Cytopathic hypoxia is a concept describing insufficient oxygen metabolism in cells despite sufficient oxygen delivery (55). This apparent tissue