Mark Wefers Bettink

Chapter 1 10 Preface and outline Disclaimer: the first 4 paragraphs of the introduction were earlier published; Wefers Bettink MA, Arbous MS, Raat NJ, Mik EG. Mind the Mitochondria! J Emerg Crit Care Med 2019;3:45. A primary goal in the care for critically ill patients is safeguarding an adequate oxygen transport to organs and tissues is. Over the last two decades it has become clear that in certain pathophysiological circumstances macrocirculatory derailment is followed, or accompanied, by microcirculatory dysfunction. 1 Resuscitation strategies to restore and optimize blood flow to organs are based on the idea that restoring oxygen supply will re-establish aerobic metabolism and lead to “healthy parenchymal cells”. 2 However, mitochondrial damage and subsequent dysfunction, or cellular adaptation to hypoxia, might attenuate or even counterbalance the positive effects of resuscitation on the cellular level. 3,4 Mitochondria are the primary consumers of oxygen and the ultimate destination of approximately 98% of oxygen reaching our tissue cells. Most of the oxygen is used for energy production by forming adenosine triphosphate (ATP) through the process of oxidative phosphorylation, but a small amount is used for generating reactive oxygen species and creating heat . 5 While ATP production is the best known function of mitochondria, they also play a key role in calcium homeostasis and cell-death mechanisms. Oxidative phosphorylation has a very high affinity for oxygen and functions well at very low oxygen levels. However, cellular respiration does adapt to changes in oxygen availability at physiological levels, a mechanism known as “oxygen conformance”. 6,7 Oxygen conformance, mitochondrial damage by certain hits (e.g. toxins and medication), mitochondrial dysfunction and autonomic metabolic reprogramming are all factors in sepsis that could contribute to what is known as “cytopathic hypoxia”. 8,9 This concept describes insufficient oxygen metabolism in cells despite sufficient oxygen delivery. Altered cellular oxygen utilization and thus reduced oxygen demand could in itself cause decreased microcirculatory blood flow, making microcirculatory dysfunction in sepsis under some circumstances a possible epiphenomenon. 10 Resuscitation and forced restoration of microcirculatory flow could lead to relative hyperoxia, and be counterproductive by increasing reactive oxygen production and intervening with protective adaptation mechanisms.