Mark Wefers Bettink

Chapter 2 20 Introduction In critical illness, one of the mainstays of therapeutic interventions is to safeguard adequate oxygen transport to organs and tissues. While in the past the focus mainly was on optimizing macrohemodynamic variables, over the last two decades, the microcirculation has become a prime subject of research and clinical thinking. The dysregulated oxygen transport to tissue in states of shock and resuscitation and the needed interventions to reverse them are still a topic of controversy. Current evidence shows that not a deterioration of systemic variables per se but rather a failure of the microcirculation to transport oxygen to parenchymal cells is the cause of circulatory compromise. Pathological heterogeneity of microcirculatory perfusion leading to functional shunting in the microcirculation causes local hypoxia and reduced cellular respiration, macroscopically manifesting as a reduction in oxygen extraction (1,2). The defect in oxygen extraction observed during states of sepsis and shock is not only due to alterations in microcirculatory function. In some cases, resuscitation in terms of restored macrohemodynamic and microcirculatory parameters does not lead to clinical improvement and indirect indications of tissue hypoxia, such as high serum lactate, remain. Reduced cellular oxygen consumption, i.e. caused by mitochondrial dysfunction, could mimic such states. Cellular metabolic adaptation could also lead to reduced oxygen extraction and subsequently to a reduced ability of the mitochondria to produce ATP. It is not even unthinkable that under specific circumstances an apparent microcirculatory dysfunction might be an epiphenomenon caused by an in itself adequate adaptation of the microcirculation to an adapted or failing utilization of oxygen and nutrients by parenchymal cells. In any case, mitochondrial alterations in states of shock and sepsis have long been observed (3). If reduced mitochondrial oxygen consumption, either caused by mitochondrial dysfunction due to direct damage or as part of an adaptation mechanism, exists in the presence of normal microcirculatory oxygen transport, then this would have a dramatic impact on the current understanding of resuscitation medicine. Recently, evidence that this might be the case is emerging from both animal and clinical studies. Current resuscitation is entirely focused on promoting oxygen transport to tissues via convection and passive diffusion (4). Research on the microcirculation in critical illness has been greatly boosted by the emergence of bedside tools that allow direct visualization of the microcirculation of a patient, for example under the tongue (5,6). To further unravel the pathophysiological mechanisms and better understand the interaction betweenmicrocirculatory impairment