Mark Wefers Bettink

Chapter 2 30 perfusion and oxygen delivery to the parenchymal cells such that they are able to perform their functional activities in support of organ function (67). There are a number of studies that show that improving systemic macrocirculatory parameters does not lead to improvement of the microcirculation (68,69). This lack of coherence was associated with increased morbidity and mortality (68-70). Additionally, we have to focus on the mitochondrial function in the different states of shock. After all, both the coupling of macrocirculation and microcirculation and the coupling of microcirculation and cellular energetics are impaired in the different states of shock and particularly in sepsis. Van Genderen showed that coherence betweenmacrocirculation andmicrocirculation existed in an obstructive shock model in pigs , but was lost in a septic shock model (71). Also in septic patients loss of coherence was frequently found (70). In a rat endotoxemia model mitochondrial respiration remained reduced by 38 % despite fluid resuscitation restoring mitochondrial oxygenation back to baseline values (45). Such restored oxygenation seems superfluous in comparison to the reduced oxygen demand. Whether this is an example of loss of coherence between cellular oxygen demand and microcirculatory oxygen delivery remains to be clarified. Furthermore, there are two more dimensions that have to be included in the discussed multidimensional approach. These are the loss of coherence in the different organ systems and the timing of resuscitation and their effect on incoherence and uncoupling. Loss of coherence can vary in the different organ systems. In animal and human studies the intestinal microcirculation particularly remained much longer unresponsive to resuscitation while the macrocirculation and sublingual microcirculation already were restored (72) (73). In septic patients the coherencebetweenmacrocirculation anddifferent microcirculatory systems could take up to 3 days to occur (73). Controversially, Ospina- Tascon found that the microcirculation was improved by early fluid resuscitation, but was unaffected by resuscitation later in the course (74). Thus, the exact timing of resuscitation and its effect of coherence and coupling of macrocirculation, microcirculation and mitochondrial function over time remain to be elucidated. Ways to measure mitochondria and current insights While there is need to assess mitochondrial function in critically ill patients, existing standard technique are invasive and ex vivo (muscle biopsies) and/or cumbersome (NMR), and not readily available 24/7 in a general hospital. Ex vivo techniques that use tissue biopsies have been mainly used to determine mitochondrial dysfunction in patients. From these tissue biopsies, cells or even mitochondria are isolated before actual