Microcirculatory and mitochondrial hypoxia in sepsis, shock, and resuscitation

Abstract

After shock, persistent oxygen extraction deficit despite the apparent adequate recovery of systemic hemodynamic and oxygen-derived variables has been a source of uncertainty and controversy. Dysfunction of oxygen transport pathways during intensive care underlies the sequelae that lead to organ failure, and the limitations of techniques used to measure tissue oxygenation in vivo have contributed to the lack of progress in this area. Novel techniques have provided detailed quantitative insight into the determinants of microcirculatory and mitochondrial oxygenation. These techniques, which are based on the oxygen-dependent quenching of phosphorescence or delayed luminescence are briefly reviewed. The application of these techniques to animal models of shock and resuscitation revealed the heterogeneous nature of oxygen distributions and the alterations in oxygen distribution in the microcirculation and in mitochondria. These studies identified functional shunting in the microcirculation as an underlying cause of oxygen extraction deficit observed in states of shock and resuscitation. The translation of these concepts to the bedside has been enabled by our development and clinical introduction of hand-held microscopy. This tool facilitates the direct observation of the microcirculation and its alterations at the bedside under the conditions of shock and resuscitation. Studies identified loss of coherence between the macrocirculation and the microcirculation, in which resuscitation successfully restored systemic circulation but did not alleviate microcirculatory perfusion alterations. Various mechanisms responsible for these alterations underlie the loss of hemodynamic coherence during unsuccessful resuscitation procedures. Therapeutic resolution of persistent heterogeneous microcirculatory alterations is expected to improve outcomes in critically ill patients.

The response of the microcirculation to cardiac surgery

“…The observation of heterogenous flow patterns in the microcirculation signals the presence of shunts and manifesting itself clinically as a reduction in oxygen extraction [7]. Establishing hemodynamic coherence between the macro and microcirculation and targeting the normalization of microcirculatory function can be considered as an important goal in the hemodynamic management of the cardiac surgical patient.…”

“…All of these elements interact and are regulated by different complex mechanisms that control microcirculatory perfusion and oxygenation. In conditions of sepsis and shock, loss of (micro)vascular regulation and parenchymal cell damage causes heterogeneity in perfusion and oxygenation at the level of the microcirculation resulting in functional shunting of oxygen transport to the tissues and manifesting itself clinically as a reduction in oxygen extraction [7].…”

Protocolised early goal-directed therapy in patients with sepsis/septic shock does not result in improved survival compared with usual care with less invasive resuscitation strategies

“…Future research considerations include whether we should aim for microcirculation goals during resuscitation7; disassemble this combination of interventions to tease out relatively beneficial early goal-directed therapy components; assess early goal-directed therapy impact on changed sepsis case-mix due to new definitions8; and whether we could identify a resuscitation responder subset of patients with sepsis.…”

The vulnerable microcirculation in the critically ill pediatric patient

“…In the absence of injury, however, (iatrogenic) dysfunction of the MC can also occur, for example, following hemodilution or nor-epinephrine infusion [1, 83, 84, 101]. Of special interest is the interaction between the MC and mitochondrial function, particularly during states of shock, sepsis, and resuscitation [102]. When mitochondrial dysfunction occurs, cells may fail to utilize oxygen regardless of the state of the MC [103].…”