Abstract
Circulatory shock is associated with marked disturbances of the macro- and microcirculation and flow heterogeneities. Furthermore, a lack of tissue adenosine trisphosphate (ATP) and mitochondrial dysfunction are directly associated with organ failure and poor patient outcome. While it remains unclear if microcirculation-targeted resuscitation strategies can even abolish shock-induced flow heterogeneity, mitochondrial dysfunction and subsequently diminished ATP production could still lead to organ dysfunction and failure even if microcirculatory function is restored or maintained. Preserved mitochondrial function is clearly associated with better patient outcome. This review elucidates the role of the microcirculation and mitochondria during circulatory shock and patient management and will give a viewpoint on the advantages and disadvantages of tailoring resuscitation to microvascular or mitochondrial targets.
Highlights
Shock can be defined as the “imbalance between oxygen supply and requirements” [1]
In resuscitated patients with septic shock, a direct relationship was noted between eventual outcome and skeletal muscle adenosine trisphosphate (ATP) [14], suggesting a perhaps more important role for cellular metabolic capacity compared
None of the promising microvasculature- or mitochondrial-targeted pre-clinical therapeutic approaches have yet translated to clinical practice
Summary
Shock can be defined as the “imbalance between oxygen supply and requirements” [1]. This imbalance can be due to “inadequate O2 transport” resulting from “hypovolemia,” “cardiogenic factors” (e.g., myocardial infarction), “obstruction” (e.g., pulmonary embolism), and/or “distributive shock” (e.g., septic shock), which is characterized by “decreased systemic vascular resistance and altered oxygen extraction” [1]. In longer-term, fluid-resuscitated large animal models, therapeutic interventions that attenuated shock-related cellular dysoxia (e.g., selective inhibition of the inducible NO synthase (iNOS), antioxidant infusion, therapeutic hyperoxia) revealed that any beneficial effect on the microcirculation coincided with improved parameters of inflammation, oxidative and nitrosative stress, and/or cellular metabolism [21, 47, 48]. The values reported for mitoPO2 of 30–110 mmHg may represent a mixture of PO2 values from different compartments rather than solely mitoPO2 Despite these limitations in determining mitochondrial function, there is ample experimental evidence that reduced (disturbed) mitochondrial respiratory activity assumes crucial importance for shock-related organ dysfunction or failure, similar to the potential role of impaired microcirculatory perfusion and oxygenation. It is tempting to speculate that this finding is related to the well-known norepinephrine-related aggravation of oxidative [126, 127] and nitrosative stress: in patients, nitrite/nitrate concentrations were inversely related to both tissue complex I activity and glutathione concentrations, but directly related to norepinephrine requirements which, in turn, coincided with low complex I activities [14]
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