In vivo mitochondrial oxygen consumption during LPS-induced endotoxemia: a controlled experimental study in swine

Abstract Background Sepsis and septic shock are life-threatening syndromes characterized by complex systemic effects, including alterations in tissue oxygenation, mitochondrial function, and organ performance. Despite advances in supportive care, management remains challenging and is largely focused on maintaining adequate perfusion through fluids and vasoactive agents. To better characterize early systemic responses to endotoxemia under different hemodynamic conditions, this study used a swine lipopolysaccharide (LPS)-induced endotoxemia model with graded hypotension exposure. Animals were allocated to a control group (MAP maintained > 80 mmHg) and two LPS-groups defined by different MAP thresholds for initiating hemodynamic support (LPS-1: <80 mmHg; LPS-2: <65 mmHg), with a focus on early mitochondrial and microcirculatory (dys)function. Results LPS administration induced marked systemic responses, including tachycardia, metabolic stress, and organ dysfunction. Microcirculatory alterations were present but quantitatively modest. In vivo mitochondrial oxygen tension (mitoPO 2 ) remained largely preserved or was only transiently affected, whereas mitochondrial oxygen consumption (mitoVO 2 ) was reduced or showed a blunted time course in the epidermis and liver. In contrast, ex vivo analyses revealed increased mitochondrial respiratory flux in peripheral blood mononuclear cells during early endotoxemia. More permissive hypotension was associated with a greater cumulative hypotension burden and stronger renal injury signals, including higher neutrophil gelatinase-associated lipocalin concentrations and reduced renal clearance. Arterial lactate concentrations increased during endotoxemia and were inversely associated with hepatic indocyanine green plasma disappearance rate. Conclusion Early LPS-induced endotoxemia was associated with reduced or blunted mitoVO 2 despite largely preserved mitoPO 2 , consistent with partial uncoupling between mitochondrial oxygen availability and utilization. Microcirculatory alterations were modest and unlikely to fully account for the observed changes in mitoVO 2 . Supportive ex vivo and organ function findings indicated increased mitochondrial respiratory activity and early renal vulnerability under more permissive hypotension. Together these findings highlight that mitoVO 2 is a valuable parameter in combination with mitoPO 2 to probe tissue-level mitochondrial function during early endotoxemia.