Noradrenaline for treatment of endotoxemic shock in pigs is associated with improved hepatic mitochondrial respiration

Introduction

The optimal mean arterial blood pressure (MAP) for sepsis resuscitation remains unclear. Growing evidence suggests that mitochondrial dysfunction plays a role in the pathogenesis of sepsis-induced organ failures. The aim of this study was to evaluate the effect of progressively increasing levels of MAP, achieved by the use of noradrenaline (NA) on liver mitochondrial function during sepsis.

Methods

Thirteen anesthetized pigs received endotoxin (Escherichia coli LPS B0111:B4, 0.4 μg/kg/hour until the mean pulmonary arterial pressure reached 35 mmHg) and were subsequently randomized to placebo or NA administration for 10 hours. The NA dose was adjusted every 2 hours to achieve 15 mmHg increases in MAP up to 95 mmHg. Systemic (thermodilution) and hepatosplanchnic blood flow (ultrasound Doppler) were measured at each step. At the end of the experiment, hepatic mitochondrial oxygen consumption (high-resolution respirometry) and citrate synthase activity (spectrophotometrically) were assessed, using the Oxygraph 2 K (Oroboros Instruments, Innsbruck, Austria) and DatLab 4.2 software for data acquisition and analysis.

Results

The MAP, cardiac output and systemic DO₂ increased in the NA group to 95 ± 7 mmHg (controls: 64 ± 3 mmHg), 8.7 ± 3.1 l/min (controls: 5.7 ± 1.4 l/min), and 33 ± 8 ml/min/kg (controls: 17.6 ± 3.4 ml/min/kg; all P < 0.05). Systemic and hepatosplanchnic VO₂ were not different between groups. Hepatic lactate uptake decreased significantly in both groups, but without differences between the groups. At the end of the experiment, liver mitochondrial function in the NA group exhibited a significant improvement in terms of maximal complex I-dependent mitochondrial respiration (from 329 ± 83 to 587 ± 195 pmol/s/mg), and of respiratory control ratio for complex I (from 3.8 ± 1.3 to 5.7 ± 0.5) and complex II (from 3.2 ± 0.5 to 3.9 ± 0.6; all P < 0.05). There were no differences in citrate synthase activity between the groups (13.9 ± 3 vs 16.8 ± 4 μmol/min/mg).

Conclusion

The use of NA to increase the MAP during endotoxemic shock was associated with an improvement in hepatic mitochondrial respiration, but was not associated with higher levels of hepatic oxygen consumption or improved hepatic lactate clearance.