Sodium thiosulfate does not affect energy metabolism or organ (dys)function during resuscitation from murine...

In murine models, controversial data have been reported on the effect of hydrogen sulfide (H₂S) administration during resuscitation from trauma-and-hemorrhage. The H₂S donor sodium thiosulfate (Na₂S₂O₃) is a recognized drug devoid of major side effects, and, hence, we determined its effects in our full scale ICU-model of resuscitated murine trauma-and-hemorrhage. We hypothesized that Na₂S₂O₃ might improve energy metabolism and thereby exert organ-protective effects as previously demonstrated in animals with genetic cystathionine-γ-lyase (CSE) deletion (CSE^-/-).

30 mice underwent combined blast wave-induced blunt chest trauma followed by 1 h of hemorrhagic shock (mean arterial pressure MAP = 35 ± 5 mmHg). Thereafter, resuscitation was initiated comprising re-transfusion of shed blood, lung-protective mechanical ventilation, fluid resuscitation and continuous i.v. noradrenaline infusion to maintain MAP > 55 mmHg over 6 h, and randomized administration of either i.v. 0.45 mg/g_bodyweight Na₂S₂O₃ or vehicle (NaCl 0.9%). Hemodynamics, lung mechanics, gas exchange, acid-base-status and organ function parameters were recorded. Metabolic pathways were quantified based on gas chromatography/mass spectrometry assessment of plasma isotope enrichment during primed-continuous infusion of stable, non-radioactive, isotope labeled substrates. Mitochondrial function was determined using high-resolution respirometry, and tissue target proteins (nitrotyrosine formation, extravascular albumin accumulation, CSE expression) were analyzed using immunohistochemistry.

Data originate from 23 mice (Na₂S₂O₃ n = 12; vehicle n = 11)_. Na₂S₂O₃ affected neither survival nor noradrenaline requirements. While minute ventilation had to be increased over time in both groups to maintain arterial PCO₂ without intergroup difference, arterial PO₂ decreased over time in Na₂S₂O₃-treated mice (p = 0.006). Although arterial pH decreased in both groups (vehicle p = 0.049; Na₂S₂O₃ p < 0.001), metabolic acidosis was more pronounced in the Na₂S₂O₃ group. Neither metabolic pathways nor tissue mitochondrial respiratory activity or tissue target proteins showed any intergroup differences.

In this model of resuscitated trauma-and-hemorrhage, Na₂S₂O₃ did not exert any beneficial metabolic or organ-protective effect and was even associated with impaired pulmonary function. These results are in contrast to our previous findings in CSE^-/- mice, but in line with more recent findings in CSE^-/- mice with pre-existing comorbidities. Hence, our studies do not support a beneficial role of Na₂S₂O₃ in trauma resuscitation.