Reversal of cerebral ischaemia and hypoxia and of sickness behaviour by megadose sodium ascorbate in ovine Gram-negative sepsis

• Published in: British journal of anaesthesia : BJA Vol. 133; no. 2; pp. 316 - 325
• Main Authors: May, Clive N., Ow, Connie P., Pustovit, Ruslan V., Lane, Darius J., Jufar, Alemayehu H., Trask-Marino, Anton, Peiris, Rachel M., Gunn, Adam, Booth, Lindsea C., Plummer, Mark P., Bellomo, Rinaldo, Lankadeva, Yugeesh R.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.08.2024
• Subjects: Animals; Antioxidants - pharmacology; ascorbate; Ascorbic Acid - pharmacology; Ascorbic Acid - therapeutic use; Behavior, Animal - drug effects; brain; Brain Ischemia - metabolism; Cerebrovascular Circulation - drug effects; Disease Models, Animal; Female; hypoxia; Hypoxia - metabolism; inflammation; ischaemia; sepsis; Sepsis - complications; Sepsis - drug therapy; Sepsis - metabolism; Sheep; sickness behaviour; hypoxia; ischaemia; sickness behaviour; inflammation; ascorbate; brain; sepsis
• ISSN: 0007-0912; 1471-6771; 1471-6771
• DOI: 10.1016/j.bja.2024.04.058

The mechanisms by which megadose sodium ascorbate improves clinical status in experimental sepsis is unclear. We determined its effects on cerebral perfusion, oxygenation, and temperature, and plasma levels of inflammatory biomarkers, nitrates, nitrites, and ascorbate in ovine Gram-negative sepsis. Sepsis was induced by i.v. infusion of live Escherichia coli for 31 h in unanaesthetised Merino ewes instrumented with a combination sensor in the frontal cerebral cortex to measure tissue perfusion, oxygenation, and temperature. Fluid resuscitation at 23 h was followed by i.v. megadose sodium ascorbate (0.5 g kg−1 over 30 min+0.5 g kg−1 h−1 for 6.5 h) or vehicle (n=6 per group). Norepinephrine was titrated to restore mean arterial pressure (MAP) to 70–80 mm Hg. At 23 h of sepsis, MAP (mean [sem]: 85 [2] to 64 [2] mm Hg) and plasma ascorbate (27 [2] to 15 [1] μM) decreased (both P<0.001). Cerebral ischaemia (901 [58] to 396 [40] units), hypoxia (34 [1] to 19 [3] mm Hg), and hyperthermia (39.5 [0.1]°C to 40.8 [0.1]°C) (all P<0.001) developed, accompanied by malaise and lethargy. Sodium ascorbate restored cerebral perfusion (703 [121] units], oxygenation (30 [2] mm Hg), temperature (39.2 [0.1]°C) (all PTreatment<0.05), and the behavioural state to normal. Sodium ascorbate slightly reduced the sepsis-induced increase in interleukin-6, returned VEGF-A to normal (both PGroupxTime<0.01), and increased plasma ascorbate (20 000 [300] μM; PGroup<0.001). The effects of sodium ascorbate were not reproduced by equimolar sodium bicarbonate. Megadose sodium ascorbate rapidly reversed sepsis-induced cerebral ischaemia, hypoxia, hyperthermia, and sickness behaviour. These effects were not reproduced by an equimolar sodium load.