背景:大量抗坏血酸钠改善实验性脓毒症临床状态的机制尚不清楚。我们确定了它对脑灌注的影响,氧合,和温度,和血浆炎症生物标志物水平,硝酸盐,亚硝酸盐,和抗坏血酸在绵羊革兰氏阴性脓毒症中的作用。
方法:在额叶大脑皮层用组合传感器测量组织灌注的未麻醉的美利诺母羊中静脉输注活大肠杆菌31小时,氧合,和温度。在23小时进行液体复苏后,静脉注射巨糖抗坏血酸钠(30分钟内0.5gkg-1+6.5小时0.5gkg-1h-1)或媒介物(每组n=6)。滴定去甲肾上腺素以将平均动脉压(MAP)恢复到70-80mmHg。
结果:脓毒症23小时时,MAP(平均[sem]:85[2]至64[2]mmHg)和血浆抗坏血酸(27[2]至15[1]μM)降低(均P<0.001)。脑缺血(901[58]至396[40]单位),缺氧(34[1]至19[3]mmHg),和高热(39.5[0.1]°C至40.8[0.1]°C)(所有P<0.001),伴随着不适和嗜睡。抗坏血酸钠恢复脑灌注(703[121]单位],氧合(30[2]mmHg),温度(39.2[0.1]°C)(所有P处理<0.05),行为状态恢复正常。抗坏血酸钠略微降低了脓毒症诱导的白细胞介素-6的增加,使VEGF-A恢复到正常(PGroupxTime均<0.01),和增加的血浆抗坏血酸(20000[300]μM;P组<0.001)。等摩尔碳酸氢钠不能再现抗坏血酸钠的作用。
结论:大糖抗坏血酸钠迅速逆转脓毒症诱导的脑缺血,缺氧,热疗,和疾病行为。等摩尔钠负荷不能再现这些效果。
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: Megadose sodium ascorbate rapidly reversed sepsis-induced cerebral ischaemia, hypoxia, hyperthermia, and sickness behaviour. These effects were not reproduced by an equimolar sodium load.