Intravenous megadose sodium ascorbate normalises elevations in intracranial pressure and restores pressor responsiveness to norepinephrine in ovine Gram-negative sepsis.

Acute brain dysfunction (delirium) is common in sepsis, and many survivors develop persistent cognitive impairment. Cerebral hypoperfusion and edema are implicated, yet it is unknown whether intracranial hypertension contributes to the neurological sequelae of sepsis, and no therapies specifically target cerebral hemodynamic dysfunction. Intravenous megadose sodium ascorbate has been reported to reverse cerebral tissue ischemia and hypoxia and reduce vasopressor requirements in preclinical and clinical studies. Here, we test for the first time the effects of sepsis and megadose sodium ascorbate on intracranial pressure (ICP), cerebral perfusion pressure (CPP) and pressor responsiveness to norepinephrine in a clinically relevant ovine model of Gram-negative sepsis. Adult Merino ewes were surgically instrumented with lateral cerebral ventricular catheters and carotid arterial and jugular venous catheters. Non-anesthetized sheep were infused with intravenous live Escherichia coli for 31-h. After 23-h of sepsis animals received bolus fluid resuscitation (30 mL/kg from 23-23.5-h; sodium lactate) and were randomized to receive intravenous 3 g/kg of sodium ascorbate (n = 7) or fluid-matched placebo (n = 6), as a bolus followed by a 7-h infusion. ICP and mean arterial pressure (MAP) were measured continuously. Changes in MAP to escalating norepinephrine doses were recorded at baseline and 23-h of sepsis, and after treatment at 27.5 and 31-h of sepsis. Sepsis reduced MAP and CPP and increased heart rate and ICP (all P < 0.01). By 31-h of sepsis, sodium ascorbate improved MAP compared with placebo (75 ± 5 to 87 ± 11 vs. 69 ± 11 to 66 ± 7 mmHg; P = 0.020). In addition, sodium ascorbate normalised ICP, whereas it remained elevated with placebo (17.0 ± 3.4 to 9.3 ± 1.9 vs. 20.6 ± 3.7 to 19.3 ± 5.0 mmHg; P = 0.024). Sodium ascorbate improved CPP versus no effect with placebo (61 ± 11 to 75 ± 5 mmHg vs. 48 ± 16 to 49 ± 12 mmHg; P = 0.046). MAP responsiveness to norepinephrine was impaired at 23-h of sepsis in both groups and was fully restored at 27.5- and 31-h of sepsis by sodium ascorbate but not by placebo. Norepinephrine did not increase ICP in either group. We demonstrate that sepsis elevates ICP to clinically relevant levels when measured directly via a lateral cerebral ventricular catheter, contributing to reduced CPP. Intravenous megadose sodium ascorbate ameliorates the intracranial hypertension, improves CPP, and reverses vasopressor hypo-responsiveness without increasing ICP in a clinically relevant ovine model of sepsis. These findings identify elevated ICP as a modifiable component of septic neuro-cardiovascular hemodynamic dysfunction and support sodium ascorbate as a potential therapy to mitigate both systemic and cerebral derangements in sepsis.