Resuscitation With Vitamin C, Hydrocortisone, and Thiamin in Children With Septic Shock: A Multicenter Randomized Pilot Study

Abstract

OBJECTIVES: Adjunctive therapy with vitamin C, hydrocortisone, and thiamin has been evaluated in adults, but randomized controlled trial (RCT) data in children are lacking. We aimed to test the feasibility of vitamin C, hydrocortisone, and thiamin in PICU patients with septic shock; and to explore whether the intervention is associated with increased survival free of organ dysfunction. DESIGN: Open-label parallel, pilot RCT multicenter study. The primary endpoint was feasibility. Clinical endpoints included survival free of organ dysfunction censored at 28 days and nine secondary outcomes, shock reversal, and two proxy measures of intervention efficacy. SETTING: Six PICUs in Australia and New Zealand. PATIENTS: Children of age between 28 days and 18 years requiring vasoactive drugs for septic shock between August 2019 and March 2021. INTERVENTIONS: Patients were assigned 1:1 to receive 1 mg/kg hydrocortisone every 6 hours (q6h), 30 mg/kg ascorbic acid q6h, and 4 mg/kg thiamin every 12 hours (n = 27), or standard septic shock management (n = 33). MEASUREMENTS AND MAIN RESULTS: Sixty of 77 (78%) eligible patients consented with 91% of approached parents providing consent. The median time from randomization to intervention was 44 (interquartile range [IQR] 29–120) min. Seventy of seventy-seven (28%) patients had received IV steroids before randomization. Median survival alive and free of organ dysfunction was 20.0 (0.0–26.0) days in the intervention and 21.0 (0.0–25.0) days in the standard care group. Median PICU length of stay was 5.3 (2.5–11.3) days in the intervention group versus 6.9 (3.0–11.5) days in the control group. Shock reversal occurred at a median of 35.2 (14.6–101.2) hours in the intervention group versus 47.3 (22.4–106.8) hours in the standard care group (median difference –12 hr; 95% CI, –56.8 to 32.7 hr). CONCLUSIONS: In children requiring vasopressors for septic shock, a protocol comparing adjunctive treatment with high-dose vitamin C, hydrocortisone, and thiamin versus standard care was feasible. These findings assist in making modifications to the trial protocol to enable a better-designed larger RCT.

Recent Data about the Use of Corticosteroids in Sepsis—Review of Recent Literature

“…The dosages of the corticosteroid treatments and their duration from the selected studies are presented below in Table 2. [27] 2024…”

“…Regarding adverse events within the safety population, the most frequently occurring serious adverse events were severe hypernatremia and fluid overload. A disturbance in blood glucose levels was noted in 27 [34]. The study aimed to explore the theory that hydrocortisone therapy correlates with higher mortality rates in patients classified under endotype A.…”

“…These results underscore the complexity of treating septic shock and the importance of ongoing research to refine and discover effective therapies. Current evidence does not support the widespread use of triple therapy to improve mortality or organ dysfunction in septic shock [27][28][29]31,35,36]. Future trials may provide further insight into whether there are specific patient populations who could benefit from this therapy.…”

“…Despite initial enthusiasm based on smaller, single-center studies, larger multicenter trials have not demonstrated a significant benefit in reducing organ failure, mortality, or other critical outcomes with this triple therapy therapy. The only consistent finding across trials has been a reduction in the duration of vasopressor support, suggesting a potential role for triple therapy in specific patient subgroups or phenotypes, rather than a universal treatment for all septic shock patients [27][28][29].…”