Vitamin C-thiamine-hydrocortisone combo yields no improvement in septic shock

A combination of intravenous (IV) vitamin C, hydrocortisone, and thiamine did not reduce mortality or dependence on vasopressors in patients with septic shock* in the intensive care unit (ICU), according to results of the VITAMINS** trial presented at the recent Critical Care Reviews meeting (CCR20).

“[T]here appears to be no immediate justification for adoption of high-dose vitamin C, alone or in combination, as a component of treatment for sepsis,” said Professor Andre Kalil from the University of Nebraska Medical Center in Omaha, Nebraska, US, in an accompanying editorial. [JAMA 2020;doi:10.1001/jama.2019.22438]

A total of 211 adults (mean age 61.7 years, 63 percent male) with septic shock (within 24 hours pre-enrolment) at 10 ICUs in Australia, New Zealand, and Brazil completed the trial. They had been randomized 1:1 to receive a combination of IV vitamin C (1.5 g every 6 hours), hydrocortisone (50 mg every 6 hours), and thiamine (200 mg every 12 hours) or IV hydrocortisone alone (50 mg every 6 hours) for up to 10 days (or until septic shock resolution). Mean treatment duration was 3.4 days in both groups.

Duration of time alive and ≥4 hours free from vasopressor use at day 7 did not significantly differ between those who received the combination or hydrocortisone alone (median, 122.1 vs 124.6 hours; median of all paired differences between groups, -0.6 hours; p=0.83). [JAMA 2020;doi:10.1001/jama.2019.22176]

All-cause mortality rate was comparable between patients who received the combination and hydrocortisone alone at 28 days (22.6 percent vs 20.4 percent; p=0.69) and 90 days (28.6 percent vs 24.5 percent; p=0.51), with a hazard ratio of death of 1.18 (p=0.54) for the combination vs hydrocortisone alone. ICU mortality (19.6 percent vs 18.3 percent; p=0.80) and hospital mortality (23.4 percent vs 20.4 percent; p=0.60) also did not differ between combination and hydrocortisone-alone recipients, nor did duration of hospitalization (median 12.3 days in both groups). There was also no between-group difference in time free from mechanical ventilation or renal replacement therapy at 28 days.

A post hoc analysis showed that death (15.9 percent vs 14.4 percent; p=0.77) or re-dependence on vasopressors (33.3 percent vs 26.7 percent; p=0.33) by day 7 did not differ between combination and hydrocortisone-alone recipients.

Adverse events (AEs) reported were one incident each of fluid overload and hyperglycaemia in the combination group and one incident of gastrointestinal bleeding in the hydrocortisone-only group. No serious AEs were reported.

Previously, a small study suggested that a hydrocortisone-thiamine-high-dose IV vitamin C combo reduced in-hospital mortality risk and vasopressor use in patients with severe sepsis or septic shock. [Chest 2017;151:1229-1238] However, as corticosteroids alone have also reduced mortality and vasopressor use, [N Engl J Med 2018;378:809-818] it remained unknown if the combination was a superior option.

“[The present study] suggests that treatment with IV vitamin C, hydrocortisone, and thiamine does not lead to a more rapid resolution of septic shock compared with IV hydrocortisone alone,” said the researchers.

Additionally, the use of the combination could also have unwanted consequences including “perpetuating false hopes for patients, families, and clinicians, and delaying proven lifesaving therapies,” noted Kalil.

“The findings of the VITAMINS trial are clear: In patients with septic shock from Australia, New Zealand, and Brazil, there was no signal of benefit with the high dose vitamin C, thiamine, and hydrocortisone cocktail. The search for treatments that might improve the outcome of these very sick patients must now focus on other interventions,” pointed out study lead investigator Professor Rinaldo Bellomo, from Austin Hospital in Heidelberg, Victoria, Australia.

One such intervention may be the rapid initiation of antibiotic therapy, commented Kalil. With two studies suggesting an increased mortality risk with every hour of delay to antibiotic administration in patients with septic shock, [Crit Care Med 2017;45:607-614; Crit Care Med 2006;34:1589-1596] “rapid initiation of appropriate antibiotics should be an absolute priority for treatment of all patients with septic shock in clinical practice as well as in clinical research,” he said.