Vitamin Cocktail For Sepsis Fails; PPI For Stress Ulcer Prevention May Be Risky: ICU Studies

A major new study of intensive care unit (ICU) patients with septic shock failed to find a benefit of giving an intravenous cocktail of vitamin C, hydrocortisone and thiamine, relative to hydrocortisone alone.

A related study hints that proton pump inhibitor therapy may raise the risk of death when used for stress ulcer prophylaxis in ICU patients.

Both studies were published online January 17 to coincide with presentations at the Critical Care Reviews Meeting 2020 in Belfast, Northern Ireland.

The VITAMINS trial
Vitamin C and thiamine levels are depleted in the setting of septic shock. In 2017, a single-center observational study found that treating septic shock patients with a combination of high-dose vitamin C, thiamine and hydrocortisone was associated with significantly reduced mortality (8.5% for combination treatment vs 40.4% for usual care).

To investigate further, researchers conducted the VITAMINS trial in 10 ICUs in Australia, New Zealand and Brazil. A total of 216 patients with septic shock participated (mean age, 61.7 years, 63% men); 109 were randomly allocated to the combination of intravenous vitamin C (1.5 g every 6 hours), hydrocortisone (50 mg every 6 hours), and thiamine (200 mg every 12 hours) and 107 to intravenous hydrocortisone (50 mg every 6 hours) alone until shock resolution or up to 10 days.

Median time alive and free of vasopressor administration through day seven (primary outcome) was nearly identical in the two study groups: 122.1 hours in the intervention group and 124.6 hours in the control group (P=0.83), study investigator Dr. Tomoko Fujii from Monash University, Melbourne, Australia, told meeting attendees.

There was also no significant difference in two key secondary outcomes: 28-day mortality (22.6% and 20.4%, respectively, P=0.69) or 90-day mortality (28.6% and 24.5%; P=0.51).

The VITAMINS trial results suggest that vitamin C, hydrocortisone, and thiamine "does not lead to a more rapid resolution of septic shock compared with intravenous hydrocortisone alone," Dr. Fujii reported.

But Dr. Paul Marik, chief of pulmonary and critical care medicine at Eastern Virginia Medical School in Norfolk, who led the earlier trial showing a benefit of the vitamin cocktail for septic shock, disagrees. After Dr. Fujii presented the VITAMINS trial data, Dr. Marik, a strong proponent of this treatment, took the stage to provide editorial invited comment, and he basically rejected the findings.

Dr. Marik said a major problem with the VITAMINS trial is that patients received the vitamin C cocktail too late in the course of their disease, rendering it ineffective. "It's like giving it to a patient who's dead. It's of no benefit. The horse was out of the barn miles beforehand," he told attendees.

Dr. Marik said, in his ICU, the vitamin C cocktail is given to patients immediately after signs of sepsis are recognized. But in a randomized controlled trial, that's not possible and treatment is invariably delayed, and he believes that's why this trial failed to replicate what he and many other clinicians have seen in the real-world.

In his experience, Dr. Marik said, the treatment is only helpful when given within 6 hours after sepsis onset. In the VITAMINS trial, treatment was given an average of 12 after ICU arrival.

In a JAMA editorial, Dr. Andre Kalil from University of Nebraska Medical Center, Omaha, notes that several more studies of vitamin C administration for sepsis are ongoing or planned. "Given that other studies are forthcoming, there appears to be no immediate justification for adoption of high-dose vitamin C, alone or in combination, as a component of treatment for sepsis," he concludes.

The PEPTIC trial
The other study addressed the safety of a proton pump inhibitor (PPI) vs a histamine-2 receptor blocker (H2RB) for stress ulcer prevention in adult ICU patients requiring invasive mechanical ventilation.

The open-label, cluster crossover PEPTIC trial involved more than 26,000 patients from 50 ICUs in Australia, Canada, England, Ireland and New Zealand. Participants were randomly allocated by site to preferential use of a PPI or H2RB. Each strategy was maintained for 6 months and then switched.

A total of 18.3% of patients admitted to the ICU when PPIs were used for stress ulcer prophylaxis and 17.5% of patients admitted when H2RBs were used died in the hospital by day 90, a difference that failed to reach statistical significance (risk ratio, 1.05; P=0.05; absolute risk difference, 0.93 percentage points).

In presenting the data, Dr. Paul Young from the ICU in Wellington Hospital in New Zealand, said the chances that PPIs reduce mortality by more than 1 percentage point has to be "astronomically low, but the possibility that they increase mortality overall, I believe, is genuinely real."

A post hoc exploratory analysis suggested that a PPI prophylaxis strategy might increase the risk of death among more severely ill patients, but not among those with less severe illness.

Clinically important upper gastrointestinal bleeding was less common with the PPI strategy than the H2RB strategy (1.3% vs 1.8%, risk ratio, 0.73; P=0.009). There were no marked differences in rates of C difficile infection and ICU and hospital length of stay.

The investigators caution, however, that an estimated 4% of patients randomized by ICU site to PPIs actually received H2RBs and roughly 20% of those randomized by ICU site to H2RBs actually received PPIs. This crossover is a big limitation of the study, one that may limit interpretation of the findings, they say.

The authors of a JAMA editorial say it should be noted that the motivation for the trial was based on safety concerns of PPIs, not a hypothesized benefit of H2RBs.

"Overall, the results do not preclude the possibility of a small increase in hospital mortality with the proton pump inhibitor prophylaxis strategy despite showing a small, statistically significant reduction in clinically important gastrointestinal bleeding," write Dr. Todd Rice from Vanderbilt University in Nashville and co-authors.

They also think the incomplete data on which patients in the trial received which drug "confounds interpretation of the results and leaves the clinician unsure of the best way to optimize benefit and avoid harm when deciding on stress ulcer prophylaxis for individual critically ill patients."

—Megan Brooks

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