Neither vitamin C nor fluid restriction improved outcomes in ICU patients with sepsis, new studies found.
The first trial, conducted in Canada, France, and New Zealand, randomized 872 patients who had been in the ICU for no longer than 24 hours with proven or suspected infection as their main diagnosis and who were receiving a vasopressor to an infusion of either vitamin C (50 mg/kg) or placebo every six hours for up to 96 hours. The primary outcome was a composite of death or persistent organ dysfunction (defined by the use of vasopressors, invasive mechanical ventilation, or new renal-replacement therapy) on day 28. Results were published the New England Journal of Medicine (NEJM) on June 15.
The primary outcome occurred in significantly more patients in the vitamin C group (44.5% vs. 38.5%; risk ratio, 1.21 [95% CI, 1.04 to 1.40]; P=0.01). At 28 days, mortality rates were 35.4% and 31.6%, respectively (risk ratio, 1.17; 95% CI, 0.98 to 1.40), and rates of persistent organ dysfunction were 9.1% and 6.9% (risk ratio, 1.30; 95% CI, 0.83 to 2.05). The two groups had similar organ-dysfunction scores, biomarkers, six-month survival, health-related quality of life, and rates of stage 3 acute kidney injury and hypoglycemic episodes. One patient in the vitamin C group had a severe hypoglycemic episode, and one had a serious anaphylaxis event.
The authors noted that the findings were surprising and differed from some previous trials of vitamin C. “One plausible explanation for the divergent findings regarding mortality is that large effect estimates from smaller trials may occur by chance. Differences in baseline characteristics, such as the presence of respiratory failure or receipt of vasopressors, may also explain such differences,” they wrote, adding that ongoing trials of vitamin C in patients with COVID-19 and acute respiratory distress syndrome may provide more information.
The other study, conducted in several European countries, included 1,554 ICU patients who had been diagnosed with septic shock within 12 hours and had received at least 1 L of IV fluid. They were randomized to either standard IV fluid therapy or restricted, in which they could only receive fluid to treat severe hypoperfusion, to replace documented fluid losses, to correct dehydration, or to ensure a total daily fluid intake of 1 L. The study was funded by the Novo Nordisk Foundation, and results were published by NEJM on June 17.
The restrictive-fluid group received a median of 1,798 mL of IV fluid (interquartile range, 500 to 4,366 mL) during their ICU stay; the standard-fluid group received a median of 3,811 mL (interquartile range, 1,861 to 6,762 mL). At 90 days, mortality rates were 42.3% in the restrictive-fluid group and 42.1% in the standard-fluid group (adjusted absolute difference, 0.1 percentage point; 95% CI, −4.7 to 4.9 percentage points; P=0.96). Serious adverse events occurred at least once in 29.4% and 30.8%, respectively (adjusted absolute difference, −1.7 percentage points; 99% CI, −7.7 to 4.3 percentage points).
“Our results add to the findings in a recent systematic review,” the authors wrote. “Our results may contrast with those of some observational studies on this topic, the majority of which have suggested harm from higher fluid volumes as compared with lower fluid volumes in patients with sepsis. However, confounding by indication and time-dependent exposure might have biased the observational studies.”
An accompanying editorial said that the small difference between groups in fluid provided might have prevented the study from showing an effect. “The amount of intravenous fluid that was received by the patients in the standard-care group in this trial was substantially less than that observed in previous national and international trials of early, goal-directed resuscitation involving patients with septic shock and in cohort studies. The results of work completed previously by the authors that suggested benefit from a more restrictive fluid management strategy might have changed clinical practice in northern Europe sufficiently that this trial was unable to answer the question it set out to address,” the editorialists wrote.