The combination of parenteral ascorbic acid, hydrocortisone, and thiamine did not show a benefit for patients with septic shock over placebo, according to results from a randomized clinical trial.
In the multi-center, randomized Ascorbic Acid, Corticosteroids, and Thiamine in Septic Shock (ACTS) trial, 200 adults hospitalized with septic shock were randomized to either a combination of 1500 mg ascorbic acid, 50 mg hydrocortisone, and 100 mg thiamine over 4 days or a placebo therapy given every 6 hours. The change in the sequential Organ Failure Assessment Score (OFSA) was not significant between the intervention and placebo arms — 4.7 versus 4.1 over 72 hours, respectively.
Ari Moskowitz, MD, Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, at Beth Israel Deaconess Medical Center, Boston, and colleagues for the ACTS Clinical Trial Investigators, also reported that there was no significant difference between the two study arms in regard to the incidence of kidney failure or 30-day mortality.
The results of the study appeared to counter results from previous studies, including an observational study that found the combination did help improve outcomes for patients with sepsis, the study authors noted. “Recent randomized trials of ascorbic acid alone [CITRIS-ALI] or in combination with corticosteroids and thaimine [VITAMINS] have had varied design and inconsistent results,” Moskowitz and colleagues wrote. This is why their trial’s hypothesis was that the combination “would reduce the SOFA [range, 0-24; 0 = best] score from enrollment to 72 hours after enrollment in this patient population,” which was their primary endpoint.
Two hundred and five patients were enrolled in the trial, of whom 200 received at least one dose of the study drug and completed the trial. There were 101 patients in the intervention group and 99 in the placebo group. The mean age of the patients was 68, less than half (44%) were women, and most of the patients were white. Baseline characteristics were similar between the two arms. Prior to the intervention period, 7 patients in the intervention group and 14 in the placebo groups received open-label corticosteroids.
Standard sepsis management guidelines were followed with the early administration of antibiotics, use of volume resuscitation and vasopressors to maintain a mean arterial pressure of at least 65mm Hg, as well as early treatment of the source of the infection.
Again, “[o]verall, there was no statistically significant interaction between time and treatment group with regard to SOFA score over the 72 hours after enrollment (mean SOFA score change from 9.1 to 4.4 [−4.7] points with intervention versus 9.2 to 5.1 [−4.1] points with placebo; adjusted mean difference, −0.8; 95% CI, −1.7 to 0.2; P = .12 for interaction),” the study authors wrote. Kidney failure occurred in 31.7% of those in the intervention arm, and 27.3% in the placebo arm, which was not statistically significant (adjusted risk difference, 0.03; 95% CI, −0.1 to 0.2; P = .58). Thirty-day mortality was also not significantly different between the two arms — 34.7% versus 29.3%, respectively (hazard ratio, 1.3; 95% CI, 0.8-2.2; P = .26).
Hyperglycemia, hypernatremia, and new hospital acquired infections were the most common serious adverse events.
“Compared with the VITAMINS study, this trial did not include corticosteroids in the control group,” Moskowitz and colleagues wrote. “Ultimately, 14 patients (14.1%) in the control group received open-label corticosteroids during the first 72 hours. As corticosteroids are known to reduce vasopressor requirements in septic shock, the improved hemodynamic parameters observed with the intervention in this trial may be related to corticosteroids, although a synergistic effect or effect from other interventions is possible. Given the number of comparisons made, results regarding days alive and vasopressor free and the cardiovascular component of the SOFA score should be considered hypothesis generating.”
The researchers noted several limitations for their study, including the fact that planned or ongoing corticosteroid use was part of the exclusion criteria. “The protocol was written prior to publication of the ADRENAL and APROCCHSS studies, which demonstrated potential benefit of corticostaroids in some septic shock populations and may have led to increased corticosteroid prescription in the study period,” the researchers wrote.
Also of note is that the study may not be generalizable, considering the number of patients who were screened in the study but not randomized.
A shorter time for vasopressor initiation may have resulted in improved outcomes. The study authors noted that some patients were discharged from the ICU within 96 hours of enrollment and did not receive the full study protocol of the intervention. Finally, because the study was not powered for subgroup analyses, patients who might have benefited from the protocol may not have been noted; this also affected the ability to detect small differences in mortality.
The combination of parenteral ascorbic acid, hydrocortisone, and thiamine did not show a benefit for patients with septic shock over placebo.
The change in the sequential Organ Failure Assessment Score (OFSA) was not significant between the intervention and placebo arms, nor was there a significant difference between the two study arms in regard to the incidence of kidney failure or 30-day mortality.
Candace Hoffmann, Managing Editor, BreakingMED
The ACTS trial was funded by a grant from Open Philanthropy.
Moskowitz disclosed a grant from the NIH, but had no other relevant relationships to disclose.
Cat ID: 190
Topic ID: 79,190,254,791,570,574,577,730,190,192,925