By Joanna Longueira, PharmD, and Arnaldo Lopez Ruiz, MD

Dr. Longueira is a pharmacist with AdventHealth, Orlando, FL. Dr. Lopez Ruiz is Attending Physician, Division of Critical Care, AdventHealth Medical Group, AdventHealth Orlando, FL.

Dr. Longueira and Dr. Lopez Ruiz report no financial relationships relevant to this field of study.

SYNOPSIS: Two double-blinded, placebo-controlled, randomized trials involving 337 patients (ORANGES, n = 137; ACTS, n = 200) with sepsis and septic shock have shown that administration of ascorbic acid, thiamine, and hydrocortisone did not reduce organ dysfunction or improve overall mortality. However, both trials showed that this combination therapy was effective in reducing the time to achieve shock resolution or shock-free days.

SOURCES: Iglesias J, Vassallo AV, Patel VV, et al. Outcomes of metabolic resuscitation using ascorbic acid, thiamine, and glucocorticoids in the early treatment of sepsis: The ORANGES Trial. Chest 2020;158:164-173.

Moskowitz A, Huang DT, Hou PC, et al. Effect of ascorbic acid, corticosteroids, and thiamine on organ injury in septic shock: The ACTS Randomized Clinical Trial. JAMA 2020;324:642-650.

Sepsis and septic shock remain major public health problems in the United States, with in-hospital mortality ranging from 30% to 50%.1 The 2016 Surviving Sepsis Campaign guidelines recommend the use of fluid resuscitation, broad-spectrum antibiotics, and vasopressors in patients with sepsis or septic shock.2 Although this approach represents the mainstay of therapy, the search for adjunctive treatments, such as the combination of intravenous (IV) ascorbic acid, thiamine, and hydrocortisone, has garnered interest after the encouraging preliminary results of Marik et al.3

Iglesias et al conducted the ORANGES trial (February 2018 to June 2019), which was a randomized, double-blinded, placebo-controlled trial in the United States involving patients with sepsis and septic shock to elucidate the role of hydrocortisone, ascorbic acid, and thiamine (HAT) therapy in sepsis management. Adult patients were eligible for inclusion in the study if they were diagnosed with sepsis or septic shock as defined by the 2016 Surviving Sepsis Campaign guidelines within 12 hours of admission to the intensive care unit (ICU).2 Subjects were randomized to receive either ascorbic acid 1,500 mg IV every six hours, thiamine IV 200 mg every 12 hours, and hydrocortisone 50 mg IV every six hours or placebo for up to four days. Notably, intensivists were permitted to use open-label hydrocortisone in the control patients if deemed clinically necessary. The primary outcome of the study was resolution of shock defined as time from starting the study medication to discontinuation of vasopressor support and change in Sequential Organ Failure Assessment (SOFA) score. Secondary outcomes included ICU and hospital mortality, ICU and hospital length of stay (LOS), ventilator-free days, renal failure, and procalcitonin clearance.

A total of 137 patients were randomized, with 68 in the treatment arm and 69 in the control group. Ninety-six percent of the patients studied were white, with an average age of 69 ± 13 years. Overall, 64% of subjects had ascorbic acid deficiency at baseline. Groups were comparable with regard to baseline Acute Physiology and Chronic Health Evaluation (APACHE) II scores (24 vs. 24.9), SOFA scores (8.3 vs. 7.9), and APACHE IV predicted mortality (34% vs. 33.6%). Investigators found a statistically significant difference for the time to shock reversal between the HAT and control groups (34 hours vs. 54 hours, P < 0.001). No statistically significant difference was found for change in SOFA score (3 vs. 2, P = 0.17). Additionally, there were no statistically significant differences in any of the secondary outcomes. A similar incidence of acute kidney injury (AKI) (79% vs. 75%, P = 0.68) and renal replacement therapy (3% vs. 11%, P = 0.098) was reported between the groups. Investigators concluded that the combination of IV ascorbic acid, thiamine, and hydrocortisone works synergistically to significantly reduce the time to resolution of shock.

The ACTS trial was a multicenter (14 centers in the United States), randomized, double-blind, placebo-controlled trial in which patients with septic shock were assigned to combination IV ascorbic acid (1,500 mg), hydrocortisone (50 mg), and thiamine (100 mg) every six hours for four days (n = 101) or placebo (n = 99). Patients were enrolled between February 2018 and October 2019. The primary outcome was change in SOFA score between enrollment and 72 hours. Key secondary outcomes included kidney failure and 30-day mortality. Of the patients who completed the study (mean age 68 ± 15 years; 44% women), 98% received at least one dose of the study drug.

Overall, there was no statistically significant improvement in SOFA score over the 72 hours after enrollment (mean SOFA score change from 9.1 to 4.4 [−4.7] points with intervention vs. 9.2 to 5.1 [−4.1] points with placebo; adjusted mean difference, −0.8; 95% confidence interval [CI], −1.7 to 0.2; P = 0.12 for interaction). There was no statistically significant difference in the incidence of kidney failure (31.7% with intervention vs. 27.3% with placebo; adjusted risk difference 0.03; 95% CI, −0.1 to 0.2; P = 0.58) or in 30-day mortality (34.7% vs. 29.3%, respectively; hazard ratio 1.3; 95% CI, 0.8 to 2.2; P = 0.26). However, the median number of shock-free days was higher in the intervention group compared with the placebo group (5 [interquartile range {IQR}, 3-5] vs. 4 [IQR, 1-5] days; median difference 1.0 day; 95% CI, 0.2 to 1.8 days; P < 0.01).

In addition, patients in the intervention group had a significantly greater reduction in cardiovascular SOFA score during the first 72 hours (mean difference −0.5; 95% CI, −0.9 to −0.1; P = 0.03 for interaction). Finally, there were similar numbers of serious adverse events in each group. The authors concluded that their data do not support the use of ascorbic acid, hydrocortisone, and thiamine in patients with septic shock.

COMMENTARY

Ascorbic acid in combination with hydrocortisone and thiamine (HAT therapy) has been proposed as adjunctive therapy in patients with sepsis and septic shock, given that many of these patients often have low levels of ascorbic acid and thiamine, or relative corticosteroid insufficiency.4 Furthermore, ascorbic acid possesses anti-inflammatory and antioxidant properties that can be useful in preserving endothelial function.5 It also serves as a cofactor for catecholamine synthesis, thereby contributing to maintain its endogenous production.6 The combination of hydrocortisone and ascorbic acid may act synergistically, since ascorbic acid reverses the oxidative damage to glucocorticoid receptors, while glucocorticoid increases the expression of the sodium-vitamin C cotransporter-2 (SVCT2), thereby allowing more ascorbic acid to be transported into cells.7,8 Thiamine also possesses antioxidant properties and serves as a necessary coenzyme to metabolize pyruvate inside the mitochondria and catalyzes the conversion of ascorbic acid to glyoxylate rather than oxalate, thereby preventing renal tubular injury (i.e., AKI).3 The proposed protective mechanisms conferred by HAT therapy, along with the finding that septic patients often have deficiencies in these factors, make this therapy seem appealing and encouraging to improve ICU outcomes.

In the ORANGES trial, Iglesias et al aimed to demonstrate the benefit of HAT therapy in patients with sepsis and septic shock based on previous small, single-center studies showing that this combination was associated with significant reductions in levels of procalcitonin, C-reactive protein (CRP), and vasopressor requirements. In addition, these studies also reported improved 28-day mortality (14.2% vs. 64.2%, P = 0.009).9,10

The ORANGES trial has an important limitation: A large proportion of patients (41%) in the placebo group received open-label hydrocortisone. Given that the primary outcome of this study was time to vasopressor independence, use of hydrocortisone in the control group can significantly confound this result. Hydrocortisone has consistently been shown in previous large, randomized trials (CORTICUS – ADRENAL) to reduce the time to shock reversal and currently is recommended by the Surviving Sepsis Campaign Guidelines in patients with refractory septic shock requiring high doses of vasopressors.2,11,12 Despite the statistical analysis and adjustment for this group of patients that received corticosteroids, the ORANGES trial found that HAT therapy still provided significant benefit in reducing the time to shock reversal, but whether this effect was a truly synergistic action of ascorbic acid with thiamine and hydrocortisone remains unclear. This beneficial effect of achieving vasopressor independence sooner with HAT therapy was not associated with improvement in any of the other outcomes, including the co-primary endpoint of reducing SOFA score. This result goes against the previous finding of Marik et al in which HAT therapy conferred significant benefit in SOFA reduction, duration and dose of vasopressor support, and ICU mortality.3 Although the study by Marik et al was a small, single-center, and retrospective trial, the fact that reduction in vasopressor requirement was not associated with reduction in SOFA score in the ORANGES trial supports the idea that HAT therapy did not affect the severity of illness or the degree of tissue injury.

Other important points to consider include the fact that most of the patients in the ORANGES trial were white and enrolled in two small community hospitals with low proportions of surgical septic shock. Moreover, the data on renal failure was not stratified based on severity of AKI, and it only considered those severe cases requiring renal replacement therapy (RRT). Therefore, the sample size of this study likely is too small to adequately assess the impact of HAT therapy on early stages of AKI and its progression.

The ACTS trial was a larger, multicenter trial that also failed to demonstrate any benefit of HAT therapy in reducing SOFA score or improving all-cause mortality over 30 days in patients with septic shock. In addition, the ACTS trial failed to demonstrate benefits in other secondary outcomes, such as renal failure requiring RRT, ventilator-free days, or ICU-free days. For this study, patients were not chosen because of vitamin deficiency unlike in the previous VITAMINS trial, and the study was not powered to analyze specific subgroups, such as those not requiring mechanical ventilation, those with acute respiratory distress syndrome (ARDS), or those requiring lower doses of vasopressor support (< 15 mcg/hour).13 However, this trial, like ORANGES, demonstrated that HAT therapy was effective in reducing the duration of vasopressor support. In fact, the median number of shock-free days was higher in the intervention group compared with the placebo group. Patients in the intervention group also had a statistically significantly greater reduction in cardiovascular SOFA score during the first 72 hours.

Overall, the current evidence after three randomized, double-blind, placebo-controlled trials (VITAMINS, ORANGES, and ACTS) using the combination of ascorbic acid, hydrocortisone, and thiamine as it was proposed by Marik et al does not support its use to improve mortality in sepsis or septic shock.3 Subsequent trials using HAT therapy must focus on identifying a specific subgroup of patients or patient phenotype in which this therapy could be effective. Currently, there are more than 30 ongoing or planned studies investigating the role of ascorbic acid or HAT combination in patients with sepsis and septic shock. One of the next to come is the VICTAS trial, which is larger than the ACTS trial and is a multicenter, double-blinded, randomized, controlled trial enrolling 500 septic patients that will evaluate the effect of HAT therapy on ventilator- and vasopressor-free days and ICU mortality.14 If this trial does not show benefits of HAT therapy on strong ICU endpoints, it will support the decision of abandoning this therapy from the armamentarium to manage sepsis.

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