By Kristin E. Cardiel Nunez and Philip R. Fischer, MD, DTM&H

Kristin E. Cardiel Nunez is a medical student and master’s degree candidate at Mayo Clinic College of Medicine and Science, Rochester, MN. Dr. Fischer is Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN.

Ms. Cardiel Nunez and Dr. Fischer report no financial relationships relevant to this field of study.

SYNOPSIS: Combination treatment with ascorbic acid (vitamin C), thiamine (vitamin B1), and corticosteroids does not improve clinical outcomes in adults with septic shock.

SOURCE: 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 is common in adults, and septic shock often results in death due to subsequent organ failure. Treatment of septic shock for the prevention of organ failure has not been optimized, but ascorbic acid, thiamine, and corticosteroids, in varying combinations, have been shown to be beneficial in the prevention of organ failure in some studies. Thus, Moskowitz and colleagues sought to determine the advantage of treatment with a combination of ascorbic acid, thiamine, and corticosteroids vs. placebo in reducing Sequential Organ Failure Assessment (SOFA) score and other adverse outcomes among adults with septic shock.

Moskowitz and colleagues conducted a randomized controlled trial among 14 medical centers in the United States from Feb. 9, 2018, through Nov. 26, 2019. Adult patients were enrolled on the basis of incident septic shock, as defined by vasopressor administration in the setting of known sepsis or suspected infection, and were randomized to receive a combination intravenous ascorbic acid (1,500 mg), thiamine (100 mg), and hydrocortisone (50 mg) or placebo (volume-matched 0.9% sodium chloride). A completed treatment regimen was defined as dosage of the treatment combination for 96 hours, but those in the treatment group receiving at least one treatment dose were analyzed as part of the intervention group.

Exclusion criteria included known reasons for potential organ failure (i.e., hemochromatosis), treatment for declined organ function (i.e., renal replacement therapy), clinical indication for any of the treatment drugs, and expected death in 24 hours of enrollment. To achieve blinding, a randomization scheme was produced by an independent statistician, and treatment and placebo preparation and allocation were conducted independently by research pharmacists at each site. Site investigators, research and clinical staff, and patients were blinded to randomization status until the study conclusion.

A total of 200 patients were evaluated, including 101 patients (50.5%) receiving the novel treatment combination and 99 (49.5%) receiving placebo. Intervention and placebo groups were balanced in several characteristics, including patient age, body mass index, sex, and race. In addition to treatment or placebo administration, standard clinical management of sepsis was maintained according to guidelines among both groups throughout the study.

In the sample population studied, no statistically significant difference in mean SOFA score from enrollment to 72 hours was demonstrated among those with septic shock treated with the novel drug combination vs. placebo (mean difference, -0.8; 95% confidence interval [CI], -1.7 to 0.2; P = 0.12). However, in a secondary aim, the mean cardiovascular SOFA score component was shown to be significantly decreased among patients in the intervention group vs. the placebo group (mean difference, -0.5; 95% CI, −0.9 to −0.1; P = 0.03). No other factor of the SOFA score demonstrated this difference.

Another measure of organ failure, risk of incident kidney failure, also was shown to have no significant difference among the intervention (31.7%) and placebo (23.7%) groups (adjusted risk difference, 0.03; 95% CI, -0.10 to 0.17, P = 0.58). Thirty-day mortality was reported similarly to have no significant difference among those with septic shock treated with (34.7%) and without (29.3%) the novel treatment combination (hazard ratio 1.3; 95% CI, 0.8-2.2; P = 0.26). Lastly, the authors also showed that there was a statistically significant difference in shock-free days in the intervention group (five days) vs. the placebo group (six days) (median difference, 1.0 day; 95% CI, 0.2 to 1.8 day; P < 0.01).

In summary, Moskowitz and colleagues demonstrated that the combination treatment of ascorbic acid, thiamine, and corticosteroids did not improve SOFA scores, rate of kidney failure, or 30-day mortality rate among adults with septic shock. However, a secondary outcome of the study established that, among the six components of the SOFA score, the cardiovascular component alone significantly improved with treatment. Lastly, although there was shown to be a statistically significant difference in shock-free days among the intervention and placebo groups, this difference of one day was determined not to be of clinical significance. Therefore, the results of this study do not support the use of the treatment combination ascorbic acid, thiamine, and corticosteroids in adults with septic shock.

COMMENTARY

Clearly, the severe and varied consequences of septic shock require more than just antibiotics to support patient recovery. Multidrug therapies, such as combination hydrocortisone, ascorbic acid, thiamine (HAT) therapy, have been considered to address this complex condition. In 2017, a retrospective study by Marik and colleagues showed a significant decrease in observed vs. expected mortality among treatment compared to control groups in adult patients with septic shock.1 Following this study, several randomized clinical trials evaluated the effectiveness of HAT therapy and its components. In 2018, the clinical trial APROCCHHS found that corticosteroids in adults with septic shock decreased 90-day all-cause mortality, whereas the ADRENAL trial found that corticosteroid use in adults with septic shock on mechanical ventilation did not decrease 90-day mortality compared to placebo.2,3

Then, in 2019, the VITAMINS trial found no significant difference in time alive and vasopressor-free days for adults with septic shock treated with HAT vs. hydrocortisone alone.4 Additionally, the 2019 CITRIS-ALI trial evaluated the benefits of vitamin C among adults with sepsis and acute respiratory distress syndrome, and similar to the study by Moskowitz and colleagues, also found no significant difference in SOFA score in adults with septic shock.5 Thus, based on several clinical trials, the role of HAT in adults with septic shock still is unclear. Because of the lack of adverse effects with ascorbic acid and thiamine administration, treatment with HAT is likely of little negative consequence, and it may promote the early delivery of hydrocortisone, which has been demonstrated to be helpful in some patients with septic shock.2

Despite the lack of improved outcomes with HAT therapy among adults with septic shock demonstrated by Moskowitz and colleagues, Wald and colleagues found evidence consistent with a reduction in mortality with HAT therapy among children with septic shock in a propensity scored retrospective study.6 The most common cause of death among pediatric patients with septic shock is refractory shock, typically occurring within the first 72 hours of sepsis, followed by multiple organ dysfunction syndrome and respiratory failure.7 In contrast, death among adults with septic shock is most commonly due to multi-organ failure, with refractory shock and respiratory failure representing fewer deaths.8

The discrepancy in the most common cause of death may explain the difference in mortality benefit of HAT observed in children, but not adults. Notably, in this study by Moskowitz and colleagues, the cardiovascular component of the SOFA score uniquely demonstrated improvement in the treatment group, whereas the five other system components did not exhibit improvement compared to placebo. Potential explanations for this single improvement include the established effect of corticosteroids on vasculature, thiamine supplementation benefiting high-energy consumption by cardiac tissues in the setting of critical illness, and antioxidant effects of ascorbic acid.4,5

If this analysis is identifying a true difference in the effectiveness of HAT therapy on the cardiovascular system vs. other organ systems, it may account for the discrepancy in mortality benefit of HAT therapy in children compared to adults. In septic children, who are more likely to die from inadequate cardiovascular response to medical therapy, HAT may demonstrate an improved mortality rate, yet in adults, who are more likely to die from multiple organ failure, HAT therapy may not affect cumulative organ system function in such a way that mortality outcomes are improved.

In addition to children, other populations not included in this trial also may benefit from HAT therapy. One criterion for exclusion in the study by Moskowitz and colleagues was clinical indication for any of the HAT combination drugs, including thiamine. Although necessary to evaluate the effectiveness of this treatment vs. placebo, the HAT treatment regimen may produce different and beneficial outcomes in adult patients with septic shock in regions with endemic thiamine deficiency, such as Southeast Asia. For example, thiamine deficiency affects 70% to 100% of infants and 27% to 100% of reproductive-age women in Cambodia, and 16% to 25% of children and 30% of elderly adults in Thailand.9 The benefits of thiamine administration in shock are supported in theory, yet among populations in which thiamine is likely not deficient in any significant number of people, a clinical impact has not been established. However, thiamine supplementation in deficient individuals may indeed improve outcomes for those experiencing septic shock on a background of thiamine deficiency. Moskowitz and colleagues noted that subjects with higher lactate levels, indicating more severe illness, also may have more benefit from HAT. One possible explanation for this difference is underlying vitamin deficiencies in patients who had unidentified risk factors for thiamine or vitamin C deficiencies.

In summary, this study by Moskowitz and colleagues contributes to the controversial record of studies on the benefits of HAT therapy among a specific group of people with septic shock. Although no overall statistically and clinically significant benefit was demonstrated in this study, more research is needed to evaluate the benefit of HAT therapy in children and vitamin-deficient populations with septic shock and to evaluate the contributions of each HAT component to patient recovery.

REFERENCES

  1. Marik PE, Khangoora V, Rivera R, et al. Hydrocortisone, vitamin C, and thiamine for the treatment of severe sepsis and septic shock: A retrospective before-after study. Chest 2017;151:1229-1238.
  2. Annane D, Renault A, Brun-Buisson C, et al. Hydrocortisone plus fludrocortisone for adults with septic shock. N Engl J Med 2018;378:809-818.
  3. Venkatesh B, Finfer S, Cohen J, et al. Adjunctive glucocorticoid therapy in patients with septic shock. N Engl J Med 2018;378:797-808.
  4. Fujii T, Luethi N, Young PJ, et al. Effect of vitamin C, hydrocortisone, and thiamine vs hydrocortisone alone on time alive and free of vasopressor support among patients with septic shock: The VITAMINS randomized clinical trial. JAMA 2020;323:423-431.
  5. Fowler AA III, Truwit JD, Hite RD, et al. Effect of vitamin C infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe septic acute respiratory failure: The CITRIS-ALI randomized clinical trial. JAMA 2019;322:1261-1270.
  6. Wald EL, Sanchez-Pinto LN, Smith CM, et al. Hydrocortisone-ascorbic acid-thiamine use associated with lower mortality in pediatric septic shock. Am J Respir Crit Care Med 2020;201:863-867.
  7. Weiss SL, Balamuth F, Hensley J, et al. The epidemiology of hospital death following pediatric severe sepsis: When, why, and how children with sepsis die. Pediatr Crit Care Med 2017;18:823-830.
  8. Vincent JL, Nelson DR, Williams MD. Is worsening multiple organ failure the cause of death in patients with severe sepsis? Crit Care Med 2011;39:1050-1055.
  9. Johnson CR, Fischer PR, Thacher TD, et al. Thiamine deficiency in low- and middle-income countries: Disorders, prevalences, previous interventions and current recommendations. Nutr Health 2019;25:127-151.