Sepsis remains one of the leading causes of childhood mortality and morbidity. However, the current armamentarium of therapies with potential to improve patient outcomes is limited to preventive measures, early detection, timely source control and antimicrobials, prudent fluid replacement, and supportive therapies that optimize oxygenation and perfusion. Hence, the recent emergence of metabolic therapies with the potential to decrease inflammation, alleviate or reverse organ dysfunction, and improve patient-centered outcomes in patients with sepsis and septic shock is exciting. The combination of Hydrocortisone with Ascorbic acid (Vitamin C), and Thiamine (Vitamin B1) (HAT) is a metabolic cocktail (or metabolic resuscitation) that is a potential adjuvant therapy for sepsis (1). Now, in this issue of Pediatric Critical Care Medicine (PCCM), the Journal presents its new format for linked publications in a “mini symposium.” It is my pleasure to introduce and comment on the work of three independent groups of investigators who describe the prevalence of low levels of vitamin C and/or thiamine in children with sepsis admitted to the PICU. First, let us begin with is some background as context for all reports.
The rationale for the HAT regimen is based on theoretical synergism between its components in the pathophysiology of sepsis, low levels of the micronutrients in patients with sepsis, and their favorable safety profile (1). Of note, some species including humans lack L-gulonolactone oxidase, a key enzyme in de novo synthesis of vitamin C. Therefore, we are dependent on dietary sources of vitamin C, which makes us vulnerable in states of deficiency and metabolic stress, including pediatric sepsis.
In 2017, combination HAT therapy received significant attention following a highly publicized single-center report of dramatic improvements in organ injury, time-to-shock reversal, and mortality in adults with sepsis compared with historical controls (2). The results of a subsequent single-center study using a similar propensity-based analysis of before-after cohorts failed to replicate these dramatic results (3). In the enthusiasm for this low-cost and potentially beneficial regimen, more than 11 randomized controlled trials (RCTs) were registered, including a new pediatric trial. These trials are designed to study either a single vitamin or a combination regimen with hydrocortisone. Six RCTs have been published, having enrolled over 1,300 adults with sepsis or septic shock-associated organ dysfunction (4–9).
INTERVENTIONAL RCTs USING VITAMIN C OR HAT
Supplemental Table 1 (https://links.lww.com/PCC/C13) summarizes the results from six RCTs using HAT therapy (4–9) and some other observational studies examining the use of metabolic HAT resuscitation in patients with sepsis-related pathophysiology (2,3,10,11). This table is not meant to be an exhaustive list as there are other studies ongoing, or in planning phase. The table highlights some of the salient features of study design and main results. One of the six RCTs was open-label, and the rest attempted some level of blinding to intervention. Patient populations enrolled in the adult studies included those with sepsis, septic shock, acute respiratory distress syndrome (ARDS), and sepsis-associated cardiac or hemodynamic dysfunction. A trial enrolling patients with severe burn injury and one with patients achieving spontaneous circulation after cardiac arrest are ongoing. The definitions of sepsis, septic shock, and organ dysfunction are well outlined with minor variations. Studies were conducted in the ICU or in the emergency department to facilitate early administration of study drugs. In the majority of these RCTs, study drugs were administered within 12 hours of meeting eligibility criteria. Placebo was used in the control group in five of the six RCTs. Due to favorable profile of hydrocortisone in adult sepsis trials, its use may be standard in some centers, or exposure to a dose may be expected in some patients on enrollment. This approach was the rationale for using hydrocortisone in the control group in the Vitamin C, Hydrocortisone and Thiamine in patients with septic shock (VITAMINS) RCT, and allowing open-label use of hydrocortisone based on clinician decision in the Ascorbic acid and Thiamine Effect in Septic Shock (ATESS), Outcomes of Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in the Early Treatment of Sepsis (ORANGES) trial, and Vitamin C, Thiamine, And Steroids in sepsis (VICTAS) RCTs (5–7,9). The groups were well-balanced for baseline characteristics and comorbidities. Change in Sequential Organ Failure Assessment (SOFA) score at 72 or 96 hours was the most common primary outcome (4,6–8). None of these RCTs reported significant improvement in SOFA scores in the intervention group. Other outcomes included clinical surrogates of resolution from organ failure such as days-free from vasopressor, ventilation, and ICU. Mortality was a secondary outcome in many of these trials. The VICTAS trial was prematurely terminated due to disruption of funding by the sponsor (9). The CITRIS-ALI (effect of vitamin C infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure) RCT enrolled septic patients with ARDS, and there was no difference in organ failure resolution (change in SOFA score at 96 hr), inflammatory profile (C-reactive protein levels), and endothelial function marker (thrombomodulin levels) between the intervention and control groups (4). The significantly lower mortality (secondary outcome) in the intervention group, in the setting of no difference in the mechanistic organ failure metric, was curious. The ORANGES trial reported a significantly faster reversal of shock (time to discontinuation of vasopressors) in the HAT therapy group compared with the placebo group (7). The trial was conducted in two community hospitals with a homogeneous (95% White) study cohort. Based on the lack of major adverse events reported in these RCTs, the use of vitamin C, thiamine, and hydrocortisone could be deemed safe (12). Vitamin C has been associated with gastrointestinal disturbances, hypersensitivity reactions, oxaluria, and kidney stones. The safety profile at higher doses of Vitamin C will need further examination, especially in patients with renal impairment. Overall, the mixed results from these already completed studies do not demonstrate a benefit for patient-centered outcomes. The heterogeneity of patients enrolled, range in interventions studied and outcomes assessed will not allow for a meta-analysis of the combined data, and sample sizes were not large enough to explore the treatment effect in subpopulations of interest. We await more data to help determine the implications of these developments in adult patients on the role of HAT regimens in pediatric sepsis.
VITAMIN C AND THIAMINE IN PEDIATRIC PATIENTS
The three reports of vitamin levels in children in this issue of PCCM help reframe the rationale for their supplementation as a therapeutic strategy in pediatric patients with sepsis. In a three-center study of 476 Turkish patients admitted to the PICU, low levels of thiamine were reported in 11% on day 1 and in 13% of the cohort on day 3 (13). A significant proportion of eligible patients (45%) were excluded from analysis for various reasons, potentially introducing bias. In a single-center study in the United States, plasma vitamin C levels were measured in two patient groups 0–21 years old: a group admitted to the PICU (n = 60) and a group receiving deep sedation for elective outpatient procedures (n = 21) (14). Vitamin C deficiency (level < 11.4 μmol/L) was detected in 18% of the PICU patients in this study, and the vitamin levels were significantly lower compared with a comparator healthy group as well as the procedural sedation group. Children with sepsis, severe acute respiratory syndrome coronavirus 2 infection, and those with multi-inflammatory syndrome in children had the lowest levels of vitamin C. In the third report, another single-center study of Swiss children (n = 61) with blood culture-proven bacterial sepsis, 36% had low vitamin C, and 72% had low thiamine levels (15). These studies highlight the prevalence of low plasma levels of vitamin C and thiamine in critically ill children and those with sepsis.
What are we to do with this new information? First, we do need to consider what can be learnt about total body stores from plasma levels. In all three studies (13–15), the research groups relied on plasma levels as the biomarker of micronutrient status and vitamin deficiency in their respective populations of critically ill patients. This approach has limitations. A variety of factors may decrease vitamin plasma levels, such as redistribution of micronutrients into the tissues, dilution from resuscitation fluids, impact of blood transfusions, and losses from wounds and dialysis. Inflammation is also associated with low circulating micronutrient levels in blood of critically ill patients (16). Thus, the true significance of low micronutrient levels in critically ill patients in the setting of an inflammatory state is unknown (17). Second, the accurate identification of micronutrient deficiency is important and whether replenishing these micronutrients could have potentially beneficial effects in the pediatric septic population is also unknown. Third, rather than plasma level as the definition of micronutrient deficiency, we would prefer to have reliable physiologic tests of functional deficiency. Such tests of functional micronutrient status and/or redox state may allow better patient selection and safe dose-titration in future RCTs of vitamin supplementation. Finally, as demonstrated in the three PCCM studies, there are challenges in collecting samples and measuring vitamin levels in blood and plasma from critically ill children. Clear guidelines for specimen handling, processing, and measurement of levels, and thresholds for low levels that are of concern are currently lacking. Laboratory resources and expertise for measurements may not be widely available. Optimizing the storage time before quantification and precautions to maintain vitamin stability during storage are factors that need consideration.
IS THERE A FUTURE OF HAT THERAPY IN THE PICU?
We now know the prevalence of low vitamin levels in subgroups of the PICU population (13–15). However, there is a major step that is needed between these observations and the idea of replenishing low levels of vitamin C and thiamine in critically ill patients with sepsis. High-quality RCT data on the impact of HAT therapy in pediatric sepsis are not available. The potential role of Vitamin C in pediatric sepsis has been previously reviewed in PCCM (12,18). In a single-center retrospective study of over 500 children with vasopressor-dependent septic shock, the group that received HAT therapy, compared with two propensity-matched groups, examined associations between HAT treatment with hydrocortisone versus not, and with a control group (11). HAT therapy was associated with significantly lower 30- and 90-day mortalities compared with the other two groups. There was no difference in vasoactive-free days between the groups. Careful selection of variables in the propensity matching helped decrease the treatment selection bias, but unmeasured confounders could not be ruled out. Together, these findings support the idea that planning an RCT to examine the impact of HAT therapy on pediatric sepsis outcomes is the next step for our community.
A recent pilot study has led the Australia and New Zealand Intensive Care Society pediatric study group to design an ongoing multicenter three-arm RCT to compare a combination of vitamin C and hydrocortisone versus hydrocortisone alone, versus standard care (10). This study involves children 8 days to 17 years old, with septic shock, and the primary outcome is vasopressor-free survival (personal communication). Future studies of HAT therapy in pediatric sepsis will need to consider a variety of additional design factors. First is definition and stratification by sepsis phenotype, with agreed criteria for septic shock and organ dysfunction. Second is whether we will need to consider using baseline measurements of vitamin C and thiamine levels to help clarify the utility of targeted supplemental therapy in people with low plasma levels of these micronutrients. Third, after clarifying the rationale and the selection of individual vitamin versus combination HAT therapy, the timing of study drug administration will be important, for example, at presentation or in the emergency department rather than the PICU. Last, for HAT therapy RCTs to be tested in pediatric sepsis with adequate power, perhaps collaborative platform Bayesian RCTs are what is really necessary. Taking all of the above together, until these and other data become available, we should follow the recent pediatric Surviving Sepsis Guidelines, which do not recommend the use of vitamin C or thiamine in the treatment of children with septic shock or other sepsis-associated organ dysfunction (19).
HAT therapy is a promising but unproven therapeutic option for pediatric sepsis-associated organ dysfunction. This PCCM Mini Symposium provides us with three articles about prevalence of low vitamin C and thiamine plasma levels in the PICU population (13–15). There are also a number of lessons to be learnt from the HAT therapy intervention studies in critically ill adults. We should therefore prioritize future exploration of metabolic resuscitation in pediatric sepsis. The new reports in the Journal should be a start to this conversation.
1. Moskowitz A, Andersen LW, Huang DT, et al.: Ascorbic acid, corticosteroids, and thiamine in sepsis: A review of the biologic rationale and the present state of clinical evaluation. Crit Care. 2018; 22:283
2. 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
3. Coloretti I, Biagioni E, Venturelli S, et al.: Adjunctive therapy with vitamin c
and thiamine in patients treated with steroids for refractory septic shock: A propensity matched before-after, case-control study. J Crit Care. 2020; 59:37–41
4. Fowler AA 3rd, 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 acute respiratory failure: The CITRIS-ALI randomized clinical trial. JAMA. 2019; 322:1261–1270
5. Fujii T, Luethi N, Young PJ, et al.; VITAMINS Trial Investigators: 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
6. Hwang SY, Ryoo SM, Park JE, et al.; Korean Shock Society (KoSS): Combination therapy of vitamin C
and thiamine for septic shock: A multi-centre, double-blinded randomized, controlled study. Intensive Care Med. 2020; 46:2015–2025
7. 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
8. Moskowitz A, Huang DT, Hou PC, et al.; ACTS Clinical Trial Investigators: Effect of ascorbic acid, corticosteroids, and thiamine on organ injury in septic shock: The ACTS randomized clinical trial. JAMA. 2020; 324:642–650
9. Sevransky JE, Rothman RE, Hager DN, et al.; VICTAS Investigators: Effect of vitamin C
, thiamine, and hydrocortisone on ventilator- and vasopressor-free days in patients with sepsis: The VICTAS randomized clinical trial. JAMA. 2021; 325:742–750
10. Schlapbach LJ, Gibbons K, Ridolfi R, et al.; RESPOND PICU study investigators and the Australian New Zealand Intensive Care Society Paediatric Study Group (ANZICS PSG): Resuscitation in paediatric sepsis using metabolic resuscitation-a randomized controlled pilot study in the paediatric intensive care unit (RESPOND PICU): Study protocol and analysis plan. Front Pediatr. 2021; 9:663435
11. 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
12. Yanase F, Raman S, Naorungroj T, et al.: Efficacy and safety of parenteral high-dose Vitamin C
therapy in pediatric patients: A scoping review. Pediatr Crit Care Med. 2021; 22:561–571
13. Akkuzu E, Yavuz S, Ozcan S : Prevalence and Time Course of Thiamine Deficiency in Critically Ill Children: A Multicenter, Prospective Cohort Study in Turkey. Pediatr Crit Care Med. 2022; 23:399–404
14. Fathi A, Downey C, Rabiee Gohar A: Vitamin C
Deficiency in Critically Ill Children: Prospective Observational Cohort Study. Pediatr Crit Care Med. 2022; 23:395–398
15. Equey L, Agyeman PKA, Veraguth R, et al.; for the Swiss Pediatric Sepsis Study Group: Serum Ascorbic Acid and Thiamine Concentrations in Sepsis: Secondary Analysis of the Swiss Pediatric Sepsis Study. Pediatr Crit Care Med. 2022; 23:390–394
16. Shenkin A: Micronutrients in health and disease. Postgrad Med J. 2006; 82:559–567
17. Mehta NM: Micronutrients in critical illness: Essential and enigmatic. Pediatr Crit Care Med. 2018; 19:907–908
18. Sanchez-Pinto LN, Wald EL: Vitamin C
, Quo Vadis? Pediatr Crit Care Med. 2021; 22:588–590
19. Weiss SL, Peters MJ, Alhazzani W, et al.: Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children. Pediatr Crit Care Med. 2020; 21:e52–e106