Metabolic resuscitation in pediatric sepsis: a narrative review

Sepsis, defined as infection with associated organ dysfunction, accounts for most childhood deaths due to infection globally. Evidence for the optimal support of children with septic shock refractory to the initial sepsis management bundle remains minimal. There is an urgent need for more effective interventions. Administration of hydrocortisone in children with septic shock might fasten shock resolution, and has been shown to dampen the systemic host immune response, augment adrenergic effects, and support the stress response. Ascorbic acid (vitamin C) is one of the most powerful naturally occurring antioxidants and has beneficial effects on multiple pathways which are severely deranged during septic shock. A regimen combining hydrocortisone, ascorbic acid, and thiamine termed "metabolic resuscitation" or "HAT therapy" has been tested in large trials in critically ill adults with sepsis with conflicting results. Available information on intravenous ascorbic acid indicates an excellent safety profile even at very high doses both in adults and children. Given the pharmacological properties and beneficial effects shown both in vitro and in animal studies, and its safety profile, ascorbic acid either as a single therapy or as part of HAT treatment represents a promising candidate for future pediatric sepsis treatments. While pediatric age groups may be more susceptible to ascorbic acid deficiency during sepsis, there is a lack of high-quality trial data on HAT therapy in this age group. A single centre retrospective study identified potential for mortality benefit in children with septic shock, and the results from a randomized controlled pilot trial are being awaited. It is imperative for pediatric research on ascorbic acid and HAT in children with sepsis to critically investigate key questions related to pharmacology, dosing, timing, feasibility, safety, effects on short- and long-term outcomes, and generalisability in view of the global burden of sepsis.