| Optimal dosing and duration of ascorbic acid therapy |
Single dose versus continuous versus intermittent treatment |
| Optimal dosing of high-dose ascorbic therapy |
| Duration |
| Timing of administration (upon diagnosis of shock, upon initiation of inotropes, when inotrope-refractory shock is diagnosed etc.) |
| Optimal dosing and duration of thiamine therapy |
Dose |
| Duration |
| Timing of administration |
| Single therapy with thiamine versus combined therapy/HAT |
| Identification of phenotypes more likely to benefit from HAT |
Severity scores |
| Serum and host transcriptomic biomarkers of oxidative stress, endothelial dysfunction, and organ dysfunction to identify subgroups |
| Ascorbic acid serum levels to guide therapy |
| Mitochondrial assays to guide thiamine therapy |
| Host immune monitoring to guide hydrocortisone therapy |
| Safety |
Safety of mega-dose and high-dose ascorbic acid |
| Safety of high-dose thiamine |
| Safety of HAT compared to standard care |
| Efficacy |
Impact of HAT therapy, or of its components, on |
| Organ dysfunction |
| Need for organ support |
| Duration of PICU stay |
| Survival |
| Survival free of organ dysfunction |
| Survival free of organ support |
| Survival free of PICU |
| Interventional trials investigating the effect of HAT and HAT components (blinded or open label) |
HAT versus standard care |
| HAT versus hydrocortisone alone versus standard care |
| Ascorbic acid alone versus standard care |
| Thiamine alone versus standard care |
| Generalisability and considerations prior to implementation |
Cost effectiveness |
| Impact of HAT or HAT components on long-term outcomes such as quality of life or functional status |
