Supplemental Digital Content 1 DIAGNOSIS PICO QUESTIONS CIRCI - Diagnosis Questions Population Diagnostic test Comparator (reference exposure) Outcomes Keywords MESH Headings Q1 Is total cortisol response to ACTH superior to random plasma total cortisol for the diagnosis of CIRCI? Adults and children (not neonates) and critical illness Plasma Peak cortisol level post ACTH Plasma Delta cortisol Plasma Basal cortisol level Primary outcome: Clinical cure as defined by primary author of studies OR Resolved CIRCI symptoms Mortality Secondary outcomes: Tissue hypoperfusion (measures with lactate or scoring systems) Multiorgan system failure Assessment Length of stay ICU, intensive care, adults, children, pediatrics, critical illness, cortisol level, plasma cortisol, ACTH, corticotrophin, adrenocorticotrophic, adrenal hormones, delta cortisol, basal cortisol, cosyntropin, CIRCI, critical illness-related corticosteroid insufficiency Critical Care, Adrenocorticotropic Hormone, Adrenal Insufficiency, Pediatrics, Adult Q2 Is plasma free cortisol level superior to plasma total cortisol level for the diagnosis of CIRCI? Adults and children (not neonates) and critical illness Plasma unstimulated free cortisol level Plasma peak free cortisol level Plasma delta free cortisol Plasma unstimulated, peak and delta total cortisol level Primary outcome: Clinical cure as defined by primary author of studies OR Resolved CIRCI symptoms Mortality Secondary outcomes: Tissue Free cortisol, peak cortisol, delta free cortisol
hypoperfusion (measures with lactate level or scoring systems) Multiorgan system failure Assessment Length of stay Q3 Is salivary free cortisol level superior to plasma total cortisol level for the diagnosis of CIRCI? Adults and children (not neonates) and critical illness Salivary free cortisol Plasma unstimulated, peak and delta total cortisol level Primary outcome: Clinical cure as defined by primary author of studies OR Resolved CIRCI symptoms Mortality Secondary outcomes: Tissue hypoperfusion (measures with lactate level or scoring systems) Multiorgan system failure Assessment Length of stay Salivary free cortisol Q4 Is 1 µg ACTH test superior to 250µg ACTH test for the diagnosis of CIRCI? Adults and children (not neonates) and critical illness Plasma peak and delta cortisol post 1 µg ACTH Plasma peak and delta cortisol post 250 µg ACTH Primary outcome: Clinical cure as defined by primary author of studies OR Resolved CIRCI symptoms Mortality Secondary outcomes: Tissue hypoperfusion (measures with ACTH Stimulation test, ACTH Stim test, cosyntropin stimulation test, corticotrophin test; tetracosactide test, Synacthen test Standard stimulation test; low dose stimulation test
lactate level or scoring systems) Multiorgan system failure Assessment Length of stay Q5 Is hemodynamic response to hydrocortisone (50 to 300 mg) superior to 250µg ACTH test for the diagnosis of CIRCI? Adults and children (not neonates) and critical illness Reduction in vasopressor therapy requirement (or equivalent measure) Plasma peak and delta cortisol post 250 µg ACTH Primary outcome: Clinical cure as defined by primary author of studies OR Resolved CIRCI symptoms Mortality Secondary outcomes: Tissue hypoperfusion (measures with lactate level or scoring systems) Multiorgan system failure Assessment Length of stay Solucortef, vasopressors, pressors, inotropes, vasoactive medications Hydrocortisone, vasoconstrictor agents Q6 Is corticotropin level superior to 250µg ACTH test for the diagnosis of CIRCI? Adults and children (not neonates) and critical illness Plasma level corticotropin Plasma peak and delta cortisol post 250 µg ACTH Primary outcome: Clinical cure as defined by primary author of studies OR Resolved CIRCI symptoms Mortality
TREATMENT PICO QUESTIONS Questions Population Intervention (experimental exposure) Comparator (reference exposure) Outcomes Keywords MESH terms Q1 Should patients with CIRCI be treated with Adults and children (not neonates) and critical illness with CIRCI sepsis ‘heterogeneous’ sepsis CAP/HCAP CAP Community acquired pneumonia Meningitis Septic shock ARDS Trauma Multiple trauma Head trauma Intravenous or oral corticosteroids (not topical) No treatment or placebo Primary outcome 1. Resolution (or improvement) of manifestations of CIRCI [shock; respiratory failure; MODS; etc.] OR clinical cure as defined by primary author of studies 2. Mortality: hospital or 28 or 90 days] Secondary outcomes: Effective response [cytokines, CRP, etc.] Duration of: treatment, ICU stay, hospital stay Medium-long-term outcome: -Mortality, QoL, functional capacity, PTSS, etc. ICU, intensive care, adults, children, pediatrics, critical illness, CIRCI, critical corticosteroid insufficiency, sepsis, infection, septic shock, SIRS, systemic inflammatory response syndrome, CAP, HCAP, pneumonia, meningitis, ARDS, ALI, acute lung injury, trauma, cardiac arrest, shock, hypotension, cardiogenic shock, steroids, corticosteroids, dexamethasone, hydrocortisone, solucortef, solumedrol, prednisone, prednisolone, betamethasone, Critical Care, Hormone, Adrenal Insufficiency, Pediatrics, Adult, sepsis, systemic inflammatory response syndrome, respiratory distress syndrome (adult), wounds and injuries, shock, hydrocortisone
Others: Tissue hypoperfusion (measures with lactate level or scoring systems) Harms: Any treatments harms fludrocortisone, cortivasol, fluorinef, mineralocorticoid, glucocorticoid adrenal hormones Q2 Are synthetic superior to for the treatment of CIRCI? Adults and children (not neonates) and critical illness with CIRCI (as defined by original studies’ authors) sepsis ‘heterogeneous’ Septic ARDS Trauma Multiple trauma Head trauma Prednisone Prednisolone Betamethasone Dexamethasone Fludrocortisone Hydrocortisone + fludrocortisone Cortivasol Primary outcome 1. Resolution (or improvement) of acute manifestations of CIRCI [shock; respiratory failure; MODS; etc.] OR clinical cure as defined by primary author of studies 2. Mortality hospital or 28 or 90 days] Secondary outcomes: Effective response [cytokines, CRP, etc.] Duration of: treatment, ICU stay, hospital stay Medium-long-term outcome: -Mortality, QoL, functional capacity, PTSS, etc.
Others: Tissue hypoperfusion (measures with lactate level or scoring systems) Harms: Any treatments harms Q3 Is response to treatment dependent on: (a) time, (b) dose, (c) duration, (d) tapering. Q3b. Does secondary prevention improve overall response to treatment? Adults and children (not neonates) and critical illness with CIRCI (as defined by original studies’ authors) Septic shock ARDS Trauma Multiple trauma Head trauma Timing: early (< 24h) Daily dose: ≤ 300 mg HC (equivalent) Duration: versus long ( ≥ 72 ≥7 days; ≥ 14 days; ≥ 21 days) Tapering: fast (≤ 4 days) OR slow (>4 days) Implementation of secondary prevention late (< 72h, < 7 days, < 14 days) >300 HC (equivalent) short (<72 hours) No tapering No of secondary prevention Primary outcome 1. Resolution (or improvement) of acute manifestations of CIRCI [shock; respiratory failure; MODS; etc.] OR clinical cure as defined by primary author of studies 2. Mortality hospital or 28 or 90 days] Secondary outcomes: Effective response [cytokines, CRP, etc.] Duration of: treatment, ICU stay, hospital stay Medium-long-term outcome: