Assessing the Efficacy of Treatment with Vitamin C and Hydrocortisone in Children Admitted to Intensive Care Unit with Septic Shock.

INTERVENTION: Patients will be allocated in a 1:1:1 ratio to the RESPOND treatment groups. Arm 1 ‐ Intervention 1 ‐ Early Metabolic Resuscitation: After initial shock treatment including fluids and a first intravenous inotrope, patients then receive concomitant treatment with Hydrocortisone, Vitamin C, and Thiamine. Ascorbic acid (Vitamin C): the dosing schedule is 100 mg/kg (maximum 5,000 mg per dose) intravenously every 6 hours for the duration of study treatment and will be infused over 30‐60 minutes. Thiamine (Vitamin B1): the dosing schedule is 4 mg/kg (maximum 200 mg per dose) intravenously every 12 hours for the duration of study treatment and will be infused over 30‐60 minutes. Hydrocortisone: The dosing schedule is 1 mg/kg (maximum 50 mg per dose) intravenously infused over 5 minutes every 6 hours for the duration of study treatment given as a slow bolus. Arm 2 ‐ Intervention 2 ‐ Hydrocortisone only. Hydrocortisone: the dosing schedule is 1mg/kg (maximum 50 mg per dose) intravenously infused over 5 minutes every 6 hours for the duration of study treatment given as a slow bolus. All three arms will be monitored for adherence to interventions by a formal data monitoring and audit of the medication records. Duration of treatment After shock resolution ‐ defined as cessation of inotropes for at least 4 hours ‐ or after a maximum of 72hours study drugs should be ceased. The treatment will continue until (whichever occurs first): ‐ Septic shock resolves defined as ability to cease inotropes for less than 4 hours with good perfusion and no signs of shock. ‐ 72 hours of treatment has been administered ‐ The patient is discharged from ICU ‐ Contraindications to Vitamin C, Thiamine or Hydrocortisone therapy arise ‐ CONDITION: Infection ‐ Other infectious diseases Sepsis;Septic Shock; ; Sepsis ; Septic Shock PRIMARY OUTCOME: PICU‐free survival[Censored at 28 days.; Patients dying within 28 days of admission to PICU will be censored as zero days to correct for the competing effect of mortality on PICU length of stay. ; Linked data from the Australia New Zealand Paediatric Intensive Care Registry will be employed to assess this outcome.] SECONDARY OUTCOME: Direct hospitalization‐related costs[At hospital discharge. Assessed by an audit of hospital financial records.] Functional status post enrolment assessed using Functional Status Score and pediatric overall performance score (POPC).[Assessment will be prospectively performed at randomization, at 28 days post randomization and at 6 months from date of index admission to PICU] Hospital length of stay [Until discharge from hospital. ; Assessed using data‐linkage to integrated medical records.] Mortality[Censored at 28 days. ; Linked data from the Australia New Zealand Paediatric Intensive Care Registry will be employed to assess this outcome.] Quality of life post enrolment assessed using PedsQL and EQ‐5D‐Y.[Assessment will be prospectively performed at randomization, at 28 days post randomization and at 6 months from date of index admission to PICU ; ] Safety outcomes: ; Proportion with major adverse events defined as death, amputations, hyperglycemia, hospital‐acquired microbiologically confirmed infection, oxalate nephropathy, hypernatremia, glucometer error, and hemolysis. ; Assessed by data‐linkage to medical records and formal data monitoring.[Censored at 28 days.] Survival free of cardiovascular support (defined as free inotropes and ECMO)[Censored at 28 days. ; Patients still requiring cardiovascular support at 28 days after admission to PICU will be censored as zero days. ; Linked data from the Australia New Zealand Paediatric Intensive Care Registry will be employed to assess this outcome.[Censored at 28 days. ; Patients still requiring ventilatory support at 28 days after admission to PICU will be censored as zero days. ; Linked data from the Australia New Zealand Paediatric Intensive Care Registry will be employed to assess this outcome.] Survival free of organ support (defined as free of ventilation, inotropes, Extracorporeal Membrane Oxygenation, and Renal Replacement Therapy). ; Patients still requiring organ support at 28 days after admission to PICU will be censored as zero days.] Survival free of ventilation (defined as free of invasive ventilation)[Censored at 28 days. ; Linked data from the Australia New Zealand Paediatric Intensive Care Registry will be employed to assess this outcome.] INCLUSION CRITERIA: Criterion 1: Child aged >=7 days and <18 years and admitted to PICU. Criterion 2: Decision by treating physician to treat as sepsis (including parenteral antibiotics and inotropes) Criterion 3: Treatment of septic shock with vasopressor/inotrope therapy for >1 hour, or at a Vasopressor‐Inotrope‐Score of at least 10. Inotrope requirement will be calculated by means of the Vasoactive‐Inotrope Score (VIS)63: VIS = dopamine dose (micgrogram/kg/min) + dobutamine dose (microgram/kg/min) + 100 x adrenaline dose (microgram/kg/min) + 100 x noradrenaline dose (microgram/kg/min) + 10 x milrinone dose (microgram/kg/min) + 10,000 x argipressin(vasopressin) dose (unit/kg/min). Note: vasopressin doses are often recorded as mU/kg/hour, which needs conversion to U/kg/min for the VIS score.