Study Title: Metabolic Resuscitation in Pediatric Septic Shock Using HAT (Hydrocortisone, Ascorbic acid and Thiamine) Therapy an Open-Label Randomized Controlled Trial Introduction: Sepsis, more recently defined as infection with associated organ dysfunction (3), thus accounts for most childhood deaths due to infection (4). Shock is an acute, complex state of circulatory or metabolic dysfunction that results in failure to deliver or use sufficient amounts of oxygen and/or other nutrients to meet tissue metabolic demands. Of patients who do not survive, most do not die in the acute hypotensive phase of shock, but rather as a result of associated complications and multiple-organ dysfunction syndrome (MODS) Recently, the combination of intravenous hydrocortisone with high dose ascorbic acid and thiamine (HAT therapy), postulated to reduce sepsis-related organ dysfunction, has been proposed as a safe approach with potential for survival benefit. A retrospective study conducted by Marik et al (11) found that the combination of hydrocortisone, ascorbic acid, and thiamine (HAT) effectively reduced mortality and prevented end organ dysfunction for sepsis and septic shock patients. However, randomized trials in pediatric patients are lacking. Given the morbidity, mortality, and financial burden associated with sepsis, newer effective, and affordable treatments are required. We hypothesize that protocolized early use of HAT therapy (“metabolic resuscitationâ€) in children with septic shock-associated organ dysfunction will result in early resolution of shock with increased survival. Knowledge gaps and priorities for research with respect to Hydrocortisone Ascorbic acid and Thiamine management of septic shock. · It is not proven whether the use of Hydrocortisone, Ascorbic acid and thiamine in septic shock management is associated with lower morbidity and morbidity. · Lack of sufficient Pediatric studies, only 1 published study (N 50), others yet to publish. Equivocal results in adults’ studies The combination of vitamin C, hydrocortisone, and vitamin B1 is hypothesized to improve outcomes in sepsis through a number of mechanisms. Vitamin C is an important contributor to endothelial integrity and severe deficiency states (eg. scurvy) can result in endothelial breakdown with resultant vascular leak and edema. In addition, vitamin C is a potent anti-oxidant and is integral to endogenous vasopressor synthesis. Hydrocortisone, a potential adjunctive therapy in septic shock may act synergistically with vitamin C. Vitamin B1, a key cofactor of pyruvate dehydrogenase, is a critical component of metabolic dysfunction without which a shift towards anaerobic energy production occurs. Vitamin B1 is also a necessary component of the pentose phosphate pathway, which reduces oxidative stress. While the physiologic effects of these drugs given in combination is not entirely known, we hypothesize that there will be synergistic effects with respect to the metabolic resuscitation of sepsis (16). Newer therapeutic approaches are needed to treat sepsis urgently. The combination of thiamine (vitamin B1), ascorbic acid (vitamin C), and corticosteroids (hydrocortisone) is a promising new therapeutic option for sepsis resuscitation but currently lacks evidence to support its widespread use in the paediatric population. This prospective interventional study aimed to identify the safety and efficacy of the Hydrocortisone, Vitamin C and Thiamine as an add on treatment on biochemical and clinical outcomes in Septic Shock patients receiving standard care in a randomized open label two arm parallel group approach Primary Objectives: To study the effectiveness of Hydrocortisone, Ascorbic acid and thiamine (HAT) therapy in patients with septic shock between age group of 2 month to 18 years admitted to PICUin attaining increased organ failure free days in the first 4 weeks of study (28 days). Secondary objectives To study the effect of Hydrocortisone, Ascorbic acid and thiamine (HAT) therapy in patients with septic shock between age group of 2 month to 18 years admitted to PICU on · Vasopressor free days at 28 days · Change in pSOFA score (Delta pSOFA) from time of randomisation to 72 hours and 7 days. · Hospital length of stay · Survival free of PICU censored at 28 days · Organ failure free days of AKI censored at 28 days Sample size: Based on preliminary data(1), we conservatively anticipate an increase in organ failure-free days from 22 (preliminary data) to 26 days. With these estimates, an alpha of 0.05 and power of 80% power the sample size is calculated as 60 (30 in each arm). Organ dysfunction is defined as pediatric Sequential Organ Failure Assessment (pSOFA) score >0, and will be assessed daily until day 28 while patients are admitted to PICU. Outcome measure The primary outcome is the total number of organ failure free days in the first 28 days following the day of randomization. Organ failure free days OFFD= 28 - Day of ICU stay after randomization when pSOFA score reaches Zero and remains zero till 28 days . OFFD 28= 0 if patient dies within 28 days of developing organ failure OFFD 28=0 if patient has organ failure more > 28 days OFFD 28=(28-x) where x is the number of organ failure days where pSOFA score is >0 If a patient has a score of 0 from D 14- 21 and then has a score of 1 from day 25- 28, his organ failure free days will be calculated as total number of days he had a score of 0 in pSOFA score, if the etiology is septic shock and not due to any co morbidity or any other explanation exists to prove other than septic shock. If the organ failure is clearly due to any other comorbidity, then the total organ failure free days due to septic shock will be calculated. pSOFA score will be calculated every 24 hours till it becomes Zero and will be followed till 28 days. Organ dysfunction defined as pediatric Sequential Organ Failure Assessment (pSOFA) score >0. Total pSOFA = Pediatric Sequential Organ Failure Assessment = sum of each organ system point score. The score is based on six different scores, one each for the respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems. The organ scores are ranging from 0-4, with the best score being 0 and the worst being 4 points. The maximal (and worst) total SOFA score is 24 points. Material and Methods Setting: Pediatric Intensive Care, HDU, AIIMS New Delhi Design: Open label, Randomised control trial Duration: 20 months (September 2023 to April 2025) Eligible patients: Children aged between1 month and <18 years who are admitted to PICUs requiring inotrope therapy for at least 2 hours and presumed septic shock(after applying exclusion criteria as mentioned below). The trial compares metabolic resuscitation, defined as hydrocortisone, ascorbic acid, and thiamine, with placebo. Standard care defined as septic shock management according to institutional protocols will be continued for both groups. Metabolic Resuscitation After initial shock treatment including fluids and intravenous inotrope(s), patients then receive additional treatment with hydrocortisone, ascorbic acid, and thiamine: Ascorbic Acid (Vitamin C) The dosing schedule is 30 mg/kg/dose (maximum 1,500 mg per dose) intravenously every 6 h for the duration of study treatment and will be infused over 30–60 min till 72 hours after first dose diluted with 5 ml/kg of D5. Thiamine (Vitamin B1) The dosing schedule is 4 mg/kg/dose (maximum 200 mg per dose) intravenously every 12 h for the duration of study treatment and will be given by slow IV push over 5 min, no dilution is required till 72 hours after the first dose. Hydrocortisone The dosing schedule is 1 mg/kg/dose (maximum 50 mg per dose) intravenously every 6 h for the duration of study treatment given as a slow bolus till 72 hours after first dose 1mg/1ml dilution with D5. Patients in the control arm will receive an equal volume of 5% dextrose. Inclusion criteria: Inclusion Age • Aged _28 days and <18 years Illness -Admitted to PICU treated for septic shock (fluid refractory shock) Treatment Received inotropes for at least 2 h Consent Parental/caregiver consent prior to or after enrolment (Definitions of surviving sepsis campaign 2020 will be followed for diagnosis of septic shock(25)) Exclusion criteria: 1. Age Preterm babies born <34 weeks’ gestation that have a corrected age of <28 days 2. Treatment - Received inotropes for >24 h pre-enrolment 3. Patient is receiving treatment for systemic fungal infection or has documented strongyloides infection at the time of randomization 4. Patient undergoing active chemotherapy for cancer treatment 5. Co-morbidities •Fulminant Myocarditis, Congenital heart disease 6. Chronic hypertension due to cardiovascular or renal disease, requiring regular antihypertensive treatment. 7. Known chronic kidney disease (defined as requiring Renal Replacement Therapy) 8. Known chronic hepatic failure 9. Known diseases affecting the steroid axis, including pituitary disease, congenital adrenal hypoplasia, Cushing or Addison’s a. disease 10. Known glucose-6 phosphate dehydrogenase (G-6PD) deficiency 11. Patients with known history of oxalate nephropathy 12. Patients with acute beri-beri disease 13. Patients with acute Wernike’s encephalopathy 14. Patients with known malaria 15. Patients with known of suspected scurvy 16. Palliative care patient/patient with limitation of treatment (not for inotropes, cardiopulmonary resuscitation, extracorporeal membrane oxygenation, intubation or ventilation) 17. Cardiopulmonary arrest in the past 2 h requiring cardiopulmonary resuscitation of >2min duration, or death is deemed to be imminent or inevitable during this admission. 18. Major bleeding with hemorrhagic shock 19. Sepsis is not likely to be the cause of shock Therapeutic end points Normal heart rate for age Appropriate for age mean arterial pressure measured non-invasively Capillary refill time < 2 seconds Normal mental status Urine output >_ 1 ml/kg/hr Data Management and statistical analysis For Primary outcome- For Primary outcome- Mean and median days of oragn failure days will be calculated for control and test arm and will be compared using Mann Whitney test (assuming data is non normally distributed) and student T test is formally distributed. For Secondary outcomes- For normally distributed data, the means (S.D) will be compared using Student’s t Test or Mann Whitney U test for non-normal data. Intention to treat analysis will be done Standard Care Patients in the standard treatment arm can receive hydrocortisone only if clinically indicated at the discretion of the attending ICU staff specialist. Patients in both arm will be treated as per surviving sepsis campaign 2020 guidelines as per standard protocol.
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