Sepsis, Septic Shock
Conditions
Keywords
sepsis, septic shock, vitamin C, thiamine, ICU
Brief summary
A great interest exists regarding substances with an immunomodulatory effect for sepsis patients. Recent data have shown that intravenous vitamin C, together with corticosteroids and thiamine, could prevent progressive organ dysfunction and reduce vasopressor use in patients with severe sepsis and septic shock. Its effect on mortality, on the other hand, is yet to be demonstrated. The Vitamins study aims to conclusively determine, through its prospective, multicentre and double-blinded design including 1090 patients, wether Vitamin C, Thiamine and Hydrocortisone in combination can reduce mortality in patients with septic shock.
Detailed description
The global burden of sepsis is substantial with an estimated 15 to 19 million cases per year, most occurring in low-income countries. With recent advances in diagnosis and supportive treatment, the 28-day mortality from sepsis in high-income countries has decreased by about 25%; however, the mortality from septic shock still remains around 45%. A large volume of experimental data has shown that both corticosteroids and intravenous vitamin C attenuate the release of pro-inflammatory mediators, reduce the endothelial lesion characteristic of sepsis (reducing endothelial permeability and improving microcirculatory flow), increase the release of endogenous catecholamines and improve vasopressor reaction. In animal models, these effects resulted in reduced organ damage and increased survival. However, its effect on critically ill humans is controvert. Results of a retrospective study brought that the early use of intravenous vitamin C, together with corticosteroids and thiamine, can prevent progressive organ dysfunction and can reduce mortality in patients with severe sepsis and septic shock. For this reason, the investigators propose a randomized, controlled, multicentre (mcRCT), pragmatic and feasibility study to investigate whether Vitamin C (1.5g 6 / 6h), along with thiamine (200 mg, 12 / 12h) and hydrocortisone (50 mg 6 / 6h) for 7 days can reduce all-cause mortality within 28 days after randomization.
Interventions
DRUGVitamin C
Patients will be allocated in a 1: 1 ratio to the treatment group, receiving intravenous Vitamin C (1.5 g every 6 hours), Thiamine (200 mg every 12 hours) and Hydrocortisone (50 mg every 6 hours) for 7 days
OTHERPlacebo
Patients will receive 2 placebos (every 6 hours and every 12 hours) + Hydrocortisone (50 mg every 6 hours) for 7 days.
Sponsors
PROADI-SUS
Ministry of Health, Brazil
Hospital Sirio-Libanes
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Above 18 years of age * Sepsis of any background * Vasopressor-dependent sepsis for at least 2 hours and vasopressor dose ≥ 0.25 µg / kg / min
Exclusion criteria
* Pregnancy; * Requests for DNR (do not resuscitate) / DNI (do not intubate); * Death is considered imminent or inevitable during this hospitalization and the attending physician, patient or substitute decision maker is not committed to active treatment; * Patients with acute cerebral vascular event, acute coronary syndrome, active gastrointestinal bleeding, burn or trauma at admission; * Patients with known HIV infection; * Patients with known glucose-6 phosphate dehydrogenase (G-6PD) deficiency; * Patients with septic shock transferred from another ICU or hospital with characteristics of septic shock for\> 12 hours; * Patients with septic shock characteristics for\> 12 hours; * Patients with a known history of oxalate nephropathy; * Patients with short bowel syndrome or severe known fat malabsorption; * Patients with acute beriberi disease; * Patients with acute Wernicke's encephalopathy; * Patients with known malaria; * Patients with known or suspected scurvy; * Patients with known or suspected Addison's disease; * Patients with known Cushing's disease; * Physician expects to prescribe or the patient has previously used (less than 15 days) systemic glucocorticoids for an indication other than septic shock (not including nebulized or inhaled corticosteroids), including the use of glucocorticoids for COVID-19; * The patient is receiving treatment for systemic fungal infection or has documented Strongyloides infection at the time of randomization; * Patient with known chronic iron overload due to iron storage and other diseases; * Patient previously enrolled in this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 28-day Mortality | 28 days | Mortality by all causes at 28 days after randomization |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of support | 28 days | Duration of use of vasoactive drugs, mechanical ventilation and renal replacement therapy |
| 90-day Mortality | 90 days | Mortality by all causes at 90 days after randomization |
| Delta SOFA | 72 hours | Change in total Sequential Organ Failure Assessment (SOFA) score, comparing SOFA score at 72 hours and SOFA score at randomisation. Range 0-24. Lower SOFA scores represent better outcome. |
| Quality of life assessment | 6 months | Difference in quality of life assessment using the EQ-5D questionnaire, from EuroQol Group. The questionnaire will be applied during intensive care unit (ICU) stay and after 6 months. Range 0-1, with 0 and 1 corresponding to death and full health, respectively. This will be applied in 30% of research sample. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Treatment-Emergent Adverse Events | 28 days | Descriptive analysis of adverse events related to the study drugs, reported as incidence of the most recurrent events during the study period. |
| Changes in Inflammatory Markers | Up to 96 hours of randomisation | Analysis of procalcitonin and C-reactive protein collected at randomisation, after 48h and 96h after randomisation. This will be applied in 30% of research sample. |
| Duration of hospital stay | Until hospital discharge or up to 90 days of randomisation | Duration of hospital stay |
Countries
Brazil
Outcome results
None listed