Sepsis, Septic Shock
Conditions
Keywords
Septic shock, Sepsis, Vitamin C, Thiamine
Brief summary
The aim of this study is to evaluate the efficacy of early metabolic resuscitation with combination therapy using vitamin C and thiamine in improving organ function and survival in patients with septic shock.
Detailed description
Sepsis is a complex disease involving life-threatening organ dysfunction caused by a dysregulated host response to infection and is still associated with unacceptably high mortality. Sepsis management should be undertaken as a medical emergency and focused on timely intervention, including early identification and treatment of infection through appropriate antimicrobial therapy and source control when applicable as well as reversing hemodynamic instability through fluid resuscitation and vasopressor use if necessary. Despite these supportive therapies, morbidity and mortality have remained high, suggesting the need for adjuvant therapies for inflammatory and oxidative stress in patients with sepsis; however, no agents have been proven to definitely improve survival. Vitamin C plays a role in mediating inflammation through antioxidant activities and is also important as a cofactor/co-substrate for the synthesis of endogenous adrenaline, cortisol, and vasopressin. Recently, several clinical trials have reported the positive effects of vitamin C on outcomes in sepsis or septic shock. During sepsis, vitamin C prevents neutrophil-induced lipid oxidation and protects against the loss of the endothelial barrier. Early intravenous supplementation is therefore needed to limit loss of microcirculation and oxidation of lipids. Thiamine is also a key cofactor for glucose metabolism, the generation of ATP (adenosine triphosphate), and the production of NADPH. Considering acute consumption in the hypermetabolic state, thiamine supplementation might be a reasonable therapeutic adjunct for patients with sepsis and was added to reduce the risk of renal oxalate crystallization. These findings led to a recent before-and-after study showing that treatment of sepsis with a combination of vitamin C, hydrocortisone, and thiamine prevented organ dysfunction and reduced the mortality rate. The aim of this study is to evaluate the efficacy of early metabolic resuscitation with combination therapy using vitamin C and thiamine in improving organ function and survival in patients with septic shock.
Interventions
DRUGCombination therapy of vitamin C and thiamine
Vitamin C (50 mg/kg up to 3 g, every 12 hours) and thiamine (200 mg every 12 hours) intravenously administered mixed in 50 mL solution bags of normal saline for 2 days
DRUGNormal saline solution
Normal saline solution in a volume to match the treatment components administered mixed in 50 mL solution bags of normal saline for 2 days
Sponsors
National Research Foundation of Korea
Tae Gun Shin
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Multi-center, Double-blinded, Randomized, Controlled Study
Eligibility
Sex/Gender
ALL
Age
19 Years to 89 Years
Healthy volunteers
No
Inclusion criteria
1. Adult patients (\> 18 years) 2. Septic shock: sepsis with persisting hypotension requiring vasopressors to maintain a mean arterial pressure ≥65 mm Hg and a serum lactate level \>2 mmol/L despite adequate volume resuscitation. Sepsis is defined as clinically suspected or confirmed infection with acute organ failure identified as an acute change in total SOFA score with 2 points or more.
Exclusion criteria
1. Transferred patients from other hospitals after application of vasopressors or mechanical ventilation 2. Patients who signed a Do not attempt resuscitation order or who had set limitations on invasive care 3. Patients who have a terminal, unresponsive illness and survival discharge is not expected (metastatic terminal cancer, etc.) 4. Patients who experienced cardiac arrest before enrollment or when death is anticipated within 24 hours despite maximal treatment 5. Patients who take more than 1g of Vitamin C per day before enrollment or who take supplemental thiamine 6. Pregnant woman 7. Known Glucose-6-phosphate dehydrogenase deficiency 8. Patients with a history of hypersensitivity to vitamin C or thiamine 9. Known Mediterranean anemia 10. Known hyperoxaluria 11. Known cystinuria 12. Acute gout attack 13. Known oxalate renal stone 14. Patients who meet the inclusion criteria 24 hours after emergency department arrival or when enrollment is delayed more than 24 hours after diagnosis of septic shock 15. Inability or refusal of a subject or legal surrogate to give informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Delta Sequential Organ Failure Assessment (SOFA) score | Enrollment to 72 hours | 72-hour change in SOFA score, which reflected recovery from organ failure (delta SOFA = SOFA at enrollment - SOFA after 72 hours) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 7-day mortality (early death) | Day 7 | The number of participants who did not survive until Day 7 will be compared between the treatment and the control group |
| Time to Shock reversal | Enrollment to Day 14 | Days from enrollment to shock reversal until Day 14. Shock reversal is defined as discontinuation of all vasopressors and mean arterial pressure is maintained at 60 mmHg or more for more than 24 hours. |
| Vasopressor free days | Enrollment to Day 14 | Days not receiving any vasopressor |
| Ventilator free days | Enrollment to Day 14 | Days not receiving mechanical ventilation |
| Ventilator duration | Up to 12 weeks | Days receiving mechanical ventilation during hospital stay |
| Renal replacement therapy (RRT) free days | Enrollment to Day 14 | Days not receiving Renal replacement therapy |
| New use of renal replacement therapy (RRT) | Up to 12 weeks | The number of participants who receive RRT during hospital stay will be compared between the treatment and the control group |
| New onset or aggravation of acute kidney injury (AKI) | Enrollment to Day 14 | The number of participants who suffer from new onset or aggravation of AKI will be compared between the treatment and the control group |
| Length of ICU stay | Up to 12 weeks | Number of days in the ICU during hospital admission |
| ICU free day | Enrollment to Day 14 | Days not being in the ICU |
| Length of hospital stay | Up to 12 weeks | Number of days in the hospital during hospital admission |
| 28-day mortality | Day 28 | The number of participants who did not survive until Day 28 will be compared between the treatment and the control group |
| 90-day mortality | Day 90 | The number of participants who did not survive until Day 90 will be compared between the treatment and the control group |
| Time to death | Enrollment to Day 28 | Days until death |
| In-hospital death | Up to 12 weeks | The number of participants who did not survive at hospital discharge will be compared between the treatment and the control group |
| Intensive care unit death (ICU) death | Up to 12 weeks | The number of participants who did not survive at ICU discharge from the first index ICU admission will be compared between the treatment and the control group |
Other
| Measure | Time frame | Description |
|---|---|---|
| Dose of vasopressor at 24-hour | Enrollment to 24 hours | Norepinephrine equivalent dose at 24 hours from enrollment |
| Dose of vasopressor at 48-hour | Enrollment to 48 hours | Norepinephrine equivalent dose at 48 hours from enrollment |
| Dose of vasopressor at 72-hour | Enrollment to 72 hours | Norepinephrine equivalent dose at 72 hours from enrollment |
| Maximum dose of vasopressor during initial 72 hours | Enrollment to 72 hours | Maximum norepinephrine equivalent dose during initial 72 hours |
| Procalcitonin change during initial 72 hours | Enrollment to 72 hours | 72-hour change in procalcitonin (%) |
| CRP (C-reactive protein) change during initial 72 hours | Enrollment to 72 hours | 72-hour change in CRP (%) |
Countries
South Korea
Outcome results
None listed