Hydrocortisone, Vitamin C, and Thiamine in Severe Sepsis and Septic Shock
What is the impact of treating adult patients in severe sepsis or septic shock with a cocktail of intravenous vitamin C, thiamine, and hydrocortisone?
In this pilot trial that matched patients receiving an intervention to historical controls, the combination of high dose Vitamin C, mid-dose hydrocortisone, and thiamine was associated with positive outcomes for sepsis/shock. The quality of evidence from this trial is overall low and multicenter RCTs are needed to confirm these findings before the protocol is incorporated into routine practice.
Sepsis is life threatening organ dysfunction caused by a dysregulated host response to infection leading to an imbalance in oxygen demand and supply, and is a leading cause of infectious death. Sepsis was originally defined in 1992 via a consensus based definition from SCCM and ACCP, defined as a systemic inflammatory response (SIRS) with a suspected source of infection. These patients were then stratified into one of three categories: sepsis, severe sepsis (with lactic acidosis or hypotension), or septic shock (severe sepsis with persistent hypotension despite fluid resuscitation). In 2016, these definitions were modified with the Sepsis-3 update, the SIRS criteria were eliminated and the SOFA and q-SOFA criteria have now been adopted. 
Multiple RCTs have investigated the potential role for steroid therapy in patients with septic shock. The Annane Trial in 2002 demonstrated a short-term mortality benefit with IV hydrocortisone and fludrocortisone among patients with evidence of adrenal insufficiency on ACTH stimulation testing. CORTICUS in 2008 investigated hydrocortisone in patients with and without adrenal insufficiency and found no benefit in either subgroup with suggestion of increased infection rates in patients receiving hydrocortisone. Most recently HYPRESS, published 2016, demonstrated little benefit in advancing septic shock but no excess infections in the treatment group. This trial was conducted between CORTICUS and HYPRESS.
Vitamin C is an antioxidant that is vital to immune function. Its role in sepsis, and if it may synergistically reduce inflammation along with hydrocortisone, is unknown. Published in 2017 in Chest, Marik and colleagues sought to understand the potential role of Vitamin C, hydrocortisone, and thiamine in severe sepsis and septic shock. This small, single-center trial administered these agents to 47 patients and compared them to historical controls. The treatment group as compared to the historical controls showed an absolute decrease of hospital mortality of 32% (P<0.001) as well as statistically significant decreases in duration of vasopressor therapy, the need of renal replacement therapy, procalcitonin clearance and decreases in SOFA score.
There were a number of limitations with this trial. The small sample size increases the risk of bias with the effect. The lack of a concurrent comparator group also must make us extremely cautious in interpreting these findings. For context, the use of historical controls has been identified as the second-lowest level of evidence quality in the Global Health Evidence Framework. The generalizability is also limited due to the single centre design. As a feasibility study, this now makes way for a larger RCT to be conducted to test this in a wider population. By itself, this study is low-quality evidence and should not be used to drive management of patients with severe sepsis and septic shock.
As of November 2018, no guidelines have been published that reflect the results of this trial.
- Single center intervention study matching to historical controls
- Vitamin C Protocol (n=47)
- Historical comparator (n=47)
- Setting: Single tertiary care hospital in Eastern Virginia, USA
- Enrollment: January 2016 and July 2016
- Mean follow-up: Not defined, but most outcomes were at 4 days
- Primary outcome: Hospital survival
- Consecutive patients admitted to the Eastern Virginia Medical School Critical Care Medicine service
- Primary diagnosis of severe sepsis or septic shock
- Procalcitonin (PCT) level ≥2 ng/mL
- <18 years of age
- Patients with limitations of care (not further described)
Treatment group displayed
- Demographics: Age 58 years, 57% male
- Comobidities, No.(%)
- None: 2 (4)
- Diabetes: 16 (34)
- Hypertension: 20 (43)
- Heart failure: 15 (32)
- Malignancy: 5 (11)
- COPD: 8 (17)
- Cirrhosis: 6 (13)
- CVA: 8 (17)
- CRF: 7 (15)
- Morbid obesity: 6 (13)
- Immunocompromised: 6 (13)
- Drug addiction: 5 (11)
- Primary diagnosis, No.(%)
- Pneumonia: 18 (38)
- Urosepsis: 11 (23)
- Primary bacteremia: 7 (15)
- GI/biliary: 6 (13)
- Other: 5 (11)
- Mechanical ventilation, No.(%): 22 (47)
- Vasopressors, No.(%): 22 (46)
- Procalcitonin, median (IQR), ng/ml: 25.8 (5.8-93.4)
- Day 1 SOFA, mean±SD: 8.3 ± 2.8
- APACHE II, mean±SD: 22.1 ± 6.3
- APACHE IV, mean±SD: 79.5 ± 16.4
- Predicted mortality, mean±SD: 39.7 ± 16.7
- Acute kidney injury, No.(%): 31 (66)
- Positive blood cultures, No.(%): 13 (28)
- WBC, mean±SD,×10^9: 20.6 ± 13.5
- Lactate, mean±SD mM: 2.7 ± 1.5
- Creatinine, mean±SD, mg/dL(mcmol/L): 1.9 ± 1.4(168 ± 124)
- Intravenous vitamin C 1.5g every 6h for 4 days or until ICU discharge
- Mixed in 100 mL D5W or 0.9% NaCl, infused over 30-60min
- Hydrocortisone 50 mg every 6h for 7 days or until ICU discharge followed by a taper over 3 days
- Intravenous thiamine 200 mg every 12h for 4 days or until ICU discharge
- Piggyback 50 mL D5W or 0.9% NaCl over 30 min infusion
Presented as treatment vs. control groups
- Hospital morality
- 8.5% vs. 40.4%, P<0.001
- Duration of vasopressor therapy, mean±SD, h
- 18.3±9.8 vs. 54.9±28.4, P<0.001
- Requirement for renal replacement therapy
- 10% vs. 33%, P=0.02
- ICU Length Of Stay, median(IRQ),d
- 4 (3-5) vs. 4 (4-10)
- Serum Procalcitonin clearance over the first 72h, median (IQR)
- 86.4% (80.1-90.8) vs. 33.9% (–62.4 to 64.3), P<0.001
- Change in SOFA score over the first 72h
- 4.8 ± 2.4 vs. 0.9 ± 2.7, P<0.001
- Met Acute Kidney Injury criteria
- 66% vs. 64%, P=NS
- 24h fluid balance
- 2.1±3.2L vs. 1.9±2.7L, P=NS
- Retrospective nature means certain details not included in the analysis
- Risk of selection bias since "Vitamin C Protocol" use was by clinician choice
- Patient information of those that did not receive Vitamin C protocol
- Treatment effect may have been masked due to cross-over in control group
- 60% received with hydrocortisone
- Thiamine exposure not reported
- Small sample size and use of historical controls introduces a tremendous risk of bias
- Decreased external validity due to single centre
The authors have reported to CHEST that no funding was received for this study.
- Singer M et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016. 315:801-10.
- American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit. Care Med. 1992. 20:864-74.
- Vincent JL et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 1996. 22:707-10.
- Shekelle PG, et al. Global Health Evidence Framework. Southern California Evidence-based Practice Center. 2013.