Hydrocortisone, vitamin C and thiamine for the treatment of severe sepsis and septic shock

Chest 2017;151(6):1229-1238

Presented by Dr A. Wood

Background

  • Sepsis has a substantial global burden estimated at 15 to 19 million cases per year
  • Timely diagnosis and treatment have improved 28 day mortality to 25% in high income countries
  • Mortality rates approach 60% in low income countries
  • As well as short term mortality patients suffer multiple short and long term complications and have a reduced quality of life and increased risk of death for up to 5 years
  • Thiamine deficiency is associated with increased mortality in sepsis
  • Vitamin C maintains endothelial boundaries and is required for catecholamine synthesis
  • Vitamin C deficiency is correlated with multi-organ failure and death

Design & Setting

  • Retrospective observational study
  • Single centre study based in US
  • June 2015 – July 2016

Trial Question

Does intravenous vitamin C, hydrocortisone and thiamine in addition to standard treatment, improve mortality in ICU patients with severe sepsis or septic shock, compared with standard treatment alone?

Subjects

  • Included all patients with severe sepsis or septic shock and a procalcitonin level of >2ng/ml (based on 1992 American College of Chest Physicians/Society of Critical Care Medicine Consensus definitions)
  • Control group was first 7 months (47 patients)
  • Intervention group next 7 months (47 patients)
  • Baseline characteristics (demographics, diagnosis, co-morbidities, positive blood cultures and interventions) similar in each group

Exclusions

  • Patients <18 years old
  • Pregnancy
  • Patients with limitations of care

Intervention

  • All patients received standard intensive care treatment
  • The intervention group also received:
  • 1.5g QDS vitamin C IV for 4 days or until ICU discharge
  • Hydrocortisone 50mg QDS IV for 7 days or until ICU discharge followed by a 3 day taper
  • 200mg thiamine BD for 4 days or until ICU discharge

Both groups

  • Received empirical broad spectrum antibiotics (then deescalated according to microbiological data/clinical progress)
  • Managed with a conservative physiologic based fluid and vasopressor strategy
  • Ventilated with lung protective strategy
  • Received limited use of sedative agents (dexmedetomidine preferred)
  • Noradrenaline was vasopressor of choice titrated to MAP >65mmHg
  • Enteral nutrition commenced within 24 hours on ICU
  • DVT thromboprophylaxis for all
  • Permissive hyperglycaemia allowed
  • Routine stress ulcer prophylaxis not administered

Outcomes

Primary outcome

  • In-hospital mortality

Secondary outcome

  • Mean duration of vasopressor therapy
  • Use of Renal Replacement Therapy
  • Median ICU length of stay
  • 72 hours SOFA score

Results

Primary outcome: hospital mortality

  • 8.5% (4 of 47) in the treatment group compared to 40.4% (19 of 47) in the control group (p<0.001)

Secondary outcomes

  • Mean duration of vasopressor therapy: 18.3 +/- 9.8 hours after staring vitamin C treatment protocol vs 54.9 +/- 28.4 hours in control group (p<0.001)
  • Requirement for RRT for AKI: 3 patients (10%) in treatment group vs 11 patients (37%) in control group (p=0.02)
  • Median ICU stay LOS: 4 days for both groups
  • 72-hour SOFA score was 4.8+/- 2.4 in the treatment group vs 0.9+/- 2.7 in the control group (p<0.001)

Conclusions

  • Early use of intravenous vitamin C, together with corticosteroids and thiamine may reduce mortality and prove to be effective in preventing progressive organ dysfunction including AKI as well as reducing mortality of patients with severe sepsis and septic shock.
  • Additional studies are needed to confirm these preliminary findings

Strengths

  • Interesting hypothesis
  • Biologically plausible explanations for benefit in sepsis
  • Patient baseline characteristics well matched between the two groups
  • Vitamin C and thiamine are cheap and relatively safe
  • Multiple supporting trials

Weaknesses

  • Not an RCT
  • Small numbers (only 47 patients in each group)
  • Single centre non-blinded design
  • Three simultaneous interventions – which one was associated and responsible for clinical improvement?
  • Treatment and control periods were not concurrent and occurred during different seasons – could be a confounding factor
  • 60% of patients in the control group received corticosteroids
  • Details given for underlying cause of death in intervention group (including advanced dementia, severe heart failure, severe COPD) but not control group

Implications

  • Inexpensive and relatively safe interventions that may improve the outcome in sepsis
  • Could be something to consider?

Potential for impact?

  • The study is hypothesis generating
  • A large multi-centre RCT is needed to study this further and determine the efficacy of vitamin C, steroids and thiamine in severe sepsis and septic shock.