Combined vitamin C, hydrocortisone, and thiamine propensity score analysis before-after cohort

In Review

Kim WY, et al. "Combined vitamin C, hydrocortisone, and thiamine therapy for patients with severe pneumonia who were admitted to the intensive care unit: Propensity score-based analysis of a before-after cohort study". J Crit Care. 2018. 47:211-218.
PubMed • Full text • PDF

Clinical Question

In adult patients with severe pneumonia requiring admission to ICU, does treatment with a combination of vitamin C, hydrocortisone, and thiamine decrease mortality?

Bottom Line

In severe pneumonia requiring ICU admission, treatment with the combination of vitamin C, hydrocortisone, and thiamine may decrease mortality, more study is needed.

Major Points

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.

Clinical research in critical care has been marred by negative outcomes in trials testing various treatments. With the publication of the publication of the trial by Marik et al. in 2017 Hydrocortisone, Vitamin C, and Thiamine in Severe Sepsis and Septic Shock the prospect of an effect therapy to reverse organ dysfunction is very attractive. The the combination of high-dose vitamin C, steroids, and thiamine may work to correct organ dysfunction by several mechanisms. Thiamine is a co-factor required for glucose metabolism and cellular energy generation. Thiamine has also been associated with improved lactate clearance and mortality in septic shock. Low vitamin levels have been observed in the critically ill previously and the addition of high-doses of vitamin C may work to decrease pro-inflammatory changes in the lung and decrease oxidative stress.

In response to the trial in 2017 by Marik et al. the authors tested the same protocol in their centre: vitamin C 1.5g IV Q6H, hydrocortisone 50mg IV Q6H, and thiamine 200mg IV Q12H. The outcomes of this trial showed no statistical difference between the combination treatment and the control until the propensity-matching analysis was done. The propensity score matched cohort demonstrated an absolute risk reduction of mortality by 22%, with a number needed to treat of 4.

This is an impressive finding, however, there are several challenges with the trial. As with the Marik trial before, there as significant cross-over steroid use in the control arm and thiamine exposure was not reported. The authors also admit that selection bias did occur, selecting those patients that they believed would most benefit from the vitamin C protocol. This trial had a small sample size and may have lack the power necessary to fully understand the treatment effect. This trial also lacking a concurrent control group means that these findings may have been influenced by other factors; something the authors attempted to control for by using historical comparators from the same time of year, the previous year. This is a single centre trial conducted in Korea so generalizability to other populations may be limited. As a follow-up to the feasibility study, this continues to beg for a larger RCT to be conducted to test this in a wider population, as evidenced by 40+ trials being currently registered to test this hypothesis.

Guidelines

As of November 2018, no guidelines have been published that reflect the results of this trial.

Design

• Single-centre, before-after cohort study
• N=99
  • Vitamin C, Hydrocortisone, Thiamine protocol (June 2016-January 2017) (n=53)
  • Control group (n=46)
• Setting: 1100 bed, university-affiliated tertiary care facility, Korea
• Enrollment: June 2016-January 2017, June 2017-January 2018
• Mean follow-up: 28 days
• Analysis: propensity matched
• Primary Outcome: hospital mortality

Population

Inclusion Criteria

• severe pneumonia
• admission to single ICU

Exclusion Criteria

• not admitted to ICU and/or required conventional oxygen therapy only
• acute diagnosis that was not severe pneumonia
• admission to the ICU occurred >48 h after hospitalization
• vitamin C protocol infusion occurred >48 h after hospitalization
• do not resuscitate order

Baseline Characteristics

Vitamin C Protocol Group displayed

• Demographics: age 73, 77% male,
• Comorbidities: Diabetes 28%, Heart Failure 8%, Chronic Neurologic Disease 32%, chronic lung disease 40%, liver cirrhosis 4%, kidney disease 15%, malignancy 9%, immunocompromised 15%
• Anthropomorphics: BMI 21.4
• Physiologic parameters: concurrent bacteremia 8%, ARDS at ICU admission 23%, APACHE II Score 28, SOFA Score 11
• Supports on ICU 1st day: mechanical ventilation 81%, neuromuscular blockers 59%, vasopressors 62%, renal replacement therapy 36%
• Labs: Temperature 37.3 degC, MAP 61 mmHg, Serum Creatinine 97 mcmol/L [1.1 mg/dL], WBC 12.4, total bilirubin 12 mcmil/L [0.7 mg/dL], CRP 189 mg/L, Lactate 2.3 mmol/L

Interventions

• Vitamin C Protocol
  • Vitamin C 1.5g IV Q6H for 4 days
  • Hydrocortisone 50mg IV Q6H for 7 days then 3 day taper
  • Thiamine 200mg IV Q12H for 4 days

Outcomes

Comparisons are Vitamin C protocol vs. Control Group.

Primary Outcomes

Hospital Mortality

21% vs. 37% (ARR 16%); P=0.07

Propensity score-matched cohort 17% vs. 39% (ARR 22%); NNT 4, P=0.04

Secondary Outcomes

Length of ICU stay

9(4-14) vs. 12(6-17); P=0.19

Vasopressor free days at 28 days

18.8 ± 11.2 vs. 19.6 ± 11.4; P=0.76

Ventilator free days at 28 days

10.7 ± 10.8 vs. 9.7 ± 10.9; P=0.66

Subgroup Analysis

Sensitivity group comparison to control, mortality

44%; P = 0.55

Multivariate analysis for mortality

Unadjusted OR 0.45 (95% CI 0.18-1.09) P=0.08

Propensity-adjusted OR 0.15 (95% CI 0.04-0.56) P=0.005

Propensity-matched OR 0.31 (95% CI 0.10-0.95) P=0.04

Adverse Events

No AKI Reported

Criticisms

• generalizability may be limited: BMI low compared to some populations
• adverse event reporting unclear as stated no renal replacement therapy during study period but renal replacement therapy reported in table 1
• Treatment effect may have been masked due to cross-over in control group
  • 65% received with hydrocortisone
  • Thiamine exposure not reported
• Single-centre, small sample size
• observational non-randomized design
• non-concurrent control group
• Selection-bais selected patients that may have benefited from vitamin C protocol
• Vitamin C levels were not tested at baseline

Funding

• Biomedical Research Institute Grant (2018B005), Pusan National University Hospital