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Intravenous vitamin C for sepsis
François Lamontagne
Université de Sherbrooke
12 November 2019
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DisclosuresI am the co-PI of a
RCT of high-dose
vitamin C for sepsis
(NCT03680274)
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Why be excited about vitamin C?
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Global burden of sepsis
• Sepsis
– 437 (334-571) /105
person-yr
– 31.5 million cases / yr
• Severe sepsis
– 270 (176-412) /105
person-yr
– 19.4 million cases / yr27 studies – 7 HICs
Am J Respir Crit Care Med 2016;193:259–272
Deaths: 5.3 million per annum
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Severe vitamin C deficiency in a critically ill adult: a case reportS Doll and B Ricou
Eur J Clin Nutr 2013;67:881–882
• Hypotension
• Microcirculatory dysfunction
• Capillary leak
• Organ dysfunction
• Susceptibility to infection
• Impaired wound healing
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Vitamin C actions
• Antioxidant
– Scavenges reactive oxygen species (plasma and cells)
– ↓ Damage to proteins, lipids, DNA
• Improves immunity
– ↑ IFN production; neutrophil phagocytic capacity and oxidative killing; lymphocyte proliferation
• Humans have limited vitamin C stores and cannot synthesize it
Curr Opin Clin Nutr Metab Care 2015;18:193–201
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Vitamin C is a cofactor for
catecholamine synthesis
Crit Care 2015;19:418
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‘Metabolic resuscitation’ for sepsis
N=94
aORmort 0.13 (0.04-0.48)
RRmort 0.21 (0.06-0.58)
NNT 3 (2-8)
Chest 2017; 151: 1229-1238
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Vitamin C: 10 trials, 1520 patients
JPEN J Parenter Enteral Nutr 2019;43:335-346
n=52
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170 patients- ARDS (mechanical ventilation, infiltrates,
PaO2/FiO2 <300)
- Suspicion of infection
- ≥2 SIRS criteria
- All criteria met within a 24h period
- <48h since ARDS criteria met
Vitamin C 50 mg/kg/dose q6h for 96h vs. placebo
Emerging evidence appears consistent…
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Mortality benefit?
HR 0.55 (0.33-0.90)
RR 0.64 (0.42-0.98)
Fragility index = 1
JAMA 2019;322:1261-1270
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Other
reasons
Feasible to implement
Inexpensive
Uses existing medications
Seems safe
Investigator-initiated
Potential global relevance
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Why be cautious about vitamin C?
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Vitamin C actions
• Antioxidant
– Scavenges reactive oxygen species (plasma and cells)
– ↓ Damage to proteins, lipids, DNA
• Improves immunity
– ↑ IFN production; neutrophil phagocytic capacity and oxidative killing; lymphocyte proliferation
• Humans have limited vitamin C stores and cannot synthesize it
Curr Opin Clin Nutr Metab Care 2015;18:193–201
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BMJ 2003;327:1459–61
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‘Parachutes’
in medicine
INSULIN FOR DIABETES
BLOOD TRANSFUSION FOR HEMORRHAGIC SHOCK
CLOSED REDUCTION AND SPLINTING FOR DISPLACED LONG BONE FRACTURES
CRICOTHYROTOMY FOR UPPER AIRWAY OBSTRUCTION
SUTURING FOR HEMORRHAGE
ETHER FOR ANESTHESIA
Glasziou P et al. BMJ 2007;334:349-51
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Treatment effect: NNT ~1.5
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Most of our interventions are not parachutes
N Engl J Med 2001;344:699-709 N Engl J Med 2001;345:1359-67
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Risks of
vitamin C
Factitious hyperglycemia
using POC devices
May be immediately life-threatening
Affects a large population of patients (anyone treated with hypoglycemic medication)
Hemolysis with G6PD
deficiencyPopulation-dependent baseline risk
Increased urinary oxalate
excretion
Stones
AKI
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So what next?
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Lessening Organ Dysfunction with
VITamin C Randomized Trial
François Lamontagne & Neill Adhikari
Funding: Lotte and John Hecht Memorial Foundation
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Eligibility
• ≥18 years old
• Admitted to ICU for infection
• Currently receiving vasopressor infusion
Inclusion criteria
• >24 h since local ICU admission
• Known kidney stones within the past 1 year
Major exclusions
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Interventions
• Duration: 96 hours
• Experimental arm: IV vitamin C, 50 mg/kg every 6 hours for 96 hours (200 mg/kg/day)
• Control arm: matching placebo prepared locally(D5W or saline)
Allocation:
- 24/7 web randomization service
- 1:1 ratio
- Permuted blocks of undisclosed and variable size
- Randomization stratified by centre
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Primary Outcome
Death or persistent organ dysfunction (POD) at 28 days
POD: Mechanical ventilation or
New renal replacement therapy or
Vasopressors
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Secondary
outcomes
1. Organ function (SOFA)
2. Persistent organ dysfunction-free
days to day 28
3. Mortality at 6 months
4. HRQoL (EQ-5D-5L) at 6 months
5. Biomarkers on days 1, 3 and 7
6. Stage 3 acute kidney injury
7. Acute hemolysis
8. Hypoglycemia
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Recruitment
• Informed consent
- In person
- By telephone if SDM
unavailable
- Deferred consent as
per local REB
• 25 sites: in Canada
and abroad
• Duration of enrollment:
36 months
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Trial Country Intervention N Status
VICTAS (J Sevransky) USA Vit C + HC + B1 2000 Oct 2021
NCT03872011 (Q Lyu) China Vit C + HC + B1 406 Aug 2020
CORVICTES (SD Mentzelopoulos) Greece Vit C + HC + B1 400 Sep 2020
VITAMINS (T Fuji, R Bellomo) Australia Vit C + HC + B1 216 Completed
HYVITS (A Mohamed) Qatar Vit C + HC + B1 212 May 2019
ACTS (M Donnino) USA Vit C + HC + B1 200 Feb 2020
ViCiS (R Martinez-Zubieta) Mexico Vit C 180 Jun 2020
CITRIS-AlI (AA Fowler) USA Vit C 170 Completed
NCT03338569 (R Reilkoff) USA Vit C 140 Mar 2020
…
Ongoing trials in clinicaltrials.gov
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Living ‘umbrella’ trials LOVIT Collaboration
RCT in
country 1
RCT in
country 2
RCT in
country 3
Masse MH et al. Trials (in press)
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Living ‘umbrella’ trials LOVIT Collaboration
P: Sepsis + vasopressors
I: Vitamin C (50 mg/kg/dose) q6h for 96h
C: Placebo
O: POD or death at 28 days
O2:
O3:
…
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Living ‘umbrella’ trials
• Requirements:
- Willingness to collaborate
- Detailed ‘Terms of collaboration’
- Relevant expertise within the team
Advantages
Simple design/well suited to overcome in-country administrative barriers
Nimble/great adaptability
Tackles multiple questions withoutlosing track of main goal (e.g. mortality)
Win-win scenario that maximizes independence/recognition for all
Efficient/economies of scale
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Summary
• Community is enthusiastic – rightly so
• Be wary of dramatic treatment effects
– In observational studies and in small trials
– Harms underestimated by current evidence
• To be efficient (and offer our patients the best care as soon as possible)
– Enroll all eligible patients in ongoing trials
– Join forces / create large trials from the start
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