Intravenous vitamin C for sepsis - François Lamontagne Université de Sherbrooke 12 November 2019 - Critical Care Canada Forum
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Intravenous vitamin C for sepsis
François Lamontagne
Université de Sherbrooke
12 November 2019
Disclosures I am the co-PI of a
RCT of high-dose
vitamin C for sepsis
(NCT03680274)
Why be excited about vitamin C?
Global burden of sepsis
• Sepsis
Deaths: 5.3 million per annum – 437 (334-571) /105
person-yr
– 31.5 million cases / yr
• Severe sepsis
– 270 (176-412) /105
person-yr
– 19.4 million cases / yr
27 studies – 7 HICs
Am J Respir Crit Care Med 2016;193:259–272
Severe vitamin C deficiency in a
critically ill adult: a case report
S 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
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
Vitamin C is a cofactor for catecholamine synthesis Crit Care 2015;19:418
‘Metabolic resuscitation’ for sepsis
Chest 2017; 151: 1229-1238
N=94
aORmort 0.13 (0.04-0.48)
RRmort 0.21 (0.06-0.58)
NNT 3 (2-8)
Vitamin C: 10 trials, 1520 patients
n=52
JPEN J Parenter Enteral Nutr 2019;43:335-346
Emerging evidence appears consistent…
170 patients
- ARDS (mechanical ventilation, infiltrates,
PaO2/FiO2Mortality benefit?
HR 0.55 (0.33-0.90)
RR 0.64 (0.42-0.98)
Fragility index = 1
JAMA 2019;322:1261-1270Feasible to implement
Inexpensive
Uses existing medications
Other
reasons Seems safe
Investigator-initiated
Potential global relevanceWhy be cautious about vitamin C?
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;18:193–201BMJ 2003;327:1459–61
INSULIN FOR DIABETES
BLOOD TRANSFUSION FOR HEMORRHAGIC
SHOCK
CLOSED REDUCTION AND SPLINTING FOR
‘Parachutes’ DISPLACED LONG BONE FRACTURES
CRICOTHYROTOMY FOR UPPER AIRWAY
in medicine OBSTRUCTION
Glasziou P et al. BMJ 2007;334:349-51 SUTURING FOR HEMORRHAGE
ETHER FOR ANESTHESIATreatment effect: NNT ~1.5
Most of our interventions are not parachutes
N Engl J Med 2001;344:699-709 N Engl J Med 2001;345:1359-67Increased Stones
urinary oxalate
excretion AKI
Risks of Hemolysis with
G6PD Population-dependent baseline risk
vitamin C deficiency
Factitious May be immediately life-threatening
hyperglycemia
using POC Affects a large population of patients (anyone
devices treated with hypoglycemic medication)So what next?
Lessening Organ Dysfunction with
VITamin C Randomized Trial
François Lamontagne & Neill Adhikari
Funding: Lotte and John Hecht Memorial FoundationInclusion criteria
• ≥18 years old
• Admitted to ICU for infection
• Currently receiving vasopressor infusion
Eligibility
Major exclusions
• >24 h since local ICU admission
• Known kidney stones within the past 1 yearInterventions
• 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 centrePrimary Outcome
Death or persistent organ dysfunction (POD) at 28 days
POD: Mechanical ventilation or
New renal replacement therapy or
Vasopressors1. Organ function (SOFA)
2. Persistent organ dysfunction-free
days to day 28
3. Mortality at 6 months
Secondary 4. HRQoL (EQ-5D-5L) at 6 months
outcomes 5. Biomarkers on days 1, 3 and 7
6. Stage 3 acute kidney injury
7. Acute hemolysis
8. Hypoglycemia• 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
RecruitmentOngoing trials in clinicaltrials.gov 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 …
RCT in
country 1
RCT in
country 2
RCT in
country 3
Living ‘umbrella’ trials LOVIT Collaboration
Masse MH et al. Trials (in press)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
O 2:
O 3:
…Living ‘umbrella’ trials Advantages
Simple design/well suited to overcome
in-country administrative barriers
• Requirements: Nimble/great adaptability
- Willingness to
collaborate Tackles multiple questions without
- Detailed ‘Terms of losing track of main goal (e.g. mortality)
collaboration’ Win-win scenario that maximizes
- Relevant expertise independence/recognition for all
within the team Efficient/economies of scale• Community is enthusiastic – rightly so
• Be wary of dramatic treatment effects
– In observational studies and in small trials
– Harms underestimated by current evidence
Summary • 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 startThank you neill.adhikari@sunnybrook.ca francois.lamontagne@usherbrooke.ca
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