Intravenous vitamin C for sepsis

François Lamontagne

Université de Sherbrooke

12 November 2019

DisclosuresI 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

– 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

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

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

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

Vitamin C: 10 trials, 1520 patients

JPEN J Parenter Enteral Nutr 2019;43:335-346

n=52

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…

Mortality benefit?

HR 0.55 (0.33-0.90)

RR 0.64 (0.42-0.98)

Fragility index = 1

JAMA 2019;322:1261-1270

Other

reasons

Feasible to implement

Inexpensive

Uses existing medications

Seems safe

Investigator-initiated

Potential global relevance

Why 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;18:193–201

BMJ 2003;327:1459–61

‘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

Treatment effect: NNT ~1.5

Most of our interventions are not parachutes

N Engl J Med 2001;344:699-709 N Engl J Med 2001;345:1359-67

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

So what next?

Lessening Organ Dysfunction with

VITamin C Randomized Trial

François Lamontagne & Neill Adhikari

Funding: Lotte and John Hecht Memorial Foundation

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

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

Primary Outcome

Death or persistent organ dysfunction (POD) at 28 days

POD: Mechanical ventilation or

New renal replacement therapy or

Vasopressors

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

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

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

Living ‘umbrella’ trials LOVIT Collaboration

RCT in

country 1

RCT in

country 2

RCT in

country 3

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

O2:

O3:

…

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

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

Thank you

neill.adhikari@sunnybrook.cafrancois.lamontagne@usherbrooke.ca