VITAMINS Trial

Sir William Osler said that “except on a few occasions, the patient appears to die from the body’s response to infection rather than from the infection”

Sepsis is a major problem across the globe. Apart from the enormous financial costs of sepsis, the human toll of this disease is staggering and new interventions that limit the ravages of this disease are urgently required. Despite numerous RCTs, we still have not found the magic bullet to cure sepsis.

The role of Vitamin C in Sepsis has been debated a lot recently.

Multiple and overlapping effects of hydrocortisone, vitamin C, and thiamine in the setting of bacterial sepsis. Vitamin C and thiamine scavenge free radicals from superoxide (O2) and inhibit activation of xanthine oxidase and NADPH oxidase. Vitamin C protects the mitochondria from oxidative stress caused by increased leakage of electrons from the dysfunctional electron transport chain and recovers tetrahydrobiopterin (BH4) from dihydrobiopterin (BH2), restoring endothelial nitric oxide synthase (eNOS) activity and increasing eNO bioavailability. Vitamin C inhibits inducible NOS (iNOS) activation, preventing profuse iNO production and peroxynitrite (ONOO􀀀) generation. Vitamin C scavenges ONOO􀀀, preventing loosening of the tight junctions of the endothelium. Vitamin C and hydrocortisone decrease the activation of nuclear factor _B (NF-_B), thereby decreasing the release of proinflammatory mediators. They restore endothelial tight junctions and increase adrenergic receptor function. Thiamine increases the activity of pyruvate dehydrogenase and alpha ketoglutarate dehydrogenase. So there is strong case based on biological plausibility.

What’s known so far?

A previous randomized trial of 24 patients showed that high-dose IV vitamin C attenuated organ failure associated with sepsis in a dose-dependent manner.9 The combination of high-dose IV vitamin C and hydrocortisone together with thiamine was assessed in a single-center retrospective before-and-after study of 94 patients with severe sepsis or septic shock.13 The intervention was associated with shorter duration of vasopressor administration and lower hospital mortality.13 However, hydrocortisone alone has also consistently demonstrated efficacy in hastening the resolution of shock compared with placebo in 2 large multicentre double blind trials.14,15 It is unclear whether the combination of vitamin C, hydrocortisone, and thiamine is more effective than hydrocortisone alone.

Question –

Does treatment with vitamin C, hydrocortisone, and thiamine lead to a more rapid resolution of a septic shock compared with hydrocortisone alone?

Design

Multicenter, unblinded, randomized controlled trial across 10 ICUs in Australia, New Zealand, and Brazil. Randomization was by computer-generated random numbers; permuted block sizes of 2, 4, and 6 were used in a 1:1 ratio, stratified by site.

Population

Patients admitted with a primary diagnosis of septic shock were screened.

Inclusion criteria:

Documented or suspected infection with an increase SOFA score by at least 2 points

Lactate level higher than 2 mmol/L

On vasopressors for a minimum of 2 hours

Exclusion criteria:

Less than 18 years old

Do-not-resuscitate status

Patients who were imminently dying

Septic shock was diagnosed more than 24 hours ago

Study drugs otherwise indicated or contraindicated

786 screened à 570 excluded à 216 randomized   

Intervention arm

Intravenous vitamin C 1.5 g every 6 hours, hydrocortisone 50 mg every 6 hours, and thiamine 200 mg every 12 hours (all open label).

Control arm

Intravenous hydrocortisone 50 mg intravenously, 6 h (open label). Thiamine administration was allowed based on physician discretion. Intravenous vitamin C was not allowed in the control arm.  

Common to both arms

The study intervention was continued until vasopressors were stopped.

Cessation of vasopressors:  All vasopressors off for 4 consecutive hours with a mean arterial pressure higher than 65 mm Hg or a MAP target set by the treating clinician.

Primary outcome

Duration of time alive and free of vasopressors at day 7 (168 hours) after randomization. Patients had to be alive and free of vasopressors for at least 4 consecutive hours. Zero vasopressor hours if the patient died during the index episode of septic shock. If a patient remained off all vasopressors for 4 consecutive hours, then all of the remaining time until 7 was vasopressor-free, even if the patient died or had vasopressors restarted after weaning within the 7-day period.

The study was powered for 90% to detect a difference in vasopressor-free period of 25 h, based on a previous retrospective study with the use of this cocktail by Marik et al.

Secondary outcomes

28-d mortality

90-d mortality

ICU mortality

Hospital mortality

28-day cumulative vasopressor-free days

28-day cumulative mechanical ventilation-free days

28-day renal replacement therapy–free days

Change in SOFA score at day 3

ICU free-days at 28 days

Hospital length of stay

Vasopressor dose within the first 10 days: Not different

The maximum stage of acute kidney injury by the KDIGO criteria during the first 7 days after randomization: Not different

Post-hoc analysis

Recommencement of vasopressors by day 7 after vasopressor-free for 4 consecutive hours: 33.3%, vs control, 26.7%; P = .33 (not different)

One patient from each group died between the initial cessation of vasopressors and day 7.

Strengths –

1. This trial provided the intervention for a longer period (ie, up to 10 days) than the previous observational study, which assessed the effect of 4 days of therapy. This provided a sufficient treatment period for the intervention to have any potential effect.
2. Multi-centre and RCT involving patients from high income and middle income countries thus has got some external validity.
3. First large RCT on this topic
4. No serious adverse events were reported.
5. This trial also demonstrated that administration of vitamins in addition to hydrocortisone during the early phase of septic shock is feasible.
6. Patients in the current study received lower daily doses of IV vitamin C compared with CITRIS-ALI. However, in the nested cohort study within the intervention group of this trial, the median plasma concentration of vitamin C increased from 28 μmol/L at baseline to 369 μmol/L 1 hour after the first dose and achieved nearly the same plasma level at 6 hours24 as reported in CITRIS-ALI at 48hours.
7. To minimize biases and strengthen the robustness of trial findings, the random allocation sequence was concealed, and permuted size blocks stratified by study centre were used.
8. Very few patients were lost to follow-up, thus minimizing attrition bias.

Limitations –

1. Open label trial
2. The possible individual effects of vitamin C and thiamine were not assessed separately.
3. Third, thiamine levels were not measured in the trial, making it uncertain whether randomized patients did or did not have hypovitaminosis.
4. Fourth, the target mean arterial pressure set for each patient by treating clinicians was not collected.
5. Fifth, time to the administration of antibiotics was not collected; however, all patients had already received antibiotics at enrolment.
6. Sixth, this trial was underpowered to detect differences in mortality or other patient-centered outcomes as well as differences in outcomes among specific subgroups.
7. Seventh, adverse events were reported only when treating clinicians adjudicated, and patients were not systematically examined for other possible adverse effects (eg,oxaluria) that might develop with high dose IV vitamin C.
8. The major limitation – Time to first dose

Conclusion –

Positive trial – as we know now there is no point in giving HAT therapy after 12 hours of ICU admission

Unable to change practices due to major limitations