ICU Journal Club – VICCSS Study

Dr Swapnil Pawar & Dr Jose Chacko

A Pilot, Randomised, Double-Blind Study of Vitamin C in the treatment of Vasoplegic Shock after Cardiac Surgery

https://doi.org/10.1053/j.jvca.2019.08.034

Background- 

High dose vitamin C has a strong biological rationale in post-cardiac surgery vasoplegia. Vitamin C scavenges reactive oxygen species, which likely contribute to vasoplegia after cardiac surgery, stimulates norepinephrine synthesis, decreases the incidence of atrial fibrillation, cardiac enzyme release, and the level of markers of oxidative stress.  In addition, cardiac surgery patients have decreased vitamin C levels compared to preoperative values suggesting increased consumption and/or dilution.

What’s Known- 

high dose intravenous vitamin C has recently been used to treat vasodilatory septic shock which is also a vasodilatory shock. Such studies used high dose (6000 mg per day in four divided doses) vitamin C in association with thiamine and hydrocortisone and found a decrease in vasopressor therapy duration. because corticosteroid or thiamine therapy for cardiac surgery patients has been shown to have no effect on hemodynamic or clinical outcomes, authors decided to use high dose intravenous vitamin C monotherapy in this study.

Question – 

to investigate the effect of high dose vitamin C in patients with vasoplegia after cardiac surgery, with the aim of establishing whether larger trials could both be successfully conducted and justified by promising preliminary findings.

Hypothesis – 

in patients admitted to ICU after cardiac surgery, high dose vitamin C therapy would be associated with earlier resolution of postoperative vasoplegia.

Methods –  a randomized, two-centre, double-blind, feasibility, safety and physiological efficacy pilot trial comparing high-dose vitamin C to placebo in the treatment of vasoplegia in patients admitted to the intensive care unit (ICU) after cardiac surgery.
Settings – The study was conducted in two tertiary ICUs, one in Australia and one in New Zealand
Design– randomly assigned eligible patients to receive either vitamin C or placebo, with a 1:1 ratio. Randomization was performed by means random number sequences utilizing permuted blocks of variable size and allocation was concealed using sequentially numbered sealed envelopes. Each envelope contained the patient’s study number and the study arm allocation.
Inclusion Criteria – 

1. adult patients (≥18 years of age) who underwent on-pump cardiac surgery
2. post-cardiac surgery vasoplegia defined as hypotension with normal or increased cardiac index (CI), and a low systemic vascular resistance and the need for any dose of continuous vasopressor (norepinephrine, vasopressin, dopamine, phenylephrine, epinephrine or metaraminol) infusion to a maintain mean arterial pressure (MAP) > 65 mmHg, in the setting of a CI ≥ 2.2 L min-1 m -2 and/or of a central venous oxygen saturation > 60%.

Exclusion Criteria – 

1. pregnancy,
2. the use of vasopressor or inotropic drugs in the preoperative period,
3. off-pump cardiac surgery,
4. corticosteroids use prior to or after surgery,
5. a history of oxalate nephropathy, haemochromatosis, and glucose 6 phosphate dehydrogenase deficiency
6. if the treating clinician believed there was an additional cause for hypotension other than vasoplegia (bleeding, fluid requirement, pneumothorax, pacemaker issues, heart failure or infection)

Sample Size – Pilot, feasibility study – to enrol 50 patients over two sites. Such a study would provide a greater than 78% power to detect a difference in the duration of vasopressor therapy equal to that reported in a recent study of septic vasoplegia.
Patients -Authors screened 456 patients from November 8, 2017, to October 29, 2018, and enrolled 50 patients (25 patients in each group) in the study.
Statistical Analysis– an intention-to-treat basis, p<0.05 considered significant.
Results- Baseline- Median age was 67.0 years in the vitamin C group and 64.0 years in the placebo group. Median EuroSCORE was 5.0 in both groups and 96.0% of the patients received norepinephrine. The median baseline norepinephrine equivalent dose was the same in both groups at 0.06 µg kg-1 min-1 norepinephrine, equivalent to approximately 5 µg min-1 in an 80 kg patient
Primary Outcomes– There was no difference between the two groups for time to postoperative vasoplegia resolution (P=0.51) 27hours vs 34.7 hours in placebo.
Secondary Outcomes- There was no statistical difference in the total norepinephrine equivalent dose administered on first 2 calendar days after randomization)-Median ICU length of stay was similar in the two groups-MAP, heart rate, cumulative norepinephrine equivalent dose and fluid administration in the first three days showed no difference between the two groups.
Strengths – 

1. the first, double-blind, randomized, controlled study of high dose intravenous vitamin C study for post-cardiac surgery vasoplegia.
2. the study protocol was successfully delivered in essentially all patients, with complete follow-up and no adverse events related to the study drug.
3. It provided information on the duration of postoperative vasoplegia in this patient population
4. Moreover, these results provide clear evidence of feasibility and an estimate of the sample size for a future trial.

Limitations- 

1. One-third of study patients received milrinone as inotropic drug and such treatment may have caused vasodilation and contributed to hypotension. However, the proportion of patients with milrinone was the same in both groups.
2. did not use the cardiac index to define the resolution of vasoplegia. Instead, authors chose a practical approach to vasoplegia resolution,
3. Authors did not investigate very high doses (≥1 g kg-1 per day) of vitamin C given intravenously as has been done in other conditions. Whether such very high doses may prove more useful remains untested.

Conclusion-   In a pilot double-blind randomized trial in cardiac surgery patients with postoperative vasoplegia, the resolution of the vasoplegic state occurs on average within 1.5 days. High dose intravenous vitamin C does not significantly decrease the duration of vasopressor therapy and appeared unlikely to have a clinically important impact on this outcome.