2023 – May E-Journal Club

Greetings! We are still working on our post-pandemic “new normal” here, but thus far have been on track with keeping to a regular journal club schedule. Our article for May is a bit unlike our usual choice of article, but we wanted to stay up to date with the literature surrounding the use of vitamin B-12 analogs for treatment of refractory hypotension/vasoplegic syndrome.

May Citation:
Patel JJ, Willoughby R, Peterson J, Carver T, Zelten J, et al. High-Dose IV Hydroxocobalamin (Vitamin B12) in Septic Shock: A Double-Blind, Allocation-Concealed, Placebo-Controlled Single-Center Pilot Randomized Controlled Trial (The Intravenous Hydroxocobalamin in Septic Shock Trial). Chest. 2023 Feb;163(2):303-312.

Summary:
This study was a single-center, double-blind, placebo controlled, randomized study comparing high-dose IV hydroxocobalamin with placebo in critically ill patients with septic shock. The study group received a single 5-g dose of intravenous hydroxocobalamin (200 mL) over 15 min via central venous catheter within 24 h of ICU admission. The placebo group received (200 mL) of 0.9% saline over 15 min through a central venous catheter within 24 h of ICU admission.

The initial primary outcome of the study was intended to be a reduction in vasopressor support. However, enrollment was interrupted due to the COVID-19 pandemic and the study design was changed to be a feasibility study with a convenience sample of 20 patients, with a primary outcome of establishing enrollment rate (per month), compliance rate with protocols, and contamination rate. Secondary outcomes included the change in monobromobimane-reactive H2S levels between time of randomization and 30-min after infusion and norepinephrine (or equivalent) dose between time of randomization and 30 min and 3 h after infusion, between groups and between survivors and nonsurvivors. Data on a large number of other “tertiary” clinical outcomes was also collected.

Inclusion and Exclusion Criteria:
Inclusion criteria:
Adult patients with a primary diagnosis of septic shock receiving norepinephrine infusion of 0.10 mg/kg/min for a minimum of 15 min (or equivalent dose phenylephrine, epinephrine, or dopamine) within 48 h of medical or surgical ICU admission.

Exclusion criteria:
Patients with a known hypersensitivity to any component of
the hydroxocobalamin formulation, pregnancy, those with a history of urinary calcium oxalate crystals, moribund patients (deemed by the attending physician), and those with active hemolysis or bleeding requiring two or more hemoglobin measurements per day.

Major Results:
The investigators screened 1,234 patients over a 19 month period, found 70 who were eligible, and 20 patients gave consent. Ten patients were randomized to each study arm, with an enrollment rate of 1.05 patients/month. There was no contamination between groups and no patient was lost to follow up.

The high-dose IV hydroxocobalamin group, compared with the placebo group, showed a greater reduction in vasopressor dose between randomization and 30 min after infusion (–36% vs 4%; P < .001) and randomization and 3 h after infusion (–28% vs 10%; P < .019).

In the high-dose IV hydroxocobalamin group, the monobromobimane-reactive H2S level was reduced over 45 min by –0.80 ±1.73 mM compared with –0.21 ± 0.64 mM in the placebo group (P = .3). Among survivors, the monobromobimane-reactive H2S level was reduced by –1.29 – 1.96 mM in the high-dose IV hydroxocobalamin group compared with –0.12 – 0.82 mM in the placebo group (P = .24)

There were no statistically significant differences in hospital mortality, ICU mortality, ICU-free days, vasopressor-free days, or any other “tertiary” outcomes between the hydoxocobalamin and placebo groups. No serious adverse events (new acute kidney injury secondary to oxalate nephropathy or unexpected death) or reports of color interference with laboratory assays occurred.

Author’s Conclusions:
“…This phase 2 double-blind, placebo-controlled single-center, pilot RCT evaluating high-dose IV hydroxocobalamin in septic shock established both feasibility and hypothesis-generating outcomes data to inform phase 2 efficacy trial design.”

Evaluation:
Hydroxocobalamin is a highly bioavailable form of vitamin B-12, which is normally used to treat hydrogen sulfide toxicity or cyanide poisoning (tradename CYANOKIT® – 5 gm hydroxocobalamin). This vitamin B-12 analog works to treat cyanide poisoning by exchanging a hydroxyl group for a CN group to form a nontoxic compound, cyanocobalamin, which is then excreted by the kidneys. In this function, hydroxocobalamin is acting as a pharmacologic agent rather than a vitamin co-factor. High-dose hydroxocobalamin was also noted to increase blood pressure via pathways that are not targeted by usual vasopressor medications. Hydroxocobalamin inhibits nitric oxide-mediated vasodilation and increases the elimination of the vasodilator hydrogen sulfide.1 The more common form of vitamin B-12 supplementation (cyanocobalamin) does not have this blood pressure-elevating effect.1

Unfortunately, due to the pandemic, this study was unable to recruit a sufficient number of patients for any of the outcomes to be investigated with confidence that the differences between groups was not the result of chance. As the authors state, these results are appropriate for hypothesis generation and to gather information necessary to allow a larger study with an adequate number of patients to be initiated.

Our group noted, as pointed out in the discussion section, that the group who received hydroxocobalamin received antibiotics an hour earlier than the placebo group, which potentially could have affected the change in norepinephrine requirements.

Our Take Home Message(s):
1. The vitamin B-12 analog hydroxocobalamin may have a role in the treatment of shock, but there is a need for larger, randomized studies.
2. The potential role for high dose parenteral hydroxocobalamin in treatment of shock appears to be distinctly different from the vitamin functions of vitamin B-12 as an enzyme cofactor for DNA synthesis, methionine regeneration and for the prevention of homocysteine accumulation.

Reference:
1. Cai Y, Mack A, Ladlie BL, Martin AK. The use of intravenous hydroxocobalamin as a rescue in methylene blue-resistant vasoplegic syndrome in cardiac surgery. Ann Card Anaesth. 2017 Oct-Dec;20(4):462-464.

Joe Krenitsky MS, RDN

PS – Please feel free to forward on to friends and colleagues.