ORIGINAL RESEARCH|ARTICLES IN PRESS
High-Dose Intravenous Hydroxocobalamin (Vitamin B12) in Septic Shock: A Double-Blind, Allocation-Concealed, Placebo-Controlled Single-Center Pilot Randomized Controlled Trial (The IV-HOCSS Trial)
Jayshil J. Patel, Rodney Willoughby, Jennifer Peterson, et al
Chest Published:September 26, 2022
DOI:https://doi.org/10.1016/j.chest.2022.09.021
Abstract
Background
Elevated hydrogen sulfide (H2S) contributes to vasodilatation and hypotension in septic shock and traditional therapies do not target this pathophysiologic mechanism. High-dose intravenous (IV) hydroxocobalamin (IV-HOC) scavenges and prevents H2S formation, which may restore vascular tone and accentuate recovery. No experimental human studies have tested IV-HOC in adults with septic shock.
Research Question
In adults with septic shock, is comparing IV-HOC to placebo feasible?
Study Design and Methods
We conducted a phase 2 single-center, double-blind, allocation-concealed, placebo controlled, parallel group pilot RCT comparing IV-HOC with placebo in critically ill adults with septic shock. Patients meeting Sepsis-3 criteria were randomized 1:1 to receive a single 5-gram dose of IV-HOC or equivalent volume 0.9% saline solution as placebo. The primary outcome was study feasibility (enrollment rate, clinical and laboratory compliance rate, and contamination rate). Secondary outcomes included between-group differences in pre- and post-infusion plasma H2S concentrations and vasopressor dose.
Results
Twenty patients were enrolled over 19 months, establishing an enrollment rate of 1.05 patients per month. Protocol adherence rates were 100% with zero contamination. In the IV-HOC group, compared to placebo, there was a greater reduction in vasopressor dose between randomization and post-infusion (-36% vs 4%, p<0.001) and randomization and 3-hours-post-infusion (-28% vs 10%, p=0.019). In the IV-HOC group, the plasma H2S level was reduced over 45 minutes by -0.80 μM (±1.73), as compared to -0.21 μM (±0.64) in the placebo group (p=0.3).
Interpretation
Our pilot trial established favorable feasibility metrics. Consistent with the proposed mechanism of benefit, IV-HOC, compared to placebo, was associated with reduced vasopressor dose and H2S levels at all time-points and without serious adverse events. These data provide first proof-of-concept for feasibility of delivering IV-HOC in septic shock.
