Faculty Collaboration Database

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

Date

09/30/2022

Pubmed ID

36174744

DOI

10.1016/j.chest.2022.09.021

Scopus ID

2-s2.0-85146132356 (requires institutional sign-in at Scopus site)   11 Citations

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 IV hydroxocobalamin scavenges and prevents H₂S formation, which may restore vascular tone and may accentuate recovery. No experimental human studies have tested high-dose IV hydroxocobalamin in adults with septic shock.

RESEARCH QUESTION: In adults with septic shock, is comparing high-dose IV hydroxocobalamin with placebo feasible?

STUDY DESIGN AND METHODS: We conducted a phase 2 single-center, double-blind, allocation-concealed, placebo-controlled, parallel-group pilot randomized controlled trial comparing high-dose IV hydroxocobalamin with placebo in critically ill adults with septic shock. Patients meeting Sepsis 3 criteria were randomized 1:1 to receive a single 5-g dose of high-dose IV hydroxocobalamin 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 plasma H₂S concentrations and vasopressor dose before and after infusion.

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 high-dose IV hydroxocobalamin group, compared to placebo, there was a greater reduction in vasopressor dose between randomization and postinfusion (-36% vs 4%, P < .001) and randomization and 3-h postinfusion (-28% vs 10%, P = .019). In the high-dose IV hydroxocobalamin group, the plasma H₂S level was reduced over 45 mins by -0.80 ± 1.73 μM, as compared with -0.21 ± 0.64 μM in the placebo group (P = .3).

INTERPRETATION: This pilot trial established favorable feasibility metrics. Consistent with the proposed mechanism of benefit, high-dose IV hydroxocobalamin compared with placebo was associated with reduced vasopressor dose and H₂S levels at all time points and without serious adverse events. These data provide the first proof of concept for feasibility of delivering high-dose IV hydroxocobalamin in septic shock.

TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03783091; URL: www.

CLINICALTRIALS: gov.

Author List

Patel JJ, Willoughby R, Peterson J, Carver T, Zelten J, Markiewicz A, Spiegelhoff K, Hipp LA, Canales B, Szabo A, Heyland DK, Stoppe C, Zielonka J, Freed JK

Authors

Bethany Canales Biostatistician II in the Institute for Health and Equity department at Medical College of Wisconsin
Thomas W. Carver MD Associate Professor in the Surgery department at Medical College of Wisconsin
Julie K. Freed MD, PhD Vice Chair, Associate Professor in the Anesthesiology department at Medical College of Wisconsin
Aniko Szabo PhD Professor in the Institute for Health and Equity department at Medical College of Wisconsin
Jacek M. Zielonka PhD Assistant Professor in the Biophysics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Double-Blind Method
Humans
Hydroxocobalamin
Hypotension
Pilot Projects
Shock, Septic
Vasoconstrictor Agents
Vitamin B 12