Background:

Septic shock is a severe and common critical illness that is managed in the emergency department.  Our current foundation of treatment includes IV fluids, empiric antibiotic coverage, vasopressor therapy, source control and corticosteroids for refractory shock.  The levels of nitric oxide (NO) and hydrogen sulfide (H2S) are elevated in sepsis and associated with worse outcomes.  Hydroxocobalamin is an inhibitor of NO activity and production and a scavenger of H2S [1,2].  Most of the current data is limited to observational studies looking at hydroxocobalamin in cardiac surgery related vasodilatory shock with few case series and reports for use in septic shock.  The available data has shown an improvement in hemodynamics and reduction in vasopressor requirements in various vasodilatory shock states [2].  Chromaturia and self-limited red skin discoloration are common side effects but current data has not shown significant adverse events [3,4].  Patel et al, performed a phase 2 single-center trial to evaluate use of high dose IV hydroxocobalamin in patients with septic shock. 

Study:

• Single-center, double-blind RCT, 20 patients (10 hydroxocobalamin, 10 placebo)
• Included patients >/= 18 years of age within 48 hours of admission with a diagnosis of septic shock (based on Sepsis 3 criteria) who were receiving norepinephrine (NE) of 0.10 mcg/kg/min for at least 15 minutes or an equivalent dose of alternative vasopressor.
• Notable exclusion criteria were patients with a history of urinary calcium oxalate crystals, active hemolysis or bleeding, impending death.
• Intervention group received a single dose of 5 grams of IV hydroxocobalamin administered over 15 minutes
• Primary outcome – Feasibility Study (*Initial primary outcome was reduction in vasopressor dose but was changed during the COVID-19 pandemic to a feasibility study*)
• Secondary outcomes – Change in H2S levels and NE dose from randomization to 30 minutes and 3 hours after IV hydroxocobalamin.

Results

• Achieved feasibility with enrollment goal, receiving intervention, no contamination and good follow up.
• For secondary outcomes the study group showed a statistically significant relative decrease in vasopressor dose compared to placebo at 30 minutes (-36% vs 4%, p < 0.001) and 3 hours after infusion (-28% vs 10%, p = 0.019). 
• Non-statistically significant reduction in H2S levels in the intervention group compared to placebo.
• Tertiary outcomes of hospital mortality, ICU mortality, ICU and vasopressor free days did not show any significant difference between the groups. (The study was not designed with the power to look for a difference in these outcomes).  

Take home

There is a low risk of serious adverse events from high dose hydroxocobalamin use [3,4].  For now, it may be reasonable to consider in cases of septic shock refractory to standard care but there isn’t enough data to support its regular use yet.

References

1. Patel, JJ, et al. High-Dose IV Hydroxocobalamin (Vitamin B12) in Septic Shock. CHEST. 2023 February; 163(2): 303-312. 10.1016/j.chest.2022.09.021
2. Brokmeier, H, et al. Hydroxocobalamin for Vasodilatory Hypotension in Shock: A Systematic Review With Meta-Analysis for Comparison to Methylene Blue. Journal of Cardiothoracic and Vascular Anesthesia. 2023 September; 37(9): 1757-1772.  https://doi.org/10.1053/j.jvca.2023.04.006
3. Borron SW, Baud FJ, Barriot P, Imbert M, Bismuth C. Prospective study of hydroxocobalamin for acute cyanide poisoning in smoke inhalation. Ann Emerg Med. 2007 Jun;49(6):794-801, 801.e1-2. doi: 10.1016/j.annemergmed.2007.01.026. Epub 2007 May 4. PMID: 17481777.
4. Uhl, W., Nolting, A., Golor, G., Ludwig Rost, K., & Kovar, A.. Safety of Hydroxocobalamin in Healthy Volunteers in a Randomized, Placebo-Controlled Study. Clinical Toxicology. 2006 May; 44(sup1): 17–28. https://doi.org/10.1080/15563650600811755