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Potential Therapeutic Targets for Sepsis: Gasotransmitters (i.e. Hydroxocobalamin)

Updated: Apr 17, 2023


Potential Therapeutic Targets for Sepsis: Hydroxocobalamin (Vitamin B12)

Sepsis is a severe medical condition that can result from the body's response to infection. It is a life-threatening condition that affects millions of people worldwide and has a mortality rate of over 40%. The standard treatment for septic shock involves intravenous fluid resuscitation, administration of broad-spectrum antibiotics, source control, and supportive care. However, the medical community is constantly seeking novel therapeutic strategies to improve patient outcomes. This article explores the potential of high-dose IV hydroxocobalamin, a form of Vitamin B12, as a promising therapy for sepsis management


At present, no medical guidelines specifically recommend treatments that directly target the underlying mechanisms involving gasotransmitters, such as nitric oxide (NO) and hydrogen sulfide (H2S), which play a role in the development and progression of septic shock. These gasotransmitters are known to contribute to the condition through their effects on vasodilation, inflammation, and other physiological processes. Addressing these underlying mechanisms could potentially lead to more effective therapeutic strategies for managing septic shock and improving patient outcomes.


Excessive NO and H2S Production in Sepsis

The overproduction of nitric oxide (NO) and hydrogen sulfide (H2S) contributes to sepsis pathophysiology. These gaseous molecules are known to regulate vascular tone, cellular respiration, oxidative stress, and inflammation. During sepsis, the expression and activity of inducible nitric oxide synthase (iNOS) and cystathionine gamma-lyase (CSE) are increased, leading to excessive NO and H2S generation. This can result in severe hypotension, impaired myocardial contractility, vascular hyporeactivity (vasodilation), mitochondrial dysfunction, and tissue damage [1].


Potential Therapeutic Approaches for Modulating NO and H2S Levels in Sepsis

Several pharmacological agents have been investigated for their ability to modulate NO and H2S levels in sepsis. Some of these agents include inhibitors of iNOS or CSE, donors or scavengers of NO or H2S, or compounds that affect the metabolism or signaling of these gases. Vitamin B12 has been found to inhibit and neutralize the formation of NO and H2S, making it a potential therapeutic strategy for sepsis [2].


Clinical Evidence of Hydroxocobalamin Effects in Septic Shock

Several case reports and a retrospective analysis suggested a sustained hemodynamic benefits for septic shock patients with improvement of blood pressure and reduction of vasopressor support after receiving high-dose hydroxocobalamin [3-4].



Several pharmacological agents have been investigated for their ability to modulate NO and H2S levels in sepsis. Some of these agents include inhibitors of iNOS or CSE, donors or scavengers of NO or H2S, or compounds that affect the metabolism or signaling of these gases. Vitamin B12 has been found to inhibit and neutralize the formation of NO and H2S, making it a potential therapeutic strategy for sepsis [5].


Expectations for the Outcomes of the Upcoming Phase 3 Trial

The phase 2 clinical trial showed promise for the use of high-dose IV hydroxocobalamin as a potential therapy for sepsis management. The phase 3 trial will involve a larger patient population and further assess the safety, efficacy, and overall impact of the treatment. The outcomes of the trial will provide a more comprehensive understanding of the potential benefits and applications of this treatment approach.

What are your expectations for the outcomes of the upcoming phase 3 trial?

  • Highly successful - significant outcomes improvement

  • Inconclusive - mixed results with no clear benefit

  • Unsuccessful - little to no improvement in patient outcomes

  • Unknown - insufficient information to form an opinion


Conclusion

Sepsis is a severe medical condition that affects millions of people worldwide. High-dose IV hydroxocobalamin, a form of Vitamin B12, has shown promise as a potential therapy for sepsis management. The upcoming phase 3 trial will provide a more comprehensive understanding of the potential benefits and applications of this treatment approach. Modulating NO and H2S levels may offer novel therapeutic opportunities for sepsis management.



REFERENCES:

  1. Zhu Z, Chambers S, Zeng Y, Bhatia M. Gases in Sepsis: Novel Mediators and Therapeutic Targets. Int J Mol Sci. 2022 Mar 27;23(7):3669. doi: 10.3390/ijms23073669. PMID: 35409029; PMCID: PMC8998565. Link

  2. Weinberg JB, Chen Y, Jiang N, Beasley BE, Salerno JC, Ghosh DK. Inhibition of nitric oxide synthase by cobalamins and cobinamides. Free Radic Biol Med. 2009 Jun 15;46(12):1626-32. doi: 10.1016/j.freeradbiomed.2009.03.017. Epub 2009 Mar 27. Erratum in: Free Radic Biol Med. 2011 Oct 1;51(7):1471. PMID: 19328848; PMCID: PMC2745708. Link

  3. Lin Y, Vu TQ. Use of High-Dose Hydroxocobalamin for Septic Shock: A Case Report. A A Pract. 2019 May 1;12(9):332-335. doi: 10.1213/XAA.0000000000000928. PMID: 30431443. Link

  4. Sacco AJ, Cunningham CA, Kosiorek HE, Sen A. Hydroxocobalamin in Refractory Septic Shock: A Retrospective Case Series. Crit Care Explor. 2021 Apr 26;3(4):e0408. doi: 10.1097/CCE.0000000000000408. PMID: 33912838; PMCID: PMC8078293. Link

  5. 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. 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. doi: 10.1016/j.chest.2022.09.021. Epub 2022 Sep 26. PMID: 36174744. Link







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