Biologic rationale and evidence for high-dose hydroxocobalamin in septic shock

The inflammatory response in sepsis raises circulatory levels of gaseous transmitters (gasotransmitters) nitric oxide (NO) and hydrogen sulfide (H 2 S), both of which generate and sustain septic shock. Current best practices, including early intravenous fluid, early antibiotics, and vasopressor support, do not target gasotransmitters. A single 5-g dose of intravenous hydroxocobalamin (high-dose HOC) is a safe intervention that targets circulating gasotransmitters. In this review, we provide an overview of the role of gasotransmitters in septic shock, outline the rationale for high-dose HOC in septic shock, and summarize clinical evidence for high-dose HOC in septic shock.

NO and H 2 S are elevated early in septic shock, activate inflammatory pathways, and higher levels correlate with greater severity of illness. Preclinical evidence demonstrates high-dose HOC improves outcomes in models of septic shock by scavenging circulating NO and H 2 S. Multiple case series and a Phase IIa trial show that high-dose HOC is a safe intervention that reduces vasopressor dose in adults with septic shock. Without high-level evidence, clinicians across the United States are using high-dose HOC for adults with septic shock.

High-dose HOC is a promising, nontoxic intervention that targets the pathophysiologic pathway of septic shock. Despite compelling observational and Phase IIa trial data, a pivotal phase III trial testing high-dose HOC in adults with septic shock is required before widespread use can be recommended.