A prospective, randomized trial of intravenous hydroxocobalamin versus noradrenaline or saline for treatment of lipopolysaccharide‐induced hypotension in a swine model

Abstract

Summary Early, non‐clinical studies support the use of hydroxocobalamin to treat sepsis‐induced hypotension, but there is no translational, large animal model. The objective of this study was to compare survival in a sepsis model where large swine had endotoxaemia induced with lipopolysaccharide (LPS) and were treated with intravenous hydroxocobalamin (HOC), noradrenaline (NA), or saline. Thirty swine (45–55 kg) were anaesthetized, intubated, and instrumented with continuous femoral and pulmonary artery pressure monitoring. Hypotension, predefined as 50% of baseline, was induced with LPS. Animals then received HOC, NA, or saline and monitored for 3 hours. The main outcome was survival to the conclusion of the study. Using a power of 80% and an alpha of 0.05, 10 animals were used per group. Secondary outcomes included: mean arterial pressure (MAP), systemic vascular resistance (SVR) and cardiac output (CO) along with several markers of sepsis. No differences were detected between groups at baseline or after hypotension. The survival distributions of the three groups were significantly different with more HOC animals surviving (10/10) compared with NA (8/10) or Saline (5/10) (log‐rank P < 0.03). MAP was found to be higher in both the HOC and NA groups and HOC achieved the highest SVR. In this large animal, translational study of an endotoxaemic model of sepsis, hydroxocobalamin improved survival when compared with saline.

High‐Dose Vitamin B12 in Vasodilatory Shock: A Narrative Review

“…MAP was higher in both the IV hydroxocobalamin and IV NE groups as compared with IV saline . In this translational study, serum inflammatory biomarkers MMP‐9, HSP‐70, and HMGB‐1 were significantly lower in the IV hydroxocobalamin group posttreatment, as compared with IV NE and IV saline …”

“…All 10 pigs that received IV hydroxocobalamin survived, compared with 8/10 that received IV NE and 5/10 that received IV saline (log‐rank P ‐value < 0.03) . MAP was higher in both the IV hydroxocobalamin and IV NE groups as compared with IV saline . In this translational study, serum inflammatory biomarkers MMP‐9, HSP‐70, and HMGB‐1 were significantly lower in the IV hydroxocobalamin group posttreatment, as compared with IV NE and IV saline …”

“…There were no baseline differences between groups. All 10 pigs that received IV hydroxocobalamin survived, compared with 8/10 that received IV NE and 5/10 that received IV saline (log‐rank P ‐value < 0.03) . MAP was higher in both the IV hydroxocobalamin and IV NE groups as compared with IV saline .…”

“…In 2018, Bebarta et al conducted a randomized controlled trial to compare survival and blood pressure in a swine model of LPS‐induced septic shock treated with IV hydroxocobalamin (200 mg/kg followed by 15 mg/kg IV infusion), IV norepinephrine (NE) to increase MAP, or IV saline (1.5 mL/kg/h) . There were no baseline differences between groups.…”

Comparison of hydroxocobalamin with other resuscitative fluids in volume-controlled and uncontrolled hemorrhage models in swine (Sus-scrofa)

“…Hydroxocobalamin (HOC), a synthetic form of vitamin B12, is a safe, Food and Drug Administration (FDA)-approved, effective xenobiotic indicated for cyanide-induced shock. Several groups have previously evaluated the use of HOC as an antidote for different toxicities in swine models, to include LPS, 16 hydrogen sulfide, 17 cyanide 18,19 and methanethiol 20 . In those studies, it was observed that HOC is not only effective against those toxicities, but it also improves hypotension by increasing systolic blood pressure (sBP), including in swine volume-controlled hemorrhagic shock models, when compared to Hextend or no treatment (control) 21,22 .…”