Is intravenous hydroxocobalamin an effective treatment for vasoplegia-associated shock?

Background
Vasoplegia is generally defined as prolonged vasodilation due to a pathological decrease in systemic vascular resistance, which causes persistent hypotension even in the setting of normal or increased cardiac output.1,2 Vasoplegia is one of the main physiological dysfunctions in shock, and managing vasoplegia along with maintaining hemodynamic stability are primary treatment goals for patients with shock.

The standard of care for management of shock-associated vasoplegia according to the Surviving Sepsis Campaign is vasopressor support with norepinephrine – the first choice over other vasopressor agents to maintain a mean arterial pressure (MAP) of 65 mmHg.3 For refractory shock-associated vasoplegia, numerous rescue or adjunctive agents have been evaluated including methylene blue or thiamine.4

Hydroxocobalamin is the injectable active form of vitamin B12, often used for treatment of cyanide poisoning and vitamin B12 deficiency.5 One known effect of high dose hydroxocobalamin is increased blood pressure due to its ability to inhibit nitric oxide (NO) and other inflammatory mediators such as NO synthase, guanylate cyclase, and hydrogen sulfide (H2S). This inhibition results in an increase in vascular smooth muscle constriction and reduced vasodilation, thus increasing blood pressure. Currently there are no guideline recommendations for or against the use of hydroxocobalamin for management of vasoplegia in shock patients.

Efficacy of Hydroxocobalamin in Shock
While the use of hydroxocobalamin is hypothesized to help with shock-associated refractory vasoplegia, there are a limited number of studies testing this hypothesis. The majority of literature to date are observational studies with only 1 randomized controlled trial.5-16

Randomized Controlled Trial
One phase 2, randomized, double-blind trial conducted at a single center compared 5 g intravenous hydroxocobalamin (200 mL over 15 minutes) as a single dose with placebo in critically ill adults with septic shock.6 The primary objective of the trial was to study feasibility in terms of enrollment, compliance, and contamination rates to help pave the way for future studies, but the secondary endpoints included clinical outcomes such as the change in H2S concentrations over time and vasopressor dose requirements.

The study enrolled adults within 48 hours of admission to the intensive care unit (ICU) with a diagnosis of septic shock who were receiving norepinephrine infusion at a minimum of 0.1 mcg/kg/min for 15 minutes (or equivalent dose of dopamine, phenylephrine, or epinephrine). Over a 19-month period (July 19, 2019 to March 16, 2020), 1,234 patients were screened with 70 eligible patients and only 20 enrolled.6 For the feasibility outcomes, the enrollment rate for the study was 1.05 patients/month with all 20 patients completing the treatment and protocol. No patients were lost to follow-up, and there was no contamination.

Thirty-minutes post-hydroxocobalamin infusion, the treatment group compared to placebo had a significant reduction in vasopressor requirements (-36% [interquartile range (IQR), -48% to -31%] vs 4% [IQR, -5% to 13%]; p<0.001) and at 3 hours post-infusion (-28% [IQR, -67% to -12%] vs 10% [IQR, -14% to 49%]; p=0.019).6 The treatment group compared to placebo also had a larger decrease in H2S over 45 minutes (-0.80 ± 1.73 μM vs -0.21 ± 0.64 μM; p=0.3), but this was not found to be statistically significant. Hospital mortality, ICU mortality, ICU-free days, and vasopressor-free days were also not statistically significant between the 2 groups. No serious adverse events occurred.

Systematic Review
A 2023 systematic review/meta-analysis of 24 studies (12 case reports, 9 case series, 3 cohort studies) evaluated the use of hydroxocobalamin for vasoplegia in a variety of settings including cardiac surgery, liver transplant, septic shock, drug-induced hypotension, and noncardiac postoperative vasoplegia.7 Similar to the RCT, the majority of studies used a 5 g bolus dose given over 10 or 15 minutes. The pooled analysis of the 3 cohort studies (N=143) comparing methylene blue and hydroxocobalamin for cardiac surgery-related vasoplegia, showed a greater increase in MAP at 1 hour with hydroxocobalamin compared to methylene blue (mean difference, 7.80; 95% CI, 2.63 to 12.98). The vasopressor requirement was similar between groups at 1 hour (mean difference -0.06; 95% CI, -0.21 to 0.09). No difference in mortality rates were noted (OR, 0.92; 95% CI, 0.42 to 2.0). For the 1 case report and 1 case series on the use of hydroxocobalamin for septic shock, a mean increase in MAP of at least 15 mmHg was reported with a corresponding decrease in vasopressor requirement. The mortality rate was high at 71.4%.

Observational Trials
The following table includes retrospective observational studies that represented at least 30 patients addressing the use of hydroxocobalamin for different etiologies of vasoplegia.5, 9, 12,13, 15

Table 1. Observational studies on the use of hydroxocobalamin for refractory vasoplegia.5, 9, 12,13, 15
Study design and durationSubjectsInterventionsResultsComments/
Conclusions
Hiruy 20235N=120 patients who received hydroxocobalamin (n=77) or MB (n=43) for vasoplegia associated with cardiopulmonary bypassHydroxocobalamin 5 g IV infusion over 15 minutes

MB (n=32 received bolus injection; n=11 received bolus followed by continuous infusion)		Vasopressor requirements were lower with hydroxocobalamin at all timepoints through 24 hours

MAP was greater with hydroxocobalamin at all timepoints through 24 hours

LOS and mortality were not significantly different between groups		The groups were significantly different at baseline with higher vasopressor requirements and lower MAP in the MB group. Although these differences were accounted for in the results of the trial, it is still notable.
Ritter 202212N=35 patients with refractory vasoplegia from various etiologiesHydroxocobalamin 5g IV single bolus dosePost-infusion MAP did not improve (73.4 mmHg pre-infusion vs 73.2 mmHg post-infusion)

No reduction in vasopressors was noted		Hydroxocobalamin was not shown to be effective, and mortality rates remained high.
Kram 202213N=142 patients that received MB (n=120) or hydroxocobalamin (n=22) for refractory vasoplegia associated with cardiopulmonary bypassHydroxocobalamin 5 g IV infusion over 15 minutes

MB 1.2 mg/kg IV bolus (median dose)		Median % change from baseline in MAP was significantly higher with MB at all timepoints

Vasopressor requirements were similar between groups

Similar mortality rate around 20% in each group		The authors considered MB and hydroxocobalamin to have similar effects in patients with cardiopulmonary bypass-related vasoplegia.
Furnish 202015N=35 patients who received MB (n=16) or hydroxocobalamin (n=19) perioperatively for suspected vasoplegia in cardiothoracic surgeryHydroxocobalamin 5 g IV

MB (dose range of 40 to 200 mg)		Vasopressor requirements were similar between groups in the first hour after MB or hydroxocobalamin administration (0.374 mg/kg/min vs 0.326 mg/kg/min; p=0.25)

Both agents increased MAP at 1 hour (10.6 mmHg with MB and 11.8 mmHg with hydroxocobalamin)		Hydroxocobalamin and MB were associated with increased MAP but not decreased vasopressor requirements in the hour after administration.
Shah 20189N=33 patients with refractory vasoplegia following cardiac surgeryHydroxocobalamin 5g IV infusion over 15 minutes9 poor responders (little or no immediate response with slowly increasing MAP up to 2 hours)

8 responders (immediate MAP increase with sustained MAP >65 mmHg)

9 sustainers (MAP increase of 10 mmHg over 110 minutes, consistently >65 mmHg)

7 rebounders (MAP >100 mmHg 30 minutes after infusion, then decrease to 65 mmHg over 1 hour)

All groups showed varying reductions in the vasopressor requirements		Inconsistent responses were seen in patients with vasoplegia treated with hydroxocobalamin.
Abbreviations: IV=intravenous; LOS=length of stay; MAP=mean arterial pressure; MB=methylene blue.

Discussion
One randomized controlled study found a significant decrease in vasopressor requirements and a decrease in H2S with hydroxocobalamin use in septic shock. However, as a feasibility study, the small sample size and other limitations prohibit widespread applicability of the trial. Positive benefits of hydroxocobalamin were also seen in a systematic review of observational trials; however, the observational nature of the included trials limits firm conclusions regarding the efficacy of hydroxocobalamin. Individual observational studies indicated an inconsistent effect of hydroxocobalamin on increasing MAP and other clinical outcomes with high mortality rates in most studies.

Conclusion
The evidence for the use of hydroxocobalamin for treatment-resistant vasoplegia is inconsistent. Some studies reported rapid, short-lived increases in MAP and decreased vasopressor requirements while others failed to find treatment benefit. Larger, randomized controlled studies with relevant clinical outcomes are needed to improve the evidence supporting the use of hydroxocobalamin. Until more data is available, hydroxocobalamin use for shock-associated refractory vasoplegia should be reserved for treatment-refractory, carefully selected patients.

References

  1. Haseer Koya H, Paul M. Shock. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK531492/
  2. Lambden S, Creagh-Brown BC, Hunt J, Summers C, Forni LG. Definitions and pathophysiology of vasoplegic shock. Crit Care. 2018;22(1):174. doi:10.1186/s13054-018-2102-1
  3. Evans L, Rhodes A, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 2021;47(11):1181-1247. doi:10.1007/s00134-021-06506-y
  4. Chow JH, Abuelkasem E, Sankova S, Henderson RA, Mazzeffi MA, Tanaka KA. Reversal of vasodilatory shock: current perspectives on conventional, rescue, and emerging vasoactive agents for the treatment of shock. Anesth Analg. 2020;130(1):15-30. doi:10.1213/ANE.0000000000004343
  5. Hiruy A, Ciapala S, Donaldson C, Wang L, Hohlfelder B. Hydroxocobalamin versus methylene blue for the treatment of vasoplegic shock associated with cardiopulmonary bypass. J Cardiothorac Vasc Anesth. 2023;37(11):2228-2235. doi:10.1053/j.jvca.2023.07.015
  6. Patel JJ, Willoughby R, Peterson J, et al. 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;163(2):303-312. doi:10.1016/j.chest.2022.09.021
  7. Brokmeier HM, Seelhammer TG, Nei SD, et al. Hydroxocobalamin for vasodilatory hypotension in shock: A systematic review with meta-analysis for comparison to methylene blue. J Cardiothorac Vasc Anesth. 2023;37(9):1757-1772. doi:10.1053/j.jvca.2023.04.006
  8. Boettcher BT, Woehlck HJ, Makker H, Pagel PS, Freed JK. Hydroxocobalamin for treatment of catecholamine-resistant vasoplegia during liver transplantation: A single-center series of 20 cases. Int J Surg Case Rep. 2022;98:107488. doi:10.1016/j.ijscr.2022.107488
  9. Shah PR, Reynolds PS, Pal N, Tang D, McCarthy H, Spiess BD. Hydroxocobalamin for the treatment of cardiac surgery-associated vasoplegia: a case series. L’hydroxocobalamine pour le traitement de la vasoplégie associée à la chirurgie cardiaque : une série de cas. Can J Anaesth. 2018;65(5):560-568. doi:10.1007/s12630-017-1029-3
  10. Bak MA, Smith JA, Murfin B, Chen Y. High-Dose Hydroxocobalamin for refractory vasoplegia post cardiac surgery. Cureus. 2022;14(8):e28267. doi:10.7759/cureus.28267
  11. Blaha M, Blais M, Olson L. The durability of intravenous hydroxocobalamin in vasoplegia. Cureus. 2023;15(4):e38307. doi:10.7759/cureus.38307
  12. Ritter LA, Maldarelli M, McCurdy MT, et al. Effects of a single bolus of hydroxocobalamin on hemodynamics in vasodilatory shock. J Crit Care. 2022;67:66-71. doi:10.1016/j.jcrc.2021.09.024
  13. Kram SJ, Kram BL, Cook JC, Ohman KL, Ghadimi K. Hydroxocobalamin or methylene blue for vasoplegic syndrome in adult cardiothoracic surgery. J Cardiothorac Vasc Anesth. 2022;36(2):469-476. doi:10.1053/j.jvca.2021.05.042
  14. Sacco AJ, Cunningham CA, Kosiorek HE, Sen A. Hydroxocobalamin in refractory septic shock: A retrospective case series. Crit Care Explor. 2021;3(4):e0408. doi:10.1097/CCE.0000000000000408
  15. Furnish C, Mueller SW, Kiser TH, Dufficy L, Sullivan B, Beyer JT. Hydroxocobalamin versus methylene blue for vasoplegic syndrome in cardiothoracic surgery: A retrospective cohort. J Cardiothorac Vasc Anesth. 2020;34(7):1763-1770. doi:10.1053/j.jvca.2020.01.033
  16. Feih JT, Rinka JRG, Zundel MT. Methylene blue monotherapy compared with combination therapy with hydroxocobalamin for the treatment of refractory vasoplegic syndrome: aretrospective cohort study. J Cardiothorac Vasc Anesth. 2019;33(5):1301-1307. doi:10.1053/j.jvca.2018.11.020

Prepared by:
Yazan Faydi
PharmD Candidate Class of 2024
University of Illinois at Chicago College of Pharmacy

Reviewed by:
Courtney Kreuger, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

April 2024

The information presented is current as February 21, 2024. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.