Hydroxycobalamin vs Methylene Blue for Vasoplegic Shock from Cardiopulmonary Bypass

Background Information:

Vasoplegic shock is defined as hypotension with normal or increased cardiac output and can commonly occur in post-cardiac surgery patients having received cardiopulmonary bypass. This dysregulation of vasodilation is associated with a mortality of close to 25%. After catecholamine vasopressors, treatment options include angiotensin II, corticosteroids, methylene blue and hydroxocobalamin. The latter two have been investigated in limited comparative studies leading to no significant differences in vasopressor requirements. The authors of this retrospective cohort study sought to evaluate the impact of hydroxocobalamin compared with methylene blue on vasopressor requirements and other hemodynamic parameters in vasoplegic shock.

Paper: Hiruy A, et al. Hydroxocobalamin Versus Methylene Blue for the Treatment of Vasoplegic Shock Associated With Cardiopulmonary Bypass. J Cardiothorac Vasc Anesth. 2023 Jul 19. Epub ahead of print. PMID: 37586951

Clinical Question:

• In patients requiring cardiopulmonary bypass and developing vasopressor-resistant vasoplegic shock, what is the impact of hydroxocobalamin compared to methylene blue in improving vasopressor requirements over the first 24 hours?

What They Did:

• Retrospective cohort analysis of post-cardiothoracic surgery patients at a single large academic center
• Methylene blue (IV bolus with or without continuous infusion) was utilized between January 2016 and August 2019, then hydroxocobalamin was the primary agent used from July 2019 to July 2021
• The dosing for the study medications were as follows:
  • Hydroxocobalamin Dose = 5g IV over 15min
  • Methylene Blue Doses:
    • Bolus: 1.2mg/kg (1 to 2mg/kg)
    • Infusion: 0.25mg/kg/hr for a median duration of 10hrs (0.25 to 1mg/kg/hr)
• Information regarding the vasopressors used in the study is as follows:
  • Norepinephrine equivalents = norepinephrine mcg/kg/min + (phenylephrine mcg/kg/min/10) + epinephrine mcg/kg/min + (vasopressin units/min x2.5)
  • Angiotensin II was not available at the institution and dopamine was not used in any patients included in the analysis during the study period
    

Inclusion Criteria:

• Adult patients > 18 years of age
• Vasopressor requirements were higher than 0.2 ug/kg/min of norepinephrine equivalent at time of hydroxocobalamin or methylene blue administration
  

Exclusion Criteria:

• Administration of hydroxocobalamin or methylene blue for non-VS indications
• Hydroxocobalamin or methylene blue given > 48 hours after CPB
• Pre-intervention cardiac index < 2.0 L/min/m2 (measured either with thermodilution or calculated using the Fick Method)
• Administration of both hydroxocobalamin and methylene blue
• Return to the OR for postoperative hemorrhage within 48 hours of initial surgery
  

Outcomes:

Primary

• Change in vasopressor requirement over time after methylene blue or hydroxocobalamin initiation assessed at 1, 3, 6, 12 and 24 hours post study drug administration
  • Expressed as Norepinephrine Equivalent (NEE)
  • NEE = Norepinephrine (ug/kg/min) + (Phenylephrine (ug/kg/min)/10) + epinephrine (ug/kg/min) + (vasopressin (units/min) x 2.5)

Secondary

• Hemodynamic outcomes such as MAP, SVR and lactate evaluated at baseline and 1, 3, 6, 12 and 24 hours post study drug administration
• ICU length of stay
• Hospital length of stay
• Hospital mortality
  

Results:

Critical Results:

Strengths:

• Largest comparative cohort of cardiothoracic surgery patients treated with hydroxocobalamin or methylene blue for refractory vasoplegic shock
• Builds upon current evidence regarding the use of these two therapies for vasoplegic shock
• Excluded patient with cardiogenic and hemorrhagic shock to only focus on those with vasoplegic shock
• Included a wide range of cardiothoracic surgery procedures (ie. CABG, Valve repair/replacement, LVAD and Heart/Lung Transplants)
• Helps answer a clinically relevant question related to a serious post-surgery complication
• Included in-depth pertinent surgical characteristics in addition to typical demographic information

Limitations:

• Limited external validity given this was done at a single large academic medical center
• Retrospective study with no placebo group
• Dosing of inotropes and other supportive factors impacting hemodynamics were not captured
• Missing secondary data such as SVR and lactate was estimated based on a model
• This study did not address potential adverse effects of either medication investigated
• Lack of patient oriented primary and secondary outcomes
• Unbalanced groups in terms of baseline characteristics and especially with regard to the amount of intraoperative vasopressors received between the two groups. More patients in the methylene blue group received vasopressin (98% vs 81%), phenylepinephrine (61% vs 1%) and dobutamine (14% vs 4%) compared to the hydroxocobalamin group 
• Patients in the methylene blue group had lower mean preoperative LVEF (35%) compared to the hydroxocobalamin group (46%)
• Methylene blue group patients received preoperative RAS inhibitors (21%) more frequently than the patients in the hydroxocobalamin group (6.5%)
• Higher baseline MAPs in hydroxocobalamin group may have led to an underestimation of treatment effect 
• Higher percentage of surgical cases were redo procedures in the methylene blue group compared to the hydroxocobalamin group (63% vs 43%)
• There are many confounding variables that may have impacted an accurate comparison between these two medications which are elaborated further in the discussion section below

Discussion:

• It’s worth noting that the baseline MAPs were higher in the hydroxocobalamin group and that it’s possible the patients who received methylene blue were in more severe shock states that may not have been amenable to pharmacologic agents alone. 
• The above point may suggest that because the patients receiving hydroxocobalamin were less sick, the results are skewed to favor that intervention over methylene blue
• There are many internal and external confounding variables that the authors suggest gives hydroxocobalamin it’s added benefit:
  • Dosing differences between the two medications (Bolus +/- continuous infusion for methylene blue vs standardized dose for hydroxocobalamin)
  • Differences in medical practice between 2016 – 2019 and 2019 – 2021
  • Differences in practice settings were the medications were administered (Methylene blue was more commonly given in the OR, which may signal a more profound state of vasoplegic shock compared in this group)
• What the authors fail to recognize, is that the above confounding variables actually serve to significantly limit the accurate comparison of these two medications for a post-surgical complication such as vasoplegic shock
• The lack of a placebo group makes it difficult to compare these medications to standard therapy/something else 
• Patients in the methylene blue group were much sicker than the hydroxocobalamin group as demonstrated by a significantly lower EF, higher percentage of redo procedures and higher use of perioperative inhibitors of RAS thus it makes sense the patients in these group got more intraoperative phenylepinephrine, vasopressin, dobutamine and milrinone. 
• So with yet another confounding variable added (sicker patients at baseline in methylene blue group), the comparison of these two medications is yet again even more difficult
• There was no difference in ICU and hospital length of stays or hospital mortality between the two groups. Which should prompt the question, how much of a difference does hydroxocobalamin actually make in decreasing the vasopressor requirement and increasing the MAP if this had no impact on ICU/hospital LOS or hospital mortality?
• Until further evidence presents itself, what this study offers is building upon what we do know. Both these medications continue to serve as options for treating post-cardiac surgery patients in vasoplegic shock. Whether one is truly better than the other remains to be seen.

Author’s Conclusions:

• Hydroxocobalamin was associated with a greater reduction in vasopressor requirements than methylene blue in treating VS associated with cardiopulmonary bypass

Our Conclusion:

• This single-center retrospective trial with no placebo group had too many confounding variables to accurately compare hydroxocobalamin to methylene blue for vasoplegic shock. From a sicker baseline patient population in the methylene blue group to variations in dosing and practice setting administration, the efficacy of hydroxocobalamin should not come as a surprise given it was set up for success. 

Clinical Bottom Line:

• This retrospective single-center study failed to accurately compare the use of hydroxocobalamin to methylene blue in reducing vasopressor requirements when treating vasoplegic shock associated with cardiopulmonary bypass. While it builds upon the current evidence suggesting either of these medications can be used, we can not definitively say one is more effective than the other without more methodological sound studies.

REFERENCES:

1. Hiruy A, et al. Hydroxocobalamin Versus Methylene Blue for the Treatment of Vasoplegic Shock Associated With Cardiopulmonary Bypass. J Cardiothorac Vasc Anesth. 2023 Jul 19. Epub ahead of print. PMID: 37586951 
2. Mehaffey JH, et al. Methylene Blue for Vasoplegic Syndrome After Cardiac Operation: Early Administration Improves Survival. Ann Thorac Surg. Epub 2017 May 24. PMID: 28551045
3. Bak MA, et al. High-Dose Hydroxocobalamin for Refractory Vasoplegia Post Cardiac Surgery. Cureus. 2022 Aug 22. PMID: 36039127
   

Post Peer Reviewed By: Salim Rezaie, MD (Twitter: @Srrezaie)