What is the evidence for using methylene blue vs hydroxocobalamin for septic shock?

Comment by InpharmD Researcher

Current guidelines do not address either methylene blue or vitamin B12 as treatments for septic shock. Multiple papers hypothesize a potential role of vitamin B12 for septic shock based on biomarkers; however, there is a lack of robust clinical data showing a benefit. The literature on methylene blue focuses on refractory or vasodilatory shock, usually after cardiac surgery. While most of the literature for either agent is based on retrospective case reports, a recent pilot study found high-dose hydroxocobalamin was better than placebo at reducing vasopressor dose in patients with septic shock; however, there were no differences in clinical outcomes between vitamin B12 and placebo.

Background

The most recent guidelines from the Surviving Sepsis Campaign, published in 2021, do not mention either methylene blue or vitamin B12 as potential options for sepsis or septic shock. [1]

Methylene blue may be considered as rescue therapy in catecholamine-resistant vasoplegic shock patients but there is insufficient evidence to support its use as a first-line agent. It can be used for norepinephrine-refractory vasoplegia developed due to cardiopulmonary bypass, systemic inflammatory response syndrome (SIRS), burns, or anaphylaxis without the development of side effects. A dose of 2 mg/kg given intravenously (IV) as a bolus followed by continuous infusion is recommended, as plasma concentrations are greatly reduced in the first 40 minutes. The lethal dose is 40 mg/kg. A single dose of 1.5 mg/kg may also be effective at reducing morbidity and mortality from vasoplegic shock. It is reported that methylene blue may lead to severe serotonin syndrome when combined with other serotonergic medications. [2]

Methylene blue is considered effective for the treatment of distributive shock caused by sepsis or anaphylaxis. There was hemodynamic improvement seen in the patients receiving methylene blue for radiocontrast-related anaphylaxis developed during coronary angiography. It is also reported that methylene blue was beneficial when used for refractory hypotension secondary to protamine during cardiac bypass surgery. Studies on the use of methylene blue show that it may lead to an increase in mean arterial pressure and a decrease in the need for pressors. Methylene blue may be effective at treating refractory distributive shock from drug overdose with a dihydropyridine calcium channel blocker. It is recommended that methylene blue be used at a dose of 1-2 mg/kg IV as a single bolus, doses > 7 mg/kg may be associated with adverse events such as induction of methemoglobinemia, acute hemolytic anemia, and negative effects on pulmonary function. Methylene blue may be considered as an alternative option after failure of cardiac support with catecholamines and volume expansion. Patients with pulmonary hypotension, G6PD deficiency and acute lung injury are not recommended to use methylene blue. [3]

A systematic review of younger patients (less than or equal to 25 year old) with refractory shock treated with methylene blue found the agent to be safe and effective for children. However, the data is limited due to poor quality of evidence. Most studies are either case reports or small, observational studies. In general, studies reported improvement in mean material pressure and being able to wean off vasoactive and inotropic support. Doses observed ranged from a bolus of 0.5 mg/kg to 2 mg/kg and were mostly single administration. One randomized study in Egypt compared methylene blue 1.5 mg/kg with norepinephrine, finding quicker improvements in mean arterial pressure. [4]

A review article discussing the potential opportunities of vitamin B12 (cobalamin) use in a critical care setting. The mechanisms by which vitamin B12 can be beneficial in critically ill states are mentioned. One mechanism was through inhibitions of intracellular peroxide production to prevent cellular apoptosis. In vitro studies also showed that it can help regulate inflammatory cytokine production. [5]

An article discussing the possible role of high-dose cobalamin in SIRS, sepsis, severe sepsis, and septic or traumatic shock states. It mentions how the elevations in transcobalamins, cobalamin carrier proteins, in acute inflammatory states suggest there is an increased demand for cobalamin during these situations. It also goes on to mention the possible ability of cobalamin to reduce inflammation by helping to regulate NFκB, TNFα, reduce nitric oxide radicals, and promote oxidative phosphorylation. [6]

One review article looked at trace elements and vitamin status during states of inflammation, based on CRP levels. Based on the articles reviewed, it was noted that there were no association of changes in vitamin B12 (reference range = 188-1059 pg/mL) levels with major inflammation (CRP ~100-200 mg/L). [7]

One review article discusses pathophysiology and treatment options for vasoplegic syndrome. Cardiopulmonary bypass can lead to the vasodilatory shock state of vasoplegic syndrome, however, the mechanism of the syndrome may vary depending on the bypass procedure. The pathophysiology of vasoplegic syndrome is similar to that of sepsis. Thus, current treatment options are extrapolated from septic shock therapy. Hydroxocobalamin is listed as a treatment option for this condition at 5 grams IV administered over 15 minutes. This article discusses some data from a study comparing Hydroxocobalamin to Methylene Blue in 58 patients, 29 in each group, pending publication from one of the co-authors. The authors found similar responses in MAP, vasopressor requirements at 1 h, time to discontinuation of vasopressors, and length of stay, and a higher incidence of renal replacement therapy in patients receiving hydroxocobalamin compared to methylene blue alone. Although a significant number of hydroxocobalamin patients also received methylene blue prior and were sicker in comparison. [8]

References:

[1] Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Crit Care Med. 2021;49(11):e1063-e1143. doi:10.1097/CCM.0000000000005337
[2] Liu H, Yu L, Yang L, Green MS. Vasoplegic syndrome: An update on perioperative considerations. J Clin Anesth. 2017;40:63-71.
[3] Jang DH, Nelson LS, Hoffman RS. Methylene blue for distributive shock: a potential new use of an old antidote. J Med Toxicol. 2013;9(3):242-9.
[4] Otero Luna AV, Johnson R, Funaro M, Canarie MF, Pierce RW. Methylene Blue for Refractory Shock in Children: A Systematic Review and Survey Practice Analysis. Pediatr Crit Care Med. 2020;21(6):e378-e386. doi:10.1097/PCC.0000000000002295
[5] Manzanares W, Hardy G. Vitamin B12: the forgotten micronutrient for critical care: Current Opinion in Clinical Nutrition and Metabolic Care. 2010;13(6):662-668.
[6] Wheatley C. A scarlet pimpernel for the resolution of inflammation? The role of supra-therapeutic doses of cobalamin, in the treatment of systemic inflammatory response syndrome (Sirs), sepsis, severe sepsis, and septic or traumatic shock. Medical Hypotheses. 2006;67(1):124-142.
[7] Galloway SP, McMillan DC, Sattar N. Effect of the inflammatory response on trace element and vitamin status. Ann Clin Biochem. 2000;37(3):289-297.
[8] Busse LW, Barker N, Petersen C. Vasoplegic syndrome following cardiothoracic surgery—review of pathophysiology and update of treatment options. Crit Care. 2020;24(1):36.
Literature Review

A search of the published medical literature revealed 8 studies investigating the researchable question:

What is the evidence for using methylene blue vs hydroxocobalamin for septic shock?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-8 for your response.

 

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)

Design

Randomized, single-center, double-blind, placebo-controlled, phase 2, pilot trial

N= 20

Objective

To establish the feasibility and fidelity of comparing high-dose hydroxocobalamin with placebo in patients with septic shock

Study Groups

Hydroxocobalamin (n= 10)

Placebo (n= 10)

Inclusion Criteria

Age ≥18; within 48 h of medical or surgical ICU admission; a primary diagnosis of septic shock receiving norepinephrine infusion of 0.10 μg/kg/min for a minimum of 15 min (or equivalent dose phenylephrine, epinephrine, or dopamine)

Exclusion Criteria

 Known hypersensitivity to the hydroxocobalamin formulation; pregnancy; a history of urinary calcium oxalate crystals; moribund patients; active hemolysis or bleeding requiring two or more hemoglobin measurements per day

Methods

Eligible intensive care unit patients diagnosed with septic shock at a single Wisconsin center were randomized to receive either a single 5 g dose of high-dose IV hydroxocobalamin (200 mL) infused over 15 min via central venous catheter or matching placebo (normal saline). 

All patients received best practice management of septic shock, including crystalloid resuscitation and broad-spectrum antibiotics. Norepinephrine was the first-choice vasopressor for all patients titrated to a MAP of 65 mm Hg; epinephrine,  phenylephrine, and vasopressin could also be initiated at the discretion of the care team.

Duration

 Follow-up: up to 28 days or discharge/death

Outcome Measures

Primary: number of study drug doses delivered; patients who completed the assigned interventions and laboratory protocols

Secondary: hydrogen sulfide levels after 30 minutes of drug delivery; vasopressor dose after 3 hours of study drug infusion

Baseline Characteristics

  

Hydroxocobalamin (n= 10)

Placebo (n= 10)

  

Age, years (IQR)

 64 (58-74) 57 (51-72)  

Female

 50% 50%  

Comorbidities

Heart failure

COPD

Cancer

Diabetes

Hypertension

 

20%

10%

20%

50%

80%

 

30%

20%

10%

40%

50%

  

Mechanical ventilation

 90% 80%  

Time to first antibiotic, hours (IQR)

 2.47 (1.09-4.27) 3.82 (2.41-4.33)  

APACHE II score (IQR)

SOFA score (IQR)

28 (26-35)

14 (10.2-14)

25 (20-37)

14 (8.2-14.8)

  

Stress dose steroids

 80% 90%  
IQR: interquartile range

Results

Endpoint

Hydroxocobalamin (n= 10)

Placebo (n= 10)

p-value

Patients who completed the assigned interventions and laboratory protocols

 100% 100% N/A

Norepinephrine (or equivalent) dose, mcg/kg/min (IQR)

Baseline

After 30 min

After 3 h

 

0.29 (0.20-0.36)

0.14 (0.10-0.21)

0.13 (0.10-0.21)

 

0.31 (0.20-0.54)

0.30 (0.20-0.72)

0.26 (0.17-0.90)

 

0.4

0.01

0.06

Hydrogen sulfide levels, mcM

Baseline

Change after drug delivery

 

6.25 ± 3.49

-0.80 ± 1.73

 

5.52 ± 1.89

-0.21 ± 0.64

 

N/A

0.3

Hospital mortality

ICU mortality

40%

30%

40%

40%

1.0

1.0

Vasopressor-free days (IQR)

 18 (0-26) 22 (0-26) 0.81

Adverse Events

No serious adverse events were reported in either group.

Study Author Conclusions

This phase 2 double-blind, placebo-controlled single-center pilot RCT evaluating high-dose IV hydroxocobalamin in septic shock established both feasibility and hypothesis-generating outcomes data to inform phase 2 efficacy trial design.

InpharmD Researcher Critique

This study was impacted by COVID-19, forcing a change in the primary endpoint to something that is clinically meaningless. While a small pilot study, tertiary clinical endpoints do not indicate a benefit with hydroxocobalamin administration; however, there is enough hypothesis-generating data to allow future studies. While this study was blinded, laboratory values may have accidentally unblinded the groups due to the potential of hydroxocobalamin to demonstrate chromaturia. 



References:

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

 

Use of High-Dose Hydroxocobalamin for Septic Shock: A Case Report

Design

Case report

Case 1

A 55-year-old male with a history of poorly controlled type 2 diabetes mellitus (T2DM) presented to the emergency department with shortness of breath and neck pain for three days. The patient was feeling ill five days prior and became progressively dyspneic with worsening odynophagia and dysarthria. Vitals on presentation were heart rate of 138 beats/min, blood pressure (BP) 89/47 mmHg, respiratory rate 22 breaths/min, temperature 37.4°C, and oxygen saturation 93% on ambient air. Emergent laryngoscopy was performed followed by an urgent tracheostomy, and neck abscess washout performed on admission day.

On postoperative day 1, the patient became increasingly unstable, requiring vasopressor support with norepinephrine, vasopressin, and epinephrine. He was diagnosed with septic shock from necrotizing fasciitis with multiple organ failure, including acute ischemic cardiac injury, acute respiratory failure, acute kidney injury, and coagulopathy. Norepinephrine was increased to 0.31 µg/kg/min and epinephrine to 0.06 µg/kg/min. Then hydroxocobalamin 5 mg IV was administered. Mean arterial pressure (MAP) immediately increased to 76 mmHg and remained >70 mmHg while norepinephrine infusion was titrated down with the rate staying below 0.12 µg/kg/min during the following 12 hours and epinephrine stopped 4 hours after hydroxocobalamin administration but restarted at 0.01 µg/kg/hr. 

He did not require any more vasopressor support six days after admission. The remainder of his hospital stay he experienced an acute ischemic stroke and required 2 days of norepinephrine and dopamine, and was later discharged to an acute care facility after 43 days.

Case 2

A 57-year-old male with hepatitis C cirrhosis and chronic bilateral lower extremity swelling presented to the emergency department with severe leg pain. His vitals were a heart rate of 107 beats/min, BP 147/85mm Hg, respiratory rate 24 breaths/min, temperature 36.9°C, and oxygen saturation 97% on ambient air. He had an initial diagnosis of sepsis due to infection in the left lower extremity. Two days after admission, he was hypotensive despite fluid resuscitation and norepinephrine at 0.18 µg/kg/min. His physical examination showed diffuse petechiae and purpura on his left shin and medial thigh, and a large hemorrhagic bulla in the posterior leg.

He required a left above the knee amputation due to a necrotic soft tissue infection. He was diagnosed with septic shock from necrotizing fasciitis, pseudomonas bacteremia, and acute oliguric renal failure. Despite surgical management, he remained unstable, requiring high-dose norepinephrine and vasopressin for the next 3 days. Hydroxocobalamin 5 g IV was administered due to refractory hypotension and a positive fluid balance of 15 L. Norepinephrine was rapidly titrated to 0.05 µg/kg/min over the next four hours. One day after hydroxocobalamin administration, he was only on norepinephrine 0.02 µg/kg/min and vasopressin 0.04 U/min to keep mean arterial pressure above 65 mmHg and tolerating continuous renal replacement therapy.

Ten days after admission, he was off vasopressor support and after twenty-one days he was transferred to the burn unit. His remaining hospital course was complicated by recurrent sepsis, respiratory failure, hepatic failure, and renal failure. He was transitioned to comfort care measures after thirty-five days and pronounced dead the following day.

Study Author's  Conclusion

High-dose hydroxocobalamin (vitamin B12a) can be used as a rescue agent in a refractory septic shock state. In both cases, hydroxocobalamin rapidly raised mean arterial pressure while significantly reducing the vasopressor requirement, making it the most likely cause for the resolution of the vasoplegia associated with sepsis. Unlike methylene blue, hydroxocobalamin had a lasting vasopressor effect; thus a second dose was not needed.

InpharmD Researcher Critique

 From the presentation of these cases, the patients experienced a favorable response after the administration of hydroxocobalamin. The rate of administration was not noted in either of these cases thoµgh, only the dose.



References:

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

 

Innovative use of hydroxocobalamin with thiamine, ascorbic acid, and hydrocortisone in the treatment of a septic shock patient with fulminant leptospirosis: a case report

Design

Case Report

Case Presentation

A 59-year-old Pacific Islander presented with two days of recurrent headache, vomiting, abdominal pain, and myalgia. He was discharged after receiving antiemetics and fluids. Patient returned two days later with worsening abdominal discomfort, persistent headaches, coughing, and black tarry stool. He was admitted with acute respiratory distress syndrome, septic shock, acute liver and renal failure. Patient was placed on mechanical ventilation; he developed cardiac arrest for a brief period but had return of spontaneous circulation. Initial Sequential Organ Failure Assessment score was 16. With his history of working barefooted in a taro farm, it prompted an order for Leptospira Immunoglobulin M antibody test, which was positive. Along with intravenous fluid and broad-spectrum antibiotics, he required continuous norepinephrine, phenylephrine, vasopressin drips, and hydrocortisone. On day 3, hydroxocobalamin, thiamine, and ascorbic arated off all vasopressors. Despite being in the intensive care unit for 16 days and a prolonged hospitalization, he was discharged home and continued to be functional and ambulatory one year later.

Study Author Conclusions

The combination of these vitamins and hydrocortisone resulted in synergistic and lasting effect of hemodynamic parameters that can potentially improve quality of health for septic shock survivors. Well-designed prospective studies are warranted to further evaluate their true efficacy.

InpharmD Researcher Critique

Although hydroxocobalamin was utilized in this case, there are additional confounding factors present making it difficult to determine the efficacy of it alone. However, based on previous randomized trials about vitamin c, hydrocortisone, and thiamine, there would be little impact on clinical outcome from these agents. Based on the available information for this case, hydroxocobalamin may have helped contribute towards a favorable outcome in this case. 



References:

Paz AG, Lo T. Innovative use of hydroxocobalamin with thiamine, ascorbic acid, and hydrocortisone in the treatment of a septic shock patient with fulminant leptospirosis: a case report. Chest. 2020;158(4):A974.

 

The Use of High-Dose Hydroxocobalamin for Vasoplegic Syndrome

Case Presentation

A 71-year-old male presented with progressive dyspnea on exertion, increasing over a three-week period. His past medical history included coronary artery disease, cardiomyopathy, heart failure, hypertension, hyperlipidemia, chronic obstructive pulmonary disease, depression, and gout. He was taking lisinopril, carvedilol, citalopram, simvastatin, budesonide/formoterol fumarate dihydrate, allopurinol, and colchicine. He was to undergo a coronary artery bypass graft due to a left anterior descending coronary artery thrombosis, a two-valve annuloplasty or repair, and patent foramen ovale closure.

He became hypotensive following anesthesia induction and was initiated on a norepinephrine drip at 0.05 ug/kg/min to 0.1 ug/kg/min, then reduced to 0.07 ug/kg/min at the start of surgery. Mean arterial pressure (MAP) was 30 to 40 mmHg with 6.5 L/min of systemic cardiopulmonary bypass pump flow. Norepinephrine was increased to 0.1 ug/kg/min along with adding a vasopressin drip at 2 U/hr. MAP declined to 20 mmHg or less, with minimal response to high-dose phenylephrine and norepinephrine boluses. After 70 minutes of cardiopulmonary bypass, a single dose of hydroxocobalamin 5 g was infused over 10 minutes, afterwhich the MAP responsed and increased to 70-80 mmHg. Norepinephrine was titrated to 0.05 ug/kg/min and vasopressin was stopped with the MAP remaining greater than 60 mmHg. He was transported to the intensive care unit after surgery while on norepinephrine at 0.05 ug/kg/min, epinephrine at 0.08 ug/kg/min, vasopressin at 2 U/hr, and inhaled epoprostinol at 50 mg/kg/min with a MAP of 80-90 mmHg. On postoperative day #1, he was extubated and only on epinephrine at 0.07 ug/kg/min for pressure support, which was discontinued later that day. He was discharged on postoperative day #11 with no noticeable decline in renal function during his stay. 

Study Author's Conclusion

This case represents the first report on the use of high-dose hydroxocobalamin for vasoplegic syndrome.  The use of hydroxocobalamin in this patient population presents a novel solution to this problem and may have additional clinical benefits beyond its effects on blood pressure, which will require further evaluation.

InpharmD Researcher Critique

 From the presentation of this case, it appears that the patient experienced a favorable response from the administration of hydroxocobalamin. There is little evidence to guide any dosing or administration rate for this drug during this condition though.



References:

Roderique JD, VanDyck K, Holman B, Tang D, Chui B, Spiess BD. The use of high-dose hydroxocobalamin for vasoplegic syndrome. Ann Thorac Surg. 2014 May;97(5):1785-6. doi: 10.1016/j.athoracsur.2013.08.050. PMID: 24792267.

 

Hydroxocobalamin for the treatment of cardiac surgery-associated vasoplegia: a case series

Design

Retrospective chart review

N=33

Objective

To describe the results from a retrospective chart review of patients from a single institution undergoing cardiac surgery with CPB, where B12 was used to reverse perioperative or post-CPB hypotension

Study Groups

Poor responders (n=9) - Showed little or no immediate response to B12 administration, but mean arterial pressure (MAP) continued to increase slowly, had little or no reduction in vasopressor doses

Responders (n=8) - Showed a response to B12 within 20 minutes of administration and sustained MAP > 65 mmHg, with approximately 50% reduction in vasopressor use over 1 hour

Sustainers (n=9) - Showed a small constant increase in MAP over duration of post-B12 monitoring period, with a total increase of approximately 10 mmHg over 110 minutes, had little or no reduction in vasopressor doses

Rebounders (n=7) - Showed an apparent hypertensive overshoot, peaking at MAP > 100 mmHg at approximately 30 minutes post-B12 administration, followed by a MAP decline to approximately 65 mmHg over the next hour, with an approximate 3-fold reduction in vasopressor doses

Methods

Inclusion criteria: age ≥18 years old, cardiac surgery patients with an emergency order for IV hydroxocobalamin

Exclusion criteria: missing data

This was a retrospective chart review from a single center in Virginia. Emergency off-label use of methylene blue and/or vitamin B12 (rescue therapy) was indicated when the attending surgeon and anesthesiologist agreed that there was significant potential for ongoing patient hemodynamic instability to contribute to vasodilatory shock and was sufficiently life-threatening to require immediate intervention. Rescue therapy was initiated if the patient was unable to maintain a mean arterial pressure (MAP) >65 mmHg despite pressor therapy.

These patients received methylene blue 1-2 mg/kg and/or hydroxocobalamin 5 g (20 mg/mL) given as a bolus over 15 minutes.

Duration

Reviewed patient charts from January 2013 to December 2015

Outcome Measures

Patient MAP response within 2 hours after administration of hydroxocobalamin

Baseline Characteristics

  

Received Hyroxocobalamin (N=33) 

Age

 53 ± 13

Weight, kg

 74 ± 14

Male

 28 (82%)

Preoperative medications

Beta-blockers within the last two weeks

Beta-blockers within the last 24 hours

Calcium channel blocker

 

7 (21%)

9 (26%)

3 (9%)

30-day mortality

 4 (12%)

Cardiac Function

Good (LVEF > 50%)

Moderate to poor (LVEF 21 - 50%)

Very poor (LVEF ≤20%)

Recent Myocardial Infarction (<90 days)

 

11 (32%)

8 (24%)

14 (44%)

2 (6%)

Results

 

Poor responders (n=9)

Responders (n=8)

Sustainers (n=9)

Rebounders (n=7)

Hydroxocobalamin timing

During Bypass

After Bypass

 

7 (78%)

2 (22%)

 

7 (88%)

1 (12%)

 

3 (33%)

6 (67%)

 

3 (43%)

4 (57%)

Methylene Blue administration

Before Bypass

During Bypass

After Bypass

 

0

3 (33%)

1 (11%)

 

1 (12%)

4 (50%)

1 (12%)

 

0

1 (11%)

1 (11%)

 

1 (14%)

2 (29%)

0

Weight, kg (IQR)

73 (71-91)

77 (67-83)

66 (65-80)

66 (64-76)

Preoperative EF, % (IQR)

22 (16-25)

20 (15-35)

30 (10-55)

35 (25-55)

Pre-B12 MAP, mmHg (IQR)

50 (46-57)

57 (54-64)

65 (64-73)

80 (70-82)

Length of stay, days (IQR)

27 (5-52)

17 (10-25)

24 (12-33)

10 (8-20)

Initial ICU duration, hours (IQR)

 337 (59-831) 266 (145-356) 137 (99-310) 100 (89-250)

Time of mechanial ventilation, hours (IQR)

 74 (44-275) 44 (18-208) 26 (9-80) 23 (14-25)

Mortality

 2 (22%)

2 (25%)

 0 0

Study Author Conclusions

Although vitamin B12 administration may provide a useful alternative therapy for refractory hypotension and vasoplegia, randomized controlled clinical trials are needed to assess efficacy, protocols for routine use, and appropriate dosing.

InpharmD Researcher Critique

Since 45% of the patients had also received methylene blue, which has a similar application in this setting, it is difficult to assess the true effect of vitamin B12 from these cases. One shortcoming of this case series is that it did not show the titration parameters for each vasopressor after the administration of vitamin B12, only what the author tells us for each group. Although there may be a role for vitamin B12 for these patients, randomized controlled trials need to be conducted to see which patients would experience the most benefit from it.



References:

Shah PR, Reynolds PS, Pal N, Tang D, McCarthy H, Spiess BD. Hydroxocobalamin for the treatment of cardiac surgery-associated vasoplegia: a case series. Can J Anesth/J Can Anesth. 2018;65(5):560-568.

 

A dose-finding study of methylene blue to inhibit nitric oxide actions in the hemodynamics of human septic shock

Design

Prospective, randomized, double-blinded, single center study

N= 15

Objective

To evaluate the benefit to risk ratio of treatment of human septic shock with help of methylene blue

Study Groups

Methylene blue at 1mg/kg (n=4)

Methylene blue at 3mg/kg (n=6)

Methylene blue at 7mg/kg (n=5)

Methods

Inclusion criteria: adults aged 18 - 80 years in intensive care unit (ICU) who had a pulmonary artery catheter inserted via the jugular or subclavian vein and after completion of initial resuscitation for septic shock

Exclusion criteria: myocardial infarction or cerebrovascular accident within the last 3 months, pregnancy, glucose-6-phosphate-dehydrogenase deficiency, anaphylactic reaction to methylene blue, creatinine >350 μmol/L and the use of nitrates within last 3 days

The acute physiology and chronic health evaluation (APACHE) II score and a chest radiograph were obtained on the day of the study. Hemodynamic parameters were measured before and after the infusion. 

Duration

Not reported

Outcome Measures

Hemodynamic, metabolic, and respiratory effects

Baseline Characteristics

   1mg/kg (n=4)

3mg/kg (n=6)

7mg/kg (n=5)

Age, years

  59.5±24.6  62.2±12.8  62.8±4.6

Male/Women

  1/3  2/4  3/2

APACHE II score

  21.3±2.1  25.7±8.3  18.8±3.3

Mortality at 28 days

  3 (75%)  3 (50%)  3 (60%)

All patients were mechanically ventilated and were treated by vasopressor therapy (norepinephrine, dobutamine, or dopamine).

Results

For hemodynamic parameters, infusion of methylene blue had a transient elevation of heart rate, cardiac index, mean arterial, pulmonary artery, pulmonary artery occlusion and central venous pressures, systemic vascular resistance, and ventricular stroke work indices. Methylene blue had a dose-dependent effect on cardiac index, mean arterial, mean pulmonary artery and pulmonary artery occlusion pressures, and left ventricular function.

For respiratory and metabolic parameters, the shunt fraction (Qs/Qt) slightly increased, the arterial PO2 fell in the 7mg/kg group, but the arterial PCO2 raised among the groups. The changes were dose-dependent and greater in the 7 mg/kg group. There were slightly increased methemoglobin levels at all doses. The gastric-arterial blood PCO2 gap was increased in the 7mg/kg group (from 4±12 to 10±10 mm Hg).

Adverse Events

Not discussed

Study Author Conclusions

Infusion of 1 to 3 mg/kg was sufficient to transiently elevate mean arterial pressure without increasing gastric-arterial blood PCO2 difference, whereas 7 mg/kg showed an increase in the gap and might compromise splanchnic perfusion adequacy.

InpharmD Researcher Critique

This is a prospective study with small size population in a single center.

 

References:

Juffermans NP, Vervloet MG, Daemen-Gubbels CR, Binnekade JM, de Jong M, Groeneveld AB. A dose-finding study of methylene blue to inhibit nitric oxide actions in the hemodynamics of human septic shock. Nitric Oxide. 2010;22(4):275-280. doi:10.1016/j.niox.2010.01.006

 

Methylene Blue Reduces Mortality and Morbidity in Vasoplegic Patients After Cardiac Surgery

Design

Randomized, placebo-controlled trial

N= 56

Objective

To analyze the incidence of the postoperative vasoplegic syndrome and to assess the impact of methylene blue treatment on morbidity and mortality

Study Groups

Methylene blue (n= 28)

Placebo (n= 28)

Methods

Inclusion criteria: patients presenting with vasoplegic syndrome following elective cardiac surgery

Exclusion criteria: not reported

Vasoplegic patients were randomized either to a placebo or methylene blue at 1.5 mg/kg dose intravenously for one hour.

Duration

Between January 2001 to June 2002

Baseline Characteristics

  

Placebo (n = 28)

Methylene blue (n = 28)

 

Age, years

  59.2  60.6  

Women

  4 4   

Coronary surgery

  26 23   

Number of grafts

  93  79  
 

Results

Endpoint

Placebo (n = 28)

Methylene blue (n = 28)

p-value

Meab arterial pressure (mm Hg)

 48.3  47.4 Not significant (NS)

Mean right atrial pressure (mm Hg)

3.9

3.7

 NS

Mean pulmonary arterial pressure (mm Hg)

14.3

13.8

 NS

Mortality 

6 (21.4%)

0

 0.01

Renal failure 

4 (14.3)

0

 0.05

Respiratory failure 

4

0

 0.05

Supraventricular arrhythmia 

8 (28.6%)

2 (7.1%)

 0.03

The overall mortality was of 27 patients (4.2%), 21 patients in the nonvasoplegic group (3.6%) and 6 patients were in the VS population (10.7%) [p value 0.02; odds ratio 0.31; CI 0.11 to 0.91]; of those 6 patients, they were in the placebo group (21.4%; p = 0.01) who died from sepsis and multi-organ failure.

Methylene blue showed a faster resolution of vasoplegia than the placebo (p = 0.002).

Adverse Events

N/A

Study Author Conclusions

The use of intravenous methylene blue at 1.5mg/kg was associated with mortality reduction compared to placebo. The drug defined a fast resolution of vasoplegia with no adverse effects.

InpharmD Researcher Critique

There are no inclusion and exclusion criteria reported.

The dose of methylene blue at 1.5mg/kg dose infused over 1 hour is safe and effective for treatment of vasoplegia after cardiac surgery.

 

References:

Levin RL, Degrange MA, Bruno GF, et al. Methylene blue reduces mortality and morbidity in vasoplegic patients after cardiac surgery. Ann Thorac Surg. 2004;77(2):496-499. doi:10.1016/S0003-4975(03)01510-8

 

Use of methylene blue in the treatment of refractory vasodilatory shock after cardiac assist device implantation: report of four consecutive cases
Study Design

Case reports
Intervention

All patients received a single dose infusion of methylene blue 2 mg/kg over 30 minutes.
Case 1

A 49-year-old male suffering from decompensated dilative cardiomyopathy had a left ventricular assist device (LVAD) implanted after not responding to conventional treatment. Postoperatively, the patient developed right heart failure, necessitating the implantation of an additional temporary right ventricular assist device. Severe postoperative bleeding required rethoracotomy and mass transfusion. Although no further bleeding occurred, the patient developed a severe vasoplegic shock, requiring very high dosages of norepinephrine (4.0 mg/h) and vasopressin (6.0 IU/h). After administration of a single dose of methylene blue, both norepinephrine and vasopressin dosages rapidly decreased and serum lactate concentrations normalized. On the fourth postoperative day, the patient developed pneumonia caused by Pseudomonas aeruginosa with severe impairment of pulmonary function. An oxygenator was connected to the right ventricular assist device to enable sufficient oxygenation. Despite inhalative application of milrinone and iloprost, right ventricular function did not recover sufficiently. The patient died ten days after methylene blue administration from multi-organ failure.
Case 2

A 46-year-old male patient with a history of myocardial infarction and limited cardiac function (LVEF 20%) underwent resection of a massive left ventricular anterior wall aneurysm combined with mitral valve annuloplasty. Despite the use of multiple inotropic agents, cardiogenic shock occurred postoperatively, and he was transferred to the operating room for venoarterial extracorporeal membrane oxygenation (ECMO) rescue therapy. After four days, a permanent left ventricular assist device (LVAD) was inserted due to weaning from ECMO. The patient suffered from right heart failure postoperatively, so venoarterial ECMO had to be re-implanted. The patient suffered from severe vasodilatory shock resistant to high dosages of norepinephrine (3.0 mg/h) and vasopressin (8.0 IU/h). Administration of methylene blue resulted in a reduction of norepinephrine and vasopressin to acceptable dosages within four hours. However, there was no suitable therapeutic option for the patient, and he died 18 hours after methylene blue administration.
Case 3

A 32-year-old male patient with decompensated dilative cardiomyopathy a biventricular assist device was implanted, as a bridge to transplant. Postoperatively, despite adequate filling pressures, 7.0 mg/h of norepinephrine and 7.0 IU/h of vasopressin were necessary to stabilize circulatory conditions. Methylene blue was given and vasoconstrictor dosages could be reduced within hours. On the fourth postoperative day, the patient suddenly developed pulmonary edema, and echocardiography revealed a thrombus in the left ventricular inflow cannula. In an immediate re-operation, the left ventricular inflow cannula was replaced from the left ventricular apex to the left atrium. During surgery, the left atrium ruptured. Surgical repair was unfeasible and the patient died intraoperatively from severe hemorrhage.
Case 4

A 70-year-old male patient with pre-existing coronary heart disease underwent coronary angiography with unstable angina pectoris. A significant stenosis of the right coronary artery was detected. The attempt to insert the wire into the right coronary artery resulted in a complete dissection of the vessel. Emergency coronary artery bypass operation with a saphenous vein graft was performed immediately, but revascularisation was technically impossible. Accordingly, the patient developed right heart failure and received venoarterial ECMO. Postoperatively, norepinephrine (1.6 mg/h) and vasopressin (8.0 IU. /h) resistant vasodilatory shock occurred. After a single dose of methylene blue vasoconstrictor dosages decreased within hours. Because the patient was considered to be too old for implantation of a definitive right ventricular assist device, therapeutic measures were terminated. The patient died 8 days after methylene blue administration.
Author's Conclusions

The intravenous administration of methylene blue at 2mg/kg in patients with vasodilatory shock after cardiac assist device implantation improved hemodynamics by showing an immediate and persistent decrease of vasopressor dosages.

 

References:

Michel S, Weis F, Sodian R, et al. Use of methylene blue in the treatment of refractory vasodilatory shock after cardiac assist device implantation: report of four consecutive cases. J Clin Med Res. 2012;4(3):212-215. doi:10.4021/jocmr804w