What is the data for methylene blue (Provayblue) in vasoplegia syndrome associated with cardiac surgery?

Comment by InpharmD Researcher

Despite the frequent use of methylene blue (Provayblue®) in the management of vasoplegic syndrome and improvement in hemodynamics and mortality associated with its use in the setting of cardiac surgery, a literature review revealed considerable variations in types of cardiac surgeries, the timing of administration (pre-, intra-, or postoperative), and optimal doses associated with its use. Commonly studied doses of methylene blue that have been found to be safe and effective range from IV 1.5 mg/kg to 3 mg/kg. One randomized controlled trial published in 2005 reported use of a 1% solution of methylene blue (see Table 1), but literature seldom reports a specific concentration. Additionally, available data do not describe the diluent used for methylene blue infusions. Methylene blue is incompatible in solutions containing sodium chloride and is recommended only to be diluted with 5% dextrose. Methylene blue should be used with caution for vasoplegic syndrome in the setting of cardiac surgery given the risk of severe adverse effects, mixed effects on hemodynamic response and vasopressor requirements, and lack of high-quality randomized controlled trials evaluating its use or appropriate dosing and preparation.

Background

A 2020 review of pathophysiology and treatment options for vasoplegia following cardiac surgery presented a treatment algorithm that utilizes catecholamines as first-line agents, followed by vasopressin. If the patient fails to achieve mean arterial pressure (MAP) goals or if lower doses of norepinephrine are desired, intravenous methylene blue is the next therapeutic option, followed by angiotensin II or hydroxocobalamin. Methylene blue has been shown to increase vascular smooth muscle tone by inhibition of endothelial nitric oxide synthase and guanylate cyclase, contributing to the reduction of vasodilation and improved hemodynamic stability. Dosing and administration of methylene blue in the literature varies, with documented use before, during, and after cardiopulmonary bypass (CPB). [1]

A cohort study (N= 100) using 2 mg/kg of methylene blue 1% 1 hour preoperatively found significant improvement in systemic vascular resistance (SVR), reduction in norepinephrine requirements, and decreased clinical signs of vasoplegia, and length of hospital/intensive care unit stay with methylene blue as compared to control. Intraoperatively, methylene blue has been used more extensively. Cohort and retrospective studies have documented the successful use of 2-3 mg/kg. In a randomized cohort study (N= 60), 2 mg/kg administered over 6 hours resulted in significantly higher diastolic blood pressure and SVR at 3 and 6 hours, respectively. Additionally, decreased TNF-alpha and nitric oxide levels after CPB reflected reduced inflammation and vasodilation. In another small cohort study (N= 30 patients taking ACE inhibitors), patients randomized to 3 mg/kg methylene blue after initiation of CPB were observed with a significant rise in MAP and reduced need for phenylephrine compared to placebo. Methylene blue was not associated with a decrease in PaO2, suggesting no impaired gas exchange in these patients. In a retrospective study comparing early (intraoperative) versus late (post-operative use) administration, more favorable results were observed in early administration, with reduced mortality and incidence of renal failure. Unfortunately, information regarding the specific diluent used was not provided. [1]

A 2019 literature review discusses various rescue therapies for vasoplegia during CPB. Overall, there are limited data evaluating methylene blue for vasoplegia during CPB. A randomized trial of 30 patients receiving preoperative angiotensin-converting enzyme inhibitors found that a dose of 3 mg/kg of methylene blue administration after the initial dose of cardioplegia significantly increased MAP during CPB. Additionally, a case report describes the resolution of severe vasodilation during and after bypass following the addition of 2 mg/kg methylene to the CPB prime. A randomized trial aimed to evaluate the hemodynamic effects of methylene blue compared to hydroxocobalamin in patients at risk of vasoplegia during cardiac surgery; however, the trial was withdrawn due to a lack of funding. [2]

Prior to using methylene blue, flows are suggested to be maximized (no more than 6 L/min), administration of catecholamine and noncatecholamine vasoconstrictors should be attempted, and other, more easily reversible causes of vasodilatory shock should be explored (e.g., adrenal insufficiency, severe anemia, and anaphylaxis). Although limited, some evidence suggested that initiating methylene blue early in the diagnosis of vasoplegia may be beneficial. Methylene blue should be used with caution due to the potential for clinically significant side effects, including serotonin syndrome, hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency, interference with pulse oximetry, elevations in pulmonary vascular resistance, methemoglobinemia, and anaphylaxis. As most research surrounding methylene blue utilized a dose of 3 mg/kg for vasoplegia, a dose of 2 to 3 mg/kg is recommended during CPB. Methylene blue infusion after a bolus dose may also be utilized to maintain the hemodynamic response, with typical dosing of 0.5 mg/kg/h for 6 hours. Again, information regarding the diluents used for methylene blue infusions was not provided in available studies. [2]

A 2021 meta-analysis evaluated the adjunctive effects of methylene blue in adult patients with vasoplegic syndrome using data from six studies (N= 317; 4 randomized controlled trials), with the majority of included studies comparing methylene blue to placebo (normal saline). Most included patients underwent coronary artery bypass grafting or valve replacement procedures and received an initial dose of methylene blue 1.5 mg/kg bolus (up to 3 mg/kg). Improvements in vasoplegic syndrome (VS) generally occurred between 2 to 8 h after methylene blue administration. Pooled analysis showed that MAP (mean difference [MD] –0.87; 95% confidence interval [CI] –4.45 to 2.71), SVR (MD –41.28; 95% CI –162.39 to 79.82), and heart rate (MD –1.12; 95% CI –4.16 to 1.91) were not statistically significant between the methylene and control groups. Additionally, methylene blue-recipients had significantly lower risks for renal failure in four studies (odds ratio [OR] 0.25; 95% CI 0.08 to 0.75) and multiple organ failures in three studies (OR 0.09; 95% CI 0.02 to 0.51) compared to control. The mortality rates of VS ranged from 4 to 21.4% in the control groups versus 0 to 3.6% in the methylene blue groups, leading to a significantly reduced mortality rate in VS patients (OR 0.12; 95% CI 0.03 to 0.46). On the other hand, changes in the length of hospital stay and risk of cerebrovascular accidents were not significantly different. Overall heterogeneity for hemodynamics change, morbidity, and mortality was considered low (I2<50%). As studies tended to report hemodynamic parameters differently, a thorough analysis of cardiovascular output was not performed. Future studies with a more consistent methodology, such as the type of surgery in addition to the dosing regimen and dilution of methylene blue, are required. [3]

Per Trissel's IV compatibility, methylene blue is only compatible with dextrose 5% in water (D5W). It has not been tested in Dextrose 10% in water (D10W). Methylene blue is also incompatible with dextrose 5% in sodium chloride 0.9% (D5NS), dextrose 5% in sodium chloride 0.45% (D5W 1/2 NS), normal saline (sodium chloride 0.9%[NS]), and sodium chloride 0.45% (1/2 NS). Methylene blue has not been tested in dextrose 5% in lactated Ringer's (D5LR), Lactated Ringer's Injection, or Ringer's injection. No results can be found on its compatibility with Plasmalyte solution, however, it can be reasoned that lactated Ringers and Plasmalyte will not be compatible due to their chloride content. [4]

References:

[1] 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. Published 2020 Feb 4. doi:10.1186/s13054-020-2743-8
[2] Ortoleva J, Shapeton A, Vanneman M, Dalia AA. Vasoplegia During Cardiopulmonary Bypass: Current Literature and Rescue Therapy Options. J Cardiothorac Vasc Anesth. 2020;34(10):2766-2775. doi:10.1053/j.jvca.2019.12.013
[3] Perdhana F, Kloping NA, Witarto AP, et al. Methylene blue for vasoplegic syndrome in cardiopulmonary bypass surgery: A systematic review and meta-analysis. Asian Cardiovasc Thorac Ann. 2021;29(8):717-728. doi:10.1177/0218492321998523
[4] Methylene Blue. Trissel’s 2™ Clinical Pharmaceutics Database. Micromedex. Greenwood Village, CO: IBM Corporation. http://www.micromedexsolutions.com/. Updated 2023.
Relevant Prescribing Information

Preparation: PROVAYBLUE ® is hypotonic and may be diluted before use in a solution of 50 mL 5% Dextrose Injection in order to avoid local pain, particularly in the pediatric population. Use the diluted solution immediately after preparation. Avoid diluting with sodium chloride solutions, because it has been demonstrated that chloride reduces the solubility of methylene blue.

References:

Methylene blue injection (Provayblue). Prescribing information. American Regent, Inc.; 2022.
Literature Review

A search of the published medical literature revealed 6 studies investigating the researchable question:

What is the data for methylene blue (Provayblue) in vasoplegia syndrome associated with cardiac surgery?

Level of evidence

B - One high-quality study or multiple studies with limitations  Read more→


Please see Tables 1-6 for your response.

 

Preoperative Methylene Blue Administration in Patients at High Risk for Vasoplegic Syndrome During Cardiac Surgery

Design

Randomized, controlled trial

N= 100

Objective

To determine whether preoperative methylene blue administration would prevent vasoplegic syndrome in high-risk patients

Study Groups

Methylene blue (n= 50)

Control (n= 50)

Inclusion Criteria

High risk of vasoplegia (pre-operative use of heparin, angiotensin-converting enzyme inhibitors, and calcium channel blockers); scheduled for elective coronary artery bypass graft surgery with cardiopulmonary bypass

Exclusion Criteria

Cardiogenic shock; left ventricular ejection fraction < 35%; postoperative low cardiac output syndrome

Methods

Eligible patients were randomized to receive either no methylene blue or intravenous methylene blue 1% solution (diluent not specified) at a dose of 2 mg/kg for more than 30 minutes, beginning 1 hour before surgery in the intensive care unit. 

Vasoplegic syndrome was defined as severe and persistent hypotension (mean arterial pressure < 50 mmHg) in the intraoperative or early postoperative period within 6 hours after weaning from cardiopulmonary bypass.

Duration

Surgery period: April 2003 to May 2004

Outcome Measures

Rate of vasoplegic syndrome, intraoperative and postoperative variables

Baseline Characteristics

  

Methylene blue (n= 50)

Control (n= 50)

  

Age, years

 65.6 64.9  

Female, n

 12 15  

Preoperative medication use, n

Angiotensin-converting enzyme inhibitors

Calcium channel blockers

Heparin

Diuretics

Beta-blockers

Nitrates

Antiarrhythmics

 

34

11

5

2

41

35

2

 

31

15

4

1

38

37

3

  

Past medical history, n

Smoking

Obesity (body mass index > 30)

Diabetes

Renal failure

Hypertension

Chronic obstructive pulmonary disease

Peripheral vascular disease

Cerebrovascular disease

Preoperative stroke

Unstable angina

Previous myocardial infarction

Previous coronary angioplasty

Previous cardiac operation

 

31

12

21

7

29

9

16

4

2

9

21

5

2

 

36

16

28

4

21

13

19

5

3

7

18

4

2 

  

Left ventricular ejection fraction, n

> 50%

35 to 50%

 

46

4

 

44

6

  

Results

Endpoint

Methylene blue (n= 50)

Control (n= 50)

p-value

Vasoplegic syndrome, n

 0 13 < 0.001

Norepinephrine-refractory vasoplegic syndrome, n

 0 6 0.027

Norepinephrine ≥ 0.5 mcg/kg/min, n

 0 13  < 0.001

Volume infusion

Crystalloid, mL

Colloids, mL

Red blood cell, units

Fresh frozen plasma, units

 

1,577.0 ± 329.4 

373.6 ± 59.9

2.2 ± 0.7

3.3 ± 0.8

 

1,749.2 ± 414.3

404.4 ± 76.5

3.3 ± 1.5

3.6 ± 0.5

 

0.024

0.027

< 0.001

0.068

Pulmonary vascular resistance index

 472.7 ± 28.0 465.3 ± 23.9 0.157

Length of stay, days

Intensive care unit

Hospital

 

1.2 ± 0.5

6.1 ± 1.7

 

2.1 ± 1.2

8.4 ± 2.0

 

< 0.001

< 0.001

Mortality, n

 0 2 0.495

Multiorgan failure, n

 0 2 0.495

Adverse Events

No adverse effects were reported

Study Author Conclusions

In conclusion, the results suggest that preoperative methylene blue administration reduces the incidence of vasoplegic syndrome in high-risk patients undergoing cardiac surgery, thus ensuring adequate systemic vascular resistance during and after surgery and shortening intensive care unit and hospital stays.

InpharmD Researcher Critique

The study is limited by its small sample size; however, the lack of strict exclusion criteria may further increase the generalizability of the results.



References:

Ozal E, Kuralay E, Yildirim V, et al. Preoperative methylene blue administration in patients at high risk for vasoplegic syndrome during cardiac surgery. Ann Thorac Surg. 2005;79(5):1615-1619. doi:10.1016/j.athoracsur.2004.10.038

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 postoperative vasoplegic syndrome (VS) and to assess the impact of methylene blue treatment on morbidity and mortality

Study Groups

Methylene blue (n= 28)

Placebo (n= 28)

Inclusion Criteria

Vasoplegic syndrome following elective cardiac surgery

Exclusion Criteria

Off-pump coronary artery bypass surgery, bacterial endocarditis, aortic dissection, urgent or emergent procedures

Methods

Vasoplegic patients were randomized either to a placebo or methylene blue at a 1.5 mg/kg (diluent not specified) dose intravenously for one hour. Vasoplegic syndrome was confirmed if patients met the following criteria: hypotension, mean arterial pressure (MAP) less than 50 mmHg, low filling pressures, central venous pressure lower than 5 mmHg, and wedge capillary pressure less than 10 mmHg, normal or elevated cardiac index more than 2.5 L/min/m2, low peripheral resistance, less than 800 dyn/s/cm-5, and vasopressor drug requirements. 

Duration

Between January 2001 to June 2002

Outcome Measures

 Hemodynamic outcomes, morbidities, and mortality

Baseline Characteristics

  

Placebo (n = 28)

Methylene blue (n = 28)

 

Age, years

 59.2 60.6  

Female

 4 4   

Surgery type

Coronary surgery

Valvular

Combined

 

26

2

0

 

23 

4

1

  

Number of grafts

 93 79  

Pump time, minutes 

 96.6 92.5  

Results

Endpoint

Placebo (n = 28)

Methylene blue (n = 28)

p-value

MAP, mmHg

 48.3  47.4 Not significant (NS)

Mean right atrial pressure, mmHg

3.9

3.7

 NS

Mean pulmonary arterial pressure, mmHg

14.3

13.8

 NS

Mortality 

6 (21.4%)

0

 0.01

Renal failure 

4 (14.3%)

0

 0.05

Respiratory failure 

4 (14.3%)

0

 0.05

Supraventricular arrhythmia 

8 (28.6%)

2 (7.1%)

 0.03

Length more than 48 h

 8 (28.6%)  0 0.002

Sepsis

 7 (25%) 0  0.005

Multi-organic dysfunction

 7 (25%)  0 0.005 

The overall mortality was of 27 patients (4.2%), 21 patients in the non-vasoplegic group (3.6%), and 6 patients in the VS population (10.7%) (p= 0.02; odds ratio 0.31; 95% confidence interval 0.11 to 0.91); of those 6 patients, all were in the placebo group (21.4%; p= 0.01) and died from sepsis and multi-organ failure.

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

Without strict inclusion criteria, clinical application to specific patient populations remains challenging. The dose of methylene blue at 1.5mg/kg infused over 1 hour is safe and effective for treating 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

Methylene Blue for Vasoplegic Syndrome after Cardiac Surgery: Early Administration Improves Survival

Design

Retrospective, single-center study

N= 3,608

Objective

To determine the incidence of cardiopulmonary bypass (CPB)-induced vasoplegic syndrome and describe contemporary practice patterns of methylene blue (MB) use at an academic cardiac surgery center

Study Groups

Received MB (n= 118)

Did not receive MB (n= 3,490)

Inclusion Criteria

Patients who underwent CPB and received MB within 72 hours of surgery
Exclusion criteria Not disclosed

Methods

Following the diagnosis of post-CPB vasoplegic syndrome, standard vasopressor support was administered with a preference for vasopressin and norepinephrine, and phenylephrine as second-line therapy. Additionally, patients received stress-dose steroids, diphenhydramine, and famotidine for inflammation. Patients with refractory vasoplegic syndrome received a bolus dose of 2 mg/kg of intravenous MB followed by a 12-hour infusion at 0.5 mg/kg/hr. The diluent utilized for the methylene blue bolus or infusion was not specified.

Duration

 Surgery period: January 2011 to March 2016

Outcome Measures

Primary: major adverse event (MAE) after administration of MB for vasoplegic syndrome

Secondary: early (operating room) vs late (intensive care unit) administration of MB

Baseline Characteristics

  

MB (n= 118)

No MB (n= 3,490)

p-value

Age, years

 63 67 0.031

Male

 69.2% 67.7% 0.720

Isolated coronary artery bypass and/or valve

 29.6% 68.2% <0.0001

Ventricular assisted device

33.9%

3.7%

 <0.0001

Prior ventricular-assisted device

27.1%

0.1%

 <0.0001

Tobacco use

39.3%

22.8%

<0.0001

Heart failure diagnosis

74.6%

49.9%

<0.0001

Ejection fraction (interquartile range [IQR])

42 (20-58)

57 (45-63)

<0.0001

Dialysis-dependent renal failure

6.9%

2.6%

 0.036

Severe chronic lung disease

8.6%

4.1%

0.008

Hypertension

65.8%

76.7%

 0.007

Prior cardiac surgery

76.1%

41.2%

 <0.0001

Preoperative amiodarone therapy

15.3%

2.2%

 <0.0001

ACE-Inhibitor within 48 hours

11.0%

11.4%

 0.896

Cross clamp time

100

75

 <0.0001

Results

Endpoint

MB (n= 118)

No MB (n= 3,490)

p-value

MAE outcomes

Postoperative atrial fibrillation

Stroke

Renal failure

Deep sternal wound infection

Reoperation

Prolonged ventilation

Operative mortality

MAE composite

 

27 (22.9%)

6 (5.1%)

25 (21.2%)

1 (0.9%)

31 (26.3%)

27 (22.9%)

25 (21.2%)

55 (46.6%)

 

725 (20.8%)

71 (2.0%)

151 (4.3%)

2 (0.1%)

222 (6.4%)

232 (6.7%)

112 (3.2%)

516 (14.8%)

 

0.579

0.025

<0.0001

0.003

<0.0001

<0.0001

<0.0001

<0.0001

Based on two graphs that demonstrated hemodynamic response and vasopressor requirements, improvement in mean arterial pressure (MAP), a gradual compensatory increase in systemic vascular resistance (SVR), a decrease in cardiac index (CI), and a reduction in vasopressor requirements were observed after MB administration (numerical data were not presented). 

Early vs late administration of MB for vasoplegic syndrome outcomes

Variable

Early MB administration (n= 48)

Late MB administration (n= 70)

p-value
Postoperative adverse event 34 (70.8%) 53 (75.7%) 0.554
Blood transfusion 44 (91.7%) 58 (82.9%) 0.170
Length of stay, days (IQR) 12 (10-18.5) 12 (6-21) 0.447
Postoperative atrial fibrillation 14 (29.2%) 13 (18.6%) 0.178
Postoperative cardiac arrest 5 (10.4%) 8 (11.4%) 0.863
Stroke 2 (4.2%) 4 (5.7%) 0.707
Renal failure 5 (10.4%) 20 (28.6%) 0.018
Reoperation 10 (20.8%) 21 (30.0%) 0.266
Deep sternal wound infection 1 (2.2%) 0 (0.00%) 0.219
Prolonged ventilation 11 (22.9%) 16 (22.9%) 0.994
Society of Thoracic Surgeons major morbidity 17 (35.4%) 37 (52.9%) 0.062
30-day mortality 5 (10.4%) 20 (28.6%) 0.018
Multivariate logistic regression demonstrated early administration of MB independently reduces the risk of MAE in patients with vasoplegic syndrome (odds ratio 0.35, p=0.037). 

Adverse Events

See Results.

Study Author Conclusions

Operative mortality is high in patients receiving methylene blue for the treatment of vasoplegia after cardiopulmonary bypass. Early administration of methylene blue improves survival and reduces the risk-adjusted rate of major adverse events in these patients.

InpharmD Researcher Critique

The study is subject to limitations and biases inherent to its retrospective nature, single-center design, and a lack of a comparator with a group of patients that had refractory vasoplegic syndrome who did not receive MB. Furthermore, there were a substantial number of significant differences in baseline characteristics between the two populations.
References:

Mehaffey JH, Johnston LE, Hawkins RB, et al. Methylene Blue for Vasoplegic Syndrome After Cardiac Operation: Early Administration Improves Survival. Ann Thorac Surg. 2017;104(1):36-41. doi:10.1016/j.athoracsur.2017.02.057

Hydroxocobalamin or Methylene Blue for Vasoplegic Syndrome in Adult Cardiothoracic Surgery 

Design

Retrospective, propensity-matched, cohort study 

N= 144

Objective

To compare hydroxocobalamin and methylene blue for the treatment of vasopressor-refractory vasoplegic syndrome (VS) after adult cardiac surgery with cardiopulmonary bypass (CPB)

Study Groups

Methylene blue (n= 120)

Hydroxocobalamin (n= 22)

Inclusion Criteria

Age > 18 years, underwent cardiothoracic surgery with CPB and VS 

Exclusion Criteria

If administered additional hydroxocobalamin or methylene blue within 120 minutes of the first dose or if patients had incomplete medical records 

Methods

Hydroxocobalamin or methylene blue was selected at discretion of healthcare providers and administered in the operating room during the index surgery or in the intensive care unit (ICU) up to 24 hours after CPB separation. Hydroxocobalamin was administered by intravenous bolus dosing of 5,000 mg over 15 minutes, and median methylene blue dose was 1.2 mg/kg. 

Duration

Underwent surgery between July 1, 2013, and May 31, 2020

Outcome Measures

Primary: percentage change in vasopressor use at 30, 60, and 120 minutes from baseline (characterized as both norepinephrine equivalents [NEE] and vasoactive inotropic score [VIS])

Secondary: percentage change in MAP at each point time after medication administration compared with baseline, the proportion of patients with vasopressor initiation or discontinuation after hydroxocobalamin or methylene blue that remained at 120 minutes, volume (mL) of crystalloid and blood product, and amount (g) of albumin infused within four hours after administration of hydroxocobalamin and methylene blue

Baseline Characteristics

  

Hydroxocobalamin (n= 22)

Methylene Blue - unmatched 
(n= 120)

Methylene Blue - matched 
(n= 66)

Age, years (IQR)

 50 (38-68)  58 (46-68)

55 (41-66)

Sex, male (%)

 13 (59.1) 94 (78.3)

50 (75.8) 

Ethnicity (%)

White

African-American 

Asian

Other 

 

16 (72.7)

5 (22.7)

0 

1 (4.6)  

 

89 (74.2) 

24 (20.0)

3 (2.5) 

4 (3.3)  

 

46 (69.7)

14 (21.2) 

3 (4.6)

3 (4.6)

Surgery (%)

Valve surgery 

VAD operation 

Heart transplant 

Thoracic aortic surgery with HCA 

CABG + other surgery 

Isolated valve surgery 

Lung transplant 

Thoracic aortic surgery without HCA 

Isolated CABG surgery

Other 

 

9 (40.9) 

6 (27.3) 

6 (27.3) 

2 (9.1) 

2 (9.1) 

2 (9.1)

2 (9.1) 

2 (9.1)

0 

2 (9.1) 

 

53 (44.2)

21 (17.5)

12 (10.0) 

13 (10.8)

12 (10) 

11 (9.2) 

9 (7.5) 

6 (5) 

13 (10.8) 

14 (11.7) 

 

32 (48.5) 

7 (10.6) 

9 (13.6) 

8 (12.1) 

7 (10.6) 

7 (10.6) 

8 (12.1) 

5 (7.6) 

3 (4.5) 

10 (15.2)  

Pre-cardiovascular medications (%)

Beta-blocker

Vasopressor 

ACE inhibitor

ARB

None

 

4 (18.2) 

3 (13.6) 

2 (9.1) 

1 (4.6) 

13 (59.1)  

 

41 (34.2) 

12 (10.0) 

10 (8.3) 

4 (3.3) 

63 (52.5)  

 

15 (22.7) 

8 (12.1) 

6 (9.1) 

1 (1.5) 

41 (62.1) 

Baseline characteristics were similar between groups.

ACE, angiotensin-converting enzyme; ARB, angiotensin II-receptor blocker; CABG, coronary artery bypass graft; HCA, hypothermic circulatory arrest; IQR, interquartile range; VAD, ventricular assist device;

Results

Endpoint

Hydroxocobalamin (n= 22)

 Methylene Blue - matched (n= 66)

p-value

Percentage change in vasopressor use (NEE)

30 minutes (IQR)

60 minutes (IQR)

120 minutes (IQR)

 

0 (-16.3, 0)

0 (-24.7, 9.0)

-5.4 (-45.5, 2.4)

 

0 (-16.3, 1.8)

0 (-31.4, 14.6)

-26.1 (-43.4, 5.0)

 

0.59

0.57

0.86

Percentage change in vasopressor use (VIS)

30 minutes (IQR)

60 minutes (IQR)

120 minutes (IQR)

 

0 (-12.5, 0)

0 (-21.5, 10.5)

-8.8 (-39.6, 2.8)

 

0 (-13.6, 43.3)

0 (-34.8, 20.4)

-17.2 (-40.6, 0)

 

0.5

0.77

0.65

Percentage change in MAP from baseline 

30 minutes (IQR)

60 minutes (IQR)

120 minutes (IQR)

 

-1.3 (-9.9, 5.7)

-6.2 (-14.1, 6.3)

-1.9 (-15.7, 13.7) 

 

11.5 (0, 33.5)

21 (0, 34.8)

13.2 (3.1, 34.1)

 

0.001

< 0.001

0.007

Vasopressor

Initiation

Discontinuation

 

31.8%

30.3%

 

18.2%

22.7%

 

0.281

0.592 

Crystalloid fluid, mL (IQR)

91.3 (0-1,630)

 120 (0-1,064) 0.83

Blood product, mL (IQR)

 725 (0-2,097) 427 (0-1,109) 0.05 

Albumin, g (IQR)

 0 (0-12.5) 0 (0-12.5) 0.79 
Endpoint values in parenthesis are presumed to be IQR. However, the study did not directly specify. 

Adverse Events

Adverse effects were similar in both groups. Methemoglobin saturation of >3% was reported in two patients in the hydroxocobalamin (9.1%) and nine patients in the methylene blue group (13.6%, p= 0.724). Serotonin syndrome was observed in one patient who received 1 mg/kg and 0.5 mg/kg methylene blue (16 hours apart). 

Study Author Conclusions

In adult patients undergoing cardiothoracic surgery using CPB with VS, the ability to reduce vasopressor use was similar to hydroxocobalamin compared with methylene blue.

InpharmD Researcher Critique

Due to the limited sample size, the ability to detect a significant difference in NEE may have been hindered. Despite the use of propensity-score matching to control for potential confounders between the two groups, some aspects may not have been accounted for, including vasopressor selection, methylene blue dosing, administration, and timing. 

 

References:

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

Hydroxocobalamin Versus Methylene Blue for Vasoplegic Syndrome in Cardiothoracic Surgery: A Retrospective Cohort

Design

Retrospective, cohort study

N= 35

Objective

To compare methylene blue with hydroxocobalamin as rescue therapy for vasoplegic syndrome.

Study Groups

Methylene blue (n= 16)

Hydroxocobalamin (n= 19)

Inclusion Criteria

Received either medication in the perioperative setting for suspected vasoplegic syndrome as a rescue therapy confirmed by clinical note documentation

Exclusion Criteria

Received both methylene blue and hydroxocobalamin for a single vasoplegia occurrence, recipient of a noncardiac solid organ transplant

Methods

Patients who received one of the two agents of interest were included in analysis. The decision to use methylene blue or hydroxocobalamin was decided at the provider's discretion. A protocol to guide management or dosing was not described. 

Duration

3.5 years (June 2015 to December 2018)

Outcome Measures

Primary outcome: change in time-averaged norepinephrine equivalent

Secondary outcomes: increase in mean arterial pressure (MAP) and decrease in vasopressor requirements versus baseline

Baseline Characteristics

  

Methylene Blue  (n= 16)

 Hydroxocobalamin (n= 19)  

Age, years

 59.9 ± 8.6 56.5 ± 16.4  

Weight, kg

 85.3 ± 19.1 83.1 ± 23.7  

Procedure types

Aorta Repair

Device placement

Heart transplant

Coronary artery bypass graft

Valve procedure

 

5

2

4

3

7

 

5

3

3

6

2

  
APACHE II Score 29.8 (23.3-36.3)

22.2 ± 9.2

  
EURO II Score (%) 26.8 (7.3-46.3)

15.1 ± 18.2

  
MAP, mmHg pre-intervention 52.2 (41.9-62.5)

59.4 ± 14.8

  

Cardiac Output, L/min

 5.5 ± 2.0 4.6 ± 1.5  

Cardiac Index, L/min/m²

 2.8 ± 0.9 2.3 ± 0.7  

Transfusions

Red blood cells

Fresh-frozen plasma

Platelets

Cryoprecipitate

 

7 (0-10)

4 (2-7)

2 (1-2)

0 (0-0)

 

2 (1-8)

4.5 (3-10)

2 (1-4)

0 (0-1)

  

Results

 

Methylene blue (n= 16)

Hydroxocobalamin (n= 19)

p-value

Change in Time-Averaged Norepinephrine Equivalent, mcg/kg/min

 0.012 ± 0.218

-0.037 ± 0.027

 0.46

Increase in MAP 1 hour following administration, mmHg

 10.6

11.8

  

Decreased vasopressor requirement versus baseline, mcg/kg/min (p-value)

At 1 hour

At 4 hours

 

0.409 ± 0.178 (p= 0.58)

0.367 ± 0.199 (p= 0.94)

 

0.255 ± 0.129 (p= 0.03)

0.247 ± 0.180 (p= 0.04)

  

Adverse Events

 None reported

Study Author Conclusions

Methylene blue and hydroxocobalamin increased mean arterial pressures and systemic vascular resistance without significantly decreasing time-averaged norepinephrine exposure in the hour after administration.

InpharmD Researcher Critique

Aside from the small patient population, methylene blue reported higher APACHE II and EURO II scores, possibly indicating a more critically ill patient population compared to hydroxocobalamin. While no adverse events were reported, the authors admit to being unable to capture all safety outcomes due to the retrospective nature of the study.



References:

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

Methylene Blue Monotherapy Compared With Combination Therapy With Hydroxocobalamin for the Treatment of Refractory Vasoplegic Syndrome: A Retrospective Cohort Study

Design

Retrospective, observational, cohort study

N= 45 doses in 20 patients 

Objective

To compare the efficacy of methylene blue with combination therapy with hydroxocobalamin in patients experiencing vasoplegic syndrome after cardiac surgery

Study Groups

Methylene blue monotherapy (n= 28 doses in 14 patients)

Methylene blue plus hydroxocobalamin (n= 17 doses in 6 patients)

Inclusion Criteria

Received a dose of methylene blue or hydroxocobalamin, calculated norepinephrine equivalent dose > 0.1 mcg/kg/min while on a vasopressin infusion of at least 0.04 U/min at study drug administration 

Exclusion Criteria

Cardiac index < 2.2 L/min/m2, supported with a temporary mechanical circulatory support device

Methods

Patient data were extracted from a single institution's electronic medical record. All doses of methylene blue and hydroxocobalamin were given at the discretion of the attending anesthesiologist based on patient-specific hemodynamics. There was no standing order or interval. All patients receive arterial catheter monitoring, but pulmonary artery catheters were not required. 

Duration

September 2012 to January 2017

Outcome Measures

Primary: Ability to maintain mean arterial pressure (MAP) > 60 mmHg at least 1 hour after study drug administration  

Secondary: Ability to maintain MAP at hours 6, 12, and 24 hours post-administration; the proportion of initial vasopressor rates and total vasopressor rates; absolute reduction in vasopressor requirements; change in pulmonary artery catheter values; net intake/output at 6 hours post-administration

Baseline Characteristics

  

Methylene blue (n= 28 doses in 14 patients)

Combination therapy (n= 17 doses in 6 patients)

  

Age, years

 63 ± 13 67 ± 13  

Male

 10 (71%) 5 (83%)  

Surgical procedure per patient

Aorta repair

CABG

Device placement

Heart transplantation

Multiple procedures

Valve procedure

 

2

2

2

3

6

2

 

1

3

0

1

1

0

  

Median cardiac index before drug administration, L/min/m2 (IQR)

 2.7 (2.5-3) 2.7 (2.2-4.1)  

Median cardiac output before drug administration, L/min (IQR)

 5.7 (4.2-6.3) 6.5 (4.4-10.6)  

Median pAM before drug administration, mmHg(IQR)

 26 (24-34) 28 (27-36)  

Median baseline NEE requirements, µg/kg/min (IQR)

 0.29 (0.21-0.67) 0.3 (0.21-0.43)  
Median net intake/output before drug administration, mL, (IQR)

1,381 (1,286)

 1,222 (1,492)  

Abbreviations: CABG, coronary artery bypass grafting; IQR, interquartile range; NEE, norepinephrine equivalents; PAM, mean pulmonary pressure

Results

Endpoint

Methylene blue (n= 28 doses in 14 patients)

Combination therapy (n= 17 doses in 6 patients)

p-value

Ability to maintain MAP goal

1 h post-dose

6 h post-dose

12 h post-dose

24 h post-dose

 

20 (71%)

18 (64%)

16 (57%)

16 (57%)

 

14 (82%)

13 (76%)

12 (71%)

9 (53%)

 

0.49

0.51

0.53

> 0.99

NEE, µg/kg/min median (IQR)

1 h post-dose

6 h post-dose

12 h post-dose

24 h post-dose

 

0.28 (0.12-0.76)

0.21 (0.13-0.57)

0.16 (0.09-0.23)

0.14 (0.07-0.2)

 

0.25 (0.15-0.33)

0.2 (0.06-0.28)

0.22 (0.10-0.27)

0.03 (0-0.2)

 

0.1

0.31

0.35

0.34

Proportion of starting dose (IQR)

1 h post-dose

6 h post-dose

12 h post-dose

24 h post-dose

 

1 (0.87-1.00)

0.86 (0.65-1.00)

0.61 (0.28-1.00)

0.52 (0.03-1.0)

 

0.83 (0.66-0.91)

0.64 (0.35-0.86)

0.59 (0.44-1.00)

0.23 (0-0.5)

 

0.003

0.034

0.88

0.15

Absolute vasopressor reductions, µg/kg/min (CI)

1 h post-dose

6 h post-dose

12 h post-dose

24 h post-dose

  

-0.015 (-0.03 to 0, p= 0.14)

-0.045 (-0.1 to -0.05, p= 0.037)

-0.11 (-0.4 to -0.04, p= 0.01)

-0.15 (-0.5 to -0.06, p= 0.006) 

 

-0.06 (-0.1 to -0.03, p= 0.003)

-0.13 (-0.19 to -0.065, p= 0.001)

-0.1 (-0.2 to -0.02, p= 0.019) 

-0.15 (-0.27 to -0.1, p= 0.48)

 

 

 

PAM post-dose, mmHg (IQR)

  26 (24-33)  29 (28-30)  0.14

Net intake/output 6 h post-dose, mL 

  1,486 ± 1,586  1,968 ± 2,089  0.56

Abbreviations: MAP, mean arterial pressure; IQR, interquartile range; NEE, norepinephrine equivalents; PAM, mean pulmonary pressure; CI, 95% confidence interval

Adverse Events

N/A

Study Author Conclusions

This is the first study to compare methylene blue monotherapy with combination therapy, which suggests there may be an advantage to combination therapy. Further characterization of ideal dosing, timing, and agent selection should be investigated on a larger scale.

InpharmD Researcher Critique

Aside from the retrospective nature and small patient population, the study did not observe the adverse events that can potentially compound in patients receiving combination therapy instead of monotherapy with methylene blue. On the other hand, the addition of hydroxocobalamin could also lower the amount of methylene blue exposure, which could decrease the risk of serotonin syndrome.

 

References:

Feih JT, Rinka JRG, Zundel MT. Methylene blue monotherapy compared with combination therapy with hydroxocobalamin for the treatment of refractory vasoplegic syndrome: a retrospective cohort study. Journal of Cardiothoracic and Vascular Anesthesia. 2019;33(5):1301-1307. doi:10.1053/j.jvca.2018.11.020