How is methylene blue infusion prepared and dosed for cardiac surgery vasoplegia?

How is methylene blue infusion prepared for cardiac surgery vasoplegia? How is methylene blue continuous infusion dosed?

Comment by InpharmD Researcher

Methylene blue boluses of 1 to 2 mg/kg followed by infusions of 0.25 to 2 mg/kg are safe and effective for the treatment of vasoplegic syndrome. Doses of methylene blue greater than 5 mg/kg can potentiate fatal serotonin syndrome; however, doses up to 7 mg/kg have been used without adverse events. A dose greater than 7 mg/kg may cause adverse effects such as paradoxical induction of methemoglobinemia, acute hemolytic anemia, and detrimental effects on pulmonary function. A dosage of 40 mg/kg can be lethal in patients. Methylene blue is incompatible in solutions containing chlorides (e.g., normal saline), so it should only be prepared with D5W.

Background

Methylene blue may be considered a 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. [1]

In a 2016 systematic review on twenty years of vasoplegic syndrome treatment in heart surgery, the authors mention that the most used dosage of methylene blue is 2 mg/kg as an intravenous bolus followed by the same continuous infusion because the plasma concentrations are greatly decreased in the first 40 minutes. Methylene blue is safe and effective in the treatment of heart surgery vasoplegia in recommended doses, but the dose of 40 mg/kg can be lethal. Some authors use a loading bolus of 2 mg/kg in the cardiopulmonary bypass (CPB) and follow with a continuous infusion of 0.25 - 2 mg/kg to ameliorate refractory hypotension for patients undergoing valve replacement surgery. Doses of methylene blue up to 7mg/kg have been used in some reports with no side effects. The authors propose a total dosage of up to 10mg/kg may be used in extreme cases. [2], [3]

A 2013 article recommends a dose of 1 to 2 mg/kg as a single bolus based on the existing literature and safety profile. The authors mention that although the dosing regimen for methylene blue used in clinical data is not completely clear, it seems to be consistent in a range of 1 to 2 mg/kg, which is similar with the treatment of methemoglobinemia. However, the article cited studies showing that a dose greater than 7mg/kg was associated with adverse effects such as paradoxical induction of methemoglobinemia, acute hemolytic anemia, and detrimental effects on pulmonary function. [4]

Another article recommends methylene blue used as a single dose of 1.5 -2 mg/kg IV over 20 min to 1hr for rescue treatment of refractory vasoplegia. This article also supports that methylene blue is safe when used in therapeutic doses (less than 2mg/kg), but it can cause toxicity in high doses due to its monoamine oxidase (MAO) inhibiting property. The authors mention that the dose greater than 5 mg/kg can precipitate fatal serotonin toxicity and rarely cause severe anaphylactic shock. [5]

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. [6]

Relevant Prescribing Information

PROVAYBLUE ® is hypotonic and may be diluted before use in a solution of 50 mL 5% Dextrose in Water (D5W) 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. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. [7]

Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

How is methylene blue infusion prepared for cardiac surgery vasoplegia? How is methylene blue continuous infusion dosed?

Level of evidence

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

Please see Tables 1-4 for your response.

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 (Q_s/Q_t) slightly increased, the arterial P_O2 fell in the 7mg/kg group, but the arterial P_CO2 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 P_CO2 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, et al. A dose-finding study of methylene blue to inhibit nitric oxide actions in the hemodynamics of human septic shock. Nitric Oxide. 2010;22(4):275-80.

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):496-9.

Methylene Blue for Vasoplegic Syndrome after Cardiac Surgery: Early Administration Improves Survival
Design	Retrospective study N=3,608
Objective	To test the hypothesis that early administration of methylene blue (MB) would improve outcomes in patients with vasoplegic syndrome after cardiopulmonary bypass
Study Groups	Received methylene blue (MB) (n=118) Did not receive methylene blue (No MB) (n=3,490)
Methods	Inclusion criteria: All patients undergoing cardiopulmonary bypass who received methylene blue within 72 hours of surgery Exclusion criteria: N/A The study compared all patients who underwent cardiopulmonary bypass within the given time-frame. Post-operative outcomes up to 30-days were included. Patients with vasoplegic syndrome received stress-dose steroids, diphenhydramine and famotidine for inflammation. Methylene blue was also given for refractory vasoplegic syndrome at 2 mg/kg IV bolus followed by 0.5 mg/kg/hr for 12 hours.
Duration	January 2011 to March 2016
Outcome Measures	Primary outcome: Various major adverse events (MAE) after MB fo vasoplegic syndrome Secondary outcome: Early and late administration of MB
Baseline Characteristics		MB (n=118)	No MB (n=3,490)	p-value
	Age, years	63	67	0.031
	Male sex	81 (69.2%)	2334 (67.7%)	0.720
	Isolated coronary artery bypass and/or valve	35 (29.6%)	2381 (68.2%)	0.0001
	Ventricular assisted device Prior ventricular assisted device	30 (33.9%) 32 (27.1%)	130 (3.7%) 28 (0.1%)	0.0001 0.0001
	Tobacco use	46 (39.3%)	785 (22.8%)	0.0001
	Heart failure diagnosis	88 (74.6%)	1740 (49.9%)	0.0001
	Dialysis dependent renal failure	7 (6.9%)	94 (2.6%)	0.036
	Severe chronic lung disease	10 (8.6%)	143 (4.1%)	0.008
	Hypertension	77 (65.8%)	2646 (76.7%)	0.007
	Prior cardiac surgery	89 (76.1%)	1435 (41.2%)	0.0001
Results	Endpoint	MB (n=118)	No MB (n=3,490)	p-value
	Adverse event outcomes Postoperative atrial fibrillation Stroke Renal failure Deep sternal wound infection Reoperation Prolonged ventilation Operative mortality Major adverse event 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
	Odds ratio of early MB administration predicting major adverse events (95% confidence interval)	0.35 (0.127 to 0.936)		0.037
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 included all patients meaning there were substantial number of differences in 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

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):212-5.