Methylene blue in the intensive care unit: A comprehensive review article

Rayan A. Qutob, MD*
Author’s affiliation:
*Rayan A Qutob, Department of Internal Medicine, College of Medicine, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia; Email: Dr.rayan.qutob@gmail.com
Correspondence: Dr Rayan A. Qutob, Email: Dr.rayan.qutob@gmail.com, Phone: 00966500175489

 

ABSTRACT

 

Methylene blue is a broad and potent therapeutic substance that is effective in treating various medical conditions in the Intensive Care Unit (ICU). Methylene blue (MB) has a multitarget mode of action that involves inhibiting nitric oxide synthase and guanylate cyclase, as well as serving as a redox agent. This makes it beneficial in treating various disorders in the intensive care unit, including septic and vasoplegic shock, methemoglobinemia, and Ifosfamide-induced encephalopathy. This comprehensive narrative review provides current evidence regarding MB use in the ICU setting, constituents of the chemical, clinical applications, its efficacy, safety, dosing, guidelines, actual recommendations for its usage, and future research directions for use in ICU. MB has demonstrated enhanced results for people who are critically unwell. However, when using MB as a supplementary medication, it is important to carefully examine the dosage and treatment schedule in order to obtain the best possible clinical outcome. This includes closely monitoring and making necessary adjustments, especially for patients with conditions such as renal or hepatic impairment, as well as Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency. Further research and clinical trials are essential for expanding the understanding and application of MB in critical care.

Abbreviations: CPB: cardiopulmonary bypass, G6PD: Glucose-6-Phosphate Dehydrogenase, ICU: Intensive Care Unit, iNOS: inducible nitric oxide synthase, MAOIs: monoamine oxidase inhibitors, MB: Methylene blue, NADH: nicotinamide adenine dinucleotide hydrogen, NO: Nitric oxide, SNRIs: serotonin and norepinephrine reuptake inhibitors, SSRIs: selective serotonin reuptake inhibitors, IV: intravenous, TCAs: tricyclic antidepressants

Keywords: Intensive care unit; Methylene blue; Review

Citation: Qutob RA. Methylene blue in the intensive care unit: A literature review. Anaesth. pain intensive care 2025;29(3):407-417. DOI: 10.35975/apic.v29i3.2829
Received: February 03, 2025; Revised: February 28, 2025; Accepted: March 05, 2025

 

1. INTRODUCTION

 

Heinrich Caro, a German chemist, first synthesized Methylene Blue (MB) in 1876 as a dye from aniline, to dye cotton.1 MB belongs to the phenothiazines family and is a cationic dye.2,3 It is characterized by its tricyclic phenothiazine structure, solubilized in some organic solvents and water,2 and is acknowledged as the first synthetic medicine applied to humans.4 MB has been widely utilized for biological staining in hematology, bacteriology, and histology.3
Paul Ehrlich found that MB could target the malarial parasite during the 1890s. Its first applications resulted in the inclusion of MB in malaria treatments due to growing resistant to different treatments.5-7 Ehrlich's description of the unique properties of MB led to its widespread use in the treatment of a wide range of disorders.8,9
The clinical utility of MB exceeds its historical applications because of its antimicrobial, neuroprotective, antioxidant, and anti-inflammatory properties.10-15 MB is considered a multifunctional drug with postoperative,16,17 curative,18 diagnostic,19,20 and preventive use.13,15 Recognizing its importance in a basic health system, the World Health Organization (WHO) includes MB on its ‘List of Essential Medicines’.21
In the intensive care unit (ICU), MB is utilized for multiple ICU applications.22 MB is even utilized in regulating excessive blood circulation in liver cirrhosis, therapeutic use against low oxygen levels, and addressing low blood pressure associated with different medical conditions.23 The Food and Drug Administration (FDA) in the United States has approved MB for a variety of indications, including cyanide poisoning, ifosfamide-induced encephalopathy, and vasoplegic syndrome.24 Also, a prior meta-analysis has shown that the use of MB can enhance survival in perioperative and critically ill patients and may also diminish the length of hospital stay in the ICU.25
The wide range of applications and critical conditions treated in the ICU demand good knowledge of the evidence supporting the use of MB. Therefore, this literature review will investigate available current evidence regarding MB use in the ICU setting, constituents of the chemical, clinical applications, its efficacy, safety, dosing, guidelines, actual recommendations for its usage, and future research directions for its use in ICU.

 

2. METHODOLOGY

 

This narrative review was performed by collecting original research articles and reviews on the use of MB in the ICU. Articles published in peer-reviewed scientific journals were included. Articles were excluded if they were not written in English or published in peer-reviewed scientific journals.

2.1. Search strategy
Literature searches were performed in PubMed and Web of Science databases from the date of database inception through June 2024. The search included the following keywords: ‘methylene blue’ and ‘intensive care unit’.

2.2. Study selection
Relevant articles were identified through our aforementioned search strategy and selected articles were screened based on the title and abstract. After that, all included articles were carefully discussed in the present review. A total of 104 articles were finally selected and discussed in the review. This narrative review presented pharmacokinetic properties of MB, its clinical indications in ICU, its safety and adverse effects, and dosing and administration procedures.

2.3. Pharmacokinetic Properties
MB shows several important pharmacokinetic properties necessary for its therapeutic use. The half-life of terminal elimination varies from 5 to 14 hours,26-29 depending on the dose and formulation: for instance, prior studies noted an approximate half-life of 5 to 6.5 hours,26-28 while another study determined a half-life of about 14 hours.29 When given orally, MB has high absolute bioavailability, with figures around 48.4% to 96.2%.30
After oral administration, MB is well absorbed; absorption rates range between 53% and 97%.28 The variability of these absorption rates might be due to inter-subject variability and the specific conditions under which the drug was administered. After being absorbed, MB is well distributed in the body,31 and crosses the blood-brain barrier32 due to its lipophilic and cationic properties.1 MB is extensively metabolized in the liver33 and reduced to leukomethylene blue.28 It is excreted in the urine, bile, and feces.28,34
2.4. Clinical indications in ICU
MB is used in numerous clinical situations in the ICU. We review the main conditions where MB has shown effective therapeutic potential.

2.4.1. Methemoglobinemia
Methemoglobinemia is a condition that can be either present from birth or acquired, with life-threatening characteristics.35 It is an uncommon condition wherein the divalent ferrous iron (Fe2+) in hemoglobin is oxidated to ferric iron (Fe3+) in methemoglobin.36 The Fe3+ state induces allosteric transitions that allow irreversible binding with oxygen.37 The diagnosis of methemoglobinemia generally occurs when the concentration of methemoglobin in the blood is more than the normal range, which is 1% to 3%.38,39 This clinically appears with symptoms such as characteristic "chocolate-colored" blood, hypoxia, and cyanosis of the extremities and the lips.40 Severe cases might result in metabolic acidosis and possibly death.22 MB is the antidote of choice for treating symptomatic methemoglobinemia.41 MB acts rapidly within red blood cells to form leukomethylene blue, a reducing agent that converts the Fe3+ in methemoglobin back to its oxygen-carrying iron state Fe2+.42
2.4.2. Septic shock and vasoplegia
Septic shock is the most serious subset of sepsis (a life-threatening condition);43,44 it is characterized by persistent low systemic vascular and low blood pressure (vasoplegia) despite effective fluid resuscitation and necessitating the administration of vasopressors to keep organ perfusion pressure.45,46 Septic shock markedly elevates the mortality risk45 and accounts for most of the non-coronary mortality and morbidity in ICU patients.47,48 Nitric oxide (NO) release is a critical contributor to the cardiovascular dysfunction associated with septic shock.35 MB is effective in treating septic shock by inhibiting the enzyme guanylate cyclase, which nitric oxide targets to cause endothelial relaxation.49 MB blocks soluble guanylate cyclase (sGC) in the smooth muscle cells of the blood vessels and inducible nitricoxide synthase (iNOS),50,51 in turn, enhancing cardiac function and arterial pressure.49
2.4.3. Vasoplegic syndrome and cardiovascular surgeries
Vasoplegic syndrome is a vasodilatory shock commonly seen after patients undergoing major cardiovascular surgeries, specifically cardiopulmonary bypass (CPB); it may affect up to 50% of patients.52-57 Compared with other cardiac surgical patients, patients with vasoplegia sydrome more frequently exhibit increased mortality after surgery, extended stays in the ICU, and higher rates of postoperative complications.58-62 MB was noticed to be an effective treatment of vasoplegic syndrome in cardiovascular surgical settings. The efficiency of MB has been demonstrated to correlate with its ability to block the NO-induced vasodilation pathway and, consequently, decrease the intensity of systemic inflammatory reactions.63,64 The early use of MB decreases the incidence of operative mortality and postoperative kidney failure.65
2.4.4. Ifosfamide-induced encephalopathy
Ifosfamide is an alkylating agent and is used as therapy for multiple types of solid tumors.66,67 Due to the incidence of specific adverse consequences, Ifosfamide usage may be restricted. One such intense adverse consequence is central nervous system depression, an adverse effect called ifosfamide-induced encephalopathy67 (an acute neurologic complication that develops during or immediately after ifosfamide infusion).68 Even though it is reversible under most usual circumstances, it is a severe and life-threatening complication that requires immediate intervention.68 MB has been reported as an effective therapy for ifosfamide-induced encephalopathy. A prior review has revealed that MB is an effective ifosfamide-induced encephalopathy therapy for both prophylactic and treatment.67 MB serves as a substitute electron acceptor, thus reversing the nicotinamide adenine dinucleotide hydrogen (NADH) blockage of hepatic gluconeogenesis.69 It also prevents the multiple activities of amine oxidases, which prevents the production of chloroacetaldehyde (toxic metabolite).69 In addition, it prevents the conversion of chloroethylamine to chloroacetaldehyde.69
2.5. Safety and Adverse Effects
MB is safe when taken at doses of less than 2 mg/kg (therapeutic dose) but has many side effects at doses higher than 7 mg/kg.35 Discoloration of body fluids is the most common of MB side effects.70,71
Other commonly experienced side effects include gastrointestinal effects such as vomiting, and nausea.22 Patients may also experience confusion, headaches, fever, or dizziness.72,73 Figure 1 below presents the most common side effects related to MB. 74
 



Figure 1: Side effects of methylene blue
 

More serious adverse effects of MB include hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, neurotoxicity, methemoglobinemia, serotonin syndrome, phototoxicity, anaphylactic reaction, skin discoloration, refractory hypotension, hypertension, dyspnea, and chest pain.28,75-81 Furthermore, MB may also cause false low oxygen saturation values due to interference with the light emission of pulse oximeters.28 Hemolytic anemia, phototoxicity, pulmonary edema, respiratory depression, and hyperbilirubinemia are among the adverse effects reported with the use of methylene blue in neonates.82,83
 

3. CONTRAINDICATIONS

 

MB administration is contraindicated in patients with Heinz body anemia, in individuals with severe renal insufficiency, in patients with G6PD because of the risk of severe hemolysis, in patients with a known hypersensitivity to the drug,28,71,75 or during pregnancy as the FDA has classified it as pregnancy category X (because of fetal death and intestinal atresia after intra-amniotic injection in the 2nd trimester).84
Moreover, combining MB with serotonergic drugs (like tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and selective serotonin reuptake inhibitors (SSRIs)) could lead to serotonin syndrome, therefore, it is contraindicated in patients who are taking serotonergic drugs.71
 

4. MONITORING

 

Maintenance of monitoring when using MB is key to both efficacy and minimization of potential side effects. Monitoring parameters include levels of methemoglobin, renal, hepatic, and pulmonary functions.

4.1. Methemoglobin Levels
Monitoring of methemoglobin levels is necessary in the treatment of methemoglobinemia with MB. Although continuous MB infusion has been used to prevent methemoglobinemia's rebound.85 This rebound methemoglobinemia is evidenced by an increase in methemoglobin levels following the end of therapy, secondary to the reverse of the reduction reaction,37 this should generally be discouraged as standard therapy.86 The proper recommended treatment method is the administration of intermittent bolus doses of MB.87 If methemoglobinemia exacerbates following MB therapy, an exchange transfusion should be performed urgently.37
4.2. Renal Function
MB use should be cautioned in cases of renal failure because it has been reported to cause a reduction in renal blood flow.35 It should be utilized with caution in severe renal insufficiency patients.88 Intensive monitoring of renal function should be maintained to ensure that the dose is well-adjusted to avoid further renal impairment.

4.3. Hepatic Function
Since the liver is the primary site of metabolism for MB, it is imperative to closely monitor for potential drug interactions and toxicities in MB-treated patients suffering from hepatic insufficiency.89 Monitoring the patients is also required for a protracted period post-MB to detect any delayed toxicities.89
4.4. Pulmonary Function
Maintaining proper monitoring of pulmonary function is very important, particularly in severe pulmonary hypertension patients, because MB can significantly raise the pressure in the pulmonary artery, which can compromise gas exchange.90 Patients with pre-existing pulmonary disease should be monitored to prevent potentially harmful effects.

Finally, as MB adversely affects the cardiovascular system91,92 and central nervous system,72 assessment of hemodynamic and neurological parameters for patients may also be required.

 

5. DOSING AND ADMINISTRATION

 

The dosing of MB for various ICU conditions has been evaluated in several studies (Table 1). The standard initial dose for methemoglobinemia is 1-2 mg/kg intravenous (IV) over 3 to 5 minutes; followed by 1 mg/kg within 30 minutes if methemoglobin does not resolve.93 For septic shock, MB is administered at 2 mg/kg IV bolus over 15 minutes as an initial dose and then is given as a continuous infusion.94 In vasoplegic syndrome, MB is administered at 1.5-2 mg /kg IV over 20 minutes to 1 hour.59,81,95-97 For cardiac surgery, 2 mg/kg was added to the CPB prime and followed with a constant infusion.98 In ifosfamide-induced encephalopathy, MB treats the condition effectively at 50 mg every 4 hours IV/orally (PO).67 MB across conditions exhibits a favorable safety profile with careful monitoring for potential adverse effects.

Table 1: Summary MB doses used in ICU conditions.
Condition Initial Dose Repeat Dose/Infusion References
Methemoglobinemia 1-2 mg/kg IV over 3-5 minutes 1 mg/kg within 30 minutes if needed (methemoglobin does not resolve) Wright et al., 199993
Septic shock 2 mg/kg IV bolus over 15 minutes 1-h infusions of 0.25, 0.5, 1, and 2 mg/kg/hr, respectively Kirov et al., 200194
Vasoplegic syndrome 1.5-2 mg /kg IV over 20 minutes to 1hr N/A Egi et al., 2007, Kofidis et al., 2001, Levin et al., 2004, Leyh et al., 2003, Ozal et al., 200559,81,95-97
Cardiac surgery (During CPB) 2 mg/kg added to CPB prime Continuous infusion at 0.25-2 mg/kg/hr Grayling and Deakin, 200398
Ifosfamide-induced Encephalopathy 50 mg every 4 hrs IV/PO Prophylaxis 50 mg every 6 hours IV/PO Pelgrims et al., 200067
IV, intravenous; N/A, not available; hr, hour; CPB, cardiopulmonary bypass; PO, orally.
 

 

6. LITERATURE REVIEW

 

Several researchers have discussed the effectiveness, safety, and clinical outcomes of MB among critically ill patients admitted to the ICU with different conditions (Table 2).

Table 2: Summary of studies on MB use in ICU.
Study ICU Condition Efficacy and Clinical Outcomes Safety
Clifton and Leikin, 200328 Methemoglobinemia Reduce back to hemoglobin Generally safe at IV dose of 1 to 2 mg/kg.
Preiser et al., 199549 Septic shock Increase mean arterial pressure (MAP).

Improve cardiac function.

Does not raise cellular oxygen.		 No adverse effect was reported.
Kirov et al., 200194 Septic shock MB reduced the plasma concentration of nitrites/ nitrates, the body temperature, and the catecholamines requirement.

Increased survival.		 No significant adverse effects were reported.
Kwok and Howes, 200699 Septic shock Increased systemic vascular resistance.

Increased MAP.

Unknown effect on mortality and oxygen delivery.		 No adverse effect was reported.
Ballarin et al., 2024100 Septic shock Reduced days on mechanical ventilation, length of ICU stay, and time to vasopressor discontinuation. No abnormal levels of methemoglobinemia were reported.
Zhao et al., 2022101 Vasodilatory shock MB along with vasopressors improved survival, improved hemodynamics, decreased lactate levels, and reduced vasopressor requirements. No serious side effects were reported.
Huang et al., 2024102 Vasodilatory shock Reduced the length of hospital stay, length of ICU stays, and duration of mechanical ventilation.

Use of MB may not decrease mortality.		 N/A
Levin et al., 200497 Vasoplegic syndrome after heart surgery Mortality reduction.

Shorten the length of vasoplegia.		 No adverse effects, except for blue or green coloring of the urine.
Evora et al., 2009103 Vasoplegic syndrome in heart surgery Facilitate the norepinephrine vasoconstrictor effect

Cheapest and best option.		 Safest option.
Park et al., 2005104 Ifosfamide-induced encephalopathy The patient recovered completely. N/A
Pelgrims et al., 200067 Ifosfamide-induced encephalopathy MB is an effective therapy (shortens the duration of ifosfamide-induced encephalopathy).

MB may also be used for ifosfamide-induced encephalopathy prevention.		 N/A
IV, intravenous; MAP, mean arterial pressure; MB, methylene blue; N/A, not available.
 

A prior study reported that MB was an effective treatment for methemoglobinemia.28 Other studies have reported that MB in patients with septic shock improved hemodynamic stability, reduced vasopressor requirement, and might or might not have led to an increased survival rate.49,94,99,100 Studies reported that MB improved the hemodynamic parameters significantly in cardiac surgery and vasoplegic syndrome, reduced morbidity, improved patient outcomes, decreased use of high dose vasopressors, and had shorter lengths of stay in the ICU.97,101-103 Studies reported for ifosfamide-induced encephalopathy report that MB had prophylactic and treatment effects that lead to a rapid resolution and improved clinical outcomes.67,104 Overall, with proper monitoring and recommended dose alterations, MB was found to be safe.

 

7. LIMITATIONS

 

There are some limitations to this research. First, this study did not include all relevant literature, and there may be missing relevant articles on the use of MB in ICU settings. Therefore, the author believes that more high-quality research on the use of MB in ICU settings is needed.

 

8. CONCLUSION

 

MB is a multifaceted, effective therapeutic agent in several therapeutic areas within the ICU. A multitarget mechanism of action of MB included inhibition of nitric oxide synthase and guanylate cyclase and acting as a redox agent, making it effective in the management of many ICU conditions, such as septic and vasoplegic shock, methemoglobinemia, and Ifosfamide-induced encephalopathy. MB has shown improved outcomes for critically ill patients. Still, utilizing MB as an adjunct in treatment should consider dosing and regimen practices to achieve optimal clinical benefit with monitoring and adjustments, particularly for specific patients (e.g., renal/hepatic impairment and G6PD deficiency). More research and clinical trials are fundamental to advancing the knowledge and the use of MB in critical care.

9. Conflict of Interest
None declared by the authors

10. Ethics considerations
Ethical approval not required.

11. Author’s contributions
Rayan A. Qutob is the sole author of this paper, responsible for Conceptualization, investigation, methodology, resources, validation, drafting original draft, review and editing.

 

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