Elmati PR, Nagaradona T, Raghove V, Jagirdhar GSK, Surani S. Methylene blue in the critical care setting. World J Crit Care Med 2025; 14(3): 105350 [DOI: 10.5492/wjccm.v14.i3.105350]
Corresponding Author of This Article
Salim Surani, MD, Professor, Department of Medicine and Pharmacology, Texas AM University, 40 Bizzell Street, College Station, TX 77843, United States. srsurani@hotmail.com
Research Domain of This Article
Critical Care Medicine
Article-Type of This Article
Minireviews
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Author contributions: Elmati PR and Jagirdhar GSK designed the overall concept and outline of the manuscript; Elmati PR, Raghove V, Jagirdhar GSK, and Nagaradona T performed the research and analyzed the data; Elmati PR, Raghove V, Jagirdhar GSK, Nagaradona T, and Surani S contributed to the manuscript’s writing and editing; and all authors have read and approved the final manuscript.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Salim Surani, MD, Professor, Department of Medicine and Pharmacology, Texas AM University, 40 Bizzell Street, College Station, TX 77843, United States. srsurani@hotmail.com
Received: January 20, 2025 Revised: March 21, 2025 Accepted: April 21, 2025 Published online: September 9, 2025 Processing time: 181 Days and 0.3 Hours
Abstract
Methylene blue (MB) is a versatile medicine with a long history of use in various medical applications, including dye, antiseptic, and treatment for methemoglobinemia. It has a role in vasoconstriction, methemoglobin reduction, inhibition of guanylate cyclase, and anti-inflammatory effects. We reviewed PubMed and Google Scholar literature for relevant studies on MB in intensive care unit (ICU). We created search criteria using a combination of free text words, including MB, critical care, intensive care, sepsis, surgery, pharmacokinetics, and pharmacodynamics. Relevant articles published in the English language were analyzed and incorporated. MB has been used in managing patients with refractory shock, including septic shock, vasoplegic shock, surgical patients, and some instances of drug-induced hypotension. In conclusion, MB in the ICU is a promising medication for sepsis and vasoplegic shock. Further research with randomized trials on its long-term safety in the ICU, time of initiation, dose, and duration is necessary.
Core Tip: Methylene blue is a promising medication with various benefits due to its inhibition of guanylate cyclase, anti-inflammatory effects, and nitric oxide inhibition. It has been researched in septic shock, distributive shock in cardiac procedures, anaphylaxis, and organ transplant procedures. It is a safe medication based on literature with rare documented adverse events at lower doses. Its role as an adjunct to vasopressors needs to be further researched, including the definition of the dose, initiation time, and usage duration.
Citation: Elmati PR, Nagaradona T, Raghove V, Jagirdhar GSK, Surani S. Methylene blue in the critical care setting. World J Crit Care Med 2025; 14(3): 105350
Methylene blue (MB) has a role in vasoconstriction, methemoglobin reduction, inhibition of guanylate cyclase[1], and anti-inflammatory effects. MB is a nitric oxide (NO) inhibitor[1]. It can reverse the vasodilation that occurs in septic shock patients[2]. It also prevents vasodilation in response to inflammatory cytokines, a sepsis hallmark. It is used in managing patients with refractory shock, including septic shock, distributive shock, surgical patients, and some instances of drug-induced hypotension. Hypotension, elevated lactate levels, and unresponsiveness to fluid administration characterize sepsis. It is a state of widespread vasodilation and decreased response to administered vasopressors. Given the reduced response to vasopressors and adverse events associated with vasopressors, research on alternative vasopressor-sparing drugs for sepsis is ongoing.
The vasoplegic syndrome is a state of sustained hypotension mean arterial pressure (MAP): 60 mmHg and low systemic vascular resistance (SVR) (< 800 dynes × second/cm5) with organ hypoperfusion in patients with cardiac surgery, cardiopulmonary bypass surgery, liver transplantation syndrome, sepsis, anaphylaxis. Patients often have a normal or increased cardiac output (cardiac index ≥ 2.2 L/minute/m2). Treatment is often with catecholamines and vasopressors[3]. MB increases vascular smooth muscle tone and is utilized in septic shock and vasoplegic shock. Ischemic reperfusion syndrome is another condition in which MB has been used for graft reperfusion[4]. Through its effects on the mitochondrial respiratory chain and NO production, MB has been used in metformin intoxication[5-10]. This article explores the current evidence on the mechanisms of action, indications, and clinical outcomes associated with MB in the intensive care unit (ICU) and perioperatively.
MECHANISM OF ACTION AND USE
MB is a versatile agent that has various effects on multiple pathways in the body. MB has been shown to restore vascular tone by inhibiting endothelial and inducible NO synthase and its downstream enzyme soluble guanylate cyclase[11]. Additionally, MB has been shown to restore vaso-regulation in vasoplegic conditions such as septic shock[11]. MB acts by inhibiting excessive NO production and alleviates its vasorelaxant effect in vascular smooth muscle, thus restoring vascular tone, allowing vasoconstriction to occur and increasing blood pressure[12].
Furthermore, MB has been evidenced to have neuroprotective effects, hypothesized to reduce brain injury and ischemia[13]. MB acts as a reducing agent for oxygen by adding electrons to the oxygen molecule. This reduction step allows methemoglobin to be converted to hemoglobin at an accelerated rate, thus decreasing the burden of patients afflicted with methemoglobinemia[14]. Figure 1 shows NO mediated vasodilation in shock and role of MB. MB has a short terminal half-life of 5.25 hours. Therefore, multiple repeated dosing of MB or continuous infusion may be required to maintain the drug's mechanism of action[15,16]. The lowest effective dose, ranging from 0.25-2 mg/kg/hour. has been documented[2,17]. Starting MB with vasopressors early in the onset of sepsis 8 hours is beneficial compared to late initiation[18]. MB is helpful as adjuvant therapy in shock rather than as rescue medication[12]. In vasoplegic syndrome, early administration while in the operating room was associated with better outcomes than postoperative ICU administration, with reduced major adverse events, including renal failure and operative mortality[19].
Figure 1 Mechanism of nitric oxide-mediated vasodilation in shock and the role of methylene blue.
IL: Interleukin; TNF: Tumor necrosis factor; GTP: Guanosine triphosphate; cGMP: cyclic guanosine monophosphate; eNOS: Endothelial nitric oxide synthase.
No adverse events were noted in the continuous infusion of MB over 48 hours[4,20]. Discoloration of skin and urine are the predominant non-fatal side effects in these patients[20]. Zhao et al[21] illustrates blue-green urine in his manuscript on methemoglobinemia due to nitrobenzene poisoning treated with MB. Adhit et al[22] illustrates similar urine on treatment of methemoglobinemia from pesticide positing with MB. High doses of MB > 7 mg/kg can compromise splanchnic perfusion[16]. MB is being studied as a potential therapy in hemorrhagic shock. Higher MAP on concomitant MB and blood transfusion administration was found in these animal studies[23-25].
INDICATIONS IN THE ICU
MB can be used in patients with distributive or vasodilatory shock including septic, vasoplegic shock or anaphylactic shock that is associated with acute circulatory failure. It is associated with low MAP, altered cardiac output, and decreased SVR. Vasoplegic shock typically occurs after cardiac surgery (such as cardiopulmonary bypass) or due to other non-infectious causes. MB has been shown to decrease cyclic guanosine monophosphate levels and alleviate its vasorelaxant effect in patients with septic shock. MB can also scavenge NO, thus further reducing the vasorelaxant effects and improving pressure control[11].
In a systematic review by Ng et al[26] on randomized controlled trials (RCTs) with the use of MB in septic shock, the authors found 5 studies that used MB at a dose of 2 mg/kg increased MAP, reduced vasopressor usage, and increased ratio of arterial oxygen partial pressure to fraction of inspired oxygen. Reduction in mortality, serum lactate levels, and hospital length of stay was noted[26]. No differences in heart rate were noted in MB and the control group for heart rate changes. Alkazemi et al[27] reported 5 RCTs and 10 non RCTs on septic shock. The authors stated that there was a decreased in mortality in mortality on overall analysis and sub analysis of RTCs alone[27]. The presence of studies with small populations and heterogeneity is a limitation in multiple studies[12]. Table 1 shows the summary of individual studies on MB for shock and vasoplegic syndromes and Table 2 shows the summary of systematic reviews and meta-analyses on the use of MB in septic shock in patients.
Table 1 Summary of individual studies on methylene blue for shock and vasoplegic syndromes.
2 mg/kg IV bolus for 2 hours, followed by stepwise infusion of 0.25 mg/kg/hour, 0.5 mg/kg/hour, 1 mg/kg/hour, and 2 mg/kg/hour, that were maintained for 1 hour each
MB increased mean arterial pressure; vasopressor use decreased 87%, 81%, 40% respectively (P < 0.001)
MB also reduced the body temperature and the plasma concentration of nitrates/nitrites and leukocytes
Methylene blue had a dose-dependent effect on cardiac index, mean arterial, mean pulmonary artery and pulmonary artery occlusion pressures, left ventricular function, O(2) delivery and consumption and lactate levels
Median bolus dose of methylene blue was 1.2 mg/kg. For patients administered a continuous infusion, the median dose was 0.25 mg/kg/hour for a median duration of 10 hours
Great reduction in vasopressor requirements and an increase in MAP were noted in the hydroxocobalamin group compared with the methylene blue group (P < 0.001)
Hydroxocobalamin vs MB: Hydroxocobalamin was associated with a significant improvement in mean arterial pressure at 1 hour (MD: 5.30 mmHg, 95%CI: 2.98-7.62), total vasopressor dose at 1 hour (MD: -0.13 mcg/kg/minute NEE, 95%CI: -0.25 to -0.01) and total vasopressor dose at 6 hours (MD: -0.15 mcg/kg/minute NEE, 95%CI: -0.21 to -0.08) compared to MB
No differences were observed in SVR or mortality between groups
Septic shock, vasoplegic syndrome after cardiac surgery and ischemic reperfusion
MB reduced the duration of mechanical ventilation (MD: -0.68; 95%CI: -1.23 to -0.14), ICU LOS and (MD: -1.54, 95%CI: -2.61 to -0.48); hospital LOS (MD: -1.97; 95%CI: -3.92 to -0.11)
Syndrome due to liver transplantation
No significant difference in mortality between the MB and placebo groups (ORs = 0.59; 95%CI: 0.32 to -1.06)
Hydroxocobalamin vs MB: Hydroxocobalamin was associated with a higher MAP at 1 hour (MD: 7.80, 95%CI: 2.63-12.98); no difference in mortality (OR = 0.92, 95%CI: 0.42-2.03)
ICU LOS decreased (MD: -1.58, 95%CI: -2.97 to -0.20, P = 0.03); ventilation days decreased (MD: -0.72, 95%CI: -1.26 to -0.17, P = 0.01); time to vasopressor discontinuation decreased (MD: -31.49 hours, 95%CI: -46.02 to -16.96, P < 0.0001)
For septic shock and vasoplegic syndrome, the dosage of MB is determined based on the clinical picture of the patient. Dosages started at an intravenous bolus of 2 mg/kg for 15 minutes, followed by escalating doses of 0.25-2 mg/kg/hour[28]. Other vasoplegic conditions, such as cardiac surgery, heart failure, and renal failure, cause an overall increase in levels of NO and activation of soluble guanylyl cyclase. NO will diffuse freely from the endothelium into the neighboring vascular smooth muscle, causing vasodilation, which may cause blood vessel relaxation by activating guanylyl cyclase. MB thus plays a role in modulating the effects of NO by decreasing levels of cyclic guanosine monophosphate and decreasing the effects of NO[29].
Huang et al[30] described the use of MB in patients with obstructive jaundice undergoing surgery. Procedures for indications include cholangiocarcinoma, duodenal adenocarcinoma, pancreatic carcinoma, hepatocellular carcinoma, chronic pancreatitis, biliary strictures, and stenosis. These patients are at risk of postoperative morbidity and mortality due to severe hypotension. 2 mg/kg of MB before anesthesia induction reduced the need to initiate noradrenaline and the dose of noradrenaline used. Biochemical indexes of liver and kidney function, including creatinine, glutamic oxalaacetic transaminase, glutamic-pyruvic transaminase, and creatine kinase, were lower post-procedure in patients in the MB group. Zhao et al[4] conducted a systematic review of 15 studies with 832 patients on MB for septic shock or vasoplegic syndrome and ischemia-reperfusion injury with similar results. The authors also saw an increase in MAP, heart rate, and peripheral vascular resistance. It has significant benefits in organ dysfunction, including lower incidence of renal failure and reduced lactate levels[4]. Luis-Silva et al[20] and Rajbanshi et al[31] state MB led to an immediate decrease in norepinephrine dosage and an earlier decrease in vasopressin dosage.
Hydroxocobalamin, a precursor of vitamin B12, inhibits NO and inflammatory mediators such as NO synthase, guanylate cyclase, and hydrogen sulfide. Administration of 5 g of hydroxocobalamin intravenous in 1-to-2 doses reduced vasopressor dose and improved MAP and SVR in refractory vasoplegic syndrome. Hiruy et al[32] compared hydroxocobalamin to MB in vasoplegic shock associated with cardiopulmonary bypass and found that hydroxocobalamin was associated with a more significant reduction in vasopressor requirements than MB. Cadd et al[33] systematically compared hydroxocobalamin and MB in vasoplegic shock. The authors found 4 observational studies with 263 patients showing lower MAP and lower norepinephrine usage 1-6 hours after hydroxocobalamin administration. No benefits were noted with MB. In a similar meta-analysis by Brokmeier et al[34] on hydroxocobalamin the authors state the similarity between both drugs in relation to MAP and vasopressor dosage. Some authors, including Busse et al[35] suggested starting both hydroxocobalamin and MB when the norepinephrine dose exceeds > 0.05 μg/kg/minute in vasodilatory shock.
Mazzeffi et al[36] conducted a cohort study on eighty patients who received MB at a dose of 1 mg/kg and 2 mg/kg for post cardiopulmonary bypass vasoplegic syndrome. There was a decrease in MAP of 8 mmHg within 2 hours of administration[36]. Patients with deep hypothermic circulatory arrest and higher MAP at the time of MB had a better response[36]. Perioperative use of MB in patients at high risk of vasoplegic syndrome at a dose of 2 mg/kg reduced vasoplegic Syndrome occurrence by 26% compared to the placebo group. Patients had a history of angiotensin-converting enzyme inhibitors, calcium channel blockers, or heparin usage. They also had shorter ICU and more extended hospital stays[37]. Maslow et al[38] conducted a similar study and initiated MB at the onset of cardiopulmonary bypass in patients on angiotensin-converting enzyme inhibitors. The administration of MB increased MAP and SVR by 40 minutes and reduced the need for vasopressor administration. Furthermore, serum lactate levels were lower in MB patients, which signified better tissue perfusion.
Huang et al[39] describe a systematic review of six RCTs with 265 patients with distributive shock. The authors state no difference in mortality in both groups. There was a decrease in the duration of mechanical ventilation and length of stay in the hospital and ICU[39]. Doses ranging from 0.5 mg/kg to 3 mg/kg were given. There was a lack of a standard dose, a high degree of heterogeneity, a lack of standardization among the vasopressors used, and variations in disease severity. The majority of the studies were of small sample size and may have a publication bias. Table 1 shows the summary of individual studies on MB for shock and vasoplegic syndromes and Table 2 shows the summary of systematic reviews and meta-analyses on the use of MB in vasoplegic shock in patients.
Case reports and case series exist on the use of MB for anaphylactic shock[40]. Evora et al[41] describes eleven patients in their systematic review of literature with anaphylactic shock that were treated with MB. Causes for anaphylaxis include protamine, iodinated dyes, penicillin and dipyrone. Administration of MB resulted in immediate recovery in all of the patients. Dosage of MB varied across case reports[41].
Methemoglobinemia
MB is the first-line treatment for methemoglobinemia. MB facilitates the reduction of methemoglobin to hemoglobin, restoring oxygen-carry capacity[42]. For methemoglobinemia, MB is started intravenously at a dosage of 1 mg/kg to 2 mg/kg. MB is generally a safe drug with dose-related hemolytic effect by interacting with methemoglobin and erythrocyte enzyme systems to reduce back to hemoglobin[43].
Drug-induced hypotension
A case report by Takahashi et al[44] states the utilization of MB for a patient with metformin toxicity and vasoplegic shock at a dose of one hundred milligrams of MB. There was a decrease in vasopressor requirement, an improvement in blood pressure, and a decrease in serum lactate level. The patient did not survive the admission. Katlan et al[45] report a similar case of metformin toxicity with 1 mg/kg, 30-60 minutes infusion of MB. The patient was discharged successfully on day 5. The authors suggest earlier administration for improved outcomes. Tackett et al[46] describe two patients in the surgical ICU with methemoglobinemia from benzocaine, a topical anesthetic, and dapsone used for pneumocystis pneumonia prophylaxis requiring MB administration.
SAFETY AND ADVERSE EFFECTS
MB has been considered a well-tolerated agent, with the main adverse effects being blue skin discoloration and, more commonly, urine. Other adverse effects that have been sighted were flushing, dizziness, nausea, and chest and limb pain[29]. MB has been shown to inhibit monoamine oxidase A in patients taking anti-depressants, which is responsible for serotonin breakdown in the brain. MB is an inhibitor of monoamine oxidase and can cause serotonin syndrome in patients taking serotonergic medications like tramadol, meperidine, fentanyl, linezolid, trazodone, serotonin-norepinephrine reuptake inhibitors, clomipramine, and selective serotonin reuptake inhibitors.
Therefore, in patients who require MB, careful consideration should be taken in patients taking anti-depressants to avoid this syndrome. Patients who are taking serotonergic agents have an increased risk of serotonergic syndrome with MB doses at 5 mg/kg[29,47]. MB also inhibits cytochrome P450; therefore, in patients who have hepatic or renal impairment, there is an increased toxicity burden[17]. MB is contraindicated in patients who have glucose-6-phosphate dehydrogenase (G6PD) deficiency due to increased risk of developing hemolytic anemia. G6PD is present in 5% of the population[48]. Vitamin C is one of the alternative medications used in G6PD deficiency patients[49-52]. It is also used when MB is unavailable, not tolerated well or as an add on agent when there is lack of improvement of methemoglobinemia with MB[53-56]. It is also used as an alternative to MB in patients with serotonergic syndrome as patients taking serotonergic medications are at high risk of serotonin toxicity with co-administration of MB [57].
Finally, MB is contraindicated in pregnant women as it is considered a pregnancy class X agent due to intestinal atresia and fetal death following an intra-amniotic injection[47]. Blue dye from MB can falsely lower the oxygen saturation on pulse oximeter readings due to the inhibition of light transmission from blue dye[35]. Alternatives for these patients include using a co-oximeter, arterial blood gas analysis or measuring methemoglobin levels in blood. Doses greater than 2 mg/kg can cause dose-dependent cardiac arrhythmia, coronary vasoconstriction, decreased gas exchange, lower cardiac output, and mesenteric and renal blood flow[58]. Mesenteric vasoconstriction and paradoxical methemoglobinemia are reported at 4 mg/kg[59].
CONCLUSION
MB is a valuable therapeutic agent in the ICU, particularly for managing refractory hypotension in septic shock, vasoplegic syndrome, and drug-induced hypotension. Further research is needed to establish its optimal dosing, administration, and impact on critical care outcomes.
Footnotes
Provenance and peer review: Invited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Critical care medicine
Country of origin: United States
Peer-review report’s classification
Scientific Quality: Grade C
Novelty: Grade B
Creativity or Innovation: Grade D
Scientific Significance: Grade C
P-Reviewer: Shelat VG S-Editor: Bai Y L-Editor: A P-Editor: Zheng XM
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