Administration of methylene blue in septic shock: pros and cons.

Septic shock typically requires the administration of vasopressors. Adrenergic agents remain the first choice, namely norepinephrine. However, their use to counteract life-threatening hypotension comes with potential adverse effects, so that non-adrenergic vasopressors may also be considered. The use of agents that act through different mechanisms may also provide an advantage. Nitric oxide (NO) is the main driver of the vasodilation that leads to hypotension in septic shock, so several agents have been tested to counteract its effects. The use of non-selective NO synthase inhibitors has been of questionable benefit. Methylene blue, an inhibitor of soluble guanylate cyclase, an important enzyme involved in the NO signaling pathway in the vascular smooth muscle cell, has also been proposed. However, more than 25 years since the first clinical evaluation of MB administration in septic shock, the safety and benefits of its use are still not fully established, and it should not be used routinely in clinical practice until further evidence of its efficacy is available.

A Rare Case of Methemoglobinemia after Ifosfamide Infusion in a 3-Year-Old Patient Treated for T-ALL.

Methemoglobinemia is a potentially life-threatening, rare condition in which the oxygen-carrying capacity of hemoglobin is diminished. We present the case of a 3-year-old boy treated for T-cell acute lymphoblastic leukemia (T-ALL) who developed methemoglobinemia (MetHb 57.1%) as a side effect of ifosfamide administration. Due to his critical condition, the patient was transferred to the intensive care unit (ICU). The therapy included methylene blue administration, an exchange transfusion, catecholamine infusion, and steroids. Improving the general condition allowed for continuing chemotherapy without ifosfamide and completion of the HR2 block. Vigilance for methemoglobinemia as a very rare side effect should be widespread when using ifosfamide in the treatment protocols.

Methylene Blue Reduces Retinal Cell Inflammation, Apoptosis, and Oxidative Stress in a Rat Model of Diabetic Retinopathy via Sirtuin 1 Activation.

Objective: Diabetic retinopathy (DR), characterized by neuronal damage in the retina, is primarily driven by oxidative stress resulting from diabetes (DM). This study investigated the potential effects of methylene blue (MB) on streptozotocin (STZ)-induced DR. Methods: A rat model of DR was established via STZ injection, while a cell model was created using high-glucose (HG) exposure of human retinal microvascular endothelial cells. Evaluation of oxidative stress markers, pro-inflammatory cytokines, and pro-apoptotic proteins was performed based on their expression profiles in human retinal microvascular endothelial cells. Results: MB treatment significantly upregulated the expression of sirtuin 1 (SIRT1), which was found to be downregulated in the retinal tissues of STZ-treated rats and HG-exposed human retinal microvascular endothelial cells, as determined by polymerase chain reaction (PCR). Furthermore, MB therapy effectively suppressed STZ-induced oxidative stress, inflammation, and cell death. Consistent with the in vivo findings, MB activated the expression of SIRT1, thereby protecting HG-treated human retinal microvascular endothelial cells against oxidative stress, inflammation, and apoptosis. Conclusion: These results support the conclusion that MB mitigates DR by activating SIRT1, leading to a reduction of inflammation, apoptosis, and oxidative stress.

Methylene blue for intractable pain from oral mucositis related to cancer treatment: a randomized phase 2 clinical trial.

BACKGROUND: Oral mucositis (OM) in patients receiving cancer therapy is thus far not well managed with standard approaches. We aimed to assess the safety and effectiveness of methylene blue (MB) oral rinse for OM pain in patients receiving cancer therapy. METHODS: In this randomized, single-blind phase 2 clinical trial, patients were randomized to one of four arms: MB 0.025%+conventional therapy (CTx) (n = 15), MB 0.05%+CTx (n = 14), MB 0.1%+CTx (n = 15), or CTx alone (n = 16). Intervention groups received MB oral rinse every 6 h for 2 days with outcomes measured at days 1-2; safety was evaluated up to 30 days. The primary outcome measured change in the pain numeric rating scale (0-10) from baseline to day 2. Secondary outcome measured change in oral function burden scores from baseline to day 2, World Health Organization OM grades, morphine equivalent daily doses, and adverse events. The trial was registered with ClinicalTrials.gov ID: NCT03469284. RESULTS: Sixty patients (mean age 43, range 22-62 years) completed the study. Compared with those who received CTx alone, those who received MB had a significant reduction of pain scores at day 2 of treatment (mean ± SD); 0.025%: 5.2 ± 2.9, 0.05%: 4.5 ± 2.9, 0.1%: 5.15 ± 2.6) and reduction of oral function burden scores (0.025%: 2.5 ± 1.55, 0.05%: 2.8 ± 1.7, 0.1%: 2.9 ± 1.60). No serious adverse events were noted, but eight patients reported burning sensation of the oral cavity with the first dose, and this caused one patient to discontinue therapy. CONCLUSIONS: MB oral rinse showed significant pain reduction and improved oral functioning with minimal adverse effects. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT03469284.

A novel case of prolonged Ifosfamide encephalopathy and long-term treatment with methylene blue: a case report and review of literature.

BACKGROUND: Encephalopathy following Ifosfamide treatment is a well-described phenomenon that is typically treated with Methylene Blue (MB). Chloroacetaldehyde, a potentially neurotoxic metabolite of Ifosfamide is hypothesized to cause this encephalopathy. Current guidelines for treatment is to stop Ifosfamide and provide supportive care. MB acts to inhibit Chloroacetaldehyde formation and has been described as a therapy and prophylaxis for Ifosfamide-encephalopathy. MB is effective within 30 min and lasts up to 3 days. Prolonged encephalopathy and MB therapy has not been described in the literature as lasting longer than 30 days following treatment. CASE PRESENTATION: We present the case of an 11-year-old female with autistic spectrum disorder and recurrent episodes of severe somnolence for 7 months following Ifosfamide therapy for her Non-Germinomatous Germ Cell Tumor (GCT). Periods of somnolence occurred prior to receiving cranial RT. Administration of MB gave immediate but limited response, with resolution of somnolence lasting 1-2 days between administrations. The somnolence could not be explained by neuroimaging or laboratory evaluation, but EEG indicated persistent encephalopathy. CONCLUSION: A literature review determines that neurotoxicity is a side effect of Ifosfamide, but this effect has not been described persisting longer than 30 days. Our case continued to require treatment with MB for 7 months following cessation of therapy. We report these novel clinical findings, and hypothesize that there could be a genetic/metabolic component linking this reaction to Ifosfamide with the case patient's pre-existing autism. This possible association may also correlate to the already-established link between autism and the development of GCTs. This hypothesis leads to further discussion on the suitable usage of Ifosfamide in children with co-morbidities and the necessity of screening prior to its usage.

Rasburicase induced methemoglobinemia: A systematic review of descriptive studies.

PURPOSE: There is an increased number of reports being published on rasburicase-induced methemoglobinemia recently. We aimed to identify and critically evaluate all the descriptive studies that described the rasburicase-induced methemoglobinemia, its treatment approach, and their outcomes. METHODOLOGY: PubMed, Scopus and grey literature databases were searched from inception to January 2022 using search terms "rasburicase" and "methemoglobinemia" without any language and date restriction. A bibliographic search was also done to find additional studies. Only descriptive studies on Rasburicase-induced methemoglobinemia were included for our review. Two contributors worked independently on study selection, data abstraction, and quality assessment, and any disagreements were resolved by consensus or discussion with a third reviewer. RESULT: A total of 24 reports including 27 patients (23 male, 3 female patients, and 1 study did not specify the gender of the patient) aged from 5 to 75 years were included in the review. Immediate withdrawal of the drug and administering methylene blue, ascorbic acid, blood transfusion, and supportive oxygen therapy are the cornerstone in the management of rasburicase-induced methemoglobinemia. CONCLUSION: Rasburicase administration should be followed by careful monitoring of patients for any severe complication and treat it as early as possible appropriately. In a patient who presents with rasburicase-induced haemolysis or methemoglobinemia, it is often important to expect a diagnosis of G6PD deficiency unless otherwise confirmed and to avoid administering methylene blue, even though the patient is from a low-risk ethnicity for G6PDD.

Foreign body removal with the assistance of ultrasound guidance and methylene blue staining in children-a cohort study.

BACKGROUND: Soft tissue foreign bodies (FBs) are very commonly observed in paediatric emergency departments. Not all FBs can be removed effectively, even via open surgery and image intensifier guidance. In the current study, we evaluated the efficiency of FB removal with the assistance of ultrasound (US) and methylene blue (MB) staining. METHODS: We enrolled 80 patients at our clinical center between May 2016 and December 2020. Eleven patients were operated upon with the assistance of US guidance and MB and were defined as group A; the other 69 patients were defined as group B. For the patients in group A, US was first used to locate the FB; MB was then injected next to the FB. Open surgery was subsequently performed. For group B, the FBs were removed by conventional methods. The surgical outcomes were evaluated according to surgical duration, incision infection rates, radiograph exposure times, and FB residue rates. RESULTS: The average surgery time for group A was 0.35 ± 0.10 hours; the corresponding time was 0.49 ± 0.50 hours in group B and there was a significant difference between the groups (p = 0.032). The radiograph exposure times were 1.33 ± 0.34 in group A and 4.65 ± 1.81 times in group B (p = 0.021). CONCLUSIONS: This study demonstrates that assistance of US and MB staining is a more efficient approach compared with traditional methods for FB removal, and this surgical method can be used effectively for FB removal in children.

Methylene blue and ifosfamide-induced encephalopathy: Myth or reality?

BACKGROUND: Ifosfamide-induced encephalopathy (IIE) is a rare and serious adverse reaction. Thus far, no standard medication has been documentedto be efficient in the reversal of IIE, and while ifosfamide infusion interruption and hydration are recommended, methylene blue (MB) administration remains controversial. METHODS: We retrospectively reviewed medical records to assess cases with IIE after ifosfamide infusion. We included all patients having received an ifosfamide infusion during their hospitalization in the medical oncology unit of the National Institute of Oncology in Rabat, Morocco, between September 2016 and September 2017. We subsequently conducted a literature review to determine the role of MB in IIE by searching PubMed using the terms "Methylene Blue" and "Ifosfamide". RESULTS: A total of 88 patients received ifosfamide, and four patients had IIE. Ifosfamide infusion was stopped immediately after the IIE occurrence, and patients underwent renal function correction with hydration. All patients received MB infusion, and three patients had an improvement of their neurological status. As regards the literature review, 34 articles were reviewed and 16 items were included in the review. Overall, 38 (65.5%) patients received MB infusion and 28 (75.6%) patients responded favorably to the treatment. CONCLUSIONS: Methylene blue can be used as a treatment for IIE owing to the severity of the IIE as well as absence of standard medication. Nonetheless, side effects such as serotonergic syndrome should be investigated. More broadly, prospective studies and controlled trials are needed to explore the contribution of MB in IIE management and encourage its use.

Evaluating the safety of oral methylene blue during swallowing assessment: a systematic review.

OBJECTIVE: Methylene blue (MB) is frequently administered during fiberoptic endoscopic evaluation of swallowing (FEES) to enhance visualization of pharyngeal bolus transit. However, the safety of MB is being questioned since serious adverse events (AEs) such as hemodynamic instability, hemolysis, and serotonin syndrome were reported. The aim of this study is a systematic analysis of the literature to obtain an evidence-based overview of AEs due to oral administration of MB and to determine its safety as a food dye during swallowing assessment. METHODS: A systematic literature search was carried out in PubMed, Embase, and Cochrane Library. Two reviewers independently selected articles describing oral administration of MB as a main diagnostic/therapeutic intervention, dosage, and AEs. Expert opinions, conference papers, sample size < 10, and animal studies were excluded. Level of evidence of the included studies was determined. RESULTS: A total of 2264 unduplicated articles were obtained. Seventeen studies met the inclusion criteria with 100% agreement between the two reviewers. Among these, twelve studies were randomized controlled trials. In a pooled population of 1902 patients receiving oral MB, three serious AEs were reported related to MB. Non-serious AEs showed a dose-related trend and were usually mild and self-limiting. A meta-analysis could not be performed as studies were methodologically too heterogeneous. CONCLUSION: Serious AEs due to oral administration of MB are rare (n = 3, 0.16%). MB-related non-serious AEs are mild, self-limiting, and show a dose-related trend. These findings indicate that it is safe to use small amounts of MB as a food dye during swallowing examinations.

Methylene blue vs methyl aminolevulinate photodynamic therapy in the treatment of mild-to-moderate toenail onychomycosis: Short- and medium-term effects.

Photodynamic therapy (PDT) has emerged as an interesting alternative option for onychomycosis treatment. The impact of a specific photosensitizer (PS) on the final result is an important factor to consider. We conducted a short- and medium-term controlled trial to compare the effectiveness of PDT in the treatment of mild-to-moderate onychomycosis when it is mediated by two different PSs. Twenty patients were randomized to receive nine sessions of PDT distributed over 16 weeks mediated either by methylene blue (MB/PDT group) or methyl aminolevulinate (MAL/PDT group). Onychomycosis severity index (OSI) and nail involvement were checked along the study. Complete cure, treatment success, and clinical improvement were tabulated at 16 and 40-week follow-ups. OSI scores decreased significantly along the study, from 12.1 ± 5.4 to 3.6 ± 3.2 (MB/PDT group) and from 14.8 ± 6.0 to 5.4 ± 4.4 (MAL/PDT group). At 16-week follow-up, only 20% of the patients in the MB/PDT group reached complete cure and none in the group of MAL/PDT. At 40-week follow-up, complete cure rates were 70% and 40% in the MB/PDT group and MAL/PDT group respectively. Both modalities showed good outcomes in treatment of moderate toenail onychomycosis. MB/PDT showed a faster action but with relapse rates slightly higher than MAL/PDT.

Cutaneous adverse effects of methylene blue in an animal skin-flap model.

Background and objectives: Sentinel lymph node biopsy is important for metastasis surveillance in the management of a number of human cancers. Identification of sentinel lymph nodes may be facilitated by the use of several methods including methylene blue injection. However tissue necrosis is a known effect of methylene blue application. This study aimed to investigate the effects of methylene blue injection on skin flaps using a rodent model.Methods: Modified McFarlane flaps were prepared using Wistar Albino rats. Local injection of methylene blue was given to one group while saline was injected into the control group. A third group received systemic methylene blue via intraperitoneal injection. Observational and histological comparison was made between the groups to investigate the necrotic effects of methylene blue on skip flaps.Results: The control group's surviving flap areas were significantly larger than local methylene blue group's surviving flap area. However, there was no significant difference in skin flap survival area between the control group and the systemic methylene blue group. Furthermore, there is no significant difference between local and systemic methylene blue group's surviving flap areas.Conclusions: Local methylene blue injection increases skin necrosis and decreases rates of surviving flap areas in an experimental rat models.

Acute edema induced by toluidine blue extravasation-first report.

Methemoglobinemia is characterized by an increased level of methemoglobin (MetHb) in the peripheral blood. MetHb levels increase after tumescent anesthesia and need to be monitored. If a patient becomes symptomatic and/or the MetHb levels increase >10%, intravenous injection of an antidote is recommended. Toluidine blue is twice as effective as methylene blue in this respect.A 27-year-old woman with advanced lipedema underwent her third liposuction under tumescent anesthesia. After surgery, her MetHb levels increased and needed injection of toluidine blue. She developed an acute and painful edema after extravasation of some toluidine blue due to a bursting vein. This is the first report in the recent medical literature. Clinical presentation, course, and treatment are described.

Evaluation of genotoxicity related to oral methylene blue chromoendoscopy.

BACKGROUND: An oral formulation of methylene blue with colonic delivery (MB-MMX) has been developed to increase detection of colorectal polys during colonoscopy. Traditionally, there have been safety concerns regarding DNA damage when methylene blue is exposed to white light. The aim of this study was to evaluate DNA damage in colonic mucosa after MB-MMX chromoendoscopy. METHODS: This was an open-label phase II safety study to assess for genotoxicity on colorectal biopsies of patients undergoing two sequential colonoscopies before and after an oral dose of 200 mg MB-MMX added to their bowel prep. Analysis of a biomarker of double-stranded DNA breaks, γH2AX, was performed on biopsy specimens. RESULTS: Ten patients were included in the study. The mean expression of γH2AX ± 95 % confidence intervals of the 50 biopsies before and after MB-MMX administration were 0.58 ± 0.08 and 0.62 ± 0.09, respectively (P = 0.24). None of the analyzed samples showed excess positive γH2AX expression, confirming the absence of DNA damage on biopsies after methylene blue exposure. No deaths or serious adverse events occurred. CONCLUSIONS: An oral dose of 200 mg of MB-MMX did not result in any detectable DNA damage.

Serotonin Toxicity and Urinary Analgesics: A Case Report and Systematic Literature Review of Methylene Blue-Induced Serotonin Syndrome.

BACKGROUND: Serotonin syndrome (SS) is a potentially serious side effect of serotonergic drugs. Cases of SS have been reported from the administration of methylene blue (MB), an agent with monoamine oxidase inhibiting properties. To date, the reported cases of MB-induced SS have all been with MB given parenterally. We report a case induced by the initiation of a MB-containing oral agent. METHODS: A case of SS felt to be induced by the initiation of an MB-containing orally-administered urinary analgesic, started in a patient concurrently treated with multiple serotonergic drugs, is presented. A systematic literature review of MB-induced SS follows. The review consisted of searches in MEDLINE databases using the key terms "methylene blue" and "serotonin syndrome". The authors read all abstracts, and articles related to MB and serotonin toxicity; non-associated articles were discarded. Results are summarized. RESULTS: 23 manuscripts were identified, resulting in 50 unique cases of MB-induced SS. The majority of cases were related to peri-operative use of MB in parathyroidectomies or for the treatment of vasoplegic shock. All cases were associated with MB given parenterally. Concurrent treatment with serotonergic antidepressants was described in all 50 cases. Symptoms of SS ranged from mild to severe. One fatality was reported. CONCLUSIONS: Methylene blue can induce SS, felt to be secondary to MAOI properties. Although previous reports have exclusively been associated with MB given via parental administration, our case suggests that SS can be induced by oral administration of MB-containing agents.

Intraoperative vasoplegia: methylene blue to the rescue!

PURPOSE OF REVIEW: To evaluate the efficacy, dosing, and safety of methylene blue (MTB) in perioperative vasoplegic syndrome (VS). RECENT FINDINGS: Vasoplegic syndrome is a state of persistent hypotension with elevated cardiac output, low filling pressures, and low systemic vascular resistance (SVR). It occurs in up to 25% of patients undergoing cardiac surgery with cardiopulmonary bypass, can last up to 72 h, and is associated with a high mortality rate. MTB has been found to increase SVR and decrease vasopressor requirements in vasoplegic syndrome by inhibiting nitric oxide synthase, thus limiting the generation of nitric oxide, while inhibiting activation of soluble guanylyl cyclase and preventing vasodilation. MTB has been used in postgraft reperfusion during liver transplantation and anaphylaxis in a limited number of cases. Additionally, this medication has been used in septic shock with promising results, but similar to the cardiac surgical population, the effects of MTB administration on clinical outcomes has yet to be elucidated. SUMMARY: MTB should be considered during vasoplegic syndrome in cardiac surgery with cardiopulmonary bypass and usage may be more effective in an early critical window, prior to end-organ hypoperfusion. Other perioperative scenarios of MTB use show promise, but additional studies are required to develop formative conclusions.

Methylene blue treatment for residual symptoms of bipolar disorder: randomised crossover study.

BACKGROUND: Residual symptoms and cognitive impairment are among important sources of disability in patients with bipolar disorder. Methylene blue could improve such symptoms because of its potential neuroprotective effects. AIMS: We conducted a double-blind crossover study of a low dose (15 mg, 'placebo') and an active dose (195 mg) of methylene blue in patients with bipolar disorder treated with lamotrigine. METHOD: Thirty-seven participants were enrolled in a 6-month trial (trial registration: NCT00214877). The outcome measures included severity of depression, mania and anxiety, and cognitive functioning. RESULTS: The active dose of methylene blue significantly improved symptoms of depression both on the Montgomery-Åsberg Depression Rating Scale and Hamilton Rating Scale for Depression (P = 0.02 and 0.05 in last-observation-carried-forward analysis). It also reduced the symptoms of anxiety measured by the Hamilton Rating Scale for Anxiety (P = 0.02). The symptoms of mania remained low and stable throughout the study. The effects of methylene blue on cognitive symptoms were not significant. The medication was well tolerated with transient and mild side-effects. CONCLUSIONS: Methylene blue used as an adjunctive medication improved residual symptoms of depression and anxiety in patients with bipolar disorder.

International, prospective haemovigilance study on methylene blue-treated plasma.

BACKGROUND AND OBJECTIVES: Methylene blue is a phenothiazine dye, which in combination with visible light has virucidal and bactericidal properties, disrupting the replication of a broad range of enveloped viruses and some non-enveloped viruses. The study objective was to collect data on adverse reactions occurring with methylene blue plasma administered in a routine clinical practice environment and document their characteristics and severity. MATERIALS AND METHODS: This was an open label, multicentre, non-controlled, non-randomized, non-interventional study. Patients who receive a methylene blue plasma transfusion were observed for any signs and symptoms (adverse reactions) within 24 h safter the start of the transfusion, in different hospitals for a study duration of at least 1 year. RESULTS: A total of 19 315 methylene blue plasma units were transfused. There were eight patients with adverse reactions recorded during the study, one of them serious. Two had more than one reaction (two and four, respectively). Three patients had previous transfusions with methylene blue plasma only. CONCLUSION: Methylene blue plasma has a very acceptable safety profile with a rate of serious adverse reactions of 0·5/10 000 units.

Computed Tomography-Guided Methylene Blue Labeling Prior to Thoracoscopic Resection of Small Deeply Placed Pulmonary Nodules. Do We Really Need Palpation?

Background Video-assisted thoracic surgery (VATS) is widely used for thoracic surgery operations, and day by day it becomes routine for the excision of undetermined pulmonary nodules. However, it is sometimes hard to reach millimetric nodules through a VATS incision. Therefore, some additional techniques were developed to reach such nodules little in size and which are settled on a challenging localization. In the literature, coils, hook wires, methylene blue, lipidol, and barium staining, and also ultrasound guidance were described for this aim. Herein we discuss our experience with CT-guided methylene blue labeling of small, deeply located pulmonary nodules just before VATS excision. Method From April 2013 to October 2016, 11 patients with millimetric pulmonary nodules (average 8, 7 mm) were evaluated in our clinic. For all these patients who had strong predisposing factors for malignancy, an 18F-FDG PET-CT scan was also performed. The patients whose nodules were decided to be excised were consulted the radiology clinic. The favorable patients were taken to CT room 2 hours prior to the operation, and CT-guided methylene blue staining were performed under sterile conditions. Results Mean nodule size of 11 patients was 8.7 mm (6, 2-12). Mean distance from the visceral pleural surface was 12.7 mm (4-29.3). Four of the nodules were located on the left (2 upper lobes, 2 lower lobes), and seven of them were on the right (four lower lobes, two upper lobes, one middle lobe). The maximum standardized uptake values (SUV max) on 18F-FDG PET/CT scan ranged between 0 and 2, 79. Conclusion CT-guided methylene blue staining of millimetric deeply located pulmonary nodules is a safe and feasible technique that helps surgeon find these undetermined nodules by VATS technique without any need of digital palpation.

Histological Features of Methylene Blue-Induced Phototoxicity Administered in the Context of Parathyroid Surgery.

Methylene blue is a chromophore dye known for its photosensitizing properties. It is also administered intravenously as a tracer in parathyroid surgery to identify abnormal glands. We describe 2 cases of acute methylene blue-induced phototoxicity in patients who underwent parathyroidectomy. Both patients developed an acute vesiculopustular inflammatory rash on the anterior neck corresponding to the site exposed intraoperatively to overhanging surgical lights. One of the patients also developed a bulla on her finger at the site of attachment of the oxygen probe. Biopsies were taken from both patients at different time points. The histological findings included destruction of sebaceous glands and deposition of diastase-periodic acid-Schiff-positive hyaline material around dermal blood vessels. These features are similar to those seen in skin treated with photodynamic therapy and systemic photosensitivity disorders such as the porphyrias. The wavelengths of light emitted by the surgical lights and oxygen probe overlap with the absorption spectrum of methylene blue. This resulted in excitation of the systemically administered methylene blue at exposed sites, with resultant local tissue damage and a phototoxic reaction.