Healing With Methylene Blue/Gentian Violet

Numerous factors may alter wound healing, a normally ordered process mediated by overlapping and interconnected biochemical interactions and cells. When healing stalls, one of the wound bed preparation players is off-balance. Whether the problem is compromised tissue needing debridement, infection (from colonization to actual infection), moisture balance, or an unhealthy wound edge, the cause(s) have to be addressed. Bacterial colonization and infection always come to mind (especially in immunocompromised populations; see cases to follow), but other factors to consider include ischemia, lack of extracellular matrix, poor nutrition (eg, compromised protein and essential nutrient uptake that commonly affect premature neonates and chronically challenged, oncologically affected immunocompromised children), medication that interferes with healing, biologic inflammatory milieu imbalance, edema, and moisture imbalance. 

Many of these factors have been discussed in previous columns. This month I discuss methylene blue (MB) and gentian violet (GV) and their topical antimicrobial and drying utility both as separate entities and in combination with an absorbent foam to help heal wounds that had been refractory to other interventions. 

GV. GV is a triarylmethane dye with antibacterial/antifungal/helminthic (immunotherapeutic) properties that hinder mitochondrial activity, decrease energy supply (altered oxidation-reduction [redox] potential, inhibition of reduced nicotinamide adenine dinucleotide phosphate oxidase, and free radical formation), and cause microbial death.¹ GV is thought to inhibit bacterial protein synthesis, uncouple oxidative phosphorylation, and inhibit formation of bacterial cell walls; it also has antitumor and antiangiogenic properties (reducing overly proliferative granulation tissue). GV is highly effective against gram-positive microbes, especially Staphylococcus aureus¹ and has been shown to be effective in treating dermatitis, particularly radiation and atopic dermatitis.² Cells with atopic dermatitis express high levels of the protein angiopoietin-2, which accounts for their vascular permeability and erythema and frequent gram-positive colonization. GV can impact bacterial colonization and proinflammatory mediators. Case reports mention the theoretical oncogenic potential of GV (if consumed systemically) because it can interact with the DNA of cells, but to date no cases of cancer have been definitively linked to GV. I initially started using a 1% solution of GV after coming across a publication describing its antimicrobial/drying effects on periostomy skin injury from exudate in children. 

MB. MB is an organic antimicrobial cationic dye with a strong affinity for dead cells. MB is especially potent for gram-negative bacteria and fungi and attaches to protein-rich exudate and infectious debris. MB affects redox potential in many electron transport components of oxidative metabolism, “short circuiting” the bacterial electron transport pathway. MB reduces antimicrobial burden, decreases hypergranulation, and has a drying effect without harming healthy cells. Similar to GV, MB is easy to apply, water-soluble, and dries quickly; its effect is potentiated with light application. 

GV and MB solutions can be used in conjunction with enzymatic debriders, hydrogels, and advanced dressings. Original research studies have shown MB has the ability to inactivate antioxidant enzymes such as superoxide dismutase, catalase, and peroxidase, leading to decreased extracellular matrix degradation. MB decreases nitric oxide-mediated vasodilation, thereby decreasing tissue ischemia, edema, and weepy/macerated wounds.

MB contraindications. Use of MB is contraindicted in persons with a history of hypersensitivity, renal insufficiency, glucose-6-phosphate dehydrogenase (G6PD) deficiency, and/or hemolytic anemia with Heinz bodies. It is not recommended for use in pregnant women or neonates due to increased hyperbilirubinemia in G6PD-deficient neonates and those with hemolytic anemia. In general, MB is used in various systemic conditions in large doses and its safety record is excellent.

Combination of MB/GV. Using a polyvinyl foam imbued with GV/MB provides all of the aforementioned effects in addition to exudate wicking, debridement, enhanced reepithelialization, prevention of rolled edges or epibole, pain relief (it is considered a nonadherent dressing when appropriately moist), and antimicrobial action without systemic absorbtion.³ 

Case 1. Ms. P was a 15 year old with chronic graft-versus-host disease (GVHD) that progressed to lichen planus-like individual and confluent plaques involving the majority of her body. Many areas of sclerosis developed, and there were open, weeping, erythematous areas of thin, atrophic skin along with areas of hypergranulation that caused bleeding and tremendous pain. Colonization and infections were common. Silver, antibiotics, honey, and collagen-based dressings were applied over time — some with no response, some with pain upon dressing application to denuded areas, others providing temporary relief — and dressing application was difficult in certain areas. 

Four (4) wounds were particularly challenging; 2 were under Ms. P’s breasts and were constantly moist, weepy, excoriated, and extremely painful. Silver product use worsened the wounds. Honey was helpful, but it was too thick to remove easily and caused pain with dressing changes. MB/GV foam (Hydrofera BLUE; Hydrofera LLC, Manchester, CT) induced some improvement but was difficult to keep in place because the surrounding skin was thin, prone to epidermal stripping, and painful to touch. Because MB was available as a 10 mg/mL injectable solution, it was decided to further dilute the MB to an equivalent of 0.1% (1 mg/mL) to utilize the solution as a topical agent based on the efficacy of the MB/GV solution. We painted Ms. P’s weepy wounds with the diluted solution of diluted MB once every 3 days and covered them with a contact layer and gauze. After 2 applications, the wounds appeared to be drier, the weepy exudate diminished, and pain subsided. After 2 weeks and 4 applications, the wounds were dry and closing. 

Three (3) months later, Ms. P developed similar wounds on her bilateral shins. Biopsy showed sclerosis of the dermis and subcutaneous tissue and broken bulla with overlaying erosions. Wounds were colonized with gram-positive organisms and were very wet, with areas of bleeding, nonhealing hypergranulation, and slough. We applied a diluted solution of MB and achieved a great response in 2 weeks (see Figure 1).

Case 2. Mr. R, a 19 year old with Diamond-Blackfan Anemia and myelodysplastic syndrome post bone marrow transplant, developed acute skin GVHD. He was treated appropriately and discharged home on an immunosuppressive regimen of cyclosporine, budesonide, and prednisone. Three (3) months posttransplant, Mr. R was admitted with culture-negative shock, intestinal GVHD, gastrointestinal bleeding, acute kidney injury, and persistent thrombocytopenia. His suppressive medications were increased. Three (3) weeks after admission, multiple abdominal striae became enlarged, engorged, drained serosanguinous fluid, and eventually evolved into partial-thickness wounds. Various absorbent dressings were used but led to epidermal stripping and skin tears, with underlying petechiae and hemorrhages due to profound pancytopenia. Constant oozing and colonization eventually developed into cellulitis. Wound cultures were positive for Klebsiella pneumonia. Due to the extensive affected area, the use of MB/GV foam dressing was not feasible, so we utilized the diluted solution as a topical agent as was done with patient 1. Mr. R was closely monitored for adverse drug reactions due to potential absorption. His wounds were painted every 3 to 4 days. Within 2 weeks, the weeping and striae breakdown ceased, the old wounds were healing, and involved areas were much smaller. I continued MB/GV foam on 1 area for an additional week. After ~4 weeks, all wounds healed (see Figure 2).

Case 3. Mr. V was a 13 year old with a past medical history of ectopic dermatitis who presented with an extensive weepy, denuded, partial-thickness wound in his left popliteal fossa secondary to eczema herpeticum superinfection. While in sports camp, he noted swelling and pain in the area normally affected by eczema. Over 5 days, vesicles, pustules, and eventually hemorrhagic bullae developed with severe pain and systemic symptoms. He was admitted for systemic antibiotics and acyclovir. His wound culture was positive for S aureus and human herpes virus. Because dressing changes were extremely challenging due to pain, slough, and weepy discharge, and new granulation tissue was not developing, I was brought on the case. 

I started painting his wound with GV 1% solution every 2 days for the first week, covered by nonadhesive dialkylcarbamoyl chloride (DACC)-impregnated contact layer and gauze. After 2 applications, the involved area improved and new granulation tissue was growing. The patient was discharged home with MB/GV dressing; the wound totally healed after 14 days (see Figure 3).

Acute and chronic GVHD are multisystem disorders that are complications of hematopoietic cell transplant. Skin involvement may present as erythema, erythroderma, poikiloderma, fasciitis, xerosis, lichen planus-like lesions, or cutaneous sclerosis, causing morphea-like plaques and joint contracture. 

The clinical pattern of GVHD cutaneous manifestations is unpredictable, and this disease is very difficult to treat, especially due to chronicity, wound locations, pain, and the terrible self-image pediatric patients develop. Systemic steroids often are used to treat GVHD, causing skin varices, thinness, and diminished healing.⁴ MB and GV solutions are unique in their ability to “paint” wounds, dry quickly, and if necessary, combine with other products/dressings while providing antibacterial, anti-inflammatory, and drying effects. As such, I did not utilize other dressings in the first and second patients once we painted the wounds because dressing removal and wound locations were the source of the issue. 

Eczema herpeticum (as described in case 3) is an extensive cutaneous vesicular eruption that arises from preexisting skin disease, usually atopic dermatitis (AD). Children with AD have a higher risk of developing eczema herpeticum, in which herpes simplex virus type 1 (HSV-1) is the most common pathogen. Eczema herpeticum can be severe, progressing to disseminated infection and death if untreated.¹ Bacterial superinfection and bacteremia are feared complications. 

Patient 3’s wound was exquisitely painful to touch, requiring morphine before dressing changes due to adherence, despite very weepy areas. New areas of trauma and bleeding were noted by the care team with every change. The infection was not well controlled despite intravenous antibiotics and antiviral. New purpuric, vesicular lesions were erupting daily. Once GV was started, development of new lesions stopped. The most impressive changes were slough clearance, edema decrease, and new granulation tissue growth. Having a DACC-coated antimicrobial contact layer also helped initially. This layer is impregnated with hydrogel, which made removal easier.

MB is available as a 10 mg/mL injectable solution; with pharmacist and hematologist consultation, we decided to further dilute MB to an equivalent of 0.1% (1 mg/mL) to utilize the solution as a topical agent. GV 1% was used as supplied. When GV and MB were applied to the wounds, we observed a decrease in slough, maceration, and edema along with general surface tightening. Farid et al⁵ commented on similar observations in their geriatric patients. 

In summation, MB and GV can be considered for use in select patients with difficult-to-heal wounds that require antimicrobial, drying, and edge-stabilizing agents. They may be of particular value in patients with GVHD and variations of the herpes virus and may be used individually or in combination with careful monitoring.

Dr. Boyar is Director of Neonatal Wound Services,  Cohen Children’s Medical Center of New York, New Hyde Park; and an Assistant Professor of Pediatrics, Zucker School of Medicine, Hofstra/Northwell, Hempstead, NY. This column was not subject to the Wound Management & Prevention peer-review process.