Is there evidence of safety and efficacy of DMSO cream or gel (50-60%) for wound healing purposes after reconstructive procedures with flaps? What are alternatives?

Comment by InpharmD Researcher

Evidence demonstrating the efficacy and safety of topical DMSO for wound healing is generally limited to small studies or animal models. Still, these data find improved skin flap viability, accelerated closure times, and improved perfusion, healing, and tissue manipulation in plastic and reconstructive surgery. The most notable alternative described in the literature appears to be topical nitroglycerin, which is associated with significant reductions in flap necrosis.
Background

A 2023 systematic review and meta-analysis evaluated non-operative adjuncts for preventing mastectomy skin flap necrosis following skin-sparing or nipple-sparing mastectomy, with or without immediate breast reconstruction. The review included 12 studies (6 prospective randomized trials, 2 prospective non-randomized trials, and 4 retrospective cohort studies), encompassing 8,439 mastectomies in 7,895 patients. Interventions included topical nitroglycerin ointment, closed-incision negative pressure wound therapy (ciNPWT), topical dimethyl sulfoxide (DMSO) ointment, oral cilostazol, transcutaneous electrical nerve stimulation (TENS), and local heat preconditioning. Evidence was most extensive for nitroglycerin (6,947 patients), whereas DMSO and cilostazol were evaluated in substantially smaller populations (66 and 60 patients, respectively). [1]

The results of the meta-analysis demonstrated significant reductions in flap necrosis with topical nitroglycerin (4.5–50 mg; relative risk [RR], 0.53; 95% confidence interval [CI], 0.44–0.64) and ciNPWT applied at −125 mmHg for 3–7 postoperative days (RR, 0.44; 95% CI, 0.28–0.71). Topical DMSO significantly reduced the mean weight of necrotic flap tissue (p= 0.03), while oral cilostazol significantly reduced the incidence and depth of necrosis (p= 0.032 and p= 0.027, respectively). Local heat preconditioning was also associated with fewer ischemic complications (p= 0.047). Overall, reported adverse effects across the interventions were minimal. These findings suggest that several perioperative adjuncts may improve mastectomy skin flap viability; however, evidence for DMSO remains limited by the small study population and the specific outcome assessed. [1]

A 2024 narrative review synthesized findings from 34 publications focusing on the application of topical DMSO in plastic and reconstructive surgery. Both clinical and animal model studies were incorporated, evaluating the effects of DMSO on skin flap perfusion, wound healing, fat graft preservation, and tissue expansion. DMSO was applied topically in concentrations ranging primarily from 20% to 70%, with treatment regimens varying from daily applications over several days to intraoperative exposure using soaked surgical sponges. Results consistently demonstrated that DMSO significantly improved skin flap viability, with multiple animal studies showing an increase in flap survival rates from approximately 57–71% in controls to 86–92% in treated groups (statistically significant, p<0.05). Clinical studies involving patients undergoing mastectomies or lymphadenectomies reported substantial reductions in ischemic flap area weights and flap edge necrosis, alongside shorter hospital stays (mean length of stay reduced by approximately 2 days, p<0.05). In wound healing models, DMSO accelerated closure times, enhanced fibroblast proliferation, improved collagen fiber organization, and reduced hypertrophic scar formation in both animal and human keratinocyte studies. Furthermore, DMSO facilitated fat graft volume preservation in rat models by increasing vascularity and graft weight compared to controls (p-values between 0.007 and 0.013). The compound also showed promise in promoting tissue expansion intraoperatively, allowing more rapid expansion with less resistance and increased inflated volumes per session in breast reconstruction patients. Collectively, these findings underscore the multifaceted therapeutic potential of topical DMSO as an adjunct to improve perfusion, healing, and tissue manipulation in plastic and reconstructive surgery. However, the evidence is limited by small sample sizes and reliance on animal studies. Additional studies are needed to establish the safety and efficacy of DMSO for wound healing in patients undergoing reconstructive flap procedures. [2]

Background References: [1] Tang N, Li H, Chow Y, Blake W. Non-operative adjuncts for the prevention of mastectomy skin flap necrosis: a systematic review and meta-analysis. ANZ J Surg. 2023;93(1-2):65-75. doi:10.1111/ans.18146
[2] Bou Zein Eddine S, Chiha T, Atallah J, Khouri K, Winograd JM, Tomczyk ERG. The use of Topical Dimethyl Sulfoxide (Dmso) in plastic and reconstructive surgery: a narrative review. Eur J Plast Surg. 2024;47(1):71. doi:10.1007/s00238-024-02213-1
Literature Review

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

Is there evidence of safety and efficacy of DMSO cream or gel (50-60%) for wound healing purposes after reconstructive procedures with flaps? What are alternatives?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-4 for your response.

Topical Dimethyl Sulfoxide for Congested Nipple–Areolar Complexes in Breast Surgery: A Pilot Study
Design

Retrospective study

N= 15
Objective To evaluate the effectiveness of topical dimethyl sulfoxide (DMSO) in rescuing congested nipple–areolar complexes (NACs) following breast surgery
Study Groups All patients (n= 15)
Inclusion Criteria Patients treated with DMSO for NAC congestion between May 2019 and October 2020
Exclusion Criteria Not specified
Methods

A retrospective chart review of 15 patients treated with DMSO for NAC congestion was conducted. DMSO 50% was applied in liquid form on a soaked gauze pad in the hospital, and patients were instructed to apply a DMSO 70% cream to the NAC twice a day following discharge. Only HBO was used as an alternative, salvage treatment if the NAC remained viable but did not show signs of improvement after 48 hours of DMSO treatment.

Data related to DMSO treatment and NAC healing were compared via univariate analysis.
Duration May 2019 to October 2020
Outcome Measures

Primary: NAC healing with DMSO treatment, converted to graft, sutures released, length of DMSO use, time to heal

Secondary: Complications related to DMSO treatment
Baseline Characteristics   All patients (n= 15)
Age, years 53.1 ± 9.3
BMI 26.8 ± 6.0
Smoking 1 (6.7%)
Diabetes 0 (0.0%)
Hypertension 1 (6.7%)
Chronic kidney disease 0 (0.0%)
Coronary artery disease 0 (0.0%)
Immunocompromised 2 (13.3%)
Unilateral 3 (20.0%)
Bilateral 12 (80.0%)
A total of 15 patients were treated with DMSO for NAC congestion during the study period. Three of those patients were treated for bilateral congestion, for a total of 18 NACs.
Results   Overall NACs (N= 18)
Healed 15 (83.3%)
Converted to graft 0 (0.0%)
Sutures released 2 (11.1%)
Length of DMSO use, days 9.4 ± 8.5
Length of DMSO use, median (range), days 1.0–22.0
Time to heal, days 9.9 ± 9.6
Time to heal, median (range), days 1.0–28.0
Adverse Events No complications related to DMSO treatment were observed.
Study Author Conclusions This pilot study shows that DMSO may be an effective topical treatment for NAC congestion following breast surgery. Given its low cost, ease of application, and lack of side effects, future studies should prospectively compare DMSO against other topical treatments, like nitroglycerin ointment.
Critique The study's small sample size and lack of a comparison group limit its statistical power and generalizability. The retrospective nature and heterogeneity in surgery types and DMSO application frequency also pose limitations. Despite these limitations, the study provides valuable preliminary data on the potential efficacy of DMSO for NAC congestion.

 

Table 1 References:
[3] Silverstein ML, McLean P, Crowley JS, Gosman AA. Topical Dimethyl Sulfoxide for Congested Nipple-areolar Complexes in Breast Surgery: A Pilot Study. Plast Reconstr Surg Glob Open. 2022;10(10):e4595. Published 2022 Oct 28. doi:10.1097/GOX.0000000000004595
Prevention of Wound Edge Necrosis by Local Application of Dimethylsulfoxide
Design

Prospective randomized study

N= 66
Objective To analyze the effect of topical dimethylsulfoxide (DMSO) on skin flap viability
Study Groups

DMSO group (n= 33)

Control group (n= 33)
Inclusion Criteria Patients with breast cancer undergoing mastectomy with skin flaps created
Exclusion Criteria Patients with conditions affecting the vascular system such as vasculitis, systemic lupus erythematosus, diabetes mellitus, collagen vascular disease, or steroid use; those who received preoperative radiation, cytotoxic chemotherapy, immunotherapy, or antihistaminic agents
Methods Topical DMSO solution (60% DMSO, 10% urea, 30% distilled water) was applied to the treatment group immediately after suturing and every 2 hours for the first 48 hours, then every 4 hours from postoperative days 3 to 7. Normal saline was applied similarly for the control group. Necrotic flap edges were recorded, excised, and weighed in a blind manner.
Duration Treatment application lasted for 7 days postoperatively
Outcome Measures

Primary: Weight of necrotic tissue in flap edges

Secondary: Hospitalization period
Baseline Characteristics   DMSO (n= 33) Control group (n= 33) p-value
Age, years 51.8 ± 1.6 51.4 ± 1.8 0.8
Number of smokers 5 5 1.0
Number of cigarettes per day (in smokers) 20.6 ± 3.8 18.6 ± 2.0 0.6
Period of surgery, hours 3.1 ± 0.8 3.1 ± 0.9 0.4
Haemoglobin level 12.7 ± 0.1 13.5 ± 1.9 0.2
Systolic BP, mmHg 135.8 ± 1.9 135.9 ± 1.9 0.9
Diastolic BP, mmHg 80.2 ± 0.7 81.9 ± 0.8 0.1
Duration of lymphatic drainage, days 7.3 ± 0.4 6.9 ± 0.4 0.3
Results   DMSO (n= 33) Control group (n= 33) p-value
Weight of necrotic tissue, µg 23.48 ± 9.5 126.27 ± 44.8 0.03
Hospitalization period, days 9.6 ± 0.5 11.8 ± 0.8 0.02
Adverse Events No side effects due to DMSO were reported, except for a garlic-like taste and breath odor.
Study Author Conclusions The topical application of DMSO reduced skin flap necrosis and improved outcome of surgical flaps. With its safety and good tolerance, it may easily be applied after mastectomy to reduce skin flap necrosis.
Critique The study's strengths include its prospective randomized design and clear demonstration of DMSO's efficacy in reducing flap necrosis. However, the study is limited by its small sample size and lack of long-term follow-up data.

 

Table 2 References:
[4] Celen O, Yildirim E, Berberolu U. Prevention of wound edge necrosis by local application of dimethylsulfoxide. Acta Chir Belg. 2005;105(3):287-290. doi:10.1080/00015458.2005.11679718

Improved Outcome of Surgical Flaps Treated with Topical Dimethylsulfoxide
Design

Randomized, prospective, single-masked study

N= 51
Objective To analyze the effect of dimethylsulfoxide (DMSO) on skin flap viability
Study Groups

DMSO treatment group (n= 24)

Control group (n= 27)
Inclusion Criteria Patients undergoing mastectomy or ilioinguinal lymphadenectomy with skin flaps created during surgery
Exclusion Criteria Conditions predisposing to compromised circulation (e.g., vasculitis, systemic lupus erythematosus, diabetes mellitus, steroid use, or collagen vascular disease); history of radiation or prior operation on the proposed operative site
Methods Topical 60% DMSO applied to flaps every 4 hours for 10 days post-operation. Control group received no treatment. Flap ischemia measured by cut and weigh technique.
Duration 1988 to 1992
Outcome Measures Area of flap ischemia 
Baseline Characteristics   Treatment Group Control Group
Mean age (yrs) 53.1 61.5
No. of smokers 4 9
Mastectomy (N) 16 17
Lymphadenectomy (N) 8 10
Results   Treatment Group Control Group p-value
Mastectomy (33) 10.38 30.00 0.08
Lymphadenectomy (18) 28.25 70.30 0.06
All patients (51) 16.33 44.93 0.01
Adverse Events Erythema and warmth at the application site, garlic-like breath odor. Vesicles developed in one patient. No other toxicities observed.
Study Author Conclusions Topical application of DMSO reduces skin flap ischemia in humans and is recommended for use after operations involving skin flaps.
Critique The study demonstrated a significant reduction in flap ischemia with DMSO treatment. However, the small sample size and single-center design may limit the generalizability of the findings. Further studies are needed to confirm these results and explore DMSO's efficacy in other settings.
Table 3 References:
[5] Rand-Luby L, Pommier RF, Williams ST, Woltering EA, Small KA, Fletcher WS. Improved outcome of surgical flaps treated with topical dimethylsulfoxide. Ann Surg. 1996;224(4):583-590. doi:10.1097/00000658-199610000-00016

Effects of Nitroglycerin Ointment on Mastectomy Flap Necrosis in Immediate Breast Reconstruction: A Randomized Controlled Trial
Design

Randomized controlled trial

N= 165
Objective To evaluate whether the application of nitroglycerin ointment to the breast skin after mastectomy and immediate reconstruction causes a decrease in the rate of mastectomy flap necrosis compared with placebo
Study Groups

Nitroglycerin ointment (n= 85)

Placebo (n= 80)
Inclusion Criteria Patients aged 21 to 69 years undergoing mastectomy and immediate breast reconstruction at the University of British Columbia–affiliated hospitals
Exclusion Criteria Patients with a medical history that precluded the administration of nitroglycerin, including cardiac insufficiency, hypotension, sensitivity to nitrites, severe liver impairment, glaucoma, hyperthyroidism, recent head trauma, severe anemia, or taking certain medications
Methods Nitroglycerin ointment (45 mg) or a placebo was applied to the mastectomy skin at the time of surgical dressing. The ointment and dressing were left in place for a minimum of 48 hours. Patients were admitted to the hospital postoperatively for a minimum of 24 hours
Duration December 2012 to February 2014
Outcome Measures

Primary: Rate of mastectomy flap necrosis

Secondary: Treatment for mastectomy flap necrosis, early complications such as seroma, hematoma, infection, explantation, and capsular contracture
Baseline Characteristics   Placebo (n= 80) Nitroglycerin (n= 85)
Age, mean ± SD 49.9 ± 9.7 50.0 ± 9.2
Body mass index, mean ± SD 24.0 ± 4.9 24.9 ± 4.6
Smoking, never 64 (80.0%) 67 (78.8%)
Diabetes 2 (2.5%) 0 (0.0%)
Hypertension 11 (13.8%) 8 (9.4%)
Results   Placebo (n= 80) Nitroglycerin (n= 85) 95% CI for Difference p-value
Mastectomy flap necrosis, n (%) 27 (33.8) 13 (15.3) 5.3–31.0 0.006
Superficial thickness 9 (11.2) 5 (5.9)    
Full thickness 18 (22.5) 8 (9.4) 1.9–24.3 0.021
Débridement and closure 16 (20.0) 8 (9.4) 0.0–21.6 0.054
Adverse Events Early complications such as seroma, hematoma, infection, and early capsular contracture occurred in 25.5% of patients and were similar in both groups. Severe headache was reported in 2.4% of patients receiving nitroglycerin ointment compared with 0% in the placebo group. Hypotension was reported in two patients who received the nitroglycerin ointment.
Study Author Conclusions In patients undergoing mastectomy and immediate reconstruction, there was a marked reduction in mastectomy flap necrosis in patients who received nitroglycerin ointment. Nitroglycerin ointment application is a simple, safe, and effective way to help prevent mastectomy flap necrosis.
Critique The study's strengths include its randomized controlled trial design, blinded ointment allocation, and high adherence to treatment allocation. However, it was conducted at a single center, which may limit generalizability. The higher incidence of mastectomy flap necrosis in the placebo group compared to estimates may affect the perceived efficacy of the intervention. Further studies are needed to determine the appropriate dose for bilateral mastectomy skin treatment and to explore the potential benefits of repeated application or combination with other topical agents.
Table 4 References:
[6] Gdalevitch P, Van Laeken N, Bahng S, et al. Effects of nitroglycerin ointment on mastectomy flap necrosis in immediate breast reconstruction: a randomized controlled trial. Plast Reconstr Surg. 2015;135(6):1530-1539. doi:10.1097/PRS.0000000000001237