Topical application of DMSO as an adjunct to tissue expansion for breast reconstruction

British Journal of Plastic Surgery (1999), 52, 194–197 © 1999 The British Association of Plastic Surgeons

Topical application of DMSO as an adjunct to tissue expansion for breast reconstruction E. Raposio and P. L. Santi Department of Plastic and Reconstructive Surgery, National Institute for Cancer Research, University of Genova, Italy SUMMARY. The aim of this study was to evaluate the effectiveness of topical 60% dimethyl sulphoxide (DMSO) prior to tissue expansion for breast reconstruction in reducing expander pressure and length of treatment. Forty patients undergoing immediate breast reconstruction with tissue expanders following modified radical mastectomy were consecutively divided into two groups of 20 subjects each: group A (control) and group B (experimental). Patients from group A underwent traditional tissue expansion, while, to patients of group B, before each filling session, topical 60% DMSO was applied to the skin overlying the expander by soaking-wet surgical sponges left in place for 30 min. The average inflated volume was 395 cc (range 250–580 cc) in group A, and 410 cc (range 240–620 cc) in group B; no statistically significant difference was found between these values. A statistically significant difference was found between the expansion time of group A (mean 6 sessions; range 4–10 sessions with one filling session per week) and group B (mean 4 sessions; range 2–6 sessions with one filling session per week). A statistically significant difference was also found between the average inflated volume per session of group A (90 cc; range 60–130 cc) and group B (120 cc; range 90–160 cc). According to the data obtained by tonometry, a statistically significant difference was found between the average pre-filling and post-filling pressures of group A (28.4 and 66.5 mmHg, respectively) and group B (22.1 and 64.3 mmHg, respectively). Clinical benefits of pre-filling topical applications of 60% DMSO observed in our trial were an enhancement of the total volume inflatable per session and a significant shortening of the total expansion period. Keywords: breast, reconstruction, tissue expansion, dimethyl sulphoxide.

The simplicity of the concept and the apparent ease of its clinical execution have made tissue expansion one of the most popular methods of breast reconstruction. However, while the benefits of this procedure are well known, patients and surgeons still have to deal with the inconveniences resulting from a multistaged procedure requiring frequent outpatient visits. In recent years, many efforts have been made to evaluate a wide range of substances with the hope of discovering a topical and/or systemic drug able to reduce one of the major drawbacks associated with tissue expansion, i.e. the length of the procedure.1–5 In this respect, it is worth remembering that two most important morphological and functional changes observed in the expanded skin are responsible for the delay of the procedure. The first change observed is the formation of a fibrous capsule surrounding the implant, composed mainly of collagen fibres.6 The capsule augments the mechanical resistance opposed by the expanded tissue. This effect has to be added to the already augmented intrinsic mechanical resistance of the expanded skin; in fact, Pasyk et al7 have found that the expanded dermis, especially in the reticular

layer, contains large bundles of compacted collagen fibres. These are interpreted as the secretion of active, elongated and flattened fibroblasts that are found endoved in the capsular tissue, and as a response to the continuous stretching effect induced by the implant. The second change is the alteration of local blood flow in the expanded skin; this is due to the compressive force applied by the underlying expander to dermal vessels, eventually leading to skin necrosis. Although there is still little known about both morphological and functional changes in this field, an excessive intraluminal expander pressure, compressing the dermal microvessels, will obviously result in ischaemia of the overlying skin. This hazards the completion of the filling procedure as well as the future viability of the expanded flap. Since it is of the greatest importance to maintain an adequate perfusion of the expanded skin during the entire expansion procedure, the total amount of time required to achieve the desired amount of expanded tissue is augmented. Therefore, the use of drugs affecting collagen synthesis and cross-linkage, both in the capsule and in the surrounding dermis, might be of some value in decreasing the mechanical resistance of the expanded tissue, while the administration of topical vasodilator drugs might increase the filling safety margin, thus reducing the risks of ischaemic complications during expansion. In this way, the expansion could proceed in a safer, more rapid and efficacious way, both saving the

Presented, in part, at the 26th Congress of the Scandinavian Society of Plastic and Reconstructive Surgery, Stockholm, Sweden, 13–16 June 1996, at the 45th National Congress of the Italian Society of Plastic, Reconstructive and Aesthetic Surgery, Perugia, Italy, 12–17 October 1996, and at the Seventh European Congress of Surgery ‘Eurosurgery 97’, Athens, Greece, 4–7 June 1997.

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Topical application of DMSO as an adjunct to tissue expansion

patients from unnecessary discomfort and lowering the total cost of the procedure. In 1987, Liang et al8 tested the use of topical dimethyl sulphoxide (DMSO) in rats to enhance tissue expansion, and they obtained a significant reduction in expansion pressures. In 1991, Vinnik and Jacob9 reported the clinical use of both topical and intravenous DMSO to significantly enhance intraoperative tissue expansion during breast reconstruction, large lesion excision and abdominoplasty. Moreover, several authors10–13 have improved the circulation in partially necrotic skin flaps, thereby increasing the amount of surviving tissue, with topical DMSO treatment. The aim of the present study was to evaluate the effectiveness of topical 60% DMSO prior to tissue expansion for breast reconstruction in reducing expander pressure and length of treatment.

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We have chosen to use a 60% concentration of DMSO because higher concentrations can cause fairly severe skin reaction, including burning discomfort, itching, erythema, scaling and dermatitis; less than a 50% concentration has little therapeutic value.9 Before and after each filling session, expander intraluminal pressure was recorded by means of an indentation tonometer (Schioetz Tonometer, Medicon Instrumente, Berlin, Germany). Indentation tonometry has proven to be a reliable and objective method for measuring breast firmness as well as internal implant pressure.14,15 The significance of differences between the two regimens was assessed with Student’s t-test, and a probability of P < 0.05 was considered significant. Results

Patients and methods From June 1994 to August 1995, 40 patients (age 32–63 years; mean 43 years) undergoing unilateral immediate breast reconstruction with tissue expanders following unilateral modified radical mastectomy were recruited voluntarily into the trial. The investigation was approved by our institute’s Ethical Committee and informed consent was obtained from all the patients. The patients were consecutively divided into two groups of 20 subjects each: group A (control) and group B (topical application of 60% DMSO saline solution 30 min before each filling session). Patients who have undergone radiation, even without postradiation stigmata, were excluded from the study. The expanders (Biocell, McGhan Medical Corporation, Santa Barbara, CA, USA) were always implanted in a submuscular–subfascial pocket, beneath the pectoralis major and the serratus anterior muscles. Expansion was commenced a minimum of 2 weeks postoperatively to ensure adequate healing of the surgical incision. Expansion was continued on a weekly basis until the volume was approximately 30% more than the anticipated volume of the permanent prosthesis. Patients from group A underwent traditional tissue expansion, while, to patients of group B, before each filling session, topical 60% DMSO was applied to the skin overlying the expander by soaking-wet surgical sponges left in place for 30 min. Each time, the surgical sponges were placed so as to cover the whole area to be expanded and 40 cc of 60% DMSO was used.

The average inflated volume was 395 cc (range 250–580 cc) in group A, and 410 cc (range 240–620 cc) in group B (Table 1); no statistically significant difference was found between these values. A statistically significant difference was found between the expansion time of group A (mean 6 weeks; range 4–10 weeks) and group B (mean 4 weeks; range 2–6 weeks) (Fig. 1, Table 1). A statistically significant difference was also found between the average inflated volume per session of group A (90 cc; range 60–130 cc) and group B (120 cc; range 90–160 cc) (Fig. 2, Table 1). All patients tolerated the complete expansion procedure without major (implant exposure, infection, haematoma, implant deflation) complications. In no situation, either in long-term follow-up or to date, was any tissue necrosis observed due to overexpansion of the implant. No wound dehiscence occurred during the expansion period. There was no significant difference in the minor-complication rate between the treated group and the untreated group. Three patients had minor complications; one patient (group A) had a minor wound infection, and two patients (group B) had leakage from the expander at the end of the expansion period. The texture of the expanded skin remained unchanged, and the inframammary sulcus continued to be well defined. According to the data obtained by tonometry, a statistically significant difference was found between the average pre-filling and post-filling pressures of group A (28.4 and 66.5 mmHg, respectively) and those of group B (22.1 and 64.3 mmHg, respectively) (Table 1).

Table 1 Different values recorded for group A (control) and group B (experimental, DMSO treated) during the whole expansion period

Mean SD SE

Inflated (final) volume group A

Inflated (final) volume group B

Expns Period (sess.) group A

Expns Period (sess.) group B

Avg inf. volume per sess. group A

Avg inf. volume per sess. group B

Pre-fill. pressure group A (mmHg)

Pre-fill. pressure group B (mmHg)

Post-fill. pressure group A (mmHg)

Post-fill. pressure group B (mmHg)

395 cc 68 15

410 cc 71 16

6 1 0.3

4 1 0.2

90 cc 19 4

120 cc 14 3

28.4 0.6 0.1

22.1 0.5 0.1

66.5 1.8 0.4

64.3 1.8 0.4

SD, standard deviation; SE, standard error; Expns, expansion; Avg inf., average inflated; Pre-fill., pre-filling; Post-fill., post-filling; sess., sessions, with one filling session per week.

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Figure 1––Mean length of expansion period (in sessions, with one filling session per week) of the control (group A) and DMSOtreated (group B) groups.

These mean pressures reflected the average compliance of the developing capsule and its overlying softtissue cover at the expander–tissue interface. Discussion Tissue expansion is a safe and reliable way to reconstruct a breast and gives good results, but it has the disadvantage of being a time-consuming procedure. DMSO, an industrial solvent and by-product of paper manufacture, was first introduced to the scientific community in 1964 by Jacob et al16 as a therapeutic principle. Wong et al17 studied the absorption, excretion and biotransformation of topical 80% DMSO gel in man. They found that its absorption rate ranged from 25 to 40% of the total dose, and that it is partly transformed into dimethyl-sulphone (DMSO2) and dimethyl-sulphide (DMS). In a similar study, Jacob et al18 reported that 30% of 70% DMSO saline solution applied to the skin is systemically absorbed through the epidermis. DMSO and DMSO2 are excreted in the urine, whereas DMS is eliminated in the expired air. DMS is responsible for the characteristic garlic-like odour from patients on DMSO medication and, because of the presence of metabolites, it may last for as long as 72 h. In 1983, Goldblum et al19 reported that topical 95% DMSO does not affect epidermal wound healing in pigs. Berliner and Ruhmann20 found that DMSO inhibited fibroblastic proliferation in vitro. Numerous animal studies have documented decreased tensile strength in tissues treated with DMSO, while light- and electron-microscopic investigation of DMSO-exposed tissues has revealed the presence of characteristic collagen fibre swelling.21 The suggested aetiology of this phenomenon is that collagen fibre intra- and inter-molecular cross-links are ruptured. Gries et al22 studied rabbit skin before and after 24 h in vitro exposure to 100% DMSO. After immersion in DMSO, the collagen fraction extractable with neutral salt solution was significantly decreased. Jacob and Herschler23 reported that topical DMSO in man exerted a significant effect on the pathological deposition of collagen in human post-irradiation subcutaneous fibrosis. This did not appear to change the equilibrium of collagen metabolism in normal tissue. Urinary hydroxyproline levels are increased in

British Journal of Plastic Surgery

Figure 2––Average inflated volume (in cc) per session in the control (group A) and DMSO-treated (group B) groups.

scleroderma patients treated with topical DMSO,24 whereas keloids biopsied in man before and after DMSO therapy show histological improvement toward normality.25 In 1967, Adamson et al10 markedly enhanced the circulation of pedicled flaps in an animal model by daily local treatment with 70% DMSO solution. Since this improvement disappeared if the animals were treated with an antihistamine at the same time, the authors postulated that the action of DMSO is similar to histamine. In 1970, Arturson and Khanna11 similarly improved the circulation in partially necrotic skin flaps in rats, thereby increasing the amount of surviving tissue, with 70% DMSO topical treatment. These results have been confirmed by our previous work,12–13 which showed significantly enhanced survival of rabbit dorsal myocutaneous flaps with the use of topical 60% DMSO. The former considerations suggest that pharmacological control of both capsular contraction and ischaemic complications in the course of tissue expansion might be possible by means of topical applications of a solution of DMSO. Indeed, pre-filling applications of 60% DMSO, as performed in this study, significantly shortened the treatment period of tissue expansion used for breast reconstruction. No significant differences were found between the treated and untreated groups regarding mean expander intraluminal pressures and the rate of both major and minor complications, although the amount of saline injected per session was, on average, 30% more in the treated group. Clinical benefits of pre-filling topical applications of 60% DMSO observed in our trial include an enhancement of the total volume inflatable per session and a significant shortening of the total expansion period. However, it should be pointed out that several complications might be associated with DMSO. Changes in the refractive index and lens opacity have been reported in monkeys, dogs and rabbits given long-term high doses (3 g/kg) of DMSO.26 Haemoglobinuria is likely to occur for DMSO concentrations over 10% when given intravenously, although a study by Waller et al27 showed that this causes no renal damage. There has been one report of fatal acute renal tubular necrosis in an elderly patient on DMSO medication for arthritis.27 Although it is highly improbable that the dosage levels required to cause the above-mentioned complications could be obtained from topical applications of

Topical application of DMSO as an adjunct to tissue expansion

DMSO for the limited time span required by tissue expansion for breast reconstruction, it is recommended that patients receiving DMSO have a complete biochemical screening (particularly renal and liver function tests), full eye evaluations (including slit lamp examinations) and a complete blood count. Moreover, DMSO can initiate the liberation of histamine and occasional hypersensitivity reactions to topical administration have been reported.18 As such, although the reported data indicate several benefits following the clinical application of 60% DMSO in tissue expansion for breast reconstruction, more experimental work is needed in order both to test the long-term safety of the solution and to accurately evaluate its mechanisms of action, timing of treatment, dosages and routes of administration. Acknowledgements We wish to acknowledge Maria Stella Leone MD for clinical assistance and Maria Antonietta Guida and Gemma Dagnino for their assistance with manuscript preparation. According to Italian legislation, it has to be specified that Dr Raposio has designed the technique, carried out the study, statistically analysed the results and written the manuscript, while Professor Santi has supervised the whole project.

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197 11. Arturson G, Khanna NN. The effects of hyperbaric oxygen, dimethyl sulfoxide and Complamin on the survival of experimental skin flaps. Scand J Plast Reconstr Surg 1970; 4: 8–10. 12. Raposio E, Cilli M, Nordström REA, Santi PL. Pharmacologic prevention of musculocutaneous flap necrosis in a rabbit model. Proceedings of the 44th National Meeting of the Italian Society of Plastic, Reconstructive, and Aesthetic Surgery, Bologna, Italy, 31 October–3 November 1995. 13. Raposio E, Santi PL. Pharmacological enhancement of cutaneous flap survival with topical dimethyl sulfoxide and hydrogen peroxide. Br J Plast Surg 1998; 51: 551–4. 14. Hayes H Jr, McLeod P. Indentation tonometry of breasts. Plast Reconstr Surg 1979; 63: 13–18. 15. Esposito G, Di Caprio G, Ziccardi P, Scuderi N. The use of tonometry during skin expansion. In UT Hinderer (ed.), Plastic Surgery 1992. Amsterdam: Elsevier, 1992. 16. Jacob SW, Bischel M, Herschler RJ. Dimethyl sulfoxide (DMSO): a new concept in pharmacotherapy. Curr Ther Res 1964; 6: 134–9. 17. Wong KK, Wang GM, Dreyfuss J, Schreiber EC. Absorption, excretion, and biotransformation of dimethyl sulfoxide in man and miniature pigs after topical application as an 80% gel. J Invest Dermatol 1971; 56: 44–8. 18. Jacob S, Rosenbaum E, Wood D. DMSO: Basic Concepts. New York: Marcel Dekker, 1971, Vol. 4; 131–43. 19. Goldblum OM, Alvarez OM, Mertz PM, Eaglstein WH. Dimethyl sulfoxide (DMSO) does not affect epidermal wound healing. Proc Soc Exp Biol Med 1983; 172: 301–7. 20. Berliner DL, Ruhmann AG. The influence of dimethyl sulfoxide on fibroblastic proliferation. Ann NY Acad Sci 1964; 141: 159–64. 21. Erk Y, Raskin DJ, Mace M Jr, Spira M. Dimethyl sulfoxide alteration of collagen. Ann NY Acad Sci 1983; 411: 364–8. 22. Gries G, Bublitz G, Lindner J. The effect of dimethyl sulfoxide on the components of connective tissue (clinical and experimental investigations). Ann NY Acad Sci 1967; 141: 630–7. 23. Jacob SW, Herschler R. Pharmacology of DMSO. Cryobiol 1986; 23: 14–27. 24. Scherbel AL, McCormack LJ, Layle JK. Further observations on the effect of dimethyl sulfoxide in patients with generalized scleroderma (progressive systemic sclerosis). Ann NY Acad Sci 1967; 141: 613–29. 25. Engle MF. Indications and contraindications for the use of DMSO in clinical dermatology. Ann NY Acad Sci 1967; 141: 638–45. 26. Rubin LF, Barnett KC. Ocular effects of oral and dermal application of dimethyl sulfoxide in animals. Ann NY Acad Sci 1967; 141: 333–45. 27. Waller FT, Tanabe CT, Paxton HD. Treatment of elevated intracranial pressure with dimethyl sulfoxide. Ann NY Acad Sci 1983; 411: 286–92.

The Authors Edoardo Raposio MD, PhD, FICS, Research Fellow, PierLuigi Santi MD, Professor and Chairman, Department of Plastic and Reconstructive Surgery, National Institute for Cancer Research, University of Genova, Italy. Correspondence to Dr Edoardo Raposio MD, PhD, FICS, Via Rodi 10/7d, 16145 Genova, Italy. Paper received 6 March 1997. Accepted 27 October 1998, after revision.