If you have never heard of this alternative treatment for painful ulcers, surely while reading this post you may think of more than one patient who could benefit from its use.

Once again, Carmen Alba Moratilla’s scientific curiosity and motivation have been important driving forces in my contact with this therapeutic alternative, which I have been able to put into practice thanks to the collaboration of Dr. Afredo Abad, head of the Anaesthesiology Service at the Infanta Leonor University Hospital. Our experience is recent and therefore very limited, but the findings are in line with those described by other authors, which we will now sees.

Pain is one of the main factors limiting the quality of life of people with chronic leg wounds and, in many cases, a therapeutic challenge for healthcare professionals. Fear of pain during treatment can trigger anticipatory anxiety, which causes much suffering in these patients. Before trying different analgesic drugs, the first thing to do is to identify the cause of the pain, especially if it has increased sharply, as it may be a sign of infection, inadequate compression, with excessive pressure points or poor control of oedema and exudate, or contact dermatitis due to the dressings used. Although any leg ulcer, regardless of its cause, can be painful, the type of pain can guide us in the etiological diagnosis.

The side effects inherent in systemic analgesics complicate decision-making on the best treatment strategy, especially in older patients or those with multiple comorbidities. Although dressings with a potential topical analgesic effect are being developed and marketed, in our clinical practice the range of products available is very limited and is usually reduced to lidocaine/prilocaine cream (EMLA), whose analgesic efficacy during sharp debridement has been proven in different clinical trials.¹ Pharmaceutical compounding allows us to transport morphine in a hydrogel for topical application. However, although the analgesic effect of topical morphine in wounds has been described in case series, the few clinical trials performed, with small sample size among other limitations, do not detect statistically significant differences in comparison with placebo.² On the other hand, the analgesic effect of advanced therapies such as platelet-rich plasma or punch grafting has been described. These therapies are especially interesting in Martorell hypertensive ischemic ulcer, which is enormously painful.

In fact, my first contact with topical sevoflurane has been in a patient with Martorell ulcers in both legs, with tendon and bone exposure, with uncontrollable despite treatment with morphine and gabapentin. This first experience could not have been more successful, since after weekly applications for a month, with excellent analgesic control from the first session, we were able to apply punch grafts on the wound and achieve complete epithelialization. Well, let’s go to what interests you: What is sevoflurane and how does it work in wounds?

Sevoflurane is an inhalation anaesthetic agent, of the group of halogenated ethers,  for use in induction and maintenance of general anesthesia. It is a colourless volatile liquid, packaged in 250 ml bottles, which is vaporised for use as an anaesthetic gas. Although it has traditionally been assumed that the analgesic action of halogenated anaesthetics is exclusively central, they are also known to have an analgesic action at the peripheral level. This concentration-dependent effect is due to the fact that, when applied locally, sevoflurane can reach sufficient partial pressure to block peripheral nociceptors. It can therefore be used off-label in its liquid form, as a local anaesthetic, applied by irrigation to painful wounds.³

Although studies published in the literature are mostly isolated cases or short series, the results are promising.^3-6 The benefit of topical sevoflurane seems not to be limited to its analgesic effect, which appears almost immediately and makes effective sharp debridement possible. It has been proposed that it can produce a healing acceleration due to its vasodilator effect and, although its mechanism of action is unknown, bactericidal action has been detected in vitro against multidrug resistant strains of S. Aureus, P. Aeruginosa and E.Coli.⁷

The benefit/risk profile is very favourable since, as side effect, only itching and perilesional erythema have been described after application. Although sevoflurane blood levels have not been measured, no systemic effects have been recorded after local use.

The first published case series⁶ includes 9 patients with painful venous ulcers resistant to systemic analgesic treatment, in which topical sevoflurane was used. The average number of dressing changes per patient was 8 (range: 4-13), but the authors do not specify the frequency of dressing changes. Irrigation of the wound bed was performed with approximately 1 ml/cm² of liquid sevoflurane, always after cleansing with physiological serum. All patients experienced a rapid reduction in pain at rest (less than 2 minutes), which was maintained over time, an average of 10 hours. This reduction in pain, measured by a verbal pain scale (0-10) was clinically and statistically significant in all applications (average pain reduction of 6 points). Complete wound healing was obtained in 4 patients.

Other Spanish authors⁵ confirm the benefit of topical sevoflurane application in painful recalcitrant wounds. They reported 36 patients with excellent pain control in 94% of cases, immediately after sevoflurane application and maintained over time (variable duration, between 2 and 48 hours). They found no loss of efficacy over time (length of treatment ranged between 3 and 24 months).

The results of a randomised clinical trial⁸ designed to assess the impact of topical sevoflurane use on pain, daily opioid dose and wound size have recently been published. In the control group (conventional management), 10 patients with leg ulcers were included, while 5 were assigned to the treatment group. The frequency of sevoflurane irrigations (1ml/cm²) ranged from 1 to 4 per day, with the aim of maintaining a pain score (VAS pain) inferior to 3. Treatment was performed for 90 days. Among the limitations of the study it must be highlighted the small sample size, the different basal characteristics between groups and the variability inherent in the application of the product by different people (health professionals or the patients themselves). A statistically significant reduction in pain, opioids uptake and wound area was found in the treatment group. As a mild side effect, already described by other authors and which we have also observed, perilesional redness appeared in 4 of the 5 patients being treated with sevoflurane.

There are still many outstanding questions that will find answers over time, thanks to experience and the conduct of more experimental studies. These include the following: what dose and frequency of application would be optimal, what type of wound would benefit most from treatment, what safety measures should be required for its use?

Do you have any experience with topical sevoflurane?

References:
1. Briggs M, Nelson EA, Martyn-St James M. Topical agents or dressings for pain in venous leg ulcers. Cochrane Database Syst Rev. 2012 Nov 14;11:CD001177. 
2. Bastami S, Frödin T, Ahlner J, Uppugunduri S. Topical morphine gel in the treatment of painful leg ulcers, a double-blind, placebo-controlled clinical trial: a pilot study. Int Wound J. 2012;9(4):419-27. 
3. Lafuente-Urrez RF, Gilaberte Y. Sevoflurane: a valid alternative for the treatment of vascular ulcers? Actas Dermosifiliogr 2014;105:202–3. 
4. Imbernón A, Blázquez C, Puebla A, Churruca M, Lobato A, Martínez M, Aguilar A, Gallego MA. Chronic venous ulcer treatment with topical sevoflurane. Int Wound J.2016;13(5):1060-2. 
5. Dámaso Fernández-Ginés F, Cortiñas-Sáenz M, Navajas-Gómez de Aranda A, Yoldi Bocanegra R, Sierra-García F. Reply: to Chronic venous ulcer treatment with topical sevoflurane by Imbernón et al. Int Wound J. 2017;14(3):591 
6. Gerónimo Pardo M, Martinez Serrano M, Martínez Molsalve A, Rueda Martínez JL. Usos alternativos del sevoflurano. Efecto analgésico tópico. Rev Electron Anestesia 2012; 4:181.
7. Martínez M, Gerónimo M, Crespo MD. Actividad bactericida del sevoflurano frente a Staphylococcus aureus, Pseudomonas aeruginosa y Escherichia coli. Enferm Infecc Microbiol Clin 2009;27:120–1.

8. Dámaso Fernández-Ginés F, Cortiñas-Sáenz M, Mateo-Carrasco H, de Aranda AN, Navarro-Muñoz E, Rodríguez-Carmona R, Fernández-Sánchez C, Sierra-García F, Morales-Molina JA. Efficacy and safety of topical sevoflurane in the
treatment of chronic skin ulcers. Am J Health Syst Pharm. 2017;74(9):e176-e182. 

In previous posts we have talked about the benefits that these two treatments have, separately, promoting healing. However, their combined use plays a fundamental role. On the one hand, their sequential use is of great interest, as the application of negative pressure promotes the formation of granulation tissue, with reduction of exudate and bacterial load, and therefore prepares the wound bed to facilitate graft taking. On the other hand, its synchronous use can improve the percentage of graft taking,^1-6 especially in certain situations that we will now point out.

As I commented in previous posts, among them “Types of skin grafts to cover chronic wounds: which one to choose“, in our wound clinic we normally use punch grafts. These partial thickness grafts are dermo-epidermal fragments more or less circular or oval, which are usually obtained with punch (punch), scalpel or curette, without deepening beyond the papillary dermis. The procedure is performed under local anaesthesia in the donor site, usually the thigh. The fragments are placed directly on the wound bed, without any type of fixation, apart from pressure and local immobilization during the first days after the procedure.

Most authors of the published studies about the benefits of negative pressure therapy in skin graft taking, use mesh skin grafting, which is another type of partial thickness graft.^3-5 However, a clinical trial involving 60 patients with chronic leg ulcers treated with punch grafts finds a statistically significant reduction in healing time, pain and treatment costs in the group that received associated negative pressure therapy.⁶

The major determinant of the success of skin grafting is its attachment to the wound bed. It also represents the greatest challenge, especially in chronic wounds in particular anatomical locations (Achilles tendon, ankle), where graft attachment to the wound bed is difficult. On the other hand, we cannot forget that advanced age is a constant feature in patients with wounds and, therefore, so is skin fragility (dermatoporosis). The pressure that must be exerted on the grafts to favour graft taking (and the friction of the material used) can produce the opposite effect in patients with skin ageing, as it can damage capillaries and trigger bleeding and haematomas. In addition, although the ideal situation is to graft wounds with optimal granulation tissue, our experience tells us that this is not easy to achieve with chronic ulcers of long evolution in elderly patients with multiple comorbidities. Conclusion: the majority of wounds that we graft do not present a perfect microenvironment for the reception of those skin fragments. Although grafts that do not take are also interesting because they release growth factors and other molecules and cells that promote healing, the more percentage of graft taking achieved, the better.

There are different negative pressure therapy devices commercially available on the market. We use a portable, single-use device with a pump that exerts a pressure of -80 mmHg on the dressing that we place on the wound covered with the grafts.

Our experience, like that of other professionals, confirms the benefit of applying negative pressure therapy on skin grafts. Its efficacy is associated, on the one hand, with a reduction in exudate and better immobilization and sealing of the grafts, with the consequent decrease in shear and, therefore, lower risk of development of seromas and hematomas.^1-6 On the other hand, it has been proposed that the mechanical stretching that produces negative pressure can both stimulate the signaling pathways that promote keratinocyte mitosis and activate neo-angiogenesis by increasing microcirculatory flow in the wound bed and edges.²

I cannot finish a post that includes the word “successful” in the title without referring to the underlying engine of every successful idea and treatment strategy in our wound clinic: I AM PART OF A WONDERFUL TEAM.

References:

1. Gupta S. Optimal use of negative pressure wound therapy for skin grafts. Int Wound J. 2012;9(Suppl 1):40–7. 
2. Azzopardi EA, Boyce DE, Dickson WA, Azzopardi E, Laing JH, Whitaker IS, Shokrollahi K. Application of topical negative pressure (vacuum-assisted closure) to split-thickness skin grafts: a structured evidence-based review. Ann Plast Surg. 2013 Jan;70(1):23-9.
3. Moisidis E, Heath T, Boorer C, Ho K, Deva AK. A prospective, blinded, randomized, controlled clinical trial of topical negative pressure use in skin grafting. Plast Reconst Surg 2004;114:917–22. 
4. Llanos S, Danilla S, Barraza C, Armijo E, Pineros JL, Quintas M, et al. Effectiveness of negative pressure closure in the integration of split thickness skin grafts. A randomized, double-masked, controlled trial. Annals of Surgery 2006;244(5):700-5. 
5. Maruccia M, Onesti MG, Sorvillo V, et al. An Alternative Treatment Strategy for Complicated Chronic Wounds: Negative Pressure Therapy over Mesh Skin Graft. BioMed Research International. 2017;2017:8395219. 
6. Vuerstaek JD, Vainas T, Wuite J, Nelemans P, Neumann MH, Veraart JC. State-of-the-art treatment of chronic leg ulcers: A randomized controlled trial comparing vacuum-assisted closure (V.A.C.) with modern wound dressings. J Vasc Surg. 2006 Nov;44(5):1029-37 

Autologous epidermal and dermo-epidermal punch grafts are two of the different options available to promote epithelialization of recalcitrant wounds despite adequate conventional treatment. As we commented in the post “Types of skin grafts to cover chronic wounds: which one should you choose?”, in our wound clinic, the dermo-epidermal punch graft is the technique commonly used. The procedure is outpatient based, simple, economical, and provides a striking analgesic effect on painful wounds. Therefore, it is a technique very well accepted by patients, which can be repeated as many times as necessary to achieve complete epithelialization of the wound. To obtain these dermo-epidermal fragments we can use a punch, scalpel or curette, so their morphology will be more or less circular or oval. The procedure is performed under local anaesthesia in the donor site, usually the thigh , and we do not go deeper than the papillary dermis.

We know that we are at the appropriate depth (papillary dermis) when we find a punctiform bleeding after obtaining each graft. In the image representing the skin layers, blood vessels are distributed vertically in the dermal papillae. If we look at it from above, the vascularization of the papillae would appear as a dotted pattern.

Anatomical knowledge of the skin and experience are key to performing the procedure systematically and quickly. The small grafts are placed directly on the wound bed. Local pressure and immobilization the first few days after the procedure is essential for graft taking. Wounds in the donor site heal by secondary intention. The risk of bleeding and infection of the area from which the grafts are obtained is minimal. One year after the procedure, only slight alterations in the pigmentation (hypo or hyperpigmentation) are observed in the donor site.

Epidermal grafts are obtained by separating the epidemis from the dermis at the dermo-epidermal junction. The epidermis is a flat polystratified epithelium composed mostly of keratinocytes, which are born in the basal layer and progresively differenciate forming the upper layers until their destruction and elimination in the horny layer (the most superficial layer of the skin, which is formed by dead cells).

As the epidermis is not vascularized (its cells are nourished by imbibition through the vessels of the papillary dermis), there will be no bleeding in the donor site and the subsequent scar will be practically imperceptible. In addition, as the dermis remains intact, only the most superficial nerve endings of the dermo-epidermal junction would be stimulated. Consequently, the procedure is practically painless. In order to obtain this type of graft, a device has been marketed which, placed on the skin of the thigh for an average of 30 minutes, produces microvesicles which separate the dermo-epidermal junction. It works by suction using negative pressure and heat, without the need for local anaesthesia. The roofs of these formed blisters are separated by a mechanical cutting system and then are directly applied to the wound.^1,2

The main benefits associated with this technique are the ease of use of the marketed device, which can be used in the consultation room without the need for local anaesthesia, and the absence of complications in the donor area by leaving virtually no scar. However, dermo-epidermal punch grafting, despite requiring local anaesthesia and subsequent dressing changes in the donor site (in our clinic we normally use alginate in the first dressing changes), is a technique with low morbidity for the patient and minimal pain and complications in the donor site. When the medical and nursing team have experience with the technique, it may be performed in a short time, resulting highly efficient.

But the differences between the two techniques are not limited to the donor site. Their action in the recipient area is also different. Dermo-epidermal grafts, placed on a wound bed in optimal conditions, achieve wound epithelialization by means of their attachment. However, epidermal grafts would enhance healing by expressing growth factors and promoting the migration of keratinocytes from the edge of the wound. To make an analogy with our observations in our clinic, the behaviour of epidermal grafts may be compared to that of the punch dermo-epidermal grafts when no graft taking is achieved.

An interesting indication for the use of epidermal grafts is the coverage of wounds in the context of pyoderma gangrenosum. Considering that the device only separates the epidermis, we would avoid the phenomenon of patergia in the donor site (a phenomenon that may cause another complicated wound in the area in these patients).³ However, if the activity of pyoderma gangrenosum is controlled with adequate immunosuppressive treatment, other autologous graft options (such as dermo-epidermal punch grafting) may be considered.

Different case series of epidermal grafts have been published (with heterogeneity of aetiologies, extension, evolution time and adjuvant treatments). One of them included 102 wounds, with excellent patient tolerance  and high percentages of epithelialized lesions at the end of follow-up time.^4-6 However, a recent systematic review including 7 studies with 209 wounds concludes that high level evidence data is needed to evaluate the real benefit of this type of autologous graft.⁷ With regard to new studies, a protocol has been designed to perform a multicentre clinical trial to compare the usefulness of dermo-epidermal and epidermal grafts, taking into account the result in the donor and recipient sites.⁸

Do you have experience with epidermal grafts?

References:

1. Kirsner RS, Bernstein B, Bhatia A, Lantis J, Le L, Lincoln K, Liu P, Rodgers L, Shaw M, Young D. Clinical experience and best practices using epidermal skin grafts on wounds. Wounds. 2015;27(11):282–92
2. Herskovitz I, Hughes OB, Macquhae F, Rakosi A, Kirsner R. Epidermal skin grafting. Int Wound J. 2016 Sep;13 Suppl 3:52-6.
3. Richmond NA, Lamel SA, Braun LR, Vivas AC, Serena T, Kirsner RS. Epidermal grafting using a novel suction blister-harvesting system for the treatment of pyoderma gangrenosum. JAMA Dermatol. 2014;150(9):999–1000.
4. Hachach-Haram N, Bystrzonowski N, Kanapathy M, Smith O, Harding K, Mosahebi A, Richards T. A prospective, multicentre study on the use of epidermal grafts to optimise outpatient wound management. Int Wound J. 2017 Feb;14(1):241-249.
5. Everts PA, Warbout M, de Veth D, Cirkel M, Spruijt NE, Buth J. Use of epidermal skin grafts in chronic wounds: a case series. Int Wound J. 2017 Dec;14(6):1213-1218.
6. Lincoln K, Hyde J. Evaluation of Epidermal Skin Grafts for the Treatment of Complex Wounds in a Wound Care Center: A 94-Patient Case Series. Wounds. 2016 ct;28(10):347-353.
7. Kanapathy M, Smith OJ, Hachach-Haram N, Bystrzonowski N, Mosahebi A, Richards T. Systematic review and meta-analysis of the efficacy of epidermal grafting for wound healing. Int Wound J. 2017 Dec;14(6):921-928.
8. Kanapathy M, Hachach-Haram N, Bystrzonowski N, Harding K, Mosahebi A, Richards T. Epidermal grafting versus split-thickness skin grafting for wound healing (EPIGRAAFT): study protocol for a randomised controlled trial. Trials. 2016 May 17;17(1):245.