Annals of Burns and Fire Disasters - vol. XXXI - n. 2 - June 2018

SUMMARY. NexobridTM is a highly selective enzymatic debriding agent used in the acute management of burns to perform escharectomy.From October 2016 to April 2017, we treated 6 patients affected with lower limb chronic ulcers of different etiologies with NexobridTM inorder to perform eschar removal by enzymatic debridement. For all patients, a dosage of NexobridTM, calculated as 2gr per 1% TBSA, wasapplied in a 2-3 mm thick uniform layer on the ulcer eschar and fibrin tissue and left for 4 hours, covered with an occlusive dressing.Patients were assessed in terms of ulcer cleansing 24 hours and 7 days post NexobridTM debridement, by wound bed score (WBS) and %of remaining necrotic tissue. A patient pain VAS was also recorded at 24 hours and 7 days post debridement. Adverse events at these timepoints were also noted. The results documented a complete removal of necrotic tissue in a time frame of 4 hours. At 24 hours, all lesionswere completely debrided. At 7 days, there was a partial recurrence of necrotic tissue, as also documented by decreased WBS. All patientsreported none to mild pain, and no adverse events were noted, except for mild erythema along the edges of the lesion on healthy skin inone case. This is a preliminary observation. Optimal dosage and application of NexobridTM in this indication needs to be validated byfurther controlled data.

Keywords: chronic ulcer, debridement, NexobridTM, enzymatic

NexobridTM est un agent de débridement hautement sélectif utilisé dans la prise en charge des brûlés pour réaliser une excisionenzymatique. Entre octobre 2016 et avril 2017, nous l’avons utilisé pour réaliser ce même type d’excision chez 6 patients souffrant d’ulcèreschroniques de jambe, d’étiologies variées. Nous avons appliqué 2g de NexobridTM par % de surface coporelle atteinte, en une couche uni-forme de 2-3 mm d’épaisseur laissée en place 4h sous pansement occlusif. À 24 h et 7 jours, nous avons évalué le score de fond de plaie(Wound Bed Score-WBS), le pourcentage restant de tissu nécrotique, la douleur (EVA) et les effets secondaires. À 4h, les tissus nécrosésavaient entièrement disparu, ne réapparaissant pas à 24 h. À J7, on notait une réapparition, sur une surface moindre, de tissus nécroiqueset une altération du WBS. Les patients étaient non ou peu douloureux. Le seul effet secondaire observé, chez un patient, a été un érythèmemodéré de la peau saine circonscrivant la lésion. À la suite de cette étude préliminaire, des études plus larges permettront de préciser lesmodalités d’utilisation de NexobridTM dans cette indication.

ulcère chonique, NexobridTM, débridement enzymatique

Introduction

Chronic wounds are a significant burden on both the patientand the healthcare system, representing a cost of over US$25billion per year.1 Wound care has therefore become increasinglyimportant. A prime concept in wound care is the role of debride-ment, the removal of non-viable tissue material. Necrotic debrisserves as fuel for infection and impedes wound healing. Theobjective is to expose well-perfused tissue that is able to pro-liferate and adequately populate the wound bed. This can beachieved through surgical, autolytic, biological or enzymaticmechanisms.1-3

NexobridTM is a commercially available enzymatic de-briding agent indicated for the acute management of burns

to perform escharectomy. NexoBridTM active substance is aconcentrate of proteolytic enzymes (mainly proteases) en-riched with bromelain extracted from the stems of the pineap-ple plant (Ananas comosus). It is a highly selective product,as it recognizes necrotic tissues without damaging healthyones. Its safety and efficacy on burn wounds have been val-idated in a number of studies,4-6 and it is today approved bythe European Medicines Agency. Approximately 3500 pa-tients have been treated across Europe, 755 of them in Italy(data as of July 2017).

The purpose of this report is to assess the potential efficacyof NexobridTM in an off label use: debriding necrotic tissue inthe context of lower limb chronic ulcers that could not be de-brided with any other therapeutic option.

___________

Corresponding author: Michelangelo Vestita, MD, Mohs Dermatologic Surgery, Brigham and Women’s Faulkner Hospital, 02131, Boston, MA, USA. Tel.: +1 857-404-6827;email: michelangelovestita@gmail.com; mvestita@bwh.harvard.eduManuscript: submitted 16/04/2018, accepted 20/06/2018

109

Annals of Burns and Fire Disasters - vol. XXXI - n. 2 - June 2018

Case series

From October 2016 to April 2017, we treated 6 patients af-fected with lower limb chronic ulcers of different etiologieswith NexobridTM in order to perform eschar removal by enzy-matic debridement (Figs. 1 and 2). The characteristics of ourcase series are summarized in Table I.

Written informed consent was obtained from all the patientsafter discussing therapeutic possibilities for debridement withthem. Since this was an off-label study, the option to use Nexo-bridTM to treat these patients was based on the high risk involvedin performing surgical debridement (due to severe systemicblood clotting disorders, see Table I) and on the failure of othernon-invasive methods (wet to dry, collagenase, urea, autolytic,maggots, etc.). NexobridTM use was further supported by itsdemonstrated selectivity for necrotic tissues and on the wealthof literature data available on its efficacy in burn wound debride-

ment, both in terms of animal and clinical studies.1-3

For all patients, a dosage of NexobridTM, calculated as 2grper 1% TBSA, was applied in a 2-3 mm thick uniform layer onthe ulcer necrotic and fibrin tissue (Figs. 3 and 4) and left for 4hours, covered with an occlusive dressing. After it was removed,saline soaks were applied for 24 hours. At 24 hours, Urgo-cleanTM dressings were applied and left in place or changed if

and when needed. Necrotic tissues were pre-treated with salinesoaks for 3-4 hours before NexobridTM application in cases inwhich the necrosis was not moist. Patients were assessed interms of ulcer cleansing 24 hours and 7 days post NexobridTM

debridement, by wound bed score (WBS) and % of remainingnecrotic tissue. A patient pain VAS was also recorded at 24 hoursand 7 days post debridement. Adverse events at these timepoints were also noted. Overall patient satisfaction VASwas also recorded at the day 7 visit. Results are reported inTable I.

110

Fig. 1 - Chronic leg ulcer of venous etiology. Patient 1, pre-treatment

Fig. 2 - Chronic venous malleolar ulcer. Patient 6, pre-treatment

MI = myocardial infarction; USD = United States Dollars

AGE SEX MAIN COMORBIDITY

WOUND SITE

WOUND AGE (months)

WOUND AREA (cm2)

WOUND ETIOLOGY

% NECROTIC TISSUE REMAINING (24 hours)

% NECROTIC TISSUE REMAINING (7 days)

WOUND BED SCORE (baseline)

WOUND BED SCORE (24 hours)

WOUND BED SCORE (7 days)

PAIN VAS (24hours)

ADVERSE EVENTS

COSTOFTREATMENT(USD)

67 F dual antiplatelet therapy/previous MI

malleolar 30 18 venous 0 70 4 10 9 3 none 77

72 F cirrhosis malleolar 25 20 venous 0 40 2 7 5 1 none 86

74 F cirrhosis foot thumb 11 3 diabetic 0 50 6 11 10 0 none 12

52 M factor XI deficiency

tibial 10 42 post-traumatic 0 25 5 10 9 3 moderate erythema on wound edges

181

62 M dual antiplatelet therapy/previous MI

tibial 9 29 post-traumatic 0 20 7 13 12 2 none 125

69 M cirrhosis malleolar 35 30 venous 0 30 4 9 7 2 none 129,3

Table I - Characteristics of the study population and results

Annals of Burns and Fire Disasters - vol. XXXI - n. 2 - June 2018

Complete cleansing and necrotic tissue removal was ob-tained in all cases (Figs. 5 and 6). Mean WBS was 4.6, 10 and8.6 respectively at baseline, at 24 hours and at 7 days. The per-centage of remaining necrotic tissue was 0 and 39.1 respec-tively at 24 hours and 7 days (Fig. 7). Mean pain VAS was 1.8at 24 hours. One patient presented mild erythema with no pru-ritus along the edges of the ulcer on healthy skin at 24 hours.No other adverse events were recorded.

111

Fig. 5 - Same lesion as Figs. 1 and 3. 24 hours post-treatment assessment.Complete debridement of the ulcer

Fig. 4 - Same lesion as Fig. 2. Application of NexobridTM in a uniform2-3mm thickness, covered with paraffin gauze to prevent product di-splacement

Fig. 6 - Same lesion as Figs. 2 and 4. 24 hours post-treatment asses-sment. Complete debridement of the ulcer

Fig. 3 - Same lesion as Fig. 1. Application of NexobridTM in a uniform 2-3mm thickness, covered with paraffin gauze to prevent product displacement

BIBLIOGRAPHY

Paquette D, Falanga V: Leg ulcers. Clin Geriatr Med, 8: 77-88, 2002.1Han G, Ceilley R: Chronic wound healing: a review of current man-2agement and treatments. Adv Ther, 34: 599-610, 2017.Jones CM, Rothermel AT, Mackay DR: Evidence-based medicine3Wound Manag, 140: 201e-216e, 2017.Rosenberg L, Krieger Y, Bogdanov-Berezovski A, Silberstein E et al.:4A novel rapid and selective enzymatic debridement agent for burnwound management: a multi-center RCT. Burns, 40: 466-474, 2014.Rosenberg L, Shoham Y, Krieger Y, Rubin G et al.: Minimally invasive5burn care: a review of seven clinical studies of rapid and selective de-bridement using a bromelain-based debriding enzyme (Nexobrid®).Ann Burns Fire Disasters, 28: 264-274, 2015.

Schulz A, Perbix W, Shoham Y, Daali S et al.: Our initial learning curve6in the enzymatic debridement of severely burned hands. Managementand pit falls of initial treatments and our development of a post de-bridement wound treatment algorithm. Burns, 43: 326-336, 2017.Giudice G, Filoni A, Maggio G, Bonamonte D, Vestita M: Cost analy-7sis of a novel enzymatic debriding agent for management of burnwounds. Biomed Res Int, 2017: 9567498, 2017.

Annals of Burns and Fire Disasters - vol. XXXI - n. 2 - June 2018

Discussion

The efficacy and safety of NexobridTM on burn injuries forearly debridement has been extensively studied.1-3 Since thisproduct recognizes moist necrotic tissue, it seems natural to tryand assess its potential use on other types of pathological con-ditions presenting necrotic tissue, such as chronic non-healingulcers. However, since the product has not been developed forthis indication, and since no pre-clinical data specific to thismodality exist, we decided to test it on lower limb chronic re-fractory wounds that we were unable to effectively debride withany other therapeutic option, including surgery, because of im-peding local or systemic conditions of the patients and/or pa-tient refusal of surgery.

The results documented complete removal of necrotic tis-

sue in a time frame of 4 hours (Fig. 3). At 24 hours, all le-sions were completely debrided: NexobridTM had returned tous a deterged wound bed ready to be treated with skin grafts,advanced dressings or regenerative surgery in order to pro-mote and lead to wound healing. However, at 7 days therewas a partial recurrence of necrotic tissue, as also docu-mented by decreased WBS, in particular regarding woundbed and fibrin scores (Table I, Fig. 4). Of note, this was ex-pected, as we know that burn wounds treated with Nexo-bridTM tend to develop a so-called pseudoeschar in thefollowing days, which can be limited by constant wound hy-dration, and which can then be easily removed by mechanicalwet to dry debridement. All patients reported none to mildpain, and no adverse events were noted, except for mild ery-thema along the edges of the lesion on healthy skin in onecase; this was managed with topical corticosteroids, withcomplete resolution in a few days, and could possibly indi-cate patient susceptibility to the product. Of note, as in burns,the wound should be made and kept moist several hours be-fore and long after NexobridTM application, in order to opti-mize the product efficacy (before) and to avoid dehydrationof tissues (after) that would lead to new non-vital tissue(pseudoeschar) development.

Concerning costs, we must take into account that a 2gr vialof NexobridTM costs about 431 USD, and that this quantity cancover 180 cm2. The mean wound area in our study was 23.6cm2, therefore the mean price per patient for NexobridTM de-bridement was 101.7 USD (see Table I). Considering thatNexobridTM debridement involves a one-time application, thesecosts are similar to those for the long term use of other non in-vasive enzymatic debriding agents (which need repeated appli-cations and are much less efficacious), and are notably lowerthan costs related to the use of the several resources involvedin a surgical debridement (anaesthetic, human resources, oper-ating room time and costs, etc.). These data are consistent witha recent study that compared the costs of NexobridTM debride-ment with the standard of care in burn patients.7

To the best of our knowledge, this is the first report on theuse of NexobridTM for the debridement of wounds other thanburn injuries. This is a preliminary observation and as such ourdata, as well as the optimal dosage and application of Nexo-bridTM for this indication will need to be validated by furthercontrolled data on larger cohorts of patients.

112

Conflict of interest. NoneFinancial disclosure statement. None

Fig. 7 - Same lesion as Figs. 1, 3 and 5. 7 days post-treatment asses-sment. Partial recurrence (40%) of the necrotic tissue