Bromelain-based enzymatic burn debridement: Spanish multidisciplinary consensus

Burns represent an important public health problem worldwide [1]. According to the World Health Organization, 180,000 deaths each year are caused by burns. Non-fatal burns are associated with temporary and permanent morbidities such as long and traumatic treatment, long hospitalization and post hospitalization care, final outcomes of disfigurement, and functional and psychological disabilities (including stigma and rejection) [1, 2]. Burn care depends on the patient’s general condition, the burn’s etiology, anatomic location, extent (frequently expressed as the percentage of total body surface area, TBSA), and depth, as well as associated comorbidities such as age or smoke inhalation [3]. The early removal of the burn eschar (or debridement) is one of the most important steps in the care of the deep partial and full thickness burns [4, 5]. Surgical, excisional debridement techniques are the current standard of care (SoC) for debridement in burn patients. However, these procedures have limitations such as significant trauma, major blood and heat loss, and potential damage to adjacent viable tissue that may be hard to differentiate from burned non-viable tissue [5]. Enzymatic debridement emerged as an alternative to cope with these limitations. It involves chemical or biological agents, including papain (from papaya) with urea, collagenases from Clostridium histolyticum, or the mixture fibrinolysin-desoxyribonuclease, that alone or in combination with surgical debridement help to remove the necrotic tissue (burn eschar) as a first stage of wound healing [2, 6]. However, currently available enzymatic agents are relatively slow and of modest efficacy [4]. In contrast, bromelain-based enzymatic debridement (NexoBrid®) has demonstrated to be highly effective, selective (removes burn eschar without harming viable tissues), and safe in deep partial-thickness and full-thickness burn wounds [4, 7, 8]. Effectively debriding burns early on admission has shown to reduce surgically related morbidities, blood and heat losses, infection rate, need for grafting, hospital stay, and costs, in comparison with SoC [8]. Since the approval of NexoBrid® in Europe in 2013, its use in burn centers has become more frequent [9]. In 2017, Martínez-Méndez et al. [10] published a consensus document on the use of enzymatic debridement with NexoBrid® in burn injuries in Spain. They involved a panel of seven experts (plastic surgeons) from major Spanish Burn Units. The objective of the present manuscript is to update the previous consensus document with additional clinical experience with bromelain-based enzymatic debridement from a larger panel of experts, integrating plastic surgeons, intensivists, and anesthesiologists.

This consensus guideline paper has been created following a modified Delphi methodology [11], with two voting rounds. The first round was completed between October 14 and 19, 2020, and the second on October 23, 2020.

Bromelain-based enzymatic debridement has gained increasing attention from burn specialists in recent years [9, 13]. NexoBrid® is indicated for the removal of the eschar in adults with deep partial- and full-thickness thermal burns [14]. According to the Summary of Product Characteristics (SmPC), it should not be used in more than 15% TBSA per session. NexoBrid® is especially useful in risky anatomical locations and those with underlying functional structures [4]. Indeed, enzymatic debridement has shown to be superior regarding tissue preservation, completeness of debridement, and wound closure compared to SoC when applied to hand and face [8, 15]. Enzymatic debridement is also effective for the avoidance of surgical escharotomy in circumferential deep burns of the distal upper extremity [9, 16]. Compared to SoC, NexoBrid® significantly reduces debridement-related blood loss [4]. Nevertheless, the risk of bleeding can increase with anticoagulant therapies or coagulation abnormalities, present in up to 40% of critical patients [5, 17]. NexoBrid® application time should not exceed 4 h because its activity decreases [18]. Pre-treatment before NexoBrid® with agents containing silver, iodine, and copper should be avoided as they inhibit bromelain activity. Presoaking with water-based solutions such as polyhexanide-containing agents is recommended [19]. NexoBrid® application is painful during the first 45–60 min, described as burning sensation [20] and necessitating adequate pain management, with analgesia and/or anesthesia. Recently, two consensus guidelines on the use of the bromelain-based enzymatic debridement have been published [5, 9]. Hirche et al. [9] updated the European consensus guidelines established in 2017 with the experience of a multiprofessional panel of plastic surgeons and burn care specialists from 12 European Burn Centers. They not only reviewed similar topics as in the present document (such as indications, pain management, post-debridement care, NexoBrid® application, and technique); but also included new topics related to the timing of application, skin grafting, outcomes, cost-effectiveness, patient’s perspective, logistic aspects, and training strategies [9]. They met consensus on 42 out of 43 statements. The only statement with no consensus was regarding the ambulatory care with NexoBrid® in minor burns. Ranno et al. [5] carried out a consensus guideline for Italian NexoBrid® users. Their 27-item survey comprised the domains of indications, pain management, application timing and technique, and post-enzymatic debridement wound care. The panel of 14 experts established consensus on 26 of the statements. The only statement that did not reach strong agreement was related to the use of NexoBrid® in pediatric population. Similar to our study, the fact that its use in pediatric patients is considered off-label and the lack of experience were the reasons for not meeting an agreement. At the time of writing the present manuscript, the use of NexoBrid® is considered off-label in patients under 18 years old, and most of our participating experts have no experience in this population. Nevertheless, those who did use NexoBrid® in children (3 centers) achieved successful results with no major complications. Scientific evidence is required to safely use NexoBrid® in pediatric population. The published literature addressing this issue is scarce. Shoham et al. [21] reviewed the experience of NexoBrid® in three clinical trials with 110 children. Of them, 77 received treatment with NexoBrid® in a phase I/II trial, and achieved complete eschar removal in 92.7% of treated areas, within 0.9 days from hospital admission. The remaining 33 children participated in a phase III randomized clinical trial (17 were treated with NexoBrid® and 16 with SoC). Complete eschar removal was reported in all individuals receiving NexoBrid® in 0.9 days from initiation (versus 6.5 days in SoC). An additional randomized controlled pediatric phase III clinical trial is currently ongoing (clinicaltrials#NCT02278718), evaluating the efficacy and safety of NexoBrid® in children with thermal burns compared with SoC. Another topic that could be considered off-label is the use of NexoBrid® on more than 15% TBSA. In the Italian consensus guideline [5], like ours, most of the experts state they have used NexoBrid® in a sequential-deferred manner, 15% TBSA sessions on different areas, and even up to 20–25% per session on the same patient with large burn areas. Effective enzymatic debridement of burn wounds depends on the denaturation status of collagen [22].

Our present consensus on the use of NexoBrid® represents an update of the previous document [10], with clinical experience from a multidisciplinary panel of experts providing user-oriented recommendations aiming to optimize its adequate application for inexperienced healthcare professionals. The presence of six intensivists and one anesthesiologist provided great insight of some aspects such as pain management, fluid therapy, and coagulation, and represent an added value regarding the previous consensus [10]. Our statements corroborate the European and Italian consensus guidelines [5, 9]. However, our document also integrates the experience of both plastic surgeons and intensivists, who are the main expert professionals using the enzymatic debridement in Burn Centers in Spain. This multidisciplinary teamwork allowed to apply treatment with Nexobrid® to patients affected by Covid-19 [23]. Moreover, in this document, we provided clarified consensus statements in those topics with no clear initial agreement, instead of presenting a percentage of consensus (as done in the first round Table 1). By following this procedure, the less experienced reader may gain insight from all statements.