Bromelain-based enzymatic burn debridement: Spanish multidisciplinary consensus

Background Bromelain-based enzymatic debridement is gaining increased interest from burn specialists in the last few years. The objective of this manuscript is to update the previous, first Spanish consensus document from 2017 (Martínez-Méndez et al. 43:193–202, 2017), on the use of enzymatic debridement with NexoBrid® in burn injuries, adding the clinical experience of a larger panel of experts, integrating plastic surgeons, intensivists, and anesthesiologists. Methods A consensus guideline was established by following a modified Delphi methodology of a 38-topic survey in two rounds of participation. Items were grouped in six domains: general indication, indication in critical patients, pain management, conditions for NexoBrid® application, NexoBrid® application technique, and post-debridement wound care. Results In the first round, experts established consensus (strongly agree or agree) on 13 of the 38 statements. After the second round, a consensus was reached on 24 of the 25 remaining statements (97.2%). Conclusions The present updated consensus document provides recommendations on the use of bromelain-based enzymatic debridement NexoBrid®, integrating the extensive clinical experience of plastic surgeons, intensivists, and anesthesiologists in Spain. Further clinical trials and studies are required to corroborate, modify, or fine tune the current statements. Level of evidence: Not ratable


Introduction
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.

Methods
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. , were invited to participate in the study. A prerequisite for every participant was vast experience in the use of NexoBrid® (all panelist have experience using Nexobrid for the last 5 years, adding up more than 1000 cases treated by the entire group of participants). Of this group, 15 (eight plastic surgeons, six intensivists, and one anesthesiologist) completed the survey and finalized the consensus paper. There are 9 certified burn centers in Spain, and only one did not participate in the consensus. The 8 burn centers which took part in the consensus treat the vast majority of burn patients in Spain. Moreover, almost the totality of the enzymatic debridements has been performed in this 8 burn units, so that all the centers that have experience in the use of Nexobrid are represented in this consensus eliminating the risk of bias.

Panelists
These units that use Nexobrid base their work on the recommendations of the technical data sheet of the manufacturer's product, on-site training performed by the producer peer-reviewed publications and the AEMPS (Spanish Agency for Medicines and Medical Devices) guidelines, so that the consensus recommendations are congruent and compatible with those given by the manufacturer and the AEMPS as well as the wealth of information by other specialists.

Survey
A 38-item survey was created based on the previous consensus document on the use of NexoBrid® in Spain [10], adding new topics from other guidelines [5]. Topics were grouped in six domains: general indications (items 1 to 10), indications in critical patients (items 11 to 17), pain management (items 18 to 21), the conditions for NexoBrid® application (items 22 to 27), technique of application (items 28 to 34), and post-debridement care (items 35 to 38). The degree of agreement or disagreement with the consensus statements was determined by using a 5-point Likert scale. Aside from six statements (14,15,16,17,37, and 38), all others were evaluated quantitatively with a Likert scale varying from 1 (strongly disagree), 2 (disagree), 3 (neither agree nor disagree), 4 (agree), to 5 (strongly agree). In these six topics, five possible statements were offered to be chosen or ordered, when appropriate. All 38 questions of the survey are based on those used in the Spanish consensus of 2017 adding new questions proposed in other papers.

Delphi rounds and agreements
During the first round, all experts anonymously completed the survey. The survey was provided to the experts via Google Forms by the coordinating group, and subsequently, the results were compiled (percentage of each response for each item). The second round consisted on online web meeting, where participating experts reviewed the results of the first round and discussed the interest and details of each statement. Consensus was established when all the participants totally or strongly agreed with each statement. In some cases, the statement had to be modified (rewritten) in order to provide a more direct and clear statement for readers.
A recent article published by Niederberger and Spranger [12] performed a systematic review of the methods used in 12 different health-related Delphi studies. As stated in the article, a large number of modifications to the Delphi technique have been developed. Usually, these studies include a deliberately selected panel of experts and are carried out in 2-3 rounds, thus allowing discussions among the panelists in order to modify consensus statements as needed.
The following are the final statements:

Agreement on general indication
1) "Enzymatic debridement is indicated for deep dermal burns. It would not make any contribution to the healing process in first degree burns." 2) "The enzymatic debridement for the treatment of burns should only be used by experienced professionals after adequate training." 3) "The enzymatic debridement is a safe tool for the removal of the eschar in adult patients and it can be safely used by following the Summary of Product Characteristics." 4) "The use of enzymatic debridement in pediatric patients is considered an off-label use and provides results comparable to those in adults in specific cases. Our results support several peer reviewed publications, including other consensus guidelines." 5) "The use of the enzymatic debridement can be very useful for the treatment of face, hands, neck, and neckline by saving vital dermal tissue; it is very useful in the treatment of thorax and abdomen for bleeding reduction in compared to tangential debridement." 6) "The clinical evaluation of burn depth performed by an expert is a sufficient indication for treating with enzymatic debridement." 7) "The enzymatic debridement can be safely used in a single application on anatomical areas up to 15% TBSA, but there are data that indicate that sequential, deferred applications up to 15% TBSA on different areas are safe." 8) "After the first application, it is possible to apply the enzymatic debridement in the same patient on different anatomical areas during the following days." 9) "The main indication for enzymatic debridement is the eschar removal in thermal burns (flame, scald, contact), there is not enough information for its use on chemical and high-voltage electrical burns." 10) "Since enzymatic debridement can be applied during the first hours after the burn injury, it can avoid the need for surgical escharotomies in patients with circumferential burns of the extremities, with or prone to develop BICS (burn induced compartment syndrome)."

11) "Enzymatic debridement can increase the systemic inflammatory response in critical patients and, in some
cases, cause hemodynamic instability." 12) "The use of enzymatic debridement requires a hemodynamically stabilized patient." 13) "Hypovolemia should be corrected before applying the enzymatic debridement." 14) "The application of enzymatic debridement in critical patients is safe but requires close monitoring and increased workload for the medical and nursing teams." 15) "In critically ill patients, NexoBrid® should not be used until the patient has been properly stabilized, except in circumferential burns where its early use will prevent the development of compartment syndrome and avoid the need for escharotomy." 16) "In critical patients, enzymatic debridement should be used in a sequential-deferred manner, depending on the response of the patient, by applying it to surfaces lower than 15% of TBSA and repeating the process as soon as the hemodynamic situation of the patient allows it, and as many times as necessary. The challenges that experts more frequently have to deal with are related to human resources and coagulation alterations." 17) "Off-label use of NexoBrid® in more than 15% of TBSA in a single application could only be considered in cases of circumferential burns on more than one limb to prevent development of compartment syndrome, and in critically ill patients for whom early surgery may not be possible (e.g., mass casualty incidents)."

Agreement on pain management
18) "The adequate management of pain is needed in all steps of debridement." 19) "The pain management strategy during the enzymatic debridement can change taking into account the type of    SA strongly agree, A agree, NAND neither agree nor disagree, D disagree, SD strongly disagree * These statements for pain management were responded by 17 participants 36) "After an effective enzymatic debridement, in absence of viable dermal tissue, a dressing with Mepilex Ag® is applied until the wound is grafted. Prior to the autograft the wound bed is usually prepared with Versajet® or surgical brush." 37) "If autografts are indicated, they should be performed between day 3 and day 5 after enzymatic debridement." 38) "If a delayed autograft is indicated for a not healing post NexoBrid® wound bed, it is recommended to wait between 21 and 30 days for this decision."

Discussion
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 debridementrelated 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  . 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 sequentialdeferred 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 useroriented 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.

Limitations
The main limitation of any consensus document is potentially rooted in its intrinsic subjective nature. Experts provide their professional experience in clinical practice. Therefore, statements cannot be considered asa scientifically based, definitive evidence. Further clinical trials and long-term clinical studies are required to corroborate or modify the current statements.

Conclusion
The present updated consensus document provides recommendations on the use of bromelain-based enzymatic debridement with NexoBrid®, merging the extensive clinical experience of plastic surgeons and intensivists in Spain.
Author contribution All authors contributed to the study conception and design.
Funding The author declare that no funding was receivedfrom any company for this article.

Declarations
Ethical approval The ethics committee of Vall d'Hebron confirmed that no ethical approval was required for this study.
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