A novel rapid and selective enzymatic debridement agent for burn wound management: A multi-center RCT
Introduction
Burns are common injuries, associated with significant morbidity and mortality often leading to disfigurement and dysfunction due to scarring. Deep partial thickness and full thickness burns are characterized by the presence of necrotic tissue (the eschar) that makes accurate diagnosis of burn depth difficult and contributes to local and systemic complications [1], [2], [3].
Early burn eschar removal (débridement) followed by autografting is a cornerstone of modern burn therapy and considered the standard of care (SOC) since it reduces early complications and late sequelae, mainly scarring [1], [2], [3]. At present, most deep burns are surgically debrided in the operating room by excision (escharectomy), mainly sequential, tangential excision of thin layers of necrotic tissue until viable, bleeding tissue is reached. While effective, excisional debridement is traumatic, resulting in loss of viable tissue, blood and heat, and requiring specialized surgical personnel and facilities and is often delayed until an accurate diagnosis of burn depth is reached confirming the necessity for surgery [1], [2], [3], [4]. Due to surgical demands, a conservative, “autolysis” based, approach is often used where the necrotic eschar slowly macerates under the activity of cellular enzymes, bacteria and antibacterial medications.
Enzymatic and chemical debridement have been proposed in the past to speed the autolytic process and as an alternative to excisional debridement (ED), but present agents are slow, of limited efficacy, and increase the risk of infection by macerating necrotic tissues [5]. We developed a debriding enzyme, NexoBridTM [1] (NXB), which is mixed with an inert carrier gel, forming a debriding gel dressing (DGD). NXB consists of a lyophilized, partially purified proteolytic protein mixture with increased specific enzymatic activity derived from Bromelain raw material extracted from pineapple plant stems.
Preliminary studies in animals and humans with NXB2 have suggested that it selectively removes the burn eschar after a single 4 h application resulting in a clean wound bed, reducing the time to complete debridement and need for ED as well as reducing burn induced elevated compartment/interstitial pressures [6], [7], [8], [9], [10], [11]. In partial thickness burns, such debridement leaves behind enough non-injured dermis that can epithelialize spontaneously, decreasing the need for ED and autografting [6], [7], [8], [9], [10]. We have coined this approach in burn care the “Minimally Invasive Modality” or MIM [12]. The current study was aimed at confirming prior preliminary results and determining whether NXB use reduces ED and autografting compared to SOC. We hypothesized that NXB if effective and selective, would reduce the need for and extent of surgery and that the reduction in excision and autografting would not impair long-term outcomes (cosmesis and quality of life) compared with the SOC.
Section snippets
Trial design
This study was a prospective, randomized, multicenter, open-label, controlled, confirmatory, phase 3 clinical trial that was conducted between 2006 and 2009. The study was approved by the institutional review boards of each of the 26 participating burn centers from 13 countries.
Study population
Patients aged 4-55 years in good health with deep partial and full thickness thermal burns covering between 5 and 30% of their total body surface area (TBSA) hospitalized in specialized burn units/centers were enrolled.
Patients
Overall, 190 patients were screened and 182 enrolled (Fig. 1) between the years 2006 and 2009. Out of the 182 enrolled, 26 were NXB training patients (the first patient at each site) and 156 patients underwent randomization. The training patients were only included in the safety analysis but were excluded from the efficacy analysis in order to maintain randomization. The study was terminated after pre-planned interim analysis that demonstrated NXB superiority in both co-primary end points. Of
Discussion
In our study we compared SOC debridement (surgical and/or non-surgical) with a novel, rapid and selective, non-surgical, enzymatic debriding agent (NXB) in patients with deep partial and full thickness burns covering ≤ 30% TBSA. NXB debridement, performed at the patient's bedside, resulted in earlier complete eschar removal consequently reducing the number and area of burns requiring surgical excision. Although full thickness defects still require autografting, because of its selectivity,
Funding
Funded by MediWound, Yavneh, Israel.
Disclosure
MediWound, the producer of DGD under the name of NexoBrid-Debrase funded the trial, which was designed by MediWound and the study group investigators and approved by the European Medicine Agency (EMA). Data was reported by the investigators and analyzed after data base lock by an independent statistician for MediWound, EMA and the primary author. The authors had full access to the data and made the decision to submit the manuscript for publication. All authors contributed to the content of the
Acknowledgements
We wish to extend our appreciation and thanks to all the physicians and nurses of the burn centers that were involved in this study. Their commitment to their patients and to progress is the driving force in this difficult and too often sad field of burn care.
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For the NexoBrid™ Debriding Enzyme Study Group. See Appendix A for list of authors.