TY - JOUR
AU - Moradi,, Mohammad
AB - Abstract Burns are a significant public health burden worldwide. In addition to those who die, millions remain with life-threatening deformities and disabilities resulting in stigma and rejection. Surgical excision is currently the standard of care for removing necrotic tissues in burn wounds to prepare the wound bed for grafting or enhancing the healing process. However, there is a growing interest on enzymatic debridement as an adjunct therapy in burn wounds. The aim of this study was to investigate clinical trials using debriding agents for burn wound in humans in a systematic review. This was a systematic review of electronic databases including CINAHL, PubMed, Ovid Medline, Web of Science, Google Scholar, and Embase from January 1969 to February 2019. The study protocol was registered in PROSPERO registry. The following keywords were searched: “burn wounds”, “enzymatic debridement”, “papain”, “papain-urea”, “pine apple”, “Bromelain”, “collagenases”, “Nexobrid”, “Debrase”, “Debridase”, “Actinidia deliciosa”, “Sutilains”, “Debrace”, “piruvat acid”. Those studies fulfilling the inclusion and exclusion criteria with low score of bias based on Cochrane Bias Tool were reviewed. Sixteen investigations fulfilled our inclusion criteria to be reviewed. Six, seven, and three clinical trials on humans were found regarding collagenase, bromelain, and miscellaneous agents. Collagenase has been reported to be effective in burns below 25% of TBSA, especially in outpatients’ clinics. However, Nexobrid has been shown to be effective in deep burns and decreases the percentage of graft without significant adverse effects. There was not enough evidence supporting the clinical values of Papain, Sutilains, Urea, etc. Surgical excision still remains the standard of care for burn wounds debridement. However, enzymatic debridement, especially Bromelain might help to reduce sessions for surgical debridement or area under graft as an adjunct treatment. Despite the fact, more studies with larger sample sizes and with less conflicts of interest are needed to clearly elucidate the exact role of Bromelain. Burns are a significant public health burden worldwide. Based on official statistics, there are more than 265,000 deaths annually only due to burns. In addition to those who die, millions remain with life-threatening deformities and disabilities resulting in stigma and rejection.1,2 The devitalized tissue and necrosis would be a good culture medium for different pathogens leading to wound infection which finally postpones the healing process.3–5 Therefore, many studies suggested that early surgical excision improves the survival of patients significantly. Several techniques are used widely for burn wound debridement; the most common ones include surgical excision and enzymatic debridement.6 Selecting between these techniques depends on many factors, including wound size and its place, presence of necrotic debris, burn grading, bacterial colonization or sepsis, the time elapsed from burn, availability, expertise of the medical team, expenses for patient, burn care system, etc.7 The most commonly used and accepted technique for debridement is surgical excision of necrotic tissues. However, surgical excision has some limitations including surface blood loss, repetitive general anesthesia, and potential damage to adjacent normal tissues, as differentiating between alive and devitalized tissues is difficult and needs much expertise.8–10 Based on the current evidences, the standard of care for human burn is still surgical debridement, however, there is a growing interest on enzymatic debridement recently as an adjunct modality to surgical excision. On the other hand, and due to some complications of surgical debridement, there is a trend toward less invasive procedures to remove necrotic debris. Some enzymatic agents have been recently used to remove necrotic tissue. They can be used alone only in superficial burn, especially in outpatient clinics or in combination with surgical wound debridement.11,12 No one claimed that enzymatic debridement per se is enough for deep burn wounds debridement or critical patients. Therefore, early surgical debridement must not be postponed. However, in some circumstances, enzymatic debridement would help. Several chemical or biologic agents have been used for enzymatic debridement including enzymes of some bacteria (ie, collagenases) such as Clostridium histolyticum and Bacillus subtilis.13–16 Plant extracts such as papain or Bromelain (Nexobrid, Debridase) derived from pineapple.17 Also, Actinidia deliciosa has been reported in some animal investigations.18 Others include streptokinase/streptodornase, papain/urea, and a combination of fibrinolysin and desoxyribonuclease.19 In selecting an enzymatic debridement agent, the speed of action, selectivity, not damaging the adjacent normal tissue, less expenses, and infection should be considered. The aim of this systematic review was to assess enzymatic agents for debridement of burn wounds in humans and comparing their efficacy in different aspects with the surgical approach. MATERIALS AND METHODS Data Sources and Registration This was a systematic review of electronic databases including CINAHL, PubMed, Ovid Medline, Web of Science, Google Scholar, and Embase from January 1960 to February 2019. The study protocol was registered in PROSPERO registry the International prospective register of systematic reviews. The following keywords were searched: “burn wounds”, “enzymatic debridement”, “papain, urea”, “papain-urea”, “pine apple”, “Bromelain”, “collagenases”, “Nexobrid”, “Debrase”, “Debridase”, “Actinidia deliciosa”, “sutilains”. Type of Studies All clinical trials either prospective or retrospective, case–control or cohort comparing enzymatic debridement with surgical approach were included. Experimental studies without a control group were also included. Case reports or case series, editorials, expert opinions, and narrative reviews were excluded. However, we tried to include the gray literature by searching abstracts published in medical congresses. All studies including burn in human were considered. Studies on animal models were excluded. Studies in English language or those with an English abstract were included. PROSPERO registry for systematic reviews and Cochrane Database for Systematic Reviews was also searched using the abovementioned keywords. Risk of Bias Assessment The modified Cochrane Collaboration tool was used for risk bias assessment. The tool has five main domains (selection, performance, attrition, reporting, and other) and scores the study bias as high, low, or unclear. Selection bias includes random sequence generation and allocation concealment. Reporting bias includes selective reporting, performance bias includes blinding (participants and personnel) and detection bias includes blinding (outcome assessment) and finally attrition bias includes incomplete outcome data and others. Studies were assessed by two independent authors for eligibility to be included. In case of disagreement between the authors, a third opinion was requested and a consensus was achieved. Also the full texts were assessed using the modified Cochrane bias tool for clinical trials by two of the authors independently to be included in our review. RESULTS At first, 1134 evidences were found. After primary survey, those who were repetitive (310 records) were excluded. After assessing these 824 evidences by titles and sometimes skipping their abstracts 115 manuscripts were considered for full-text assessment. Then, 99 studies were excluded due to various reasons presented in Figure 1. Six of the remaining manuscripts were excluded due to high bias using the Cochrane bias tool and 16 studies remained to be analyzed. Figure 1. Open in new tabDownload slide The study flow chart. Figure 1. Open in new tabDownload slide The study flow chart. Our results were categorized into five main topics including collagenase, bromelain, papain/urea, Sutilains, and miscellaneous agents. Factors important for review of the literature included burn surface area, age of patients, comorbidities, the grade of burn, hospitalization, complications such as bleeding time, pain, infection, morbidity and mortality, graft percentage, etc. if available in the full texts. Collagenase Collagenase is the first chemical agent approved by the US Food and Drug Administration (FDA) for enzymatic debridement of chronic or burn wounds.20 Nineteen studies were found regarding collagenase. Two were systematic reviews, four on animal models and three in vitro researches. Finally, six clinical trials were selected regarding the efficacy of collagenase in burn wounds. All except one with unclear status (due to old publication) had low bias score based on Cochrane modified tool. Marazzi et al assessed the effect of collagenase in a larger number of patients (979) referred to outpatient clinics due to second-degree burns or chronic ulcers due to various reasons. Noruxol or Iruxol was used. They finally concluded that patients with burns affecting ≤15% BSA or those suffering chronic ulcers due to various reasons might benefit from collagenase.21 However, Ozcan et al assessed 78 pediatric burn patients who received collagenase clostridiopeptidase A and compared them to 41 patients who underwent surgical excision for burn wounds. In 29 patients (37.2%), enzymatic debridement was stopped due to burn wound infection and converted to surgical excision. They concluded that collagenase provided a shorter hospital stay, decreased the amount of blood transfusions and overall need for surgery in patients with partial-thickness burns.10 In another investigation, 114 children aged 3 months to 17 years with scald burns of deep dermal partial-thickness were treated using five techniques of tangential necrectomy and skin grafting, mechanical dermabrasion, hydrocolloid dressings, Iruxol Mono enzymatic dressings, or Aquacel hydrofiber dressings with silver ions. In the Iruxol Mono® group, the overall rate of conversion was 21% (4 patients). Wound infection reported in four children (21%). They concluded that enzymatic dressings could be used for some of the deep dermal partial-thickness wounds, but it did not act in a short period of time.22 Despite the fact, Ostlie et al found no significant difference regarding clinical course, outcome, or need for skin grafting in a clinical trial comparing collagenase and silver sulfadiazine in burns of less than 25% TBSA.23 Two older investigations by Soroff24 and Hansbrough25 in 1994 and 1995 proved the superiority of collagenase over silver sulfadiazine in 14 patients below 25% of TBSA and 79 adults between 2% and 30% TBSA with partial-thickness burns, respectively. A clean wound bed achieved faster and more rapid healing than silver sulfadiazine was found. A summary of investigations regarding the efficacy of collagenase on wound debridement is presented in Table 1. Table 1. A summary of investigations regarding the efficacy of collagenase on wound debridement Study . Subjects . Study Design . Cochrane Bias Score . Outcome . Publish . Marazzi et al21 979 patients with second- degree burns or chronic ulcers Retrospective analysis Low Acceptable in patients with burns ≤15% BSA or those with chronic ulcers 2006 Ozcan et al10 78 children in collagenase group 41 in surgical debridement group RCT Low A shorter hospitalization, decreased amount of blood transfusions and overall need for surgery in patients with partial-thickness burns 2002 Kaźmierski et al22 Children of 3 months to 17 years with deep dermal partial-thickness burns RCT Low In noncomplicated burns of 10% to 20% TBSA, conservative treatment with or without mechanical dermabrasion was effective 2007 Comparing five techniques Ostlie et al23 100 patients from 2 months to 18 years with burns less than 25% TBSA RCT Low No differences between surgical excision or collagenase in the treatment of childhood burns 2012 Soroff et al24 15 adult patients with partial-thickness burns less than 25% TBSA RCT Unclear A clean bed achieved faster significantly and more rapid healing compared with silver sulfadiazine 1994 Hansbrough et al25 79 patients aged 5 to 60 years with partial-thickness burns from 2% to 30% TBSA RCT Low Collagenase sites healed faster and cleaned in less time compared with silver sulfadiazine significantly 1995 Study . Subjects . Study Design . Cochrane Bias Score . Outcome . Publish . Marazzi et al21 979 patients with second- degree burns or chronic ulcers Retrospective analysis Low Acceptable in patients with burns ≤15% BSA or those with chronic ulcers 2006 Ozcan et al10 78 children in collagenase group 41 in surgical debridement group RCT Low A shorter hospitalization, decreased amount of blood transfusions and overall need for surgery in patients with partial-thickness burns 2002 Kaźmierski et al22 Children of 3 months to 17 years with deep dermal partial-thickness burns RCT Low In noncomplicated burns of 10% to 20% TBSA, conservative treatment with or without mechanical dermabrasion was effective 2007 Comparing five techniques Ostlie et al23 100 patients from 2 months to 18 years with burns less than 25% TBSA RCT Low No differences between surgical excision or collagenase in the treatment of childhood burns 2012 Soroff et al24 15 adult patients with partial-thickness burns less than 25% TBSA RCT Unclear A clean bed achieved faster significantly and more rapid healing compared with silver sulfadiazine 1994 Hansbrough et al25 79 patients aged 5 to 60 years with partial-thickness burns from 2% to 30% TBSA RCT Low Collagenase sites healed faster and cleaned in less time compared with silver sulfadiazine significantly 1995 RCT, randomized control trial. Open in new tab Table 1. A summary of investigations regarding the efficacy of collagenase on wound debridement Study . Subjects . Study Design . Cochrane Bias Score . Outcome . Publish . Marazzi et al21 979 patients with second- degree burns or chronic ulcers Retrospective analysis Low Acceptable in patients with burns ≤15% BSA or those with chronic ulcers 2006 Ozcan et al10 78 children in collagenase group 41 in surgical debridement group RCT Low A shorter hospitalization, decreased amount of blood transfusions and overall need for surgery in patients with partial-thickness burns 2002 Kaźmierski et al22 Children of 3 months to 17 years with deep dermal partial-thickness burns RCT Low In noncomplicated burns of 10% to 20% TBSA, conservative treatment with or without mechanical dermabrasion was effective 2007 Comparing five techniques Ostlie et al23 100 patients from 2 months to 18 years with burns less than 25% TBSA RCT Low No differences between surgical excision or collagenase in the treatment of childhood burns 2012 Soroff et al24 15 adult patients with partial-thickness burns less than 25% TBSA RCT Unclear A clean bed achieved faster significantly and more rapid healing compared with silver sulfadiazine 1994 Hansbrough et al25 79 patients aged 5 to 60 years with partial-thickness burns from 2% to 30% TBSA RCT Low Collagenase sites healed faster and cleaned in less time compared with silver sulfadiazine significantly 1995 Study . Subjects . Study Design . Cochrane Bias Score . Outcome . Publish . Marazzi et al21 979 patients with second- degree burns or chronic ulcers Retrospective analysis Low Acceptable in patients with burns ≤15% BSA or those with chronic ulcers 2006 Ozcan et al10 78 children in collagenase group 41 in surgical debridement group RCT Low A shorter hospitalization, decreased amount of blood transfusions and overall need for surgery in patients with partial-thickness burns 2002 Kaźmierski et al22 Children of 3 months to 17 years with deep dermal partial-thickness burns RCT Low In noncomplicated burns of 10% to 20% TBSA, conservative treatment with or without mechanical dermabrasion was effective 2007 Comparing five techniques Ostlie et al23 100 patients from 2 months to 18 years with burns less than 25% TBSA RCT Low No differences between surgical excision or collagenase in the treatment of childhood burns 2012 Soroff et al24 15 adult patients with partial-thickness burns less than 25% TBSA RCT Unclear A clean bed achieved faster significantly and more rapid healing compared with silver sulfadiazine 1994 Hansbrough et al25 79 patients aged 5 to 60 years with partial-thickness burns from 2% to 30% TBSA RCT Low Collagenase sites healed faster and cleaned in less time compared with silver sulfadiazine significantly 1995 RCT, randomized control trial. Open in new tab Bromelain Seven well-designed prospective studies including four randomized trials and three experimental studies without a control group met the inclusion criteria to be reviewed. Krieger assessed the efficacy of Debrase in hand burns in 275 hospitalized burn patients. They reported that surgical intervention was required in 36% of burn wounds after enzymatic debridement. Skin graft in deep burn wounds was necessary for 28.6% of total burned area estimated initially. They concluded that enzymatic debridement in deep-hand burns decreased skin-graft use and perceived full-thickness wound area.26 Moreover, Cordts in 2016 assessed the effects of Nexobrid in 16 patients with deep partial- to full-thickness burns in the upper extremity. They found that in 53.8% of the study population no further surgical intervention was needed. Moreover, skin-grafted area decreased by 37.0% compared with primary evaluation.27 Rosenberg in 2004 published a trial for the first time regarding the efficacy of Debridase in 130 patients with deep second- or third-degree burns admitted during 1984 to 1999. They found that the percentage of surgical debridement decreased by the number of enzymatic agent applications significantly. However, no major side effects were reported.28 Again in 2014 he performed a randomized controlled trial comparing the effects of Debridase and surgical excision. They found that Nexobrid decreased the time to reach complete debridement significantly (2.2 vs 8.7 days, P < .0001). Also, need for surgical excision (24.5% vs 70.0%, P < .0001), the area under excision (13.1% vs 56.7%, P < .0001), and need for grafting (17.9% vs 34.1%, P = .01) were significantly decreased. Despite the fact, there was no difference regarding adverse effects, scar quality, or quality of life scores between the two groups.29 Schulz et al is another researcher who published three trials in 2016. In one, they assessed 20 patients with deeply burned hands limited to 15% TBSA in adult patients. They concluded that Nexobrid can be used in deep burned hands with promising results.30 In addition, they compared surgical excision and Nexobrid in patients with deep dermal burns of the hand in another investigation. They concluded that compared with traditional surgical debridement, bromelain was superior regarding adjacent normal tissue preservation, providing complete debridement, and wound closure. However, scar quality was the same between the two groups after 3 months.31 Also, they performed an investigation on deep dermal facial burns using bromelain. They found that wound closure after admission was significantly reduced compared with surgical group (19.85 vs 42.23 days, P = .002). Besides, eschar removal occurred faster by enzymatic debridement (18.92 vs 35.62 days, P = .042). However, number of sessions for complete debridement (1.00 vs 1.77, P = .003) and autografting of wounds with any size (15% vs 77%, P = .002) decreased significantly in enzymatic debridement group.32 As reported in these seven trials, Nexobrid could significantly decrease the area of burns excised, reduced time to complete debridement, and the need for autografting without any significant complication or need for blood transfusion. However, this cannot be the only thing done for patients with large surface area burns, critical patients, deep burn wounds, etc. Nexobrid might help as an adjunct modality for burn wounds to decrease hospitalization, area under graft, and some others as claimed by the abovementioned studies. A summary of these seven trials is presented in Table 2. Table 2. Clinical trials assessing the effect of Nexobrid on burn wounds in humans Researcher . Subjects . Study Design . Cochrane Bias Score . Outcome . Year . Krieger et al26 69 hands with deep burns Experimental without control Low Enzymatic debridement decreased the perceived full-thickness wound area and skin-graft use 2012 Cordts et al27 16 patients with deep partial- to full-thickness burns of the upper extremities Experimental without control Low No surgical intervention was required in most patients. skin-grafted area decreased significantly 2016 Rosenberg et al28 130 patients with deep second- or third- degree burn Prospective, noncomparative study Low Nexobrid was fast-acting, reliable and had no adverse effects 2004 Rosenberg et al29 182 patients with 5% to 30% BSA burns RCT Low Reduced need for further surgical debridement and good long-term outcomes 2014 Surgical vs Nexobrid groups Schulz et al30 20 adult patients with deep burns in hands below 15% TBSA Experimental Low Shorter duration of treatment, ease of use, efficiency, selectivity, and early rehabilitation 2017 Without control Schulz et al31 40 patients with deep burns in hands aged 18 to 76 years RCT Low Bromelain was superior regarding adjacent normal tissue preservation, providing complete debridement and wound closure. Scar quality was the same between the two groups after 3 months 2017 Surgical vs Nexobrid groups Schulz et al32 26 patients aged 18 to 78 years with deep dermal or deeper facial burns RCT Low Bromelain was superior to surgical approach in many aspects 2017 Surgical vs Nexobrid groups Researcher . Subjects . Study Design . Cochrane Bias Score . Outcome . Year . Krieger et al26 69 hands with deep burns Experimental without control Low Enzymatic debridement decreased the perceived full-thickness wound area and skin-graft use 2012 Cordts et al27 16 patients with deep partial- to full-thickness burns of the upper extremities Experimental without control Low No surgical intervention was required in most patients. skin-grafted area decreased significantly 2016 Rosenberg et al28 130 patients with deep second- or third- degree burn Prospective, noncomparative study Low Nexobrid was fast-acting, reliable and had no adverse effects 2004 Rosenberg et al29 182 patients with 5% to 30% BSA burns RCT Low Reduced need for further surgical debridement and good long-term outcomes 2014 Surgical vs Nexobrid groups Schulz et al30 20 adult patients with deep burns in hands below 15% TBSA Experimental Low Shorter duration of treatment, ease of use, efficiency, selectivity, and early rehabilitation 2017 Without control Schulz et al31 40 patients with deep burns in hands aged 18 to 76 years RCT Low Bromelain was superior regarding adjacent normal tissue preservation, providing complete debridement and wound closure. Scar quality was the same between the two groups after 3 months 2017 Surgical vs Nexobrid groups Schulz et al32 26 patients aged 18 to 78 years with deep dermal or deeper facial burns RCT Low Bromelain was superior to surgical approach in many aspects 2017 Surgical vs Nexobrid groups RCT, randomized control trial. Open in new tab Table 2. Clinical trials assessing the effect of Nexobrid on burn wounds in humans Researcher . Subjects . Study Design . Cochrane Bias Score . Outcome . Year . Krieger et al26 69 hands with deep burns Experimental without control Low Enzymatic debridement decreased the perceived full-thickness wound area and skin-graft use 2012 Cordts et al27 16 patients with deep partial- to full-thickness burns of the upper extremities Experimental without control Low No surgical intervention was required in most patients. skin-grafted area decreased significantly 2016 Rosenberg et al28 130 patients with deep second- or third- degree burn Prospective, noncomparative study Low Nexobrid was fast-acting, reliable and had no adverse effects 2004 Rosenberg et al29 182 patients with 5% to 30% BSA burns RCT Low Reduced need for further surgical debridement and good long-term outcomes 2014 Surgical vs Nexobrid groups Schulz et al30 20 adult patients with deep burns in hands below 15% TBSA Experimental Low Shorter duration of treatment, ease of use, efficiency, selectivity, and early rehabilitation 2017 Without control Schulz et al31 40 patients with deep burns in hands aged 18 to 76 years RCT Low Bromelain was superior regarding adjacent normal tissue preservation, providing complete debridement and wound closure. Scar quality was the same between the two groups after 3 months 2017 Surgical vs Nexobrid groups Schulz et al32 26 patients aged 18 to 78 years with deep dermal or deeper facial burns RCT Low Bromelain was superior to surgical approach in many aspects 2017 Surgical vs Nexobrid groups Researcher . Subjects . Study Design . Cochrane Bias Score . Outcome . Year . Krieger et al26 69 hands with deep burns Experimental without control Low Enzymatic debridement decreased the perceived full-thickness wound area and skin-graft use 2012 Cordts et al27 16 patients with deep partial- to full-thickness burns of the upper extremities Experimental without control Low No surgical intervention was required in most patients. skin-grafted area decreased significantly 2016 Rosenberg et al28 130 patients with deep second- or third- degree burn Prospective, noncomparative study Low Nexobrid was fast-acting, reliable and had no adverse effects 2004 Rosenberg et al29 182 patients with 5% to 30% BSA burns RCT Low Reduced need for further surgical debridement and good long-term outcomes 2014 Surgical vs Nexobrid groups Schulz et al30 20 adult patients with deep burns in hands below 15% TBSA Experimental Low Shorter duration of treatment, ease of use, efficiency, selectivity, and early rehabilitation 2017 Without control Schulz et al31 40 patients with deep burns in hands aged 18 to 76 years RCT Low Bromelain was superior regarding adjacent normal tissue preservation, providing complete debridement and wound closure. Scar quality was the same between the two groups after 3 months 2017 Surgical vs Nexobrid groups Schulz et al32 26 patients aged 18 to 78 years with deep dermal or deeper facial burns RCT Low Bromelain was superior to surgical approach in many aspects 2017 Surgical vs Nexobrid groups RCT, randomized control trial. Open in new tab Papain Papain use gained much attention during the fifties but little heard afterwards.33,34 Only one investigation was found recently with a low bias based on Cochrane tool. Langer in 2013 performed a clinical trial on 30 patients aged 9 to 80 years with burns covering 5% to 20% of BSA. They concluded that Debridace, a papain-urea product, is not enough effective in deep burn wounds and is not suggested.35 Sutilains Sutilains derived from filtration of cultures of a strain of B. subtilis was first introduced in 1973 and produced under commercially brand name of Travase (Flint Laboratories, Division of Travenol Laboratories). Garrett was one of the firsts to assess its clinical efficacy in 1969 on 110 patients with burns. Effective debridement occurred in 95 of 101 patients.16 Another investigation by Pennisi et al also assessed the efficacy of Travase for burn wound debridement in 1973. They reported that 58 of the 68 patients were treated successfully.36 Sutilains proteinases got its highest popularity in seventies, however, its use was limited due to possible water and salt imbalances and risks of bacterial colonization and bacteremia.37 Miscellaneous Many other agents have been used for enzymatic debridement of burn wounds. Some of them include trypsin, blow fly larvae, vibriolysin, papaya, fig tree enzymes, and some acids such as pyruvic acid and phosphoric acid.19 Each of them was abandoned due to very low efficacy or side effects. Also, many investigations are available on animal models which are not the scope of this systematic review. Some of these investigations are presented in Table 3. Table 3. A summary of some clinical trials assessing papain-urea, papaya, and hydrocolloid dressings in debriding burn wounds Author . Subjects . Study Design . Cochrane Bias Score . Outcome . Year . Langer et al35 30 patients with burns from 5% to 20% BSA Experimental low Debridace a papain-urea product was not enough effective for enzymatic debridement 2013 Jayarajan et al38 50 patients with second- or third-degree burns, aged 15 to 60 years. 10% to 60% TBSA Experimental Low Papaya pulp was very effective as a debriding agent in all cases. Deep dermal wounds cleared up in 5 to 6 days 2016 Zacharevskij et al39 87 patients aged 18 to 65 years with burns below 30% of TBSA RCT Low Hydrocolloid dressings provided the fastest epithelialization of deep partial-thickness skin burns in hands 2018 Author . Subjects . Study Design . Cochrane Bias Score . Outcome . Year . Langer et al35 30 patients with burns from 5% to 20% BSA Experimental low Debridace a papain-urea product was not enough effective for enzymatic debridement 2013 Jayarajan et al38 50 patients with second- or third-degree burns, aged 15 to 60 years. 10% to 60% TBSA Experimental Low Papaya pulp was very effective as a debriding agent in all cases. Deep dermal wounds cleared up in 5 to 6 days 2016 Zacharevskij et al39 87 patients aged 18 to 65 years with burns below 30% of TBSA RCT Low Hydrocolloid dressings provided the fastest epithelialization of deep partial-thickness skin burns in hands 2018 RCT, randomized control trial. Open in new tab Table 3. A summary of some clinical trials assessing papain-urea, papaya, and hydrocolloid dressings in debriding burn wounds Author . Subjects . Study Design . Cochrane Bias Score . Outcome . Year . Langer et al35 30 patients with burns from 5% to 20% BSA Experimental low Debridace a papain-urea product was not enough effective for enzymatic debridement 2013 Jayarajan et al38 50 patients with second- or third-degree burns, aged 15 to 60 years. 10% to 60% TBSA Experimental Low Papaya pulp was very effective as a debriding agent in all cases. Deep dermal wounds cleared up in 5 to 6 days 2016 Zacharevskij et al39 87 patients aged 18 to 65 years with burns below 30% of TBSA RCT Low Hydrocolloid dressings provided the fastest epithelialization of deep partial-thickness skin burns in hands 2018 Author . Subjects . Study Design . Cochrane Bias Score . Outcome . Year . Langer et al35 30 patients with burns from 5% to 20% BSA Experimental low Debridace a papain-urea product was not enough effective for enzymatic debridement 2013 Jayarajan et al38 50 patients with second- or third-degree burns, aged 15 to 60 years. 10% to 60% TBSA Experimental Low Papaya pulp was very effective as a debriding agent in all cases. Deep dermal wounds cleared up in 5 to 6 days 2016 Zacharevskij et al39 87 patients aged 18 to 65 years with burns below 30% of TBSA RCT Low Hydrocolloid dressings provided the fastest epithelialization of deep partial-thickness skin burns in hands 2018 RCT, randomized control trial. Open in new tab DISCUSSION Interest regarding a method for fast and effective debriding burn wounds backs to the Second World War, in which early surgical excision and using chemical agents to remove necrotic tissues were evolved.40,41 In some circumstances in which surgical approach is dangerous, such as patients’ inability to undergo general anesthesia due to underlying medical conditions or coagulopathies, enzymatic debridement can be used to decrease blood loss, session of surgical debridement, etc. Only one systematic review exists regarding enzymatic burn debridement in humans including all agents by Klasen in 2000 who clearly highlighted the history of enzymatic debridement with details.19 There is no recent review on the current evidence regarding enzymatic debridement in human burns. Glasser was one of the first researchers who published his work in 194042 regarding chemical debridement in 58 patients with burn wounds. He used papain derived from the juice and the leaves of Carica papaya (the melon tree). Papain has been combined with other substances such as urea or chlorophyll in the literature. A lot was written on papain till fifties. But, it did not show promising results in clinical trials and its popularity decreased. As the last clinical trial found in the literature by Langer in 2013 which showed that Debridace, a papain-urea product is not enough effective, especially those with deep burn wounds.35 Moreover, many organic and inorganic acids were examined by Connor and Harvey in 1944 to assess their efficacy for promotion of enzymatic debridement.43 In 1946, pyruvic acid was shown to be effective for the treatment of 30 patients with burn wounds. Afterward in 1964, there were some investigations regarding the effects of phosphoric acid on burns debridement by Benedito et al. They believed that acids would help to digest necrotic tissues and also act against most bacteria.44 However, due to nonspecific action of acids and possible damage to adjacent tissues their use was abandoned. Moreover, proteolytic enzymes of bacterial origin got much interest in 1951. Action of proteolytic enzymes derived from Clostridia cultures (C. histolyticum), Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa, Bacillus proteus) were assessed by Altemeier et al and continued by Connell and Rousselot. They were then abandoned due to their adverse effects, and not efficacy on human collagen.45,46 Later in 1970s, sutilains, the neutral proteinase derived from filtrates of B. subtilis got much attention. Travase (Flint Laboratories, Division of Travenol Laboratories) was used by some researchers. Garrett and Pennisi performed the first studies on sutilains and showed its efficacy. however, its use was limited due to possible water and salt imbalances and risks of bacterial colonization and bacteremia.16,36 Collagenase has been a matter of debate since 1940. Ramundo et al in his systematic review assessed 12 manuscripts regarding the effects of collagenase on different wounds including burns.7 They finally concluded that collagenase ointment is available, easily mixed with other agents and is selective to necrotic tissue without injury to adjacent normal tissues. Some investigations in molecular level also verified that collagenase could excite keratinocyte cellular responses and can be used as a novel therapeutic modality for enhancing burn wound care.47 A large trial on the effects of collagenase on 979 patients (647 with burns affecting ≤15% BSA and 332 patients with chronic ulcers) showed some promising results. This study displayed that collagenase could be effective in outpatient clinics, especially for those with burns affecting ≤15% BSA or having chronic ulcers due to any reason.21 Among other five clinical trials presented in the results, only Ostlie et al found no difference regarding the outcomes between collagenase and surgical excision in childhood burns.23 However, other four trials showed that collagenase sites healed faster and cleaned in less time (Table 1). Totally, it seems that collagenase might be effective in partial-thickness burns less than 25% of BSA, especially in those referred to burn clinics but cannot be substituted for surgical excision in deep burns. A summary of clinical trials regarding collagenase efficacy on burn wounds is presented in Table 1. Several other agents were introduced in the recent years including trypsin, chymotrypsin, fibrinolysin–desoxyribonuclease, blowfly larvae extract, vibriolysin, fig tree extract, or Actinidia deliciosa. But due to their slow action and increased risk of complications such as infection and sepsis, they were not used widely.19 However, there are some ongoing researches on humans regarding the effect of Actinidia deliciosa on burn wounds and its animal phase has been published recently.18 Despite the fact, the most challenging agent in the recent years has been Bromelain. It is very interesting that all the seven clinical trials found in the literature showed its significant effects on debriding burn wounds even deeper ones. Rosenberg and Schulz the authors of five of these seven articles insist on its high efficacy to decrease the percentage of graft without significant adverse effects. Also, they declared that Nexobrid significantly reduced the time needed for complete debridement, further need for surgery, total area excised, and autografting. Also, 77% of facial burns that undergone enzymatic debridement were more superficially burned than primary evaluation, which indicates its safety for preserving adjacent normal tissues.31 Nonetheless, there were no meaningful differences regarding adverse effects, scar quality, and quality of life scores between the two groups. Even so, Rosenberg has declared his financial interest in Mediwound the manufacturer of Nexobrid in the chapter of enzymatic debridement in Total Burn Care book.48 However, it is clear that early surgical debridement must not be postponed in burn wounds in critical patients. Early surgical debridement has saved lives of many patients till now and enzymatic debridement has still a long way toward to find a place in early management of patients with burn wounds in our idea. Based on the current evidences, Nexobrid can be added to standard surgical debridement as an adjunct modality to help decrease area under graft, session for surgical intervention, blood loss, etc. CONCLUSION Surgical excision still remains the standard of care for burn wounds debridement. Further randomized clinical trials with multicentric design and larger sample size could more clearly elucidate the role of promising agents such as Bromelain as adjunct to standard surgical treatment for burn wounds. Conflict of interest statement. The authors have no conflicts to disclose. Funding: None. Authors’ contribution: All the authors contributed equally in writing the manuscript. REFERENCES 1. Woods JF , Quinlan CS, Shelley OP. Predicting mortality in severe burns—what is the score? Evaluation and comparison of 4 mortality prediction scores in an Irish population . Plast Reconstr Surg Glob Open 2016 ; 4 : e606 . Google Scholar Crossref Search ADS PubMed WorldCat 2. 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Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC © The Author(s) 2020. Published by Oxford University Press on behalf of the American Burn Association. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
TI - Clinical Value of Debriding Enzymes as an Adjunct to Standard Early Surgical Excision in Human Burns: A Systematic Review
JF - Journal of Burn Care & Research
DO - 10.1093/jbcr/iraa074
DA - 2020-11-30
UR - https://www.deepdyve.com/lp/oxford-university-press/clinical-value-of-debriding-enzymes-as-an-adjunct-to-standard-early-L04Qxftivk
SP - 1224
EP - 1230
VL - 41
IS - 6
DP - DeepDyve
ER -