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Introduction
Debridement, or the removal of devitalized or contaminated tissue from the wound bed until surrounding
healthy tissue is exposed, is advocated for healing
chronic, nonhealing, or indolent wounds stalled in the
inflammatory phase of wound healing.1-3 Although supporting evidence is limited,4,5 clinical experience and expert opinion agree that debridement is essential for
removing necrotic tissue from the wound bed. The clinical significance of debridement is reflected in its dominant placement in the conceptual framework called
Wound Bed Preparation, which was initially defined and
subsequently refined by Schultz and colleagues.6 Wound
Bed Preparation is a synthesis of research and clinical experience in the management of chronic, indolent, or nonhealing wounds. It includes 4 factors that must be
addressed when formulating a treatment plan for a
chronic wound, collectively referred to using the acronym
TIME, where T indicates nonviable or deficient tissue,
I indicates infection or inflammation, M indicates
moisture imbalance, and E indicates a nonadvancing or
undermined wound edge. Debridement not only removes
nonviable tissue from the wound bed but also inhibits
production of inflammatory cytokines, fibronectin, and
metalloproteinases, and promotes DNA synthesis, production of keratinocytes.7-11
While there is broad-based consensus that debridement
removes harmful necrotic tissue from the wound bed and
promotes healing, no single method has been found to be
superior and no single technique is appropriate for every
patient.3,6,12 In addition to autolytic, surgical, biologic, and
Methods
We completed a systematic review beginning with a
search of the electronic databases MEDLINE and CINAHL
Janet Ramundo, MSN, RN, CWOCN, Emory University Wound
Ostomy and Continence Nursing Education Program, Atlanta,
Georgia.
Mikel Gray, PhD, FNP, PNP, CUNP, CCCN, FAANP, FAAN,
Professor and Nurse Practitioner, Department of Urology, University
of Virginia, Charlottesville.
Neither Dr. Ramundo nor Dr. Gray are affiliated with Healthpoint Ltd.
Corresponding author: Mikel Gray, PhD, FNP, PNP, CUNP, CCCN,
FAANP, FAAN, Department of Urology, PO Box 800422, UVA HSC,
Charlottesville, VA 22908 (mg5k@virginia.edu).
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from January 1960 to August 14, 2009. We used the following key words, debridement and collagenase. This
search returned 36 citations from the MEDLINE database
and 32 citations from the CINAHL database. We also
searched the Cochrane Library to identify any systematic
reviews that included debridement with collagenase, but
none was found. The Web-based search engine, Google
Scholar, was searched using the key terms debridement,
enzymatic debridement, and collagenase. This search revealed supplemental sources and in vitro research results
but no clinical studies were identified that met inclusion
criteria.
All prospective and retrospective studies comparing
enzymatic debridement using a collagenase ointment on
pressure ulcers, leg ulcers, or burn wounds were included
in the review, regardless of quality. Nevertheless, results of
all included studies were reviewed by both authors, and
judgments related to their quality and associated impact
on strength of evidence and clinical implications are discussed within our review. While randomized clinical trials
and comparison cohort studies were included, prospective
and retrospective case studies and multiple case series were
excluded. Studies published in English and those with an
English language abstract were included.
We identified 11 studies that compared collagenase with
a petrolatum-based or other ointment, autolytic debridement via a hydrogel or polyacrylate dressing, surgical excision, silver sulfadiazine, and alternative enzymatic agents
(papain-urea and trypsin/chymotrypsin)15-25 (Table 1).
Six randomized clinical trials were identified that compared collagenase derived from a bacterial source to a
placebo, comprising a heat-inactivated collagenase ointment or a petrolatum-based ointment never charged with
the enzymatic agent.15-19
S5
distinguish eschar from slough. The efficiency of debridement was operationally defined as a visual estimate of the
percentage of reduction (varying from 0% to 100%) in the
wound area covered by necrotic tissue and differences in
the observed thickness of necrotic tissue. Wounds were
cleansed with sterile water and water-soaked gauze. The
ointment or gum preparation was applied directly to the
wound bed. Collagenase was administered until complete
debridement was obtained; treatment duration varied
from 1 to 14 weeks. Significantly more wounds (58 out of
62; 94%) managed by the collagenase preparations
achieved complete debridement as compared to 1 of 8
lesions (13%) of the wounds treated by the sham ointment
(P .01). Data analysis revealed no difference in the
efficiency of debridement when the collagenase ointment
and hydrophilic gum with neomycin were compared. No
hypersensitivity reactions occurred. No clinically relevant
adverse side effects occurred; some subjects treated with
collagenase over a period of multiple weeks developed
mild erythema adjacent to the wound that subsided when
application of the enzymatic agent was discontinued.
Wound healing outcomes were not reported.
Lee and Ambrus16 compared collagenase to a sham
ointment in 14 subjects with 28 pressure ulcers in a randomized controlled trial. Pressure ulcers were randomly allocated to treatment with 250 units of collagenase per
gram in a petrolatum-based or a heat-inactivated ointment. The wound was cleansed with saline and the ointment applied twice daily; treatment was continued for 4
weeks. The primary outcome variable was a global improvement scale that included time to visible removal of
necrotic tissue, change in inflammation, and volume or
purulent exudate in the wound bed. A 4-point scale was reported, where 0 indicated no necrotic or purulent materials, 1 indicated mild inflammation and necrotic materials,
2 indicated moderate inflammation and necrotic material,
and 3 indicated severe inflammation and necrosis. Wound
size was quantified as diameter of the ulcer, and its volume
was measured via a dental impression mold. Fourteen out
of 17 wounds (82%) treated with the collagenase ointment
improved during the 4-week treatment course, as compared to no improvement in any of the wounds treated
with the sham ointment (P .01). Analysis of differences
in wound diameter and wound volume was not reported,
but the researchers did observe that some wounds that
were ranked as improved on the global scale during the
course of treatment were found to have an increased
wound volume. This unanticipated increase in wound volume was attributed to successful removal of necrotic and
inflammatory debris from the wound.
Varma and associates17 compared a petrolatum-based
ointment containing 250 units of collagenase per gram
with a heat-inactivated sham ointment in a double-blind,
placebo-controlled, randomized, clinical trial. Twenty subjects were enrolled in the trial, and one wound was treated
in each subject; this ulcer was selected randomly in
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TABLE 1.
Enzymatic Agents for Debriding Pressure Ulcers, Leg Ulcers, or Partial-Thickness Burn Wounds
Study
Subjects
Study Design
Debriding Agent
Outcomes
Boxer and
coworkers15
RCT
RCT
Collagenase (Santyla) vs
placebo ointment
RCT
RCT
RCT
RCT
RCT
Collagenase ointment
(Santyl) vs hydrogel
(SoloSite)
Collagenase (Santyl) vs silver
sulfadiazine
Konig and
coworkers22
RCT
Alvarez and
coworkers23
RCT
Collagenase (Santyl) vs
Papain-Urea Ointment
(Accuzyme)d
Comparison cohort
(random
allocation not
reported in
study report)
Comparison Cohort
Collagenase ointment
(derived from liver of king
crab) vs trypsin.
Chymotrypsin ointment
RCT
Collagenase (Novuxol) vs
fibrinolysin/DNAase
ointment
Varma and
coworkers17
Fu and coworkers19,c
Milne20
Glyantsev and
coworkers24
Ozcan and
coworkers25
Pullen et al25
Collagenase ointment
(Novuxol)e
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bridement applied a polyacrylate dressing daily; the dressing was activated by wetting it with Ringers solution.
Subjects randomized to treatment with collagenase applied the ointment once daily and covered the wound
with dry gauze. All participants applied short-stretch compression bandages during waking hours. The original
study design specified a data collection period of 14 days,
but this was extended to 21 days owing to considerable
variability and lack of meaningful changes during the first
2 weeks of treatment. During the initial 14 days, subjects
managed by autolytic debridement experienced a mean
20% reduction in necrotic tissue and those managed by
collagenase experienced a mean reduction of 10%. During
the following week, subjects managed by autolytic debridement experienced an additional mean reduction in
necrotic tissue of 11% while those managed by collagenase
had a mean increase in necrotic tissue burden of 11%. No
statistically significant differences were found when results were compared between the groups.
Three studies were identified that compared collagenase
to other enzymatic debriding agents. Alvarez and coworkers23
compared a petrolatum ointment containing 250 units of
collagenase per gram with a hydrophilic ointment
containing the enzymatic debriding agent papain (8.3
105 USP activity/g) and urea (100 mg/g) in a randomized
clinical trial of 26 patients with pressure ulcers. Neither
subjects nor investigators were blinded to treatment
group. Wounds were cleansed with sterile normal saline
before application of the enzymatic debriding agent, and
black eschar was crosshatched using a No. 10 blade prior
to treatment. The enzymatic ointment was applied directly to the wound bed once daily, and the wound was
dressed with moist gauze and covered by dry gauze sufficient to ensure a moist environment. If the wound became
soiled, dressings were changed and as many as one additional application of the enzymatic debriding ointment
per day was permitted. Patients were maintained on pressure redistribution surfaces when indicated; use or type of
surface was not standardized for study subjects. Wounds
were evaluated daily for week 1 and then twice weekly for
the following 3 weeks of data collection.
Necrotic tissue was characterized as adherent yellow/
gray or white slough, soft adherent black eschar, or adherent, hard black eschar. The line of demarcation between
nonviable and viable tissue was estimated and a global
evaluation of the wound was completed based on evaluation of wound edges, odor, pain, exudate, edema,
erythema, granulation tissue, reepithelialization, and periwound skin irritation. Wound size was determined based
on computer planimetry of surface tracings. The primary
endpoint of the study was removal of necrotic tissue;
wound healing was evaluated via the ordinal scale
described above and presence of granulation tissue. The
papain-urea ointment dissolved necrotic tissue more
rapidly than did wounds treated by the collagenase
ointment, resulting in significantly greater presence of
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ticipated in the study. In addition to these groups, the authors reported on 29 patients who were begun on debridement using collagenase ointment, but treatment was
discontinued because they developed a wound infection
(n 17), or their physician decided that wound grafting was
indicated (n 12). The time required for complete removal
of necrotic tissue using these 3 methods (collagenase alone,
collagenase plus surgical management, or surgical management only) was not significantly different. Patients managed
with collagenase alone were less likely to require blood transfusion than those managed with collagenase and surgical
intervention or those managed by surgical means alone.
Patients initially managed with collagenase were less likely
to require surgical excision than those managed exclusively by surgical means. Patients managed with collagenase also had a shorter length of stay in hospital than those
managed by surgery alone or collagenase followed by surgical intervention.
Findings from these studies provide limited evidence
that collagenase is a more effective debriding agent than
silver sulfadiazine cream and equivalent to a fibrinolysin/
DNAase ointment. Equivocal results were found in 2 studies comparing collagenase to autolytic debridement, but
the quality of these studies is not sufficient to allow us to
reach definitive conclusions.20,22 Results suggest that collagenase may remove slough more rapidly than a trypsin/
chymotrypsin debriding ointment commercially available
in Russia,24 but another study found that collagenase ointment removed necrotic tissue more slowly than a papainureabased ointment.23 Nevertheless, this latter outcome
must be carefully weighed against the studys other main
outcome, wound closure, which revealed no differences between the collagenase ointment and the papain-urea ointment. Results of a comparison cohort study suggest that
debridement with collagenase is equivocal to surgical excision alone in children with partial-thickness burns and
that treatment with collagenase may reduce the need for
excision if the techniques are combined. However, the lack
of randomization to treatment group severely limits our
ability to draw firm conclusions.
Only one study reported wound healing outcomes as
well as time to complete debridement.21 It revealed that
treatment of partial-thickness burns covering less than
25% of total body surface area healed more quickly using
collagenase as compared to silver sulfadiazine.
Clinical Implications
Collagenase is an effective, selective method of removing
necrotic tissue from pressure ulcers, leg ulcers, and burns.
This product has been safely used in the adult, geriatric,
and pediatric population.
Clinicians often combine enzymatic debriding agents
with other methods of debridement such as surgical
debridement, autolysis, and conservative sharp would
debridement. A typical approach might be initial surgical
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debridement of the ulcer or burn, application of collagenase to the remaining necrotic tissue, coverage with an
occlusive dressing to promote autolysis, and conservative
sharp wound debridement of nonadherent tissue at the
time of the dressing change.
Collagenase is applied daily, although it may be applied
more frequently if the dressing becomes soiled in order to
provide ongoing debridement. When applying collagenase
ointment, the clinician should bear in mind that optimal results rely on maintenance of a moist environment in the
wound bed because the enzyme requires moisture to exert
its intended biologic activity. Moisture may be obtained via
endogenous exudate or exogenously applied moisture from
a hydrogel. The ointment may be applied directly to the
wound bed, but dry eschar should be crosshatched and hydrated when treating with collagenase.
Dressing selection for use with enzymes is based on
accurate wound assessment. Factors such as absence or
presence of infection, amount and type of drainage,
wound location, and wound size and depth must be considered. A sacral wound in an incontinent patient may
benefit from a dressing that will provide protection from
urine or stool, whereas a leg ulcer with small amounts of
drainage can be effectively covered with gauze and secured
with a wrap to avoid adhesive on fragile skin. Initial studies with collagenase were performed with gauze, but clinical experience has shown that this enzyme can be safely
and effectively used with other types of dressings such as
thing foams or gauze that is covered with transparent
adherent dressings. The clinician should also consider the
need for daily application of collagenase for maximum
effectiveness when selecting a dressing; dressings meant
to be left in place for more than 1 day will not be costeffective.
Specific ions, including several commonly incorporated into antimicrobial dressings and antiseptic solutions,
may inhibit the debriding activity of collagenase.27 For example, antimicrobial dressings containing ionic silver produces minimal inhibition of collagenase activity, while
silver dressings reduced its activity by more than 50% and
cadexomer iodine inhibited its activity by approximately
90%.28 In addition, pH levels below 6.0 or above 8.0 found
in some antiseptic cleansers containing heavy metal ions,
acetic acid, or hyperchlorite also reduce the biologic activity of collagenase and should be avoided or removed
from the wound bed via cleansing with saline before
collagen is applied.
Collagenase is selective to necrotic tissue but is not
harmful to clean tissue when applied to the wound bed. It
may be applied directly to the wound bed, or if the tissue
is slick, it may be easier to apply to the dressing. The
wound should be cleansed with normal saline or a pH balanced wound cleanser. If eschar covers the wound, the collagenase can be applied at the periphery of the wound to
enhance separation. An alternative is to crosshatch the eschar with a No. 10 blade, which will allow collagenase to
November/December 2009
Summary
Collagenase ointment is widely available, easily combined
with other methods of debridement, selective to necrotic
tissue, and has shown to be an effective method of debridement. Concerns associated with the use of collagenase are few and focus on the cost of the product as well
as questions about effectiveness when compared to other
methods of debridement. The evidence summarized in
this systematic review reveals that collagenase ointment is
a safe and effective choice for wound debridement.
KEY POINTS
Limited evidence suggests that treatment of partialthickness burn wounds in children with collagenase ointment
may require an equivocal time to treatment with surgical
excision and that combination treatment may reduce the need
for surgical excision (level of evidence: 2).
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