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J Wound Ostomy Continence Nurs. 2009;36(6S):S4-S11.


Published by Lippincott Williams & Wilkins

Collagenase for Enzymatic


Debridement
A Systematic Review
Janet Ramundo Mikel Gray
Debridement is an essential component of wound bed preparation. Various techniques of debridement are commonly used in
clinical practice. This systematic review summarizes and ranks
evidence concerning the safety and efficacy of the selective
enzymatic debriding agent collagenase. Studies were identified
comparing collagenase to inactive (sham) ointment and to
alternate techniques for debridement including autolytic and
surgical. A preponderance of evidence from this systematic review confirms that collagenase ointment is a safe and effective
choice for debridement of cutaneous ulcers and burn wounds.

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

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mechanical techniques, various enzymatic agents have


been used to debride wounds. Enzymes degrade necrotic
tissue in the wound and exert variable effects on fibrin collagen, elastin, platelet-derived growth factor, and substances essential to wound healing. Enzymatic agents are
frequently used for initial debridement when anticoagulant therapy renders surgical debridement unfeasible. They
may be used to debride a wound with significant bacterial
bioburden (critically colonized or infected). Enzymatic
agents can be used on yellow slough or black eschar. At the
current time, only one agent, collagenase, is approved by
the US Food and Drug Administration (FDA) for debridement of necrotic tissue from chronic cutaneous wounds
and burns. Collagenase ointment (Santyl, Healthpoint Ltd,
Fort Worth, Texas) is a selective debriding agent derived
from the bacterial strain Clostridium histolyticum; it is available in 15- and 30-g tubes.13 The ointment is charged with
250 collagenase units per gram of white petrolatum United
States Pharmacopeia (USP). Collagenase ointment is characterized as selective because it cleaves only one type of
protein, collagen.
This systematic literature review updates an evidencebased report card that summarized clinical evidence on
the effectiveness of several enzymatic debriding substances.14 However, it has been updated and differs from
that review in its exclusive focus on collagenase ointment,
the only debriding agent approved by the US FDA for debridement of dermal and burn wounds.

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).

Copyright 2009 by the Wound, Ostomy and Continence Nurses Society

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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

Collagenase Versus Inactive (Sham) Ointment


Boxer and coinvestigators15 compared 2 collagenase preparations to a heat-inactivated sham ointment in a randomized controlled trial in 47 subjects. Sixty-two pressure or
lower extremity ulcers were randomly allocated to treatment with collagenase ointment, collagenase hydrophilic
gum, or an inactive (sham) ointment. Collagenase was
administered in a petrolatum-based ointment or as a
hydrophilic gum; both vehicles were charged with a 0.5%
of collagenase. The gum preparation also contained
neomycin; the authors did not comment on what actions
were taken to maintain the blind when the hydrophilic
gum was administered. The majority of their study population had more than 1 ulcer, and findings were based on
62 wounds in 47 subjects. The volume of necrotic tissue at
baseline was evaluated using an ordinal scale, where 1 indicated minimal debris in the wound bed with subclinical
necrosis, 2 indicated a thin layer of necrotic tissue, 3 indicated a thick layer of necrotic tissue, and 4 indicated
marked, heaped-up necrotic materials. The research report
does not state whether the investigators attempted to

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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

Elderly adults, mean age or


gender ratios not reported with
pressure or leg ulcers
(N  47)
Adults with multiple comorbidities
and pressure ulcers, 3 men and
11 women, age range 47-90 y
(N  14)
Adults with pressure ulcers or leg
ulcers, ages or gender ratios not
specified
(N  20)
Adults with leg ulcers
(N  30)

RCT

Collagenase (brand not


specified) vs placebo
ointment

Collagenase provided more rapid


removal of necrotic tissue from
the wound bed than placebo

RCT

Collagenase (Santyla) vs
placebo ointment

Collagenase provided more rapid


removal of necrotic tissue from
the wound bed than placebo

RCT

Collagenase (brand not


specified) vs placebo
ointment

Collagenase provided more


rapid removal of necrotic
tissue from the wound bed
than placebo

RCT

Collagenase (Iruxol monob)


vs placebo ointment

Adults with partial-thickness burn


wounds, age and gender ratio
not specified
(N  62)
Adults with pressure ulcers
(N  6)

RCT

Collagenase (Iruxol mono) vs


placebo ointment

Collagenase provided more


rapid removal of necrotic
tissue from the wound bed
than placebo
Collagenase provided more
rapid removal of necrotic
tissue from the wound bed
than placebo

RCT

Soroff and Sasvary21

Adults with burn wounds, 14 men


and 1 woman, mean age or age
range not reported
(N  15)

RCT

Collagenase ointment
(Santyl) vs hydrogel
(SoloSite)
Collagenase (Santyl) vs silver
sulfadiazine

Konig and
coworkers22

Adults with leg ulcers, mean age


71.7 y, 28 were women

RCT

Collagenase (Iruxol mono) vs


autolysis

Alvarez and
coworkers23

Adults with pressure ulcers, mean


age for collagenase group was
76 y, range 25-92 y, mean age
for papain-urea group was 74 y,
range 21-101 y; 15 women
(N  26)
21 adults with venous leg ulcers

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

Lee and Ambrus16

Varma and
coworkers17

Palmieri and Magri18

Fu and coworkers19,c

Milne20

Glyantsev and
coworkers24

Ozcan and
coworkers25

Pullen et al25

Children with partial-thickness burn


wounds, mean age for children
in collagenase only group 2.8 y,
mean age for surgical excision
only groups 3.4 y, mean age for
combined enzymatic debridement and surgery was
3.4 y, 78 subjects were male
Elderly subjects residing in a
longterm care facility with Seiler
Grade 2 to 4 PU
(N  135)

Abbreviation: RCT, randomized clinical trial.


a
Santyl, HealthPoint, Fort Worth, Texas.
b
Iruxol Mono, Knoll AG Pharma, Ludwigshafen, Germany.
c
English language abstract only.
d
Accuzyme Ointment, HealthPoint, Fort Worth, Texas.
e
Novuxol, Knoll, Uetersen, Germany.

Collagenase ointment
(Novuxol)e

No inferential statistics reported


in available abstract
Collagenase treated wounds
became free of visible
necrotic tissue and healed
than wounds managed with
silver sulfadiazine
No differences noted when
autolysis with polyacrylate
dressing was compared to
debridement with
collagenase ointment
Wounds dbrided with papainurea had more rapid removal
of necrotic tissue from the
wound bed but change in
wound size did not differ
between groups
Wounds treated with collagenase
ointment became free from
necrotic tissue more rapidly
than those treated with trypsin/
chymotrypsin ointment
Debridement times for children
managed with enzymatic
debridement alone were
equivocal to those managed
by surgical excision alone

Both formulations reduced


necrotic tissue in the wound
bed and reduced wound area,
no statistically significant
differences when formulations
were compared

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subjects who presented with multiple pressure ulcers. Ten


ulcers were treated with the collagenase ointment, and 10
were treated with the placebo ointment; participants had
either pressure ulcers or leg ulcers. Subjects with eschar
underwent crosshatching using a No. 10 blade prior to
treatment. After cleansing, all ulcers were also dusted
with a powder containing polymyxin B, bacitracin, and
neomycin. Treatment continued over a 2-week period.
Similar to Lee and Ambrus,16 the efficiency of debridement
was evaluated using a 4-point ordinal scale that ranked the
degree of necrotic material in wound bed, purulent
discharge, and signs of inflammation. The researchers reported that wound area was measured, but the technique
used was not described. When compared with the inactive
ointment, wounds treated with collagenase showed a
significant reduction in necrosis and inflammation
(P  .01). No significant difference in wound size was
found (P  .07) after 2 weeks of treatment. No adverse reactions were observed, with the exception of erythema in
one subject when the ointment was applied to the periwound skin as well as the wound bed. This response subsided within 24 hours after application, and it remained
limited to the wound bed.
Palmieri and Magri18 reported a placebo-controlled,
double-blind, randomized, clinical trial of 30 subjects with
leg ulcers. Subjects were randomly assigned to treatment
with a collagenase-based ointment or petrolatum ointment applied once daily to the wound over a 2-week period. They also combined elements of wound healing with
magnitude of necrotic tissue removal, using a 5-point
Likert scale that evaluated debridement, reepithelialization, inflammation, granulation, and a global efficacy
score. After 6 days, wounds managed by collagenase were
ranked as having significantly less necrotic materials than
those managed with the placebo ointment (P  .01). After
14 days, subjects treated by the collagenase ointment
achieved statistically significant differences on all variables ranked in the 5-point scale when compared to those
managed by the petrolatum ointment (P  .001). Five
subjects in each group experienced adverse reactions including a burning sensation experienced after application
of the ointment and erythema of the wound bed. All
events were characterized as mild, and none led to study
withdrawal.
Fu and coinvestigators19 compared an ointment-based
collagenase preparation with a petrolatum ointment in
a double-blind, placebo-controlled, randomized, clinical
trial. This study was published in the Chinese Medical
Sciences Journal; it contains an English language abstract
only. Sixty-two subjects with burn wounds were enrolled; 33 were randomized to treatment with the collagenase ointment and 29 were randomized to treatment
with the petrolatum ointment. The collagenase ointment was applied to the wound daily and covered with
saline-soaked gauze. The primary study outcomes were

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changes in proportion of the wound bed covered by


necrotic tissue, proportion of the wound bed covered by
granulation, reepithelialization, inflammatory state, and
wound size. The wound area was measured by tracing
the wound edges on a clear plastic overlay, and an ordinal global efficacy score was calculated based on assessment of debridement effect, reepithelialization, and
granulation tissue. Wounds treated with both collagenase and inactive ointment achieved reductions in
necrotic tissue burden over the 2-week data collection
period, but a greater number of wounds managed by the
collagenase ointment had a reduction of 50% or more as
compared to ulcers managed by the inactive petrolatum
ointment. Wound area, reepithelialization, granulation
tissue formation, and global efficacy scores were reported to be significantly better in those allocated to
treatment with the collagenase ointment at 4, 7, 11, and
14 days. Twenty-two of 33 subjects (67%) treated by the
collagenase ointment achieved wound closure by day
14; the number of wounds in the control group that
closed by day 14 was not reported in the abstract. A
global tolerability rating revealed that 100% of subjects
managed by petrolatum ointment and 97% of those
managed by the collagenase ointment had a very good
tolerance of treatment.
Collectively, these studies provide evidence that collagenase ointment provides more rapid debridement
than an inactive, sham ointment. Four studies comparing collagenase to an inactive (sham) ointment also
showed a reduction in wound inflammation.16-19 The reports reveal mixed findings, concerning the effect of collagenase ointment on wound healing (closure) or
reduction in wound size. Fu and coinvestigators19 found
that significantly more subjects treated with collagenase
experienced wound closure than subjects allocated to
treatment with the sham ointment after 2 weeks of treatment. Varma and associates17 found no differences in
wound size after 2 weeks of treatment. In contrast to
these findings, Lee and Ambrus16 reported that some
wounds in their study were larger after treatment with
collagenase ointment after 4 weeks of treatment, but this
difference was attributed to removal of necrotic tissue
from the wound bed. Multiple factors appear to have influenced these findings including differences in wound
etiology and size at baseline evaluation and differences in
treatment duration (2-4 weeks). Additional research,
based on a study endpoint of wound closure, is needed to
provide definitive conclusions. The quality of these randomized controlled trials also vary, but the time frame of
these studies must be considered when comparing pivotal trials used to achieve an indication from the US FDA
in the 1970s as compared to the approval process
required in the early 21st century. Adverse side effects
tended to be mild and transient. No hypersensitivity
responses were reported during these trials.

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Collagenase Ointment Versus Other


Active Treatments
Seven studies were identified that compared collagenase
ointment to other active treatments. Milne20 reported results of a randomized controlled trial comparing debridement using collagenase ointment with a hydrogel
(SoloSite Gel, Smith & Nephew, Largo, Florida) in 9 patients
with pressure ulcers. The main study outcome was time to
debridement during a treatment period of up to 42 days.
Following this first phase of treatment, the time to wound
healing was measured as a secondary outcome during an
additional 42-day period. The study involved a single
blind; a second data collector evaluated time to debridement and wound healing. This person was blinded to
group allocation; evaluations were based on photographs
of the wounds using a digital planimetry software package
(PictZar, Medline Industries, Mundelein, Illinois). Six subjects (67%) completed the study. Three patients, 1 managed by collagenase ointment and 2 managed by the
hydrogel, failed to achieve complete debridement by day
42. Milne20 reported that subjects allocated to treatment
with collagenase ointment achieved more rapid improvement based on wound healing outcomes but no inferential statistical analyses were reported.
Soroff and Sasvary21 reported a randomized controlled
trial of 15 subjects with partial-thickness burn wounds
covering less than 25% of their body surface area.
Participants were randomly allocated to treatment with
collagenase ointment (250 collagenase units per gram)
and a polymyxin B sulfate/bacitracin spray or a silver sulfadiazine cream applied twice daily. Wounds were
cleansed with saline; the collagenase ointment or silver
sulfadiazine cream was applied directly to the wound
using a tongue depressor or sterile, gloved hand. The main
study outcomes were the number of days until the wound
bed was clean (operationally defined as free from injured
dermis) and the number of days until wound healing (operationally defined as appearance of a new layer of epithelium). The median time to a clean wound bed was 6 days
for wounds allocated to collagenase ointment, versus 12
days for those treated with silver sulfadiazine (P  .0021),
and the median time to wound healing was faster among
subjects randomized to the collagenase ointment group
(10 vs 15 days, P  .0007). Adverse events included 3 subjects who experienced burning at the site treated with collagenase; this led one subject to discontinue participation
in the study.
Konig and coinvestigators22 compared collagenase
ointment to autolytic debridements, using a polyacrylate
dressing in a randomized clinical trial of 42 adult subjects
with lower extremity (venous) ulcers. Fifteen subjects were
allocated to autolytic debridement, and 27 were allocated
to treatment with the collagenase ointment. All subjects
underwent a 7-day washout period where they used no
topical treatments other than a dressing used to cover and
protect the leg ulcer. Subjects allocated to autolytic de-

J WOCN

November/December 2009

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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granulation tissue in the wound bed (P  .016). However,


the rate of reepithelialization and wound closure did not
differ between subjects treated with collagenase versus
papain-ureabased ointments.
Glyantsev and associates24 reported in vitro, in vivo,
and clinical studies, comparing a collagenase-based ointment to a trypsin/chymotrypsin debriding agent commercially available in Russia. This review is limited to the
results reported from the patient-based trial. Unlike the
previous studies, the collagenase evaluated by Glyantsevs
group was derived from the liver of the king crab rather
than a bacterial source. Twenty-one subjects with chronic
venous leg ulcers varying in size from 5.5 to 40.0 mm2
were assigned to treatment with either the 0.5% collagenase ointment or a 0.5% trypsin/chymotrypsin ointment.
The research report does not specify whether subjects were
randomly allocated to treatment group. The ulcers had
been present for an average of 7.5 months in the collagenase group and 9 months in the comparison group; all ulcers had signs of infection and yellow slough. Treatment
comprised twice daily application of the enzymatic debriding agent (collagenase vs trypsin/chymotrypsin) as
part of a wet to moist dressing technique. The periwound
skin was dressed with povidone-iodine foam pads and
moderate compression bandages. Subjects managed by
collagenase became free from visible slough in the wound
bed significantly sooner than subjects managed by the
trypsin/chymotrypsin debriding agent (5.6  0.3 days vs
10.3  0.9 days, P  .01).
Pullen and coinvestigators25 compared collagenase ointment (1.2 units per gram ointment) to a fibrinolysin/
DNAase ointment administered over a period of 26-30 days
in a randomized controlled trial. One hundred thirty five
elderly subjects managed in a long-term care facility in
Germany were randomly allocated to twice daily application
of collagenase or fibrinolysin/DNAase ointment. The
primary outcome measure was change in the area of the
wound be covered by necrotic tissue; secondary outcomes
including wound healing, operationally defined as change
in wound area over the course of treatment. An intention to
treat analysis revealed that both groups experienced reduction in necrotic tissue in the wound and reduction in wound
area. No statistically differences in the primary outcome
variable (change in the area of wound covered necrotic tissue) or secondary outcome variables (wound area) when the
ointments were compared after an average of 28 days of
treatment (range 26-30 days). No serious adverse events
related to treatment were reported in either group.
Finally, a single study was identified that compared debridement using a bacterial-derived collagenase ointment to
surgical excision. Ozcan and colleagues26 compared 78 children managed by collagenase to a group of 41 subjects managed by surgical excision. Participants were not randomly
allocated to treatment; the authors state that decisions were
based on clinical judgment. One hundred nineteen children with noninfected partial-thickness burn wounds par-

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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

work on the anchoring strands of slough below the eschar.


At dressing removal the clinician should assess for any
loose slough that can safely be removed with conservative
sharp wound debridement.
Topical application of antibiotic powder may be combined with the use of collagenase if the wound shows signs
of infection or excessive bioburden.21 Clinicians report
effectiveness and this provides an alternate to the use of
silver-impregnated dressings. Collagenase is to be discontinued when debridement is achieved and granulation
tissue is visible.
Adverse side effects tend to be mild and transient.
Application of collagenase may produce a transient stinging sensation that some patients find distressing.
Collagenase is contraindicated in patients who are hypersensitive to the enzyme; a single case of hypersensitivity
has been reported in a patient who was treated with collagenase ointment and cortisone for more than 1 year.13
Documentation should include the wound status,
application of collagenase, the dressing selected to cover,
response of the wound to treatment, and any patients
response (eg, burning, stinging, or allergic response). As
with any product, discontinue with any signs of an allergic
response.

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

Collagenase ointment is more effective than inactive (sham)


ointment for debridement of necrotic tissue from pressure
ulcers, leg ulcers, and partial-thickness burn wounds (level of
evidence: 1).
There is insufficient evidence to determine whether collagenase ointment removes necrotic tissue from leg ulcers more or
less rapidly than autolytic debridement enhanced by a polyacrylate dressing (level of evidence: N/A).

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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