A Retrospective Study of the Effects of Clostridial Collagenase Ointment and Negative Pressure Wound Therapy for the Treatment of Chronic Pressure Ulcers

Nonhealing, chronic pressure ulcers present a continuous challenge in the global health care venue, with decreased mobility and the effects of aging on skin placing the elderly at particular risk. Debridement is an important process to decrease risk of infection and promote healing. Enzymatic debridement with, for example, clostridial collagenase ointment (CCO) has been shown to assist with the achievement and maintenance of a clean wound bed in preparation for closure. Negative pressure wound therapy (NPWT) has also been used successfully for the treatment of wounds. Although conclusive research has demonstrated positive independent effects of both CCO and NPWT as treatments for chronic pressure ulcers, there are no known published studies that have investigated the 2 as a conjunctive treatment. Materials and Methods. A retrospective analysis of 114 adult patients was conducted to assess wound healing of chronic pressure ulcers in a setting with medically complex patients. Two groups were established comparing those who received NPWT alone to those who received NPWT plus CCO. The study sample included 67 patients treated with NPWT + CCO and 47 patients who received only NPWT. Results. Results were similar for both treatment groups with mean values indicating the cohorts were closely aligned with respect to wound size, complexity, length of long-term acute care hospital stay, and duration of NPWT. The patients who received NPWT + CCO demonstrated statistically significant changes in several key areas including initial Bates-Jensen Wound Assessment Tool (BWAT) score, changes in the overall BWAT score and in the necrotic tissue domain. Conclusion. Data analysis from this retrospective study indicates patients who received both therapies (NPWT + CCO) demonstrated improved outcomes in speed of debridement and rate of wound closure compared to those who received NPWT alone.

  Nonhealing, chronic pressure ulcers present dramatic clinical and economic challenges for health care providers. Pressure ulcers are most frequently seen in the sacral, ischial, trochanteric, and calcaneal regions and are commonly caused by unrelieved pressure on soft tissue over bony prominences resulting in ischemia and necrosis.¹ Further, immobility, decreased sensation, and advanced age all increase an individual’s risk of developing pressure-related wounds.² Additional risk factors include compromised nutritional status and excessive exposure to friction, shear forces, and moisture.³ Economically, the cost of chronic wound treatment has escalated due to prolonged hospital stays and extensive medical interventions, among other factors.^4,5

  Debridement of pressure ulcers is recognized as an important process to remove impediments to wound healing, decrease risk of infection, and promote proliferation of granulation tissue.^6,7 Sharp debridement is a method of debridement in which necrotic tissue is excised from the wound bed using instruments such as scalpels and curettes.⁸ Enzymatic debridement is another beneficial approach for wound bed preparation in which topically applied enzymes are used to digest and dissolve devitalized tissue in the wound.⁹ Bacterial collagenase isolated from Clostridium histolyticum is a selective enzymatic agent that has been found to cause hydrolytic cleavage of collagen molecules, which are a major component of nonviable tissue in the wound bed.¹⁰ Clostridial collagenase ointment (CCO) has been used in conjunction with other forms of debridement, such as surgical/sharp, for initial and continuous debridement.² Studies have indicated that CCO provides effective debridement in a variety of wound types including pressure ulcers, venous/arterial ulcers, diabetic foot ulcers, and burns.¹¹ Clostridial collaganese ointment can also provide ongoing debridement of necrotic tissue throughout the wound healing continuum through an action described in the literature as “maintenance debridement.”¹² Falanga¹² first defined maintenance debridement as the process by which CCO continuously inhibits reaccumulation of necrotic tissue and restores the healing mode by a process of continuously debriding the wound bed. Clostridial collaganese ointment is currently the only enzymatic debriding ointment that has US Food and Drug Administration approval (Collagenase Santyl Ointment, Smith and Nephew, Hull, UK).

  Negative pressure wound therapy (NPWT) is another treatment used extensively to expedite the healing of wounds of multiple etiologies including pressure ulcers.^6,13 Negative pressure wound therapy has been clinically demonstrated to accelerate the healing process of acute, subacute, and chronic wounds through the application of subatmospheric negative pressure.^3,14-18 Promotion of a moist wound environment, removal of cytotoxic metalloproteases, edema reduction, and cell proliferation are among the proposed mechanisms of action for NPWT.¹⁰ Negative pressure wound therapy is available worldwide in commercial applications from several different companies.

  Pharmacoeconomic data indicates CCO may reduce overall wound care costs by accelerating the healing process and lowering resource utilization.¹⁹ Likewise, data indicates that NPWT may have a similar cost benefit advantage over standard care.^20,21 The purpose of this study was to evaluate the effectiveness of wound closure using CCO in conjunction with NPWT vs NPWT alone for the treatment of chronic pressure ulcers. Previous research has demonstrated the efficacy of enzymatic debridement or subatmospheric negative pressure for healing of chronic pressure ulcers; however, no known studies have evaluated the conjunctive effects of CCO and NPWT. The primary author’s clinical observation and experience with the conjunctive use of the 2 therapies indicated a potential clinical benefit that merited further study. The research question posed was whether the addition of CCO to the wound would improve certain healing characteristics for patients with chronic pressure ulcers who were also receiving NPWT. Specifically, would the addition of CCO affect the rate of wound debridement and wound closure.

  The authors undertook a retrospective study of adult inpatients who were treated at 2 long-term acute care hospitals (LTAC) (Promise Hospitals of Louisiana, Shreveport and Bossier City) between October 2007 and April 2013. Institutional review board approval and data sharing agreements were sought and obtained prior to study initiation. The authors performed the study in adherence to state and national patient privacy laws.

  Long-term acute care hospitals provide post-acute care to medically complex patients who are more stable than patients in an intensive care unit (ICU) but who have unresolved underlying complex medical conditions, which may include chronic wounds. By regulatory licensure guidelines, LTAC facilities are required by the Centers for Medicare and Medicaid Services (CMS) to maintain a 25-day length of stay averaged across their patient population.²²

  All of the pressure ulcers included in this study had been treated in the LTAC setting with NPWT. Negative pressure wound therapy was delivered with either V.A.C. Therapy (KCI, Inc, an Acelity Company, San Antonio, TX) or Renasys (Smith and Nephew, Hull, UK) using a sterile, open cell polyurethane foam wound interface per facility practice and manufacturer specifications. The ordering physician, in accordance with accepted practice guidelines, prescribed the NPWT frequency and pressure settings in each case. All subjects included for this study had NPWT ordered for thrice-weekly (TIW) dressing changes at 100 mm Hg - 125 mm Hg continuous pressure.

  In addition to NPWT, some of the patients also had CCO prescribed by a physician. The LTAC wound nurses followed manufacturer recommendations as to the amount of CCO to be used per treatment. Clostridial collaganese ointment is typically applied to the wound bed daily but due to the frequency of the NPWT dressing change, the CCO was applied directly to the wound tissue using sterile gauze or tongue blade TIW.

  All wound treatments were performed TIW by 1 of 4 experienced, certified wound nurses using established facility protocols. These staff nurses utilized the Bates-Jensen Wound Assessment Tool (BWAT) weekly to assess the progress of the patient’s wound during their LTAC stay. The BWAT is a validated wound assessment tool used by clinicians to objectively collect information about the wound including dimensions, inflammation, necrotic tissue, granulation tissue, and other characteristics.²³ The BWAT is used for wounds of all etiologies and was modified from an earlier version called the Pressure Sore Status Tool.²⁴ Using the BWAT for their weekly wound assessments, the LTAC wound nurses rated a total of 13 wound items using a modified Likert scale, with a score of 1 indicating the healthiest and 5 indicating the least healthy attribute for each characteristic (Table 1 and continued).

  Inclusion criteria for this retrospective chart review included adult patients with the presence of a chronic pressure ulcer (duration > 30 days) with National Pressure Ulcer Advisory Panel (NPUAP) classification of Stage III or Stage IV.²⁵ Further inclusion criteria included use of NPWT with or without the addition of CCO. Comprehensive chart reviews were conducted to assimilate wound healing, medical, and demographic data on patients who had received treatment of qualifying chronic pressure ulcers. The investigators in this study created an electronic data collection system using software (FileMaker Pro, FileMaker, Inc, an Apple subsidiary, Santa Clara, CA) and an iPad (Apple, Cupertino, CA). All data was de-identified and then entered from the patient medical records into the electronic form. This information was then evaluated using statistical software (IBM SPSS Statistics for Windows, Version 21, IBM Corp, Armonk, NY) to determine if any statistically significant differences could be identified. The data analysis was conducted in strict adherence with accepted research standards.

 In this study, 114 medical charts each pertaining to 1 patient wound were identified for further analysis. Two groups were established comparing patients who were treated with NPWT alone compared to patients who were treated with NPWT + CCO. Table 2 demonstrates homogeneity between the 2 groups with respect to age, body mass index, albumin, hemoglobin, hematocrit, glucose, blood urea nitrogen, creatinine, and initial wound surface area with no significant differences for the parameters observed. Data suggests these patients were medically compromised with respect to their general condition. On average, many of the patients studied were elderly, overweight, anemic, and had endocrine/renal compromise noted on their baseline laboratory tests (Table 2). Labs also indicated that many of the subjects were in a state of protein calorie malnutrition with albumin values substantially diminished compared to well elderly patients.²⁶ The mean wound starting size was > 50 cm² and many wounds were located on the posterior or lateral pelvis (Table 3).

  Thorough analysis was conducted using an independent group t test with unequal variance assumption to attain P values and determine if any attributes, such as wound area reduction, LTAC length of stay, debridement effectiveness and/or BWAT change, were statistically significant. A P value ≤ 0.05 was determined to be indicative of statistical significance.

  The study sample included 67 patients treated with NPWT + CCO and 47 patients who received only NPWT (Table 4). Results were similar for both treatment groups with mean values indicating the cohorts were closely aligned with respect to wound size, complexity, length of LTAC stay, and duration of NPWT treatment. The patients who received NPWT + CCO demonstrated statistically significant changes in several key areas including starting BWAT score, changes in the overall BWAT score, and the necrotic tissue domain. For clarification, the term “necrotic tissue domain of BWAT” combines items number 5 (necrotic tissue type) and 6 (necrotic tissue amount) from the BWAT scale (Table 1).

  Analysis also identified statistical differences between patients who had or had not received sharp debridement during their LTAC stays (Table 5). Of the 41 patients who had received sharp debridement, 10 received NPWT alone and 31 received NPWT + CCO. Results indicated significance of the NPWT + CCO group with respect to overall BWAT change (P = 0.045) and the change in necrotic tissue domain of BWAT (P = 0.002). Additionally, a sensitivity analysis was performed to identify any differences between 2 specific subgroups. The treatment subgroup (n = 31) was defined as patients who received sharp debridement and CCO, and the control subgroup (n = 37) was defined as patients who had no sharp debridement and no CCO. Statistically significant differences (P < 0.05) were observed between treatment and control groups on overall BWAT score change (-2.34) and BWAT necrotic domain score change (-2.39) (Figure 1). The treatment subgroup was statistically more likely to have diabetes (OR = 5.20; 95% CI: 1.76-15.40) and arterial disease (OR = 12.52; 95% CI: 1.46-23.82).

  Results of this retrospective study can be put in perspective by considering the clinical challenges of this particular patient population. The LTAC setting is reserved for patients who meet criteria for long-term acute care admission due to medical complexity. Multiple comorbid conditions such as arterial disease, obesity, end stage renal disease, and protein malnutrition were seen in the patient groups. Stage III and IV pressure ulcers, as defined by NPUAP classification, are wounds with tissue destruction down through the dermis to deeper structures such as subcutaneous fat, muscle, and bone. Most of the pressure ulcers in this study were very large (mean size > 55 cm²) and located on the posterior or lateral pelvic region, presenting significant challenges for offloading and pressure redistribution.

  In this study, the cohorts (NPWT and NPWT + CCO) were similar in all key evaluation parameters and the size of the cohort data sets allowed for statistically relevant comparisons. Results indicate both treatment groups showed evidence of progressive wound healing with NPWT (Table 4), which is consistent with the literature indicating the efficacy of NPWT in the treatment of chronic pressure ulcers.^3,14 Negative pressure wound therapy works well to manage wound exudate and promote granulation tissue formation in large, deep wounds such as the stage III and IV pressure ulcers included in this study. The addition of CCO did not substantially alter the duration of NPWT or LTAC length of stay, but did demonstrate improved wound healing in some key areas such as speed of wound healing (as measured by the reduction of BWAT score) and reduction of necrotic tissue (as measured by the reduction of BWAT items 5 and 6). In evaluating the changes of the BWAT score, it is important to remember that a lower score indicates a wound that is on a healing trajectory. Correspondingly, mean values reported as negative values in Tables 4 and 5 indicate favorable changes in wound BWAT scores and wound size.

  Current clinical guidelines encourage removal of necrotic tissue before the initiation of NPWT.²⁷ However, at times, NPWT was initiated in the LTAC setting at the discretion of the ordering physician when a small amount of soft, firmly adherent necrotic tissue was still present in the wound bed. This is common clinical practice according to the authors’ experience and the anecdotal comments of many colleagues. With the addition of CCO to the wound bed and to the necrotic tissue, a clinician can make the case for earlier initiation of NPWT to maximize the effects of this modality and manage clinical resources more effectively.

  The adjunctive benefits of debridement and NPWT for the treatment of pressure ulcers are recognized in the literature.^28,29 Proper wound bed preparation requires the effective management of several factors including removal of impediments to wound healing using debridement techniques. In addition to the benefits of NPWT, this retrospective study suggests the beneficial effect of sharp debridement is enhanced by the continuous application of an exogenous enzyme between the episodes of sharp debridement.

  Sharp debridement had been performed on 41 of the 114 patient wounds during their LTAC stay. Statistical analysis indicated that pressure ulcers treated with NPWT, sharp debridement, and CCO demonstrated the following statistically significant findings (Table 5) vs NPWT and sharp debridement alone: increased rate of debridement (lower necrotic score on BWAT items 5 and 6) and increased rate of healing (overall reduction in BWAT score). These findings were demonstrated despite a higher likelihood for this subgroup to have diabetes and arterial disease.

  This suggests a possible synergistic effect between the use of sharp debridement and CCO for the treatment of pressure ulcers. A similar synergistic effect from sharp and enzymatic debridement was observed in a recent clinical trial involving diabetic foot ulcers.³⁰

  The purpose of this study was to evaluate the effectiveness of wound closure using CCO in conjunction with NPWT vs NPWT alone for chronic pressure ulcer treatment in the LTAC setting. The retrospective data analysis indicates patients who received both NPWT and CCO demonstrated improved wound healing in several key categories.

  Similar to all retrospective studies, this study is limited by its very nature. There is no way to control interventions or manage confounding variables. However, this fact is mitigated to some extent in this study by virtue of the provider protocol observed in this case. A group of 4 certified wound nurses followed a well-established protocol to treat the subjects and to obtain consistent, objective measurements on a weekly basis and record the same on a validated wound assessment tool. In addition, all the subjects were hospitalized in an LTAC facility, which provided comprehensive medical treatment including management of conditions such as diabetes and protein calorie malnutrition as well as placement of patients on appropriate pressure redistribution surfaces. An important clinical consideration in dealing with this medically complex patient population is the inclusion of an interdisciplinary team to address nutritional, medical, wound management, and therapeutic needs.

  Future studies would ideally include randomized, prospective evaluations. The identification of a possible beneficial link between sharp and enzymatic debridement could be further explored as well as defining the optimal enzyme application frequency. It would also be beneficial to study the long-term effects of maintenance debridement with CCO on complete wound closure and rate of recurrence. Additional studies may also shed light on the cost effectiveness of the combination of these therapies.

  The authors wish to thank Kelly Browning, RN, CWS; Jason Cardin, LPN, CWCA; Ginger Zeda, LPN, CWCA, and Promise Hospitals of Louisiana, Shreveport and Bossier City, LA for their assistance with this study.

The authors are from the LSU Health Sciences Center Shreveport, Shreveport, LA.

Address correspondence to:
Stanley K. McCallon, PT, DPT, CWS
smccal@lsuhsc.edu

Disclosures: This study was funded in part through an unrestricted grant from Smith and Nephew Biotherapeutics, Fort Worth, TX. The grantor had no input on study design, data collection, or statistical analysis.

Portions of this work were previously presented at the Symposium on Advanced Wound Care Fall, September 27-29, 2013, Las Vegas, NV, and at the 28th Annual Clinical Symposium on Advances in Skin and Wound Care, October 24-27, 2013, Lake Buena Vista, FL.