Preliminary Use of a Hydrogel Containing Enzymes in the Treatment of Stage II and Stage III Pressure Ulcers

    A pressure ulcer is defined as any lesion caused by unrelieved pressure resulting in damage to underlying tissue.¹ Many predisposing factors acting in combination with pressure put a patient at risk for developing pressure ulcers, including being bed- or chairbound, malnourished, and/or incontinent and/or having an altered level of consciousness.^2-5

Incidence of pressure ulcers ranges from 0% to 17% for home care settings, 0.4% to 38% for hospitals, and 2.2% to 23.9% for long-term care facilities.⁶ A meta-analysis of published literature specific for nursing home populations found 17% to 35% of patients had pressure ulcers at the time of admission and the prevalence range was 7% to 23%.⁵ Pressure ulcer treatment varies from site to site but relieving sustained pressure and using dressings that keep the ulcer bed continuously moist are preferred over dry dressings¹ and are considered standard.

    Hydrovase (Swiss-American Products, Inc. Dallas, Tex.) is an amorphous hydrogel used in the management of all open stages of pressure ulcers. This greaseless, glycerin hydrogel contains a combination of endopeptidase enzymes (see Table 1) and is designed to maintain a moist wound environment for a minimum of 24 hours to facilitate wound healing. The controlled moisture delivery of the gel hydrates the skin and wounded area; plus, it can absorb approximately twice its weight in exudate, depending on the condition of the healing wound.⁷ Sufficient gel viscosity keeps the product confined to the area applied and at a thickness that provides protection from factors such as outside contaminants, dehydration, and trauma. Additionally, the product transparency allows assessment of the wound bed without the need for a complete dressing change. Because the product is readily soluble in water, traumatic and painful dressing changes can be avoided, allowing the gel to be gently rinsed away.

    The inclusion of endopeptidase enzymes distinguishes this product from other hydrogels. The combination of natural enzymes may help the wound healing process by activating several immunomodulatory effects, particularly within macrophages and eosinophils.^8-10 One specific enzyme administered orally has been shown to have anti-bradykinin and anti-inflammatory activity when tested in a murine paw injury model.¹¹ Administration of a combination of enzymes also has been shown clinically to reduce postoperative pain, hematoma formation, and edema in acute wounds.^7,10,12 The results would suggest the enzymes work with the immune system and in cytokine pathways to more efficiently to enhance healing.^7-9

    This preliminary study was conducted to initially assess the enzyme product use under controlled conditions during a 12-week prospective study of a small population (n = 10) of nursing home residents. Because partial-thickness Stage II ulcers heal differently (re-epithelialization) than full-thickness Stage III ulcers (granulation tissue deposition followed by re-epithelialization), data from these two ulcer types were used to assess the study hydrogel. Stage I and Stage IV ulcers were excluded to minimize the variables involved in addressing the entire spectrum of pressure ulcers.

Materials and Methods

    Consents and approvals. Informed consent, approved by a centralized institutional review board (IRB), was obtained from each subject or legal representative. The clinical research protocol and case report forms (CRFs) also were approved by the central IRB and are summarized below. Subjects served as their own historical control from the previous 3 months. The research nurse, an experienced wound clinician trained in wound assessment, measurement, documentation, and Food and Drug Administration current Good Clinical Practices (cGCPs), reviewed the patient medical records for wound for measurements, description, and treatment regimen in order to assess if the wound was healing, stalled, or deteriorating. Only patients with wounds that were stalled or deteriorating during this time were considered as candidates for the study. Response to the study hydrogel was monitored on a weekly basis until the ulcer healed or for up to 12 weeks, whichever occurred first.

    Inclusion criteria. Subjects were screened and examined to ascertain study eligibility by the research nurse. To be enrolled in the study, subjects must have had at least one Stage II or Stage III pressure ulcer as defined by the 1994 Agency for Health Care Policy and Research (AHCPR) guidelines (see Table 2) with a minimum area of 1.0 cm² and have used a low-air-loss support surface (DynaMedics Corporation; Keller, Tex.) for at least the previous 14 days. Use of the low-air-loss support surface was continued throughout the study. If a subject had more than one qualifying ulcer, the largest was studied. Ulcers with a treatment history that included enzymatic debridement had to be at least 7 days post-treatment to avoid any residual chemical or debridement affects on healing.

    Exclusion criteria. Subject exclusion criteria for the study were: 1) presence of a severe medical condition that could lead to death within the study period; 2) current use of systemic steroids, chemotherapeutic agents, or other immunosuppressives; 3) HIV-positive; 4) hypersensitivity to fruit and vegetables or enzymes from fruits and vegetables; or 5) history of alcohol or drug abuse. Exclusion criteria for the study ulcer were: 1) undermining or serious sinus tracts ≥1.0 cm; 2) clinical or laboratory signs of infection; 3) required topical medications; 4) required debridement; or 5) ulcer present for more than 3 months before study enrollment.

    Laboratory tests. Within 1 week following study enrollment and 1 week before the last week on the study, the blood serum albumin, serum creatinine, serum transferrin, hemoglobin, total protein levels, and total lymphocyte and white blood count of each subject were obtained. The results of these laboratory tests were used to help assess the nutritional and immunological status of the subject.

    Procedure. The research nurse provided oversight for the study. Subject caregivers employed by the nursing home were mostly LPNs with RN supervision and were not given any additional training except how to apply the study hydrogel and change the study dressings. Between evaluations by the research nurse, the subject caregivers cleansed the ulcer on a daily basis with normal saline using aseptic technique in accordance with the clinical research protocol. Following cleansing and pat drying of the wound bed with gauze, a thin layer of hydrogel (approximately 1/4 inch thick) was applied and covered with a secondary gauze dressing. Wounds were dressed once a day unless the dressing became soiled or displaced from the wound. All other regimens (ie, turning, bathing, and similar activities) were performed per each facility’s policies and procedures (unchanged from the previous 3 months).

    At baseline and weekly thereafter, the clinical research nurse monitored and evaluated the ulcers. All research data and comments collected were captured on NCR CRFs. Healing was the primary endpoint and was based on wound closure by re-epithelialization as determined by area measurement and clinical assessment. Wound length, width, depth, volume, area, and perimeter were determined using a Computerized Imaging System (CIS) (DynaMedics Corporation, Keller, Tex). Before each imaging, the CIS machine was calibrated and identifiers were placed by the clinical research nurse. The secondary endpoints captured during the observation period were descriptive quantifiers for wound improvement and wound characteristics that included infection, exudate, odor, maceration, inflammation, edema, pruritus, hematoma, cellulitis, pain, healing, and overall subject acceptance of the dressing (see Table 3). Wound characteristics were evaluated using pre-established scales developed by Precision Consulting specifically for this clinical evaluation (see Limitations).

    Device-related adverse events and all serious adverse events were collected on the CRFs and, when appropriate, reported on a MedWatch 3500A form.¹³ The incidence and severity of all collected events were assessed to evaluate safety parameters. Objective and descriptive statistics were used by stage to summarize data from all study participants by intent-to-treat (ITT) analysis. Based on wound closure by epithelialization as determined by area measurement and clinical assessment, each study ulcer was categorized as healed (complete re-epithelialization), healing (improvement ≥60% from baseline measurements), or a treatment failure (improvement <60% from baseline measurements).

Results

    Baseline data. Of the 10 subjects enrolled, three had a Stage II and seven had a Stage III ulcer. Of the seven subjects who completed the study, three had Stage II and four had Stage III ulcers. Average ulcer area at baseline was 3.15 cm² (median 2.51 cm²) and 10.49 cm² (median 9.54 cm²) for Stage II and Stage III ulcers, respectively. Average ulcer volume at baseline was 1.07 cm³ (median 0.45 cm³) and 1.83 cm³ (median 2.11 cm³) for Stage II and Stage III ulcers, respectively.

    Laboratory data. Baseline and end-of-study laboratory results showed that all enrolled subjects, regardless of baseline ulcer stage, had acceptable immunological and nutritional parameters, which did not change during the study. None of the subjects required additional nutritional supplements while in the study.

    Outcomes. Of the 10 patients initially enrolled, five had ulcers that healed (three Stage II and two Stage III), four had Stage III ulcers that improved, and one had a Stage III ulcer that was considered a treatment failure. The average time to healing for Stage II and Stage III wounds was 3.3 weeks (range: 1 to 7 weeks), and 6.5 weeks (range: 2 to 11 weeks), respectively. Wound locations, baseline severity, and outcomes are described in Table 4.

    Historical comparison. During the 3 months before the study, the ulcer of each subject was slow to progress (heal) as documented by chart measurements and nursing notes. Following study enrollment, only one ulcer failed to show improvement and the subject unexpectedly died 2 weeks following study enrollment. During the study, all three of the Stage II enrolled ulcers healed (100%). Using ITT analysis, six of the seven Stage III enrolled ulcers were healed and healing (86%). Although three of the patients with Stage III ulcers could not complete the study, nine of the 10 study participants exhibited a better wound outcome during the study than during the 3-month pre-study period.

    Adverse events. No dressing-related adverse events were reported. Two serious adverse events, the deaths of two subjects were not related to the treatment or the wound.
The subject with the ulcer categorized as “treatment failure” died within 2 weeks of enrollment from causes unrelated to the wound. One subject died of unrelated causes at week 8 but the wound had improved 95% at this time. One subject was discontinued from the study when transferred to another facility but the wound had improved 69% at week 8.

    Dressing acceptance. Six study participants rated the dressing “excellent” and four rated it “good” (see Table 3). Special attention was given for recording pain, itching, burning, and/or irritation upon application; subjects offered no complaints when specifically asked and several indicated the product was soothing.

Case Examples

    Ms. M (see Figures 1, 2, and 3 and Table 5) was enrolled with a Stage III pressure ulcer on the thoracic vertebrae over an area of kyphosis. Her wound had been treated previously with an enzymatic debriding agent and another commercial non-study hydrogel. Because her wound was not improving, the ulcer was eligible for this study. The wound was red/yellow with light serous drainage and no granulation and epithelial tissues (see Figure 1) and measured 4.93 cm x 2.66 cm x 0.2 cm. The surrounding skin was red with a well-defined border of erythema. At 5 weeks, the wound was pink with light serous drainage (see Figure 2), granulating, had improved epithelialization, and measured 2.21 cm x 1.49 cm x 0.1 cm. By 11 weeks, Ms. M’s wound completely healed (see Figure 3).

    Mr. O (see Figures 4, 5, and 6 and Table 5) was enrolled with a Stage II coccyx pressure ulcer. His wound had been treated previously with silver sulfadiazine and a drying agent (the specific product could not be determined from medical chart or interviews with staff) followed by a commercial non-study hydrogel dressing without improvement. The surrounding skin was excoriated. The wound was red with light serous drainage, no granulation or epithelial tissue, and measured 2.18 cm x 2.06 cm x 0.1 cm (see Figure 4). Mr. O reported mild wound pain. A smaller ulceration similar to the study ulcer also was treated with the study hydrogel due to its proximity but no data were collected for that wound. At 1 week, Mr. O’s pain had resolved, granulation tissue was apparent, and his wound measured 0.95 cm x 0.74 cm x 0.1 cm (see Figure 5). Mr. O’s wound was completely re-epithelialized at 2 weeks (see Figure 6).

Discussion

    Moist saline, hydrogels, occlusive and non-occlusive dressings, alginates, and topical creams and ointments have been used to treat pressure ulcers, making dressing choice a challenge. To compound the problem, many recommendations for treating pressure ulcers come from theory or anecdotal data as opposed to controlled clinical trial results. One reason so few such trials exist may be that prospective clinical trials with large numbers of subjects are expensive to conduct and require a staff dedicated to the research study.

    The current study was prospectively designed to provide a preliminary assessment of the study hydrogel in Stage II and Stage III pressure ulcers (staging assessments were made according to AHCPR guidelines in use at the time). The study was conducted in a nursing home population as inexpensively as possible while maintaining a clinically relevant environment and population where confounding factors (eg, pressure relief and nutrition) could be controlled to avoid skewing the data. To keep expenses to a minimum yet provide a reference control group, each subject served as his/her own control when the ulcer was treated in the facility using any other treatment yet did not heal. An experienced clinical research nurse trained in both wound care and clinical research conducted baseline and weekly evaluations on all subjects. Although the number of subjects enrolled in the study was small, the data generated provided specific information on the use of the study hydrogel in this clinical population. All three Stage II ulcers healed and six of the seven Stage III ulcers healed or were healing.

    Reports of treatment outcomes of pressure ulcers in the literature vary and depend on the type of wound treatment, ulcer stage, study duration, and clinical setting. In a prospective multicenter study of wound healing outcomes in clinical practice,¹⁴ 297 patients with 821 Stage II to Stage IV pressure ulcers were enrolled from home care, long-term care, and long-term acute care hospital settings. Healing rates within 12 weeks were 52% in home care, 31% in long-term, and 2% in the long-term, acute care hospital. With regard to stage, 61% of partial-thickness (Stage II) ulcers averaged 31 days and 36% of full-thickness (Stage III and IV) ulcers averaged 62 days to heal. The follow-up analysis of the first 18 months’ data showed wounds larger than the wound median area averaged 50 days to healing for partial-thickness ulcers and 167 days for full-thickness ulcers.¹⁵ These data support results of the current study that ulcer severity affects treatment outcome and time to healing — ie, Stage II pressure ulcers healed in an average of 23 days and Stage III ulcers took almost twice as long to heal (an average of 45 days).

    Stage I ulcers were excluded in this study because the primary endpoint of the study was healing, defined as re-epithelialization. Stage IV ulcers were excluded to minimize the variables involved in trying to cover the entire spectrum of pressure ulcers and because they typically take longer than 12 weeks to heal.^16,17 The delay in healing is probably due to the extensive destruction associated with full-thickness skin loss and the fact that such ulcers are prone to bacterial contamination and infections, which can further delay healing, regardless of treatment.¹⁴ Finally, as with any clinical trial, an increase in study time leads to an increase in expense.
With so many dressing choices available and so few trials to guide the clinician, finding an inexpensive, easy-to-use treatment that can improve or heal ulcerations is a high priority for clinicians. Due to health and cost issues, conservative approaches are generally preferred for the elderly or debilitated patient. This study indicates healing can occur in Stage II and III pressure ulcers in a nursing home setting when the study hydrogel is utilized. The product can be used by staff with little wound care experience with good results. The specialized container and slender applicator tip allows one-handed application so the product can be applied to a specific area, is easy to use, and minimizes waste. A 30-mL container provides multiple wound treatments, depending on wound size, at a reasonable institutional cost of $4.20 per tube. Assuming a large wound required 2 mL of hydrogel at each treatment, one application would cost $0.28, excluding secondary dressing and labor costs. Although this was not a cost effectiveness study, the study hydrogel used seems to be an inexpensive option.

    Compared to other marketed hydrogels, the study hydrogel contains a relatively low level of a mixture of endopeptidase enzymes that have been reported to play a role in part of the inflammatory cycle during the initial phase of wound healing.^8,9 Enzyme use in wound healing is not a new concept; several prescription products with high concentrations of various enzymes are available for wound debridement. The enzymes in the study hydrogel, however, are not intended for eschar debridement; rather, they enhance the wound healing process by affecting immunomodulatory cells, cytokine pathways, and possibly cell-secreted proteins.⁷ Also, unlike enzymatic debriding agents, the study hydrogel is a wound dressing available without prescription. Similar to other hydrogels, the study hydrogel facilitates autolysis and provides a moist healing environment, complemented by the effect of the enzymes on wound healing to provide an ideal healing environment. The extent of the impact of the enzymes in the study hydrogel on wound healing has not been elucidated but is being studied.

Limitations

    Study limitations are often present due to prohibitive costs. In this study, pre-established scales, developed specifically for this evaluation were used in this instrument (see Table 3) but formal validity and reliability studies were not conducted. However, many of the variables of this scale were used previously and accurately by several experienced wound care nurses.¹⁸ In the current study, the experienced wound care nurse utilizing the scale was trained in its use.

    Retrospective review of the medical charts for the 3-month historical control was also a limitation. Although wound measurements, treatment regimens, and nursing notes provided useful information for control data inexpensively, the historical perspective lacks the direct comparison of placebo and test articles between subjects.

Conclusion

    Pressure ulcers appear to respond well when treated with the study hydrogel. Compared with healing rates noted in the literature, Stage II and III pressure ulcers treated with the study hydrogel had acceptable outcomes that were slightly better than rates cited in the literature. Subject acceptance of the product, including comfort, was high. No adverse events associated with the product were reported. The dressing cost is reasonable and the only secondary dressing used was gauze. Additional studies could be performed with film or foam dressings to determine increased wear time; thereby, reducing dressing and associated labor costs.
Based on the study results, additional studies to define the possible contribution of endopeptidase enzymes in wound healing would be worthwhile.

1. Bergstrom N, Bennett MA, Carlson CE, et al. Clinical Practice Guideline No. 15: Treatment of pressure ulcers. AHCPR Publication No. 950652. Rockville, MD: Agency for Health Care Policy and Research; 1994.

2. Berlowitz DR, Wilking SVB. Risk factors for pressure sores. JAGS. 1989;37:1043–1050.

3. Allman RM, Laprade CA, Noel L.B. et al. Pressure sores among hospitalized patients. Ann Int Med. 1986;105:337–342.

4. Ek AC, Boman G. A descriptive study of pressure sores: the prevalence of pressure sores and the characteristics of the patients. J Adv Nurs. 1982;7:51–57.

5. Smith DM. Pressure ulcers in the nursing home. Ann Intern Med. 1995:123(6):433–442.

6. Cuddigan J, Ayello EA, Sussman C, et al, eds. Pressure Ulcers in America: Prevalence, Incidence, and Implications for the Future. Reston, Va.: National Pressure Ulcer Advisory Panel; 2001.

7. Data on file. Swiss-American Products Inc., Dallas, Tex.

8. Miike S, Kita H. Human eosinophils are activated by cysteine proteases and release inflammatory mediators. J Allergy Clin Immuno. 2003;11(4):704–713.

9. Rao CN, Peavey CL, Liu YY, et al. Partial characterization of matrix-associated serine protease inhibitors from human skin cells. J Invest Derm. 1995;104:379–383.

10. Lomax JE. The use of oral proteolytic enzymes in the post-lipoplasty patient. Lipoplasty. 1998-1999;Winter edition:1–4.

11. Emele JF, Shanaman J, Winbury MM. The analgesic anti-inflammatory activity of papain. Arch Int Pharmacodyn. 1966;159(1):126–134.

12. Bouteselis JG, Sollars RJ. The effect of proteolytic enzymes on episiotomy pain and swelling. Ohio State Med J. 1964:551–553.

13. Food and Drug Administration Medwatch Homepage. Available at: www.fda.gov/medwatch. Accessed July 12, 2005.

14. Bolton L, McNees P, van Rijswijk L, et al. Wound healing outcomes using standardized assessment and care in clinical practice. JWOCN. 2004:31(2):65–71.

15. Smitten A, Simon T, Bolton L. The burden of pressure ulcer care: a real world outcomes study. Presentation at the Symposium for Advances in Wound Care. San Diego, Calif. April 21-24, 2005.

16. Gorse GJ, Messner RL. Improved pressure sore healing with hydrocolloid dressings. Arch Derm. 1987;123:766–771.

17. Thomas DR, Goode PS, LaMaster K, et al. Acemannan hydrogel dressing versus saline dressing for pressure ulcers. Adv Wound Care. 1998;11(6):273–276.

18. Thomas DR, LaMaster KV, Tenneyson T, et al. Comparison of Flexzan topical wound dressings v. Op-Site topical wound dressing in the management of skin tears in institutionalized subjects. Ostomy Wound Manage. 1999;45(6):22–28.