Introduction

Pressure ulcers (PUs) are recognised worldwide as serious adverse events, not only in hospitals but also in social care facilities. Their treatment must be comprehensive and include multiple interacting interventions that must be evidence-based, effective, and cost-effective [1]. A number of treatment methods and technologies are available for chronic wounds, ranging from moist wound therapy, negative pressure therapy, hyperbaric oxygen therapy, ozone therapy, and phototherapy, to surgical treatment – including the application of skin grafts, which is the domain of plastic surgery, stem cell therapy, ultrasound therapy, electrical stimulation, growth factor therapy, and extracellular matrix substitutes [2, 3]. The therapeutic modalities for wound treatment in the category of “other technologies” [3] or as “advanced wound therapy” [2], include products containing hyaluronic acid (HA). Hyaluronic acid maintains a moist environment that stimulates growth factors, fibroblasts, and keratinocyte proliferation, absorbs wound exudate, and enhances cell migration [4]. In vivo, HA is a negatively charged linear polysaccharide consisting of disaccharides of D-glucuronic acid (G_lcA) and N-acetyl-D-glucosamine (G_lcNAc), linked by alternating -(1,4) and -(1,3) glycosidic bonds [5]. Hyaluronic acid polymers are available in various lengths, with each molecular size playing a unique role in every phase of wound healing. In the inflammatory phase, it facilitates the passive diffusion of water into the interstitial space, leading to oedema. This promotes the migration of inflammatory cells into the wound, supports the activation, infiltration, and maturation of immune cells, including neutrophils and monocytes, which further trigger inflammatory cascades. In the proliferative phase, it attracts fibroblasts, fills gaps in the newly formed extracellular matrix, stimulates matrix metalloproteinases for angiogenesis, and promotes the migration and proliferation of keratinocytes. Granulation tissue fills the wound bed with collagen and neovascularization. Subsequently, the wound begins to contract, epithelializes, and closes. In the remodelling phase, it contributes to normal scarring [4, 6].

Most recently, Huerta-Ángeles and Mixcoha [5] analysed recent advances, research trends, and the clinical significance of HA in wound healing and regeneration. They provide an overview of several HA-based products and evaluate various methods of chemically modified HA. Clinical evidence has shown that dressings and topical agents containing HA are safe, effective, and well-tolerated, with some studies reporting very positive results in terms of wound closure and high healing rates compared to other dressings [5]. Products containing HA are indicated for the treatment of second-degree burns, PUs, chronic venous ulcers, diabetic ulcers, surgical wounds, traumatic wounds, and weeping wounds [7]. In Slovakia, there is a scientifically proven standard procedure available for nurses: Comprehensive Nursing Management of Patients with Pressure Ulcers (1^st revision). In this document, the use of HA is listed among the recommended therapeutic agents in the category of dressings containing HA [8]. The selection of a therapeutic strategy for patients with non-healing chronic wounds must be preceded by an accurate assessment of the wound. An effective wound management strategy depends on the method and scope of assessment of non-healing chronic wounds established in clinical practice [9, 10].

Material and methods

The aim of our study was to describe the healing process of PUs following a change in local pharmacotherapy to HA (a sterile viscous solution of sodium hyaluronate in a gel formulation modified with iodine – hyaluronic acid and iodine complex (HA-I)). We set the following sub-goals: to describe the causative treatment of pressure injuries (pressure relief/redistribution, positioning, moisture/incontinence management, nutrition, and optimisation of comorbidities), identify the stage of PU according to The National Pressure Ulcer Advisory Panel (NPUAP) during HA-I application, assess risk factors for infection; monitor general and local signs of infection, and evaluate the healing process at regular intervals using assessment and measurement tools.

Design

We present a diachronic single-case study, a case study that tracks the healing process of a PU over time in response to changes in local pharmacotherapy as part of the primary causal treatment of PUs (pressure relief/redistribution, positioning, moisture/incontinence management, nutrition, and optimisation of comorbidities). A single-embedded design was used. The subunits are the monitored categories of wound healing. Empirical data were analysed according to Yin’s recommendations [11]. For our single-case study, we used temporal analysis and pattern comparison. The research process consisted of five components recommended by Yin [11]: study questions, preposition, units of study analysis, linking logic, and criteria for interpreting findings.

Participant

The research sample was selected purposefully based on predefined inclusion criteria (PUs unresponsive to local treatment using hydrocolloids, hydrogels, silver), causal management of PU treatment provided according to standard procedures of the Ministry of Health of the Slovak Republic (comprehensive nursing management of a patient with PU – pressure redistribution mattress, repositioning protocol, nutritional support, skin/incontinence care), treatment of comorbidities, application of a preparation containing HA with iodine and exclusion criteria (acute surgical wounds healing per primam).

A 76-year-old polymorbid female patient with a PU (NPUAP Stage IV) residing in a Social Services Home (SSH) in central Slovakia and cared for by SSH nurses met our criteria. In our study, we focused specifically on 5 time points.

Methods of collecting empirical data

The empirical data collection was conducted in accordance with the recommendations of Yin [11], who suggests using documents and archival records as sources of empirical data for single-case studies. We used records from the SSH information system. We prepared a study plan. We developed an empirical data collection protocol with a chronological list of individual items – subunits monitoring the course of wound healing in accordance with the recommendations of the standard procedures of the Ministry of Health of the Slovak Republic (Comprehensive Nursing Management of Patients with Pressure Ulcers [8], Wound Management [12], Comprehensive Nursing Management of the Immobile Patient [13]), adapted and supplemented: PU location, stage of injury (NPUAP I–IV, suspected injury, unclassifiable stage), healing phase (inflammatory, granulation, epithelialization, size (length, width, and depth), bed, exudate, odour, edges, complications (tunnelling, fistulas, crepitation), surrounding area, previous treatment, allergies, risk of wound infection (wound and risk score – WAR score), infection, nutritional status (mini nutritional assessment), immobility (classification based on Mobility Gallery A through E), pain (visual analogue scale – VAS, 0–10), self-care (Barthel Index), other findings, photographic documentation [2, 14–17].

The research was conducted over a period of 6 months (June through December 2024). The empirical data collected are confidential; they have been processed and interpreted while maintaining anonymity and are used solely for the purposes of this publication. We respect the ethical principles of biomedical research and the Declaration of Helsinki. The research was conducted with the consent of the facility’s management, who provided us with approval to process empirical data and photographic documentation through a retrospective analysis of the selected patient’s medical records. The patient also provided us with informed consent to use photographic documentation of the wound.

Results

A 76-year-old patient with multiple comorbidities, living with her husband in her second SSH within a year. The reason for admission to the SSH is her condition following a sudden stroke (10/2022). Communication with the patient is difficult (due to her condition following the stroke and the presence of multifactorial encephalopathy), but she understands basic instructions when assisted by her husband. The patient is being monitored at a haematology clinic for anaemia and at a cardiology clinic; she is on antiplatelet therapy, taking clopidogrel and antihypertensives. Additional diagnoses include chronic obstructive bronchitis; she inhales salbutamol. No diabetes mellitus. In 2023, she was repeatedly admitted to the university hospital for dehydration and loss of appetite; lactose intolerance was confirmed. During her most recent admission, a PU developed on the 7^th day. Upon returning to the SSH, a Stage IV PU (NPUAP) was diagnosed in the sacral region (Figure 1 A). For the first 3 months, the PU was treated in collaboration with the surgical outpatient clinic at the university hospital; a surgical debridement-necrectomy – was performed twice, followed by wound cleansing with 3% povidone-iodine. At the SSH, treatment continued with wound irrigation using an antimicrobial polyhexamethylene biguanide hydrochloride (PHMB) solution, primary coverage with polyurethane foam and silicone adhesive, a superabsorbent dressing for exudate management, and secondary silicone coverage. After 3 months of treatment, the wound had reduced to 8 × 8 cm in size and 1 cm in depth; the wound bed was red and only partially covered, the edges were inflamed, there was mild exudate, and eschar formation was present (Figure 1 B). As part of wound management, regular wound irrigations were performed with antimicrobial NaOCl/HOCl (sodium hypochlorite/hypochlorous acid), primary dressings with activated charcoal and silver, and later silver with enhanced efficacy (sodium carboxymethylcellulose impregnated with 1.2% silver ions with the addition of ethylenediaminetetraacetic acid disodium salt and benzethonium chloride), and a secondary silicone absorbent dressing, changed every 48 h.

After six months of PU treatment at the SSH, the wound was still exuding, the bed of the wound was red, and healing had stalled. After consulting with a wound care nurse from abroad, the patient was recommended treatment with HA-I, which is not yet covered by the health insurance system in Slovakia, and the patient paid for it in full. It was determined that the patient has no allergy to iodine (Figure 2 A).

Initial assessment prior to HA application, factors influencing wound healing

Systemic factors influencing wound healing include multimorbidity and the patient’s comorbidities – ischaemic heart disease, arterial hypertension (The New York Heart Association Functional Classification Class III), haematological disorders (anaemia), post-stroke condition, high risk of a transient ischaemic attack, advanced age, dehydration, incontinence, and parchment-like and dry skin. Through the medical history and physical examination, we specifically focused on assessing other indicators of effective PU healing (nutrition, mobility). For nutritional assessment, the mini nutritional assessment was used; the patient was at risk of malnutrition (21 points). Intake of milk proteins was problematic as the patient had been diagnosed with lactose intolerance. When assessing immobility using the Mobility Gallery A–E scale, the patient was rated D (immobile, unable to support herself at all, unable to shift weight, dependent on a wheelchair, unable to manoeuvre the wheelchair independently); the Barthel Index for activities of daily living was 20 points (high dependency). Among the local factors affecting wound healing, we identified frequent dressings, inappropriate treatment methods, lack of laboratory monitoring for infection, and a WAR score of 4 points (risk of infection).

Assessment of wound healing, pain, and infection

After one month of local treatment of the PU with HA (Figure 2 B), the wound had shrunk to 3.5 × 3.5 cm in size, 1 cm in depth, the wound bed was red, without necrosis, slightly coated, the edges clearly visible and regular, the surrounding area (up to 10–15 cm) was reddened, the skin was irritated and peeling, the wound was odourless with only mild exudate, and the granulation phase was underway, NPUAP Stage III, biofilm, colonization. In Figure 2 C (close-up of granulation), we can see a significant improvement in wound healing after two months of HA application. The wound bed is granulating; islands of granulation are visible in the close-up photograph, NPUAP Stage II. After 4 months, the wound size remains unchanged; the PU bed, after biofilm removal, is well-perfused, with no exudate and no odour; the distant edges are pink; the skin is moist due to incontinence and likely prolonged secondary coverage without staff monitoring (Figure 2 D). After 6 months, the wound was nearly closed, measuring 3 × 1 cm; the bed was granulating, new epithelisation was intact, the surrounding area was dry, without inflammation or exudate, NPUAP Stage II (Figure 2 E). The final image documents the condition without HA-I application 7 months after the start of HA-I treatment, NPUAP Stage I, with only a small, narrow wound measuring 1.5 cm, nearly closed (Figure 2 F).

The visual analogue scale ranged 1–3, indicating mild pain. During wound care, the pain sometimes increased to moderate intensity (VAS 4–5).

Causative management and local therapy of pressure ulcer

Prior to each application of HA-I, the wound was rinsed with an antiseptic PHMB solution, which was replaced with NaOCl/HOCl after 3 months. Hyaluronic acid and iodine was applied in gel form, followed by a foam dressing with a silicone border designed for the sacrum; the dressing was changed and the wound healing process monitored every 48 h. Between the application of NaOCl/HOCl and HA-I gel, the wound was rinsed with a neutral solution (0.9% saline), according to the wound irrigation protocol. The healing process and wound condition were assessed by a physician once a month at the surgical outpatient clinic at the university hospital; otherwise, the healing process was assessed by a SSH nurse three times a week. Pain was monitored using the VAS scale before each dressing change, during the dressing change, and otherwise three times daily. Analgesics in tablet form were administered regularly twice daily (before dressing changes or at lunchtime and in the evening before bed, 1 tablet containing 37.5 mg tramadol hydrochloride/325 mg paracetamol). A bio lamp was applied daily as adjunctive therapy. During each wound dressing change and exposure of the wound, the surrounding area was warmed with the bio lamp for 8 min. The patient was provided with a lactose-free diet enriched with vitamin C and zinc and was administered sipping enteral nutrition specifically formulated for patients with lactose intolerance. Chronic pharmacotherapy was administered, including treatment for anaemia. Due to the patient’s immobility, an adjustable bed with an anti-decubitus mattress was provided; repositioning was performed by the nursing staff (a healthcare assistant together with a nurse) using anti-decubitus aids. Pressure prone areas were regularly treated with professional protective creams containing panthenol, creatine, amino
acids, and almond oil, with a balanced pH of 4.5–5.5. At least twice a day, with the help of staff, the patient was seated in a chair for social activities. She was encouraged to participate in active and passive exercises with the assistance of a physical therapist. Table 1 provides an overview of factors influencing PU healing and planning of nursing interventions to support the PU healing process with a final evaluation.

Discussion

Chronic wounds represent a long-term burden for patients, their families, and healthcare systems. Despite the use of modern treatment products, the management of PUs in older adults remains challenging and is often protracted. This is due to the presence of several factors that slow down the healing process. In the care of patients with chronic wounds, the advanced practice nurse plays a crucial role, for example as a case manager coordinating patient assessment, diagnosis, treatment protocols, and nursing care and services related to the patient’s condition [18, 19]. The aim of our study was to describe the healing process of PUs following a change in local pharmacotherapy to hyaluronic acid. Our case report is an example of a timely and correct decision to change local treatment, based in part on consultation with experts in PU care, specifically, advanced practice nurses, who recommended HA-I. We present 6 months of treatment for a sacral PU in an immobile, polymorbid patient using HA-I (a sterile viscous sodium hyaluronate solution in a gel form modified with iodine-HA-I complex). Its application accelerated healing, the wound bed cleared, and granulation and epithelialisation were initiated.

In the management of PU treatment, causative management is primary, while local products support healing. Causative management includes offloading/pressure redistribution, repositioning, moisture/incontinence management, nutrition, and comorbidity optimisation. Immobility exposes patients to constant pressure, friction and so-called shear force in the Fowler position. Redistribution of pressure and relief, positioning should be priority nursing interventions. According to international [20, 21] and national guidelines [8, 22, 23], the nurse uses supportive anti-PU devices for secondary to quaternary prevention of worsening of existing PUs (anti-PU mattresses, foam, air or gel positioning devices), the nurse positions the patient in accordance with the positioning plan. It is important to ensure adequate fluid and nutritional intake. Insufficient food intake, poor nutritional status (malnutrition) in combination with multiple comorbidities have been identified as key factors in the healing of PUs. Randomised controlled trials have clearly demonstrated an association between enteral nutrition with high protein, arginine, vitamin C and zinc and PU healing [24]. General recommendations for PU healing include nutritional support of 25–35 kcal/kg per day. Increased intake of vitamin C with zinc is required for wound healing, collagen formation. Zinc is a cofactor for collagen formation, an antioxidant, and is important for protein, DNA and RNA synthesis and the proliferation of inflammatory cells and epithelial cells. If clinical signs of zinc deficiency are present, zinc should be supplemented, but not more than 40 mg per day. High doses of zinc (> 40 mg/day) are not recommended because they adversely affect copper status and may result in anaemia. In patients with PUs, both in outpatient care and in the SSH, prealbumin levels (reflecting recent protein intake) and serum albumin levels (reflecting long-term protein intake) should be examined. In cases where oral intake is not possible, enteral nutrition via percutaneous endoscopic gastrostomy tube should be considered.

In the presented case report, despite adequate causal management during 6 months in the SSH, the wound was still compromised, the wound bed was red and healing was stagnant, therefore local treatment with HA-I was indicated. The HA and iodine impregnated gauze contact layer can regulate an excessive or, conversely, too mild inflammatory response and helps guide the healing process in the right direction. It promotes tissue remodelling and enhances angiogenesis. As a result, natural healing processes are rapidly initiated, and the overall healing time is shortened. Hyaluronic acid regulates collagen production and deposition, so after healing, the new tissue is of higher quality, the skin is firmer, and significantly smaller scars are formed [4, 5, 25]. Experience with the use of HA and its derivatives in the treatment of chronic wounds has been the subject of several literature reviews and studies. Antoszewska et al. [7] conducted a review study to summarise the latest findings and experiences with the use of HA and its derivatives in tissue regeneration and wound healing, as well as in the management of hard-to-heal wounds. Many approaches of HA had been described in wound management, such as topical formulations, gauze, bandages, hydrogels, sponges, films, and other HA-based scaffolds. Their use depends on the type of chronic wound. Due to properties such as biocompatibility, biodegradability, bacteriostatic properties, and hydrophilic nature, HA-based materials offer a wide range of applications in the wound healing process, such as restoring skin integrity, maintaining a hydrated environment, promoting skin re-epithelialisation, and reducing the growth and migration of cells (keratinocytes, fibroblasts, etc.) into the wound bed, among others. The Cochrane Library contains a review [26] aimed at evaluating the effects of HA on the healing of chronic wounds (ulcus cruris, PUs, diabetic foot ulcers). Hyaluronic acid has been compared with other types of wound dressings or solutions that maintain a moist wound environment, reduce the presence of bacteria in the wound, and prevent infection. The authors of the review by Roehrs et al. [26] state that we cannot say with certainty whether there is any difference in efficacy between HA and other types of topical preparations due to a lack of data in the analysed studies, small sample sizes, and methodological flaws. The studies examined the effect of HA on wound healing and the incidence of adverse effects but did not, for example, assess its impact on quality of life or wound recurrence. We can evaluate the quality of life in a patient with a chronic wound using the wound quality of life questionnaire [27, 28].

In our clinical case, HA was applied in a gel form modified with iodine (HA-I). Iodine is a potent antiseptic active against Gram-positive and Gram-negative bacteria, viruses, fungi, and spores. The complex of hyaluronan and molecular iodine in the form of a viscous fluid is considered a modern dressing for chronic wounds [29]. Its efficacy was evaluated by Pecova et al. [30] in a sample of patients with various types of hard-to-heal wounds, such as PUs, venous leg ulcers, diabetic ulcers, and postoperative wounds. Treatment with HA-I successfully led either to complete closure or to a significant improvement in wound healing. Therefore, the hyaluronic acid-iodine complex is suitable for the treatment of hard-to-heal wounds of various aetiologies.

Hyaluronic acid can also be combined with amino acids. Romanelli [31] analysed studies from the past 15 years, suggesting significant benefits of the combination of HA and amino acids in terms of healing speed and the induction of granulation tissue formation compared to HA alone. The combination of HA and amino acids (which act as collagen precursors in wound healing) promotes wound re-epithelialisation and stimulates the activation and proliferation of fibroblasts, resulting in a significant increase in epithelial cell regeneration [31]. An international team of experts presented their clinical experience with the use of a combination of HA and amino acids in hard-to-heal wounds. Their goal was to reach a consensus on how and when to use these unique combination products to provide a cost-effective and convenient option in all healthcare settings, improving the quality of life for patients and their caregivers. The clinical cases presented by the expert panel provide further evidence that the unique combination of HA and amino acids across a range of formulations comes close to providing the ideal properties needed for effective wound healing [32].

Our case study also highlights the complexity of PU treatment. In addition to the proper selection of a topical wound care product, wound hygiene prior to the application of the therapeutic product and the selection of the appropriate antiseptic also have a significant impact on wound healing. Antiseptics should be used in the treatment of chronic wounds only in indicated cases, such as critical wound colonization and the treatment of clinically manifest infection [33]. The wound at risk score can also help determine the appropriateness of the indication. If the WAR score reaches or exceeds 3 points, antiseptic treatment is warranted [16]. Cleaning wounds with irrigation solutions and dressings alone is not sufficient; it does not permanently reduce the microbial load in wounds infiltrated by biofilm. The persistence of biofilm causes wound healing to stagnate. In translational testing of the most widely recognised antimicrobial agents, only octenidine dihydrochloride-phenoxyethanol and PHMB demonstrated (delayed) efficacy against it. Iodine-containing wound dressings showed very good efficacy against biofilm. An infected or critically colonized wound should be microbiologically examined to ensure the correct treatment is selected. We determine whether local application of antiseptics will be sufficient or whether systemic antibiotic therapy will be necessary. If the wound is at risk of infection, a locally applied antiseptic can prevent its development [34]. This led Kramer et al. [33] to review antiseptic therapy and develop a consensus. In patients with critical colonization and wound infection, the first-line antiseptic is PHMB, and the second-line options are octenidine (OCT), NaOCl/HCl, and silver. For colonization and infection with multidrug-resistant strains, the first-line antiseptic is OCT/phenoxyethanol (PE), and the second-line antiseptics are OCT, PHMB, and silver [34].

In line with the IWII, EWMA and the 2023 Nair et al. [35] antiseptic consensus, it should be kept in mind that these agents should be used with caution due to the spread of antimicrobial resistance [36, 37]. There is still ongoing debate among experts about the most appropriate handling and proper use of antiseptics in terms of the risk of cytotoxicity, especially for preparations containing hypochlorous acid, sodium hypochlorite and iodine. The current concentration for NaOCl and HOCl amounts is 0.004% each and < 0.06% for NaOCl being a mono-substance of a physiological bactericidal mechanism. Typically, NaOCl/HOCl and NaOCl are highly effective against vegetative bacteria, bacterial spores, aspergilli, cryptosporidium oocysts, and coated viruses, but they are not or barely irritating on mammal cells. Moreover, no evidence of cytotoxicity is found, and no evidence that poses a carcinogenic hazard is found. Kramer et al. [33] in a consensus on wound antisepsis state that no evidence of cytotoxicity is found, and no evidence that they pose a carcinogenic hazard is found. Other authors also report that overall the evidence points to no cytotoxicity of superoxidised solutions [38, 39]. The risk of cytotoxicity is associated with incorrect application and improper wound dressing, especially with the combination of different classes of active topical agents (such as strong oxidants, e.g. hypochlorites and iodine-based preparations). In our clinical case, this was the combination of strong oxidants with HA and iodine. Hypochlorous acid and hypochlorites are strong oxidants that cause depolymerization and fragmentation of HA chains [40, 41]. Hypochlorites can oxidise active iodine to inactive iodates [33]. Leaving active HOCl/NaOCl residues in the wound bed before HA-I application could theoretically compromise the structural integrity of the HA scaffold and the antimicrobial efficacy of iodine. Therefore, it is necessary to follow the protocol of intermediate rinsing with neutral solutions (e.g. 0.9% NaCl) to minimise the risk of mutual inactivation and increased cytotoxicity [42].

Limitations

One limitation of our study is that we present only a single clinical case. Controlled clinical trials are the most appropriate for studies investigating the efficacy of wound care products. Another limitation is that we did not have an objective measurement tool to assess the course of wound healing, such as the pressure ulcer scale for healing, Bates-Jensen scale, or others. The description of the healing process was only verbal, and photographic documentation was not part of any electronic program monitoring wound healing. The quality of life of the patient with a chronic wound was not assessed.

Conclusions

The treatment of PUs in seniors, despite comprehensive nursing care focused on causal management, is lengthy and can last several months, often more than one year. Part of the management is supportive local treatment, which must be reassessed at regular intervals and it is essential to make a timely and correct decision about a change.

The availability of new products and strategies for wound care has made tremendous progress in recent years. The problem is that, despite significant advances in our understanding of the wound healing process and biotechnological developments, changes in clinical practice are occurring much more slowly. We present a clinical case of successful PU healing in a polymorbid, immobile patient using HA-I. Hyaluronic acid is involved in all phases of wound healing, and iodine is a potent antiseptic. The availability of HA-containing products through health insurance in individual countries remains an issue; therefore, it is necessary to present a series of clinical cases and controlled studies so that products containing HA, HA-I, and other modifications can be included in the catalogue of medical devices. Furthermore, we would recommend standardising the use of objective measurement tools to assess the course of wound healing in clinical practice, evaluating the quality of life of patients with chronic wounds using wound quality of life questionnaire, and utilising an electronic program to document the course of wound healing.

Disclosures

1. Institutional review board statement: We respect the ethical principles of biomedical research and the Declaration of Helsinki. This study was approved by the Ethics Committee of the University Hospital Martin (approval decision no: 137/2023, dated: 30.11.2023). The research was conducted with the consent of the facility’s management, who provided us with approval to process empirical data and photographic documentation through a retrospective analysis of the selected patient’s medical records.

2. Assistance with the article: None.

3. Financial support and sponsorship: None.

4. Conflicts of interest: None.

5. Patient consent: Written informed consent was obtained from the patient for publication of this manuscript and any accompanying images.

References