Hypertonic Glucose Combined with Negative Pressure Wound Therapy to Prepare Wounds with Pseudomonas aeruginosa Infection for Skin Grafting: A Report of 3 Cases
Soft tissue losses from acute or chronic trauma are a challenge for surgeons. To explore a method to expedite granulation tissue formation in preparation for a split-thickness skin graft (STSG), the medical records of 3 patients — 2 adult men with wounds related to trauma injury and 1 infant with necrotizing fasciitis, all infected with Pseudomonas aeruginosa — were reviewed. All wounds were surgically debrided and managed by applying gauze soaked in 50% glucose followed by continuous negative pressure wound therapy (NPWT) before definitive skin grafting.
NPWT pressure was applied at -80 mm Hg for the 2 adult males (ages 39 and 25 years) and -50 mm Hg for the 7-month-old male infant.The dressings were changed every 2 to 3 days. No adverse events occurred, and wounds were successfully closed with a STSG after an average of 7 days. In 1 case, NPWT was able to help affix dressings in a difficult-to-dress area (genital region). The combination of hypertonic glucose and hand-made, gauze-based NPWT was found to be safe, well-tolerated, and effective in preparing the wound bed for grafting. Prospective, randomized, controlled clinical studies are needed to compare the safety, effectiveness, and efficacy of this method to other treatment approaches for P. aeruginosa-infected wounds.
Potential Conflicts of Interest: none disclosed
Soft tissue loss from traumatic disorders, chronic diseases, and dehisced surgical wounds may result in poor healing, painful wound care, and the possibility of repeated surgeries.1 In addition, wound infection is a risk factor for delayed wound healing and prolonged hospital stay, increasing the economic burden and often leading to unsatisfactory appearance after healing.2,3
Pseudomonas aeruginosa is a common opportunistic pathogen and a major source of wound infection. In a longitudinal study (N = 50), Gjødsbøl et al4 reported P. aeruginosa was 1 of the 2 most common resident bacterial species (52.2%) and its presence can induce ulcer enlargement and/or cause delayed healing. Similarly, in a review of the epidemiology of burn wound infections, Mayhall5 also reported P. aeruginosa was the second most common isolate, with morbidity of 20.9% in 1,984 isolates recovered from 1,267 burn wound infections in 1 phase of study and 19.3% in 1,830 isolates recovered from 1,234 burn wound infections in an additional phase of study.
Multiple methods, including antimicrobial and nonantimicrobial treatments, are available to manage wounds infected with P. aeruginosa. Antiseptics have been shown effective in the treatment of soft tissue wounds infected with P. aeruginosa. Nagoba et al6 reviewed various organic acids commonly used as a substitute for antiseptics to control Pseudomonal wound infections and found acetic acid can act as a useful alternative when infection is caused by multiple antibiotic resistant strains of P. aeruginosa. In addition, in an open, uncontrolled, multicenter pilot study (N = 19), Danielsen et al7 evaluated the clinical and bacteriological efficacy of topical cadexomer iodine on venous leg ulcers colonized with P. aeruginosa. The authors found cadexomer iodine paste to be the treatment of choice for venous leg ulcers colonized with P. aeruginosa. However, a review by Hirsch et al8 and clinical research by Lineaweaver et al9 suggest the cytotoxic, cross-reactivity with certain wound dressings and delay in wound healing associated with traditional antiseptics may discourage their use in open wounds.
Silver dressings (including silver sulfadiazine, silver nitrate, and nanocrystalline silver dressings) have been in widespread use in wound management for many years,10-12 and several commercial products are available, such as Aquacel Ag™ (ConvaTec, Skillman, NJ), Acticoat™ (Smith & Nephew, Inc, London, UK), Arglaes™ (Maersk Medical Inc, NY), Urgotul-SSD™ (Urgo Medical, Chenove, France), and Silvasorb™ (Medline Industries, Munedelein, IL ). Although silver dressings generally are thought to exhibit low toxicity in humans and redundant reports of successful experiences are available, the potential for silver products to cause toxic reactions, although not common, should not be overlooked. Retrospective reviews by White12 and Lansdown13 demonstrate argyria, caused by silver deposition, is the most common side effect. In a prospective clinical study, Coombs et al14 reported an increase in serum silver levels among people with burns receiving treatment with silver sulphadiazine. Trop et al15 reported a case in which raised liver enzymes and argyria-like symptoms were observed when 30% total body surface area mixed depth burns were treated with Acticoat™.
Microcyn (Oculus Innovative Sciences, Petaluma, Calif), a local super-oxidized solution with neutral pH, exerts broad antimicrobial and disinfectant activity; in vitro and clinical studies16-19 have demonstrated the satisfactory antimicrobial and antiviral activities of this product as a wound disinfectant. Newer formulations of antiseptics such as cadexomer iodine and novel silver delivery systems appear to be relatively safe and efficient in preventing infection in human wounds, and their value in wound care management should be considered, albeit with caution.20
Alternative therapies to control microbial populations in wounds include debridement (surgical or enzymatic), honey, and hypertonic solution dressings. In vitro studies have shown honey may exhibit particularly high antibacterial activity in the management of wounds infected with P. aeruginosa.21,22 However, a potential risk of allergic reaction related to this natural substance exists.23
Hypertonic saline. Hypertonic saline solution dressings provide an alternative antimicrobial therapy intended to promote the autolytic debridement process and absorb exudate, bacteria, and necrotic material to provide a natural barrier between infectious and regenerating tissue.24,25 Hypertonic saline dressing has been reported to be effective for management of chronic, ulcerating, metastatic skin lesions in a clinical study26 (N = 11) and in healing a traumatic wound in a case report.27 A clinical study24 (N = 53) indicates the associated resultant high osmotic pressure is able to desiccate necrotic tissue in wounds; meanwhile, the resultant osmotic effect may reduce interstitial edema of the tissue and subsequently alleviate the pressure on the capillaries and improve blood perfusion in the wound bed. Commercial products available include Curasalt Sodium Chloride Dressing (Covidien Kendall, Mansfield, MA) and Mesalt Hypertonic Saline Dressing and Hypergel (Mölnlycke Health Care, Inc, Vastra Gotaland, Sweden). Although hypertonic saline may be used for the management of skin defects per these studies, more research is necessary to determine its effectiveness in managing wounds with P. aeruginosa infection.28
Additionally, hypertonic glucose, the commonly used prolotherapy solution,29 can accelerate granulation tissue proliferation and improve microcirculation of the wound,30 which will shorten the time needed for healing or further management. Hypertonic glucose has been reported to be effective in the treatment of chronic musculoskeletal conditions resulting from suspected or confirmed connective tissue (usually ligamentous) injury. In a rabbit model, Yoshii et al31 found hypertonic dextrose injected into the rabbit forepaw carpal tunnel can thicken subsynovial connective tissue compared to saline injection, and multiple injections can enhance this fibrosis effect. In an in vitro study with cultured cells derived from 9 nondiabetic and 3 insulin-dependent persons with diabetes, Ohgi and Johnson32 evaluated the growth responses of gingival fibroblast and periodontal ligament cells cultured in 20 mM glucose. Enhanced proliferation of gingival fibroblasts was observed after 1 week; in response to high glucose, fibroblasts also exhibited increased expression of basic growth factor. McGinn et al33 compared the results of endothelial cells exposed to 5 mM glucose (control), 25 mM (high) glucose, or osmotic control; this study found high glucose and hyperosmolarity increased endothelial transforming growth factor-β1 secretion (P <0.0001) and bioactivity (P <0.0001), which altered the growth, apoptosis, and cell cycle progression of endothelial cells.
In addition to the osmotic advantages of hypertonic saline, hypertonic glucose also accelerates wound healing. Shi et al’s34 meta-analysis and systematic review of randomized controlled trials to determine whether subcutaneous injection of insulin with hypertonic glucose promotes healing in postoperative incisions with aseptic fat liquefaction showed significantly reduced time to healing by 6.33 days compared with conventional management (P <0.01) and with less cost. The authors concluded as much as 50% glucose is hypertonic, which may inhibit bacterial growth and prevent edema of granulation tissue and stimulate its growth. In a clinical observational study, Zhou et al30 reported hypertonic glucose can significantly shorten the average healing time of a Stage III pressure ulcer (24.8 ± 3.9 versus 22.3 ± 4 days, respectively; P <0.05) .
Negative pressure wound therapy (NPWT). NPWT has been a popular therapy for wound management for years.35-37 Numerous beneficial effects have been well documented. In a case study, Nease38 obtained satisfactory outcomes with low-pressure (75 mm Hg), commercial NPWT in 3 patients with extensive soft tissue wounds. In Dunn et al’s39 prospective, multicenter, noncomparative clinical investigation among 131 patients, gauze-based NPWT was found to significantly reduce wound volume (P <0.001) and improve exudate status (P <0.001) and wound bed quality. A randomized, double-masked, controlled trial40 (N = 60) demonstrated use of polyurethane dressing-based NPWT significantly diminished the loss of skin graft area (P = 0.001) and shortened length of hospital stay (P <0.001); the researchers recommended its routine use for patients with wounds with skin loss that cannot be primarily closed.
A literature review41 of NPWT used in wound healing reports a wide variation of negative pressure (from -50 mm Hg to -125 mm Hg) can be implemented, connecting either to the central suction system in the hospital or a commercial suction device. Most existing clinical evidence involves use of open-cell polyurethane foam at -125 mm Hg in adults.36,42 However, in a clinical study (N = 1,369), Iusupov and Epifanov43 reported extensive tissue edema, inflammatory infiltration, separation and splitting of muscle fiber, and fresh hemorrhages were noted in wounds treated with a negative pressure above 100–125 mm Hg. Serial animal studies by Wakenfors et al44,45 demonstrate negative pressure is transduced differently in soft and dense tissue, and a low negative pressure of 75 mm Hg for soft tissue and 100 mm Hg for muscle during treatment may be beneficial.
Retrospective literature reviews concerning 68 infants and children with 82 wounds46 and regarding the essence of NPWT47 indicate the clinical efficacy of NPWT may not be related to the use of specific wound filler materials or use of a specific level of negative pressure. In 1989, Chariker et al48 introduced an alternative NPWT system that used medical gauze at approximately -80 mm Hg negative pressure. Currently, alternative commercial negative pressure systems using gauze at -80 mm Hg have become available.49,50 In a retrospective study (N = 30), Campbell et al51 evaluated the outcomes of continuous gauze-based NPWT at -80 mm Hg negative pressure in a mixed group of patients with challenging wounds in a long-term care setting. Their study demonstrates an overall median reduction in wound volume of 88.0% (P <0.001) and a 68.0% reduction in area (P <0.001) compared with baseline were observed over the course of NPWT. The overall rate of volume reduction (15.1% per week) compares favorably with previously published data for foam-based systems. In a retrospective review (N = 68), McCord et al46 suggest that, to ensure safe use of NPWT in children < 4 years of age, lower negative pressure (-50 to -75 mm Hg) should be utilized, with similar results compared to older children in whom more negative pressure was used.
Despite previous experimental studies in mice52,53 and goats54 indicating NPWT may play a key role in reducing or cleansing P. aeruginosa load and subsequently accelerate wound healing process, some research brings NPWT’s ability to control bacterial loads in wounds into question. In a 54-patient, prospective randomized trial, Moues et al55 compared the efficacy of commercial open-cell foam dressing-based NPWT to conventional moist gauze therapy in open wounds and found although commercial NPWT proved to be effective in decreasing the size of the wound (P <0.05), no significant difference in total quantitative bacterial load was observed between the therapies, a finding supported by other studies. For example, in a prospective, randomized trial by Moues et al,56 no decrease in the number of bacteria colonizing the wound was observed via tissue biopsy examination after use of commercial polyurethane foam dressing-based NPWT. Similarly, in a 16-week, 18-center, randomized controlled trial (N = 162), Armstrong et al57 found commercial NPWT could lead to faster (P = 0.005) and higher rates (P = 0.040) of wound healing and granulation tissue formation (P = 0.002), but the frequency and severity of wound infection in NPWT were similar when compared with standard moist wound care (17% and 6%, respectively).
Recently published trials have further demonstrated the poor ability of NPWT to control wound infection. In a multicenter, randomized clinical trial (N = 342) by Blume et al,58 no statistical significance in the incidence of clinical wound infection between commercial NPWT and advanced moist wound therapy was noted (P = 0.371). Therefore, some variations of traditional NPWT were tested and reported. For example, periodic or simultaneous irrigation using antimicrobial solutions was added to NPWT (NPWTi) in a porcine wound model with P. aeruginosa infection that showed NPWTi reduced bioburden further than application of NPWT alone.59,60 Brem et al61 reported the case of a child with a large wound infected by P. aeruginosa that was managed successfully with NPWTi.
The effect of adding silver to NPWT has been investigated in animal models and a case report62-65 and demonstrated silver dressings augment the ability of NPWT to reduce the degree of P. aeruginosa infection. However, in an in vivo study, Boone et al66 reported bacterial burden in wounds infected by P. aeruginosa continued to increase and broadened to local skin flora in either commercial NPWT foam or silver NPWT foam. In addition, clinicians need to be mindful of the cellular toxicity and potential for adverse events during silver application.15,67
A method that is safe and efficacious in reducing bacterial load and at the same time has a synergistic effect with NPWT to stimulate the formation of granulation tissue or facilitate healing inevitably will have great practical value in treatment of wounds infected with P. aeruginosa. To the authors’ knowledge, no report of the use of hypertonic glucose in preparation for STSG in patients with P. aeruginosa-infected wounds alone or in combination with NPWT has been published to date. The purpose of this case study is to describe the effect of 50% glucose and gauze-based NPWT on wounds infected with P. aeruginosa. Three representative cases are described.
The authors retrospectively reviewed the medical records of patients admitted to their facility (First Hospital of Jilin University) for charts of patients with refractory wounds and P.
Essential debridement of the wound and irrigation with normal saline was performed at the beginning of each dressing change. The hand-made NPWT system consists of cotton gauze squares soaked with 50% glucose, covered with an impermeable dressing, and connected to the central suction system on the wall for continuous drainage (see Figures 1a,b). The dressings were changed every 2 to 3 days. Meshed STSG was performed when fresh granulation tissue formed and no necrotic tissue was noted. The involved areas were immobilized after the surgery until the dressings were removed, and antibiotics appropriate to the most recent culture results were administered intravenously before and after the surgery to prevent infection.
Case 1. Mr. Z, an otherwise healthy 39-year-old, was involved in a traffic accident that injured his genital area; 14 days after the accident, the skin of the genital region became necrotic. Cultures of wound swabs from fluid beneath the eschar showed the combined growth of P. aeruginosa and Enterobacter cloacea. Surgical debridement was performed immediately (see Figure 2a). Dressings were changedevery day postoperatively. During the dressing
change 3 days postop, the wound was covered by secretions and necrotic tissue (see Figure 2b); after rigorous debridement and irrigation with normal saline, the authors dried the wound with dry clean gauze before placing a gauze soaked with 50% glucose over the wound. NPWT was applied at -80 mm Hgcontinuously for the duration of therapy (see Figures 2c-2f). At the beginning of each dressing change, essential debridement and irrigation with normal saline were performed. Mr. Z complained of mild pain during irrigation which was relieved with 5 mg, 325 mg, respectively, of oxycodone and acetaminophen orally. No other complications related to use of this device, including pain and increased level of blood sugar, were noted. Meshed STSG was performed 7 days after application of NPWT when granulation tissue formed (see Figure 2g). NPWT was used again to stabilize the dressings. When the dressings were removed 5 days after the operation, the skin graft survived intact. Ten days after the surgery, satisfactory cosmetic and functional outcomes were obtained (see Figure 2h).
Case 2. A 7-month-old baby boy presented with swelling of the lower legs, high fever, dyspnea, oliguria, and subsequent necrosis of several parts of the body (lower legs, hypogastrium, bilateral iliac region) (see Figure 3a). Blood culture and wound bacterial culture were performed and both were positive for P. aeruginosa. Necrotizing fasciitis was diagnosed, and fasciectomy and
extensive surgical debridement were performed immediately. Standard moist wound care was performed every day postoperatively. Twelve days later, the wound was covered by secretions and necrotic tissue during the dressing change (see Figure 3b); a second debridement was performed before the application of NPWT. Gauze soaked with 50% glucose was placed over the wound at the introductory application of NPWT. The pressure was applied at -50 mm Hg continuously for the duration of therapy. Dressings were changed at day 15 under intravenous sedation. The infant tolerated this approach well; no device-related complications (ie, pain or infection) were noted. Meshed STSG was performed at day 22 when granulation tissue was present and no secretions were observed (culture result of wound swab returned negative) (see Figure 3c). The grafted skin survived completely when the dressings were removed 3 days after the surgery (see Figure 3d).
Case 3. Mr. X, an otherwise healthy 25-year-old, was involved in a traffic accident and sustained abdominal injury and rupture of the small intestine. General surgeons immediately debrided and sutured the small intestine and abdominal skin. Mr. X recovered well postoperatively, but the abdominal incision dehisced and was covered with blue-green odorous secretions 10 days after the surgery, determined to be the result of P. aeruginosa infection. Mr. X was transferred to the authors’ unit 18 days postoperatively (see Figure 4a). Gauze soaked with 50% glucose was placed over the wound and NPWT was applied at -80 mm Hg continuously for the duration of therapy. Dressings were changed every 2 days. Mr. X complained of mild pain due to wound debridement during dressing change when granulation tissue appeared on the wound bed, which was alleviated using an IV injection of Flurbiprofen Axetil (100 mg, Beijing Tide Pharmaceutical Co, Ltd, China). No other complaints or complications related to use of this therapy were noted. Meshed STSG was performed when ample granulation tissue was present and no secretions were observed (see Figure 4b), 6 days after initiation of NPWT. When the dressings were removed 3 days postoperatively, the grafted skin appeared to have a satisfactory take.
Until now, no studies have been published regarding topical use of hypertonic glucose in combination with hand-made NPWT for the treatment of wounds infected with P. aeruginosa. This approach was explored for several reasons. First, the osmotic pressure of 50% glucose is much higher than normal tissue30 and therefore can act as a dehydrating agent to minimize or eliminate edema and inflammatory secretions of the wound bed. Second, the higher osmotic environment provided by hypertonic glucose may foster bacterial dehydration and death,68 which can help control infection. The authors believed that, when used in combination with NPWT, hypertonic glucose can compensate for NPWT’s lack of infection control in severely infected wounds.
In this case series, wounds infected with P. aeruginosa achieved satisfactory outcomes and a good graft take after meshed STSG. Moreover, hypertonic glucose can accelerate granulation tissue formation and improve microcirculation of the wound bed,30 which can shorten the time needed for healing or definitive management. In the authors’ experience, this protocol can be safe, effective, easily incorporated into the wound management regimen, and well tolerated as an alternative method in wound bed preparation and provide a versatile tool in the treatment of infected, chronic, or refractory wounds when other treatment modalities have failed, especially when used concurrently with NPWT. Studies to evaluate the safety, effectiveness, and efficacy of this treatment approach using larger sample sizes and control groups, as well studies to ascertain its mode of action, are needed.
Although a prospective, multicenter, noncomparative clinical investigation39 (N = 131), retrospective noncomparative analysis51 (N = 30), and a case study69 indicate hand-made gauze-based NPWT is a cost-effective treatment for wound management and yielded results comparable to those of the more expensive commercial NPWT system, further study to compare the difference between wound management outcomes of gauze-based and foam-based NPWT is warranted. In addition, the effects of hypertonic glucose on cell growth and proliferation and on mechanisms to reduce bacterial load must be evaluated in order to validate its use as an alternative method in the treatment of infected wounds.
This study has several limitations. The sample size is very small and much of the study is retrospective and observational. The authors did not try to assess any mechanisms of the action, and no biopsies were performed to quantify changes in wound bacterial counts.
Another limitation is the authors did not measure the local concentration of glucose during and after the dress changing. In vitro research by Russell et al70 indicates an increase in pericellular glucose concentration above 35 mM induces hyperglycemic stress and cell injury. The initial dose used in this study is far greater, but although the results were satisfactory, the local pericellular concentration cannot be estimated and increases in the level of blood sugar were not monitored.
The use of 50% glucose and NPWT to manage wounds infected with P. aeruginosa was found to be safe and effective in the 3 patients described. No serious adverse events occurred, and all wounds were successfully closed with a meshed STSG. More in vivo studies are required to elucidate the potential mechanisms of action of this treatment approach, and controlled clinical studies are needed to establish the safety and effectiveness of this protocol of care.
Dr. Zhao is a senior attending surgeon; Dr. Xian is a registered nurse; Dr. Yu is the director, Burns and Plastic Reconstruction Unit; Dr. Shi is an associate professor; and Dr. Hong is a resident surgeon, First Hospital of Jilin University, Changchun, Jilin Province, China. Please address correspondence to: Kai Shi, MD, PhD, Burns and Plastic Reconstruction Unit, First Hospital of Jilin University, No. 3302 Jilin Road, Changchun 130031, Jilin Province, People’s Republic of China; email: email@example.com.
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