WHS guidelines for the treatment of pressure ulcers-2023 update.

The major populations at risk for developing pressure ulcers are older adults who have multiple risk factors that increase their vulnerability, people who are critically ill and those with spinal cord injury/disease. The reported prevalence of pressure ulcers in the United States is 2.5 million. However, this estimate is derived from acute care facilities and does not include people who are living at home or in nursing facilities. Despite the implementation of hospital and facility-based preventive measures, the incidence of pressure ulcers has not decreased in decades. In addition to the burden of pain, infection and death, it is estimated that hospital-acquired pressure ulcers cost the health system $26.8 billion annually with over 50% of the cost attributed to treating Stage 3 and 4 pressure injuries. Thus, it is critical to examine the literature and develop guidelines that will improve the outcomes of this complex and costly condition. This guideline update is a compendium of the best available evidence for the treatment of Pressure Ulcers published since the last update in 2015 and includes a new section based on changing demographics entitled 'Palliative wound care for seriously ill patients with pressure ulcers'. The overall goal of the Wound Healing Society Guideline project is to present clear, concise and commercial free guidelines that clinicians can use to guide care, that researchers can use to develop studies that will improve treatment and that both clinicians and researchers can use to understand the gaps in our knowledge base.

The Economic Impact of Living Cell Tissue Products in Treating Diabetic Foot Ulcers and Venous Leg Ulcers in Patients with Commercial Insurance: A Retrospective Matched-Cohort Study.

OBJECTIVE: Previous studies demonstrated that costs paid on behalf of Medicare recipients for diabetic foot ulcers and venous leg ulcers treated with cellular and/or tissue-based products (CTPs) varied in part based on the CTP chosen. This study extends previous work to determine how costs vary when paid by commercial insurance carriers. METHODS: A retrospective matched-cohort intent-to-treat design was used to analyze commercial insurance claims data between January 2010 and June 2018. Study participants were matched using Charlson Comorbidity Index, age, sex, type of wound, and geographic location within the US. Patients treated with a bilayered living cell construct (BLCC), dermal skin substitute (DSS), or cryopreserved human skin (CHSA) were included. RESULTS: Wound-related costs and number of CTP applications were significantly lower for CHSA relative to BLCC and DSS at all time intervals (60, 90, and 180 days and 1 year after first application of the CTP). Further, CHSA was associated with significantly fewer amputations at 1 year relative to DSS (14.9% vs 19.7%, P = .03). CONCLUSIONS: There was a statistically significant reduction in cost of treating diabetic foot ulcers (BLCC, DSS, CHSA) and venous leg ulcers (BLCC, CHSA) with CHSA as compared with the other CTPs. These findings are attributed to fewer applications, lower wound care costs, and comparable or reduced incidence of amputation. These commercial insurance data are consistent with prior studies that examined Medicare expenditures.

Matched-cohort study comparing bioactive human split-thickness skin allograft plus standard of care to standard of care alone in the treatment of diabetic ulcers: A retrospective analysis across 470 institutions.

This retrospective, matched-cohort study analyzed 1,556 patients with diabetic ulcers treated at 470 wound centers throughout the United States to determine the effectiveness of a cryopreserved bioactive split-thickness skin allograft plus standard of care when compared to standard of care alone. There were 778 patients treated with the graft in the treatment cohort, who were paired with 778 patients drawn from a pool of 126,864 candidates treated with standard of care alone (controls), by using propensity matching to create nearly identical cohorts. Both cohorts received standard wound care, including surgical debridement, moist wound care, and offloading. Logistic regression analysis of healing rates according to wound size, wound location, wound duration, volume reduction, exposed deep structures, and Wagner grade was performed. Amputation rates and recidivism at 3 months, 6 months, and 1 year after wound closure were analyzed. Diabetic ulcers were 59% more likely to close in the treatment cohort compared to the control cohort (p = 0.0045). The healing rate with the graft was better than standard of care across multiple subsets, but the most significant improvement was noted in the worst wounds that had a duration of 90-179 days prior to treatment (p = 0.0073), exposed deep structures (p = 0.036), and/or Wagner Grade 4 ulcers (p = 0.04). Furthermore, the decrease in recidivism was statistically significant at 3 months, 6 months, and 1 year, with and without initially exposed deep structures (p < 0.05). The amputation rate in the treatment cohort was 41.7% less than that of the control cohort at 20 weeks (0.9% vs. 1.5%, respectively). This study demonstrated that diabetic ulcers treated with a cryopreserved bioactive split-thickness skin allograft were more likely to heal and remain closed compared to ulcers treated with standard of care alone.

The Health Economic Impact of Living Cell Tissue Products in the Treatment of Chronic Wounds: A Retrospective Analysis of Medicare Claims Data.

OBJECTIVE: To investigate differences in wound-related costs; product waste; lower-extremity amputations; and number of applications, hospitalizations, and emergency room visits among patients treated with three cellular and/or tissue-based products. METHODS: This retrospective intent-to-treat matched-cohort study analyzed the full Medicare claims dataset from 2011 to 2014. Patients who received either a bilayer cellular construct (BLCC), dermal skin substitute (DSS), or cryopreserved human skin allograft (CHSA) were concurrently matched for Charlson Comorbidity Index, age, sex, and region, resulting in 14,546 study patients. Key variables were reported at 60, 90, and 180 days after the first product application. RESULTS: There were no statistically significant differences in the distribution of Charlson Comorbidity Index, age, sex, and region among cohorts. Wound-related costs and product wastage were lower for CHSA patients relative to both BLCC and DSS patients at all time intervals (P < .05). Patients treated with CHSA received fewer product applications than DSS at 90 and 180 days (P < .05). Amputations were significantly higher among patients treated with DSS than either CHSA or BLCC (P < .0001). CONCLUSIONS: The data demonstrate that wound-related costs, product waste, amputations, and frequency of applications are lower for CHSA than DSS. Wound-related costs and product waste are lower for CHSA compared with BLCC. Further claims analysis and prospective clinical trials could help develop appropriate quality measures and reimbursement models to ensure smarter spending for the growing population of patients with chronic wounds.

Gastrointestinal symptoms in postural tachycardia syndrome: a systematic review.

Gastrointestinal symptoms are among the most common complaints in patients with postural tachycardia syndrome (POTS). In some cases, they dominate the clinical presentation and cause substantial disabilities, including significant weight loss and malnutrition, that require the use of invasive treatment to support caloric intake. Multiple cross-sectional studies have reported a high prevalence of gastrointestinal symptoms in POTS patients with connective tissue diseases, such as Ehlers-Danlos, hypermobile type, and in patients with evidence of autonomic neuropathy. Previous studies that evaluated gastric motility in these patients reported a wide range of abnormalities, particularly delayed gastric emptying. The pathophysiology of gastrointestinal symptoms in POTS is likely multifactorial and probably depends on the co-morbid conditions. In patients with POTS and Ehlers-Danlos syndromes, structural and functional abnormalities in the gastrointestinal connective tissue may play a significant role, whereas in neuropathic POTS, the gastrointestinal tract motility and gut hormonal secretion may be directly impaired due to localized autonomic denervation. In patients with normal gastrointestinal motility but persistent gastrointestinal symptoms, gastrointestinal functional disorders should be considered. We performed a systematic review of the literature related to POTS and gastrointestinal symptoms have proposed possible mechanisms and discussed diagnosis and treatment approaches for delayed gastric emptying, the most common gastrointestinal abnormality reported in patients with POTS.

Proline Precursors and Collagen Synthesis: Biochemical Challenges of Nutrient Supplementation and Wound Healing.

Wound healing is a complex process marked by highly coordinated immune fluxes into an area of tissue injury; these are required for re-establishment of normal tissue integrity. Along with this cascade of cellular players, wound healing also requires coordinated flux through a number of biochemical pathways, leading to synthesis of collagen and recycling or removal of damaged tissues. The availability of nutrients, especially amino acids, is critical for wound healing, and enteral supplementation has been intensely studied as a potential mechanism to augment wound healing-either by increasing tensile strength, decreasing healing time, or both. From a practical standpoint, although enteral nutrient supplementation may seem like a reasonable strategy to augment healing, a number of biochemical and physiologic barriers exist that limit this strategy. In this critical review, the physiology of enteral amino acid metabolism and supplementation and challenges therein are discussed in the context of splanchnic physiology and biochemistry. Additionally, a review of studies examining various methods of amino acid supplementation and the associated effects on wound outcomes are discussed.

Arginine-Dual roles as an onconutrient and immunonutrient.

Arginine is an important player in numerous biologic processes and studies have demonstrated its importance for cellular growth that becomes limiting in states of rapid turnover (e.g., malignancy). Thus, arginine deprivation therapy is being examined as an adjuvant cancer therapy, however, arginine is also necessary for immune destruction of malignant cells. Herein we review the data supporting arginine deprivation or supplementation in cancer treatment and the currently registered trials aimed at understanding these divergent strategies. J. Surg. Oncol. 2017;115:273-280. © 2016 Wiley Periodicals, Inc.

Excessive nitric oxide impairs wound collagen accumulation.

BACKGROUND: Nitric oxide (NO) plays a major regulatory role in wound collagen synthesis. We hypothesized that this regulatory role is tightly controlled by the levels of NO in the wound environment and that supranormal wound NO generation impairs wound collagen accumulation. MATERIALS AND METHODS: We used the model of turpentine-induced granuloma in male Sprague-Dawley rats as a sterile inflammatory stimulus generating large amounts of NO. In this environment, NO generation increased by 260%, whereas collagen deposition was significantly reduced by 38.5% (729.7 ± 81.5 versus 449.4 ± 76.3 µg hydroxyproline/100 mg sponge, P<0.05). Inhibition of NO synthase activity using 300 mM L-N6-(1-iminoethyl)-lysine, a highly potent and selective inhibitor of inducible NO synthase, significantly reduced NO elevation by 43.3% and increased wound collagen deposition by 37.3% (P<0.05). These effects occurred without any anti-inflammatory effects of L-N6-(1-iminoethyl)-lysine as assessed by the white blood cell counts and levels of interleukins 1 and 6. CONCLUSIONS: The data show that high levels of NO within the wound environment significantly reduce wound collagen deposition. Inhibition of NO generation restores collagen levels to normal levels. The regulatory effects of NO on wound collagen appear to be highly correlated with the amount of NO generated.

Changes in the negative logarithm of end-tidal hydrogen partial pressure indicate the variation of electrode potential in healthy Japanese subjects.

Molecular hydrogen (H2) is produced by human colon microbiomes and exhaled. End-tidal H2 sampling is a simple method of measuring alveolar H2. The logarithm of the hydrogen ion (H+)/H2 ratio suggests the electrode potential in the solution according to the Nernst equation. As pH is defined as the negative logarithm of the H+ concentration, pH2 is defined as the negative logarithm of the H2 effective pressure in this study. We investigated whether changes in pH2 indicated the variation of electrode potential in the solution and whether changes in end-tidal pH2 could be measured using a portable breath H2 sensor. Changes in the electrode potential were proportional to ([Formula: see text]) in phosphate-buffered solution (pH = 7.1). End-tidal H2 was measured in the morning (baseline) and at noon (after daily activities) in 149 healthy Japanese subjects using a handheld H2 sensor. The median pH2 at the baseline was 4.89, and it increased by 0.15 after daily activities. The variation of electrode potential was obtained by multiplying the pH2 difference, which suggested approximately + 4.6 mV oxidation after daily activities. These data suggested that changes in end-tidal pH2 indicate the variation of electrode potential during daily activities in healthy human subjects.

Role of high mobility group box 1 (HMGB1) in wound healing.

BACKGROUND: HMGB1, a non-histone chromosomal protein, can bind to the receptor for advanced glycation end products (RAGE) and act as an inflammatory mediator. We examined the role of HMGB1 in incisional wound healing and its possible mechanism of action through receptor for advanced glycation end products (RAGE). METHODS: Male Sprague-Dawley rats undergoing full-thickness incisional wounding with subcutaneous implantation of PVA sponges were given daily injections of ethyl pyruvate (EP) (40 mg/kg, i.p.), a potent inhibitor of HMGB1 release. At 7 d post-wounding, wound breaking strength, sponge collagen content, and wound fluid HMGB1 levels were assessed. In vitro rat dermal or wound-derived fibroblasts were cultured with recombinant HMGB1 or advanced glycation end product (AGE). Some cultures were co-treated with a RAGE-blocking antibody. Fibroblast proliferation and collagen synthesis were assayed. RESULTS: In vivo treatment with EP significantly decreased wound HMGB1 levels (P < 0.05), which was paralleled by increased wound breaking strength (P < 0.05) and wound collagen content (P < 0.05). In vitro treatment with HMGB1 (100 ng/mL) had no effect on fibroblast proliferation but significantly reduced collagen synthesis (P < 0.05). This effect was abrogated by co-treatment with anti-RAGE antibody. Fibroblasts treated with AGE had lower collagen synthesis (P < 0.01), which was restored by anti-RAGE antibody treatment. CONCLUSION: HMGB1 impairs fibroblast collagen synthesis. Reducing wound HMGB1 levels lead to increased tensile strength and collagen synthesis. The data suggest that HMGB1 affects collagen synthesis through activation of RAGE.

Reactive oxygen species-degradable polythioketal urethane foam dressings to promote porcine skin wound repair.

Porous, resorbable biomaterials can serve as temporary scaffolds that support cell infiltration, tissue formation, and remodeling of nonhealing skin wounds. Synthetic biomaterials are less expensive to manufacture than biologic dressings and can achieve a broader range of physiochemical properties, but opportunities remain to tailor these materials for ideal host immune and regenerative responses. Polyesters are a well-established class of synthetic biomaterials; however, acidic degradation products released by their hydrolysis can cause poorly controlled autocatalytic degradation. Here, we systemically explored reactive oxygen species (ROS)-degradable polythioketal (PTK) urethane (UR) foams with varied hydrophilicity for skin wound healing. The most hydrophilic PTK-UR variant, with seven ethylene glycol (EG7) repeats flanking each side of a thioketal bond, exhibited the highest ROS reactivity and promoted optimal tissue infiltration, extracellular matrix (ECM) deposition, and reepithelialization in porcine skin wounds. EG7 induced lower foreign body response, greater recruitment of regenerative immune cell populations, and resolution of type 1 inflammation compared to more hydrophobic PTK-UR scaffolds. Porcine wounds treated with EG7 PTK-UR foams had greater ECM production, vascularization, and resolution of proinflammatory immune cells compared to polyester UR foam-based NovoSorb Biodegradable Temporizing Matrix (BTM)-treated wounds and greater early vascular perfusion and similar wound resurfacing relative to clinical gold standard Integra Bilayer Wound Matrix (BWM). In a porcine ischemic flap excisional wound model, EG7 PTK-UR treatment led to higher wound healing scores driven by lower inflammation and higher reepithelialization compared to NovoSorb BTM. PTK-UR foams warrant further investigation as synthetic biomaterials for wound healing applications.

Peptide inhibitors of MK2 show promise for inhibition of abdominal adhesions.

BACKGROUND: Abdominal adhesions are a common side effect of surgical procedures with complications including infertility, chronic pain, and bowel obstruction, which may lead to the need for surgical lyses of the adhesions. Mitogen-activated protein kinase-activated protein kinase 2 (MK2) has been implicated in several diseases, involving inflammation and fibrosis. Thus, the development of a cell-penetrating peptide (CPP) that modulates MK2 activity may confer therapeutic benefit after abdominal surgery in general and more specifically after bowel anastomosis. METHODS: This study evaluated the function of a CPP inhibitor of MK2 in human mesothelial cells and in a rat bowel anastomosis model. To determine IC50 and basic specificity, kinase inhibition was performed using a radiometric assay. Enzyme-linked immunoassay (ELISA) was used to evaluate interleukin-6 (IL-6) expression in response to IL-1ß and tumor necrosis factor-α (TNF-α) stimulation in vitro to validate MK2 kinase inhibition. Following bowel anastomosis (10 rats for each control and treatment at 4 and 10 d), the rats were evaluated for weight loss, normal healing (colonic burst strength and hydroxyproline content at the anastomosis), and number and density of adhesions. RESULTS: The IC50 of the MK2 inhibitor peptide (22 µM) was similar to that of the nonspecific small molecule rottlerin (IC50 = 5 µM). The MK2 inhibitor peptide was effective at suppressing IL-1ß and TNF-α stimulated IL-6 expression in mesothelial cells. In vivo, the MK2 inhibitor peptide was effective at suppressing both the density and number of adhesions formed as a result of bowel an anastamosis. Importantly, the peptide had no negative effect on normal healing. CONCLUSIONS: In conclusion, the peptide inhibitor of MK2, MMI-0100, has the potential to significantly reduce inflammation through suppression of inflammatory cytokine expression and showed promise as a therapeutic for abdominal adhesions.

Effect of preinjury statin use on mortality and septic shock in elderly burn patients.

BACKGROUND: Premorbid statin use has been associated with decreased mortality in septic and trauma patients. This has been ascribed to the pleiotropic, anti-inflammatory effects of HMG-CoA reductase inhibitors. This association has not been investigated in burn victims. METHODS: A retrospective review of 223 consecutive patients, aged 55 years and older admitted to Vanderbilt University Regional Burn Center from January 2006 to December 2008, was performed. Multivariate regression analysis determined odds ratios of death and sepsis by statin use, adjusting for cardiovascular comorbidities. RESULTS: Of 223 patients, 70 (31.4%) were taking statins before admission. Mean age and mean total body surface area burn were not significantly different by statin use. The odds ratio of inhospital death was 0.17 (95% confidence interval 0.05-0.57; p = 0.004) if on statins. The odds ratio of mortality when stratified by cardiovascular comorbidities did not change. Sepsis developed in 30 patients (13.5%), with an odds ratio in statin users of 0.50 (95% confidence interval 0.20-1.30; p = 0.155). CONCLUSION: Preinjury statin use was associated with an 83% reduction in the odds of death after thermal injury. The odds of sepsis decreased by 50%, although not statistically significant. Further study is warranted to investigate the potential benefits of statin therapy in the management of burn victims.

The Effect of Comorbidities on Wound Healing.

Wound healing is affected by several factors. Preexisting diagnoses may significantly alter, delay, or inhibit normal wound healing. This is most commonly seen with chronic disorders, such as diabetes and renal failure, but also occurs secondary to aging and substance abuse. Less commonly, genetic or inflammatory disorders are the cause of delayed wound healing. In some cases, it is not the illness, but the treatment that can inhibit wound healing. This is seen in patients getting chemotherapy, radiation, steroids, methotrexate, and a host of other medications. Understanding these processes may help treat or avoid wound healing problems.

African Americans show increased risk for pressure ulcers: a retrospective analysis of acute care hospitals in America.

In an earlier study, we reported a significantly increased risk of pressure ulcer hospital discharge diagnoses in African Americans, higher age groups, and those with certain medical conditions. The objectives of the present study were to: (a) investigate the demographics associated with a higher odds ratio (OR) in African Americans and (b) determine whether African Americans have different rates of medical risk factors. The 2003 Nationwide Inpatient Sample database was queried. Patients with pressure ulcers were identified by discharge diagnoses using ICD-9 codes 707.0-707.09. Discharge diagnosis was examined using the agency for healthcare research and quality clinical classifications software (CCS). The present study used identified CCS discharge diagnoses present in at least 5% of all patients, with an OR>2. African Americans exhibited a higher incidence of an OR>2 for 28 identified CCS risk factors for pressure ulcers. The pressure ulcer diagnoses tended to occur at younger ages in African Americans. No significant differences were noted in African Americans with pressure ulcers when a subanalysis was conducted by zip code income quartile, region of the country, or teaching status of the hospital. Hospitalized African Americans exhibit an age-dependent, higher prevalence of pressure ulcers compared with Caucasians. Socioeconomic factors tracked within the Nationwide Inpatient Sample do not provide an explanation for this phenomenon.

The Role of Vitamin A in Wound Healing.

Vitamin A is an essential micronutrient that comes in multiple forms, including retinols, retinals, and retinoic acids. Dietary vitamin A is absorbed as retinol from preformed retinoids or as pro-vitamin A carotenoids that are converted into retinol in the enterocyte. These are then delivered to the liver for storage via chylomicrons and later released into the circulation and to its biologically active tissues bound to retinol-binding protein. Vitamin A is a crucial component of many important and diverse biological functions, including reproduction, embryological development, cellular differentiation, growth, immunity, and vision. Vitamin A functions mostly through nuclear retinoic acid receptors, retinoid X receptors, and peroxisome proliferator-activated receptors. Retinoids regulate the growth and differentiation of many cell types within skin, and its deficiency leads to abnormal epithelial keratinization. In wounded tissue, vitamin A stimulates epidermal turnover, increases the rate of re-epithelialization, and restores epithelial structure. Retinoids have the unique ability to reverse the inhibitory effects of anti-inflammatory steroids on wound healing. In addition to its role in the inflammatory phase of wound healing, retinoic acid has been demonstrated to enhance production of extracellular matrix components such as collagen type I and fibronectin, increase proliferation of keratinocytes and fibroblasts, and decrease levels of degrading matrix metalloproteinases.

Proline precursors to sustain Mammalian collagen synthesis.

Biochemically, one-third of the collagen molecule is composed of glycine. The next largest amino acid component is formed by proline (PRO) and hydroxyproline, which together comprise approximately 23% of the collagen molecule. The best method to support wound collagen biosynthesis is to provide adequate host nutrition, assuring adequate provision of calories and protein. However, despite adequate nutrition, clinically, there is a need to enhance collagen synthesis and research has focused on methods to enhance collagen precursor availability. PRO biosynthesis is related to both the citric acid cycle and the urea cycle. During the early phases of wound healing, wound fluid PRO levels are at least 50% higher than plasma levels, suggesting active import of PRO into the wound. Providing additional PRO in the diet to enhance PRO bioavailability for collagen biosynthesis does not result in increased collagen accumulation. Provision of other citric cycle precursors such as glutamine also does not enhance wound collagen synthesis. In looking at other PRO biosynthetic pathways, the arginine (ARG) --> ornithine (ORN) --> glutamic semialdehyde --> PRO pathway looks the most promising. ARG administration in quantities above those required for growth and reproduction results in a marked enhancement in wound collagen deposition. This effect is also shared by ORN, which cannot replace ARG for growth requirement but shares many of its biological and pharmacological activities. Several mechanisms have been postulated to explain the positive effect of ARG on wound healing, although none have been firmly proven. In conclusion, ARG and ORN supplementation are most effective in increasing collagen deposition, but whether this is accomplished by conversion to PRO is uncertain.

Risk factors for pressure ulcers in acute care hospitals.

Selection of patients for preventive measures to protect against pressure ulcers relies on clinical scales and provider judgment, which vary widely. Our objectives were to: (a) identify risk factors by clinical classification and report demographic differences in pressure ulcer risk and (b) develop criteria for identification of high-risk patients. Patients with pressure ulcer as a discharge diagnosis were identified from the 2003 Nationwide Inpatient Sample (NIS). The effect of discharge diagnosis was examined using the Agency for Healthcare Research and Quality Clinical Classification Software (CCS). Multiple regression analysis for survey data was used to assess risk factors. The 2003 NIS listed 94,758 with a discharge diagnosis of pressure ulcer, identified as International Classification of Disease-9 code 707.0-707.09, for an overall incidence of 143 per 10,000. Forty-five CCS discharge diagnoses were present in at least 5% of these patients and 28 of these CCS diagnoses had odds ratios >2.0. African-American race and advanced age were identified as risk factors for pressure ulcer diagnosis. Disorders of skin integrity, organ system failure, and infection were found to be broad categories of risk factors as well. Using the NIS, risk factors for pressure ulcer including diagnoses and demographic factors have been identified.