Pressure Ulcer Management

PRESSURE ULCER SUMMARY FOR SCIENTIFIC READERS Pressure ulcers represent the fourth most common deficiency found in long-term care facilities.1 The Center for Medicare, Medicaid Services (CMS) cited over 45% of long-term care facilities in 2002.1 It has been reported that 11.6% of long term care residents are plagued with pressure ulcers costing the health care system $1.3 B annually.1 Liability and risk factors have caused premiums to skyrocket by over 300%, due to median settlements of $450,000 and average verdict awards of nearly $3 M per case.1 In spite of the escalating risk, liability, and cost to facilities, not to mention the pain and suffering of the residents, little progress in the reduction of pressure ulcer incidence has occurred. Under even the best of circumstances, barely 50% of pressure ulcers are healed in 12 weeks.2 Due to this lengthy course of treatment, costs are considerable, ranging from $1,190 to $10,185 to heal one pressure ulcer.3 Even the "simple" protocol of twice daily gauze dressing change costs $2,179 per pressure ulcer due to the intensive labor costs.3 The pathogenesis of pressure ulcers may involve several mechanisms including impaired mobility, fecal or urinary incontinence, and decreased healing capacity. These factors lead to an increase in shear stress, friction, and pressure which are generally accepted as the primary causative factors in pressure ulcer development.4 Pressure induces ischemia and recent studies have shown that cyclic ischemia-reperfusion injuries play an important role in the formation of pressure ulcers.5 The ischemia-reperfusion model of tissue damage describes the damage that initially occurs with hypoxic injuries (ischemia), which are then exacerbated with the restoration of oxygen (reperfusion). The initial lack of oxygen causes the production of toxic metabolites and depletes the cellular antioxidant defenses. The return of oxygen is accompanied by biochemical reactions that are normally controlled by antioxidants. Without the protection of antioxidants, additional tissue damage

occurs. Ischemia-reperfusion has been demonstrated to be an important mechanism of cellular injury in transplantation, myocardial, hepatic, intestinal, cerebral, renal, and other ischemic syndromes.6 Important antioxidants, such as the peptide glutathione (GSH), are depleted during the stress of hypoxia (ischemia), reoxygenation (reperfusion) and infection (sepsis). Pressure alone in a defined area causes a significant decrease in reduced GSH and total GSH, suggesting oxidative stress.7 GSH is synthesized from glutamate, cysteine, and glycine. Cysteine is the rate limiting amino acid substrate of GSH. Pressure ulcers are often associated with infection. Cysteine and GSH appear to play a defensive role in infective states including the most severe form, sepsis. Cysteine usage increases dramatically during sepsis.8 At least 40% of the cysteine requirement during sepsis is used for GSH synthesis.9 Augmenting GSH and cysteine significantly increase survival in endotoxic shock studies.10 Supplemental dietary cysteine may increase GSH synthesis and ameliorate the adverse effects of oxidative damage.11 When local defenses against free radicals are lost, oxidative damage can occur directly under ischemic skin due to free radical interaction with protein and lipid membranes in the fat-containing subcutaneous layer. Cellular damage can spread in a chain reaction fashion to tissue around or below the initial damage site resulting in the typical tissue loss seen in pressure ulcers. In addition to the direct damage, excess free radicals also act as a trigger for cell signals that call in inflammatory cells that add further tissue loss.12 This combination of events begins to explain the rapid development of pressure ulcers. Cell and tissue rebuilding, as well as maintenance of antioxidant defenses, are demonstrated to be related to the availability of specific protein building amino acids required for wound healing, GSH synthesis and energy

production. GSH synthesis is of particular interest since hydroxyproline synthesis in wound healing is shown to be related to the availability of the precursors for GSH synthesis.13 A deficiency of key nutrients is known as Protein Energy Malnutrition (PEM). PEM is now recognized as the fundamental deficit in a number of conditions including pressure ulcers. Numerous nutritional products have been used in an attempt to overcome this challenge, with a recent focus on products that provide high doses of glutamine and arginine. Recent studies shed light on why these materials are less than optimal even though glutamine is recognized as the primary fuel for fibroblasts and enterocytes.14 Animal studies show that direct glutamine supplementation does not increase plasma or tissue glutamine levels and that arginine actually decreases whole body glutamine stores.15 Another study shows glutamine to have limited effect in aged subjects stressed by endotoxin exposure.16 On the other hand, glutamate appears to be the preferred substitute for glutamine 17; and glutamate is also a specific precursor for GSH, arginine and proline synthesis in the small intestine 18. Functionally, glutamate is not just a nutrient, it is also an energy source, a building block of proteins, a communication molecule for nerve cells 19 and regulator of hepatic nitrogen balance 20. It appears to be the ideal precursor for glutamine. The ability to yield energy and provide structural precursors appears to be the key in overcoming PEM. In patients with pressure ulcers, the challenge is to obtain the highest amount of the specific amino acids in the most absorbable form that can provide energy and the building blocks for wound repair. Rapidly growing cells such as the cells that line the intestines and absorb nutrients (enterocytes) and those that repair wounds (fibroblasts) use glutamate as an energy source. In fact, glutamate appears to be the most important single contributor to mucosal energy generation in the enterocyte 21, 22.

PEM is also associated with low blood GSH, oxidative stress, and hepatic injury, even in mild to moderate PEM.23 GSH supplementation has been recommended for severe forms of malnutrition for years 24 and GSH deficiency due to cysteine shortage is characteristic of severe forms of PEM 25. Glutamate levels are highly associated with the GSH level in mucosa.26 When muscles are low in GSH, myofibrillar damage is seen and results in calcium leakage.27 Skeletal muscle GSH deficiency occurs after surgical trauma 28 and critical illness 29. An understanding of the contribution of ischemia-reperfusion, depletion of the antioxidant GSH, cysteine supplementation, free radical generated inflammatory cell activation, protein energy malnutrition, glutamate versus glutamine metabolism is necessary to effectively reverse the tissue damage associated with pressure ulcer formation. The ideal material for pressure ulcer nutritional intervention should be a protein or hydrolysate 30 rich in the bioactive form of glutamate and cysteine. Together, glutamate and cysteine appear to allow the liver to optimally produce glutamine and GSH. Understanding the mechanisms of tissue damage seen in pressure ulcers and recognizing the need for a high quality peptide source of amino acid precursors has led many caregivers to use Immunocal®, a patented milk protein isolate that provides glutamate and cysteine in a bioactive form to maximize energy production, help rebuild the damaged tissue and optimize intracellular GSH production 31, all of which are required for optimal wound healing.

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