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CME/CE Released: 05/30/2003; Valid for credit through 03/22/2004

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This activity is intended for nurses, surgeons, pharmacists and physicians focusing on critical care, primary care, family medicine, dermatology, and internal medicine.

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The goal of this activity is to improve the care of high-risk patient populations with wounds by facilitating more rapid diagnosis and treatment of any underlying nutritional deficiency.

Learning Objectives
On completion of this continuing medical education offering, participants will be able to: 1. Describe the function of skin and the normal cutaneous wound healing process with specific focus on the requirements for adequate energy, protein intake, and anabolic activity. 2. Identify the negative effect of involuntary weight loss, lost lean mass, and proteinenergy malnutrition (PEM) on healing of both the acute and chronic wound. 3. List the populations at high risk for PEM and impaired healing. 4. Describe the evolution of the nonhealing wound as it relates to PEM. 5. Describe the correction of the problem of nonhealing wounds, using nutritional support. 6. Specify the adjuvant use of anabolic agents, to restore the wound healing.

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Physicians - maximum of 1.50 AMA PRA Category 1 Credit(s) Nurses - 1.80 ANCC Contact Hour(s) (0 contact hours are in the area of pharmacology) Pharmacists - 1.50 ACPE Contact Hour(s) (0.150 CEUs) All other healthcare professionals completing continuing education credit for this activity will be issued a certificate of participation. Physicians should only claim credit commensurate with the extent of their participation in the activity.

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should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity online during the valid credit period that is noted on the title page. Follow these steps to earn CME/CE credit: 1. Read the target audience, learning objectives, and author disclosures. 2. Study the educational content online or printed out. 3. Online, choose the best answer to each test question. To receive a certificate, you must receive a passing score as designated at the top of the test. Medscape encourages you to complete the Activity Evaluation to provide feedback for future programming. You may now view or print the certificate from your CME/CE Tracker. You may print the certificate but you cannot alter it. Credits will be tallied in your CME/CE Tracker and archived for 5 years; at any point within this time period you can print out the tally as well as the certificates by accessing "Edit Your Profile" at the top of your Medscape homepage. The credit that you receive is based on your user profile.

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Protein-Energy Malnutrition, and the Nonhealing Cutaneous Wound

Authors: Robert H. Demling, MD; Leslie DeSanti, RN Posted: 06/20/2001; Updated: 05/30/2003

Introduction

The negative impact of involuntary weight loss and protein-energy malnutrition (PEM) on local wound healing has long been recognized. Yet PEM and the resulting impaired wound healing remain common health problems. The majority of patients with new stage III and IV pressure ulcers requiring hospitalization have PEM. In 1990, the average cost of management of a patient with a new pressure ulcer was between US $40,000 and $60,000. The cost is certainly greater today. The relationship between PEM and wounds holds true for the general population of patients with nonhealing wounds.[1,2] There are a number of factors that contribute to the continuing increase in the morbidity and mortality associated with involuntary weight loss and PEM. The first is the increase in the number of patients at highest risk for these syndromes; specifically, the elderly, the disabled, and the chronically ill populations suffering with wounds. In addition, the incidence of traumatic injuries has remained stable, as has the incidence of insults, such as infections requiring hospitalization. Both injury and infection activate the "stress response," which leads to pronounced catabolism and an inevitable loss of lean body mass (LBM), especially muscle. The elderly, the disabled, and the chronically ill suffer more frequently from these traumatic insults or infections, due to the aging process, osteoporosis, loss of muscle strength, and immune impairment. The second factor contributing to the increase in patients with involuntary weight loss and PEM is the rapid transition of patients from the acute care setting to either rehabilitation or home care (or chronic care) settings. This more rapid transition decreases the possibility of restoring good nutrition and regaining lost weight from any prior insult because aggressive nutritional support, exercise, and increased anabolic stimulation are more difficult to achieve in short-stay situations. Therefore, the PEM persists and may worsen as decreased activity and less than optimum nutrition continues the process. Fat may be restored, but LBM is not, which is the essential element in recovery. As mentioned previously, wounds have played a prominent role in the increased number of cases of PEM. There is a direct correlation between impaired and nonhealing wounds and the incidence of PEM. All aspects of wound healing depend on the prevention and reversal of PEM, optimum nutrition, increased anabolic activity with increased energy and protein needs, along with good local wound care. To manage this health problem better, it is critical that these concepts be better understood by healthcare professionals dealing with high-risk populations and patients with wounds. This educational program will discuss the pathogenesis and treatment of wounds where healing is impaired by the systemic process of PEM and involuntary weight loss. The objectives of this program are:

To describe the function of skin and the normal cutaneous wound healing process with specific focus on the requirements for adequate energy, protein intake, and anabolic activity; To describe the negative effect of involuntary weight loss, lost LBM, and PEM on healing of both the acute and chronic wound; To identify the populations at high risk for PEM and impaired healing; To describe the evolution of the nonhealing wound as it relates to PEM;

To describe the correction of the problem of nonhealing wounds using nutritional support; and To specify the adjuvant use of anabolic agents to restore the wound healing.

Skin (Biologic Properties)

Skin is a bilayer organ whose functions are essential for survival (Figure 1, Figure 2, and Figure 3). Although the two layers work as a unit, Table 1 highlights the specific properties of each component.[3-7]

Figure 1. Normal skin function.

Figure 2. Components of skin.

Figure 3. Anatomy of normal skin.

Table 1. Skin Functions

Component Function

Epidermis

Protection from desiccation Protection from bacterial entry Protection from toxins Fluid balance: avoiding excess evaporative loss Neurosensory Social-interactive

Dermis

Protection from trauma due to elasticity and durability Fluid balance through regulation of skin blood flow Thermoregulation through control of skin blood flow Growth factors and contact direction for epidermal replication and dermal repair

Epidermis

The outer thinner layer known as the epidermis is composed mainly of epithelial cells. The outermost cells contain the protein keratin and are known as keratinocytes. The basal or deepest epidermal cells are anchored to the basement membrane by adhesion molecules (or glue) called fibronectin. These

immature cells are continually dividing and migrating toward the surface to replace lost surface cells (eg, after an injury). The same type of regenerating epidermal cells is found in hair follicles and other skin appendages, which are anchored in the dermis. As the cells mature and migrate to the surface, they form keratin, which becomes an effective barrier to environmental hazards such as infection and to excess water evaporation.[1-4] Replacement of the epidermal layer by this regenerative process takes 2 to 3 weeks. Cues and biologic stimuli at the wound surface are necessary to direct proper orientation and mitotic response of the epidermal cells. Many of the cues come from dermal elements, especially the matrix proteins and matrix glycosaminoglycan (GAG) (Table 2).[8,9]

Table 2. Epidermal Characteristics

Protection from environmental insults

Ability to regenerate every 2-3 weeks resulting from biologic cues and contact direction provided by dermis, basement membrane

Dermis[1,2,5,9]

The dermis is a dynamic layer of thick connective tissue, which is also in constant turnover. The dermis is divided into a thin superficial layer known as the papillary dermis, which contains the anchoring epidermal rete pegs (a network of ridges), and the thicker deeper portion known as the reticular dermis. The papillary dermis is the major factory for the proteins providing direction for epidermal replication. The upper dermis also contains the greatest blood flow. The primary cell type is the fibroblast, which produces the key structural extracellular matrix proteins collagen and elastin, as well as matrix or ground substance. In addition, these cells produce the key adhesion proteins used to attach epidermal cells to the basement membrane and for spent used epidermal cell migration and replication (Table 3).

Table 3. Dermal Characteristics

Provides durability, flexibility of skin Faster for all the components required for replication and repair of epidermis and

dermis Scaffolding for cell migration and the conduit for nutrient delivery

Fibronectin is a key fibroblast-derived signal protein for the orchestration of healing.[8] The ground substance or matrix is made up of a complex polysaccharide -- a protein complex known as the GAG component, as well as hyaluronic acid. The matrix provides a semifluid, which allows for cell and connective tissue orientation as well as nutrient diffusion to the cells and a scaffolding for cell migration.[9]

Epithelial Cell Types

Epithelial cells make up the majority of the epidermis.[1-4] Immature cells are programmed to divide, migrate, and mature to keratin-producing cells called keratinocytes. The signals to activate this process come from messenger proteins called growth factors as well as through contact direction from key dermal adhesive proteins, especially collagen (Table 4).

Table 4. Cell Types

Skin Component Cell Type

Epidermis

Keratinocytes Epithelial cells Langerhan's cells

Dermis

Fibroblasts Macrophages

Fibroblasts. These cells of mesenchymal origin are normally present in the dermis and produce dermal replacement components. After injury, these cells migrate into the wound and proliferate, resulting in increased quantities of dermal proteins and matrix.[5] Endothelial cells. These cells make up the lining of micro- and macrovessels as well as the lining of new capillaries produced after injury. Like fibroblasts, these differentiate from local mesenchymal cells. They are also attracted into the wound by local signals.[6] Macrophages. These cells of mesenchymal origin are normally present in tissue but increase in number after injury, attracted by chemical messages released by the activation of inflammation. The long-lived cells release the protein chemical messages, growth factors, and growth stimulants that orchestrate healing in an organized fashion.[7] Platelets. These factor-rich particles release a host of growth factors and adherence proteins during the initial postburn period. A large variety of "polypeptide growth factors" have been identified and named (Table 5). Although each has a specific function, it now appears that the growth factors also have other responsibilities.[10-13] Epidermal growth factor (EGF) is a key component for re-epithelialization of a partial-thickness burn, and, therefore, the addition of EGF to a wound surface can increase the rate of healing. Keratinocyte growth factor is an important fibroblast-derived stimulant for epithelialization. Monocytes and macrophages are thought to be the main producers of growth factors; however, all skin cells, including fibroblasts and keratinocytes, play an important role in secreting growth factors. Because skin growth factors work via protein synthesis, energy and protein substrate must be available in the form of good nutrition and normal body composition.[14]

Table 5. Functions of Skin Growth Factors

Cell proliferation: epithelial, endothelial, and fibroblast Cell migration: epithelial, endothelial, fibroblast, white blood Structure formation: capillaries, epidermis Production of proteins: collagen, matrix proteins, keratin

cells

All fibroblast products are proteins or peptides and part of the LBM compartment (Table 6).

Table 6. Fibroblast Products[5,8]

Collagen (type 1 in skin) Matrix proteins (fibronectin, tenascin, others) Proteoglycans, glycosaminoglycans, hyaluronic acid, other matrix components Cytokines and other growth stimulants

The Cutaneous Wound Healing Process: Key Concepts

Wound healing may be defined as the process whereby an injured tissue is repaired, resulting in regeneration of the cell lining of the tissue with the reorganization of the deep tissue components into scar. This process occurs in all organ systems in the body. Cutaneous wound healing can be categorized, in clinical terms, into first, second, and third intention.[14-17] Primary healing, or healing by first intention, is the process by which an incision or open wound is immediately closed (ie, elective surgery incision). Secondary healing, or healing by second intention, is the process by which an open wound closes by new tissue formation with subsequent wound contraction and re-epithelialization. Healing by third intention, or delayed primary closure, is the process by which a wound is temporarily left open, with the intention of closure at a later date (4 to 7 days) using a primary closure technique. This program focuses on wound healing by secondary intent or delayed primary closure because most wounds induced by traumatic infection or disease[14,15] are not closed by primary intention. Since local new tissue synthesis is required, increased energy demands and increased protein synthesis are required. In addition, the wound itself activates a systemic hypermetabolic and catabolic state, further increasing nutritional demands. This latter concept will be discussed in a later section. Although the type of wound, timing of wound closure, and wound care techniques used may vary, the process of healing and the factors affecting the healing process are basically the same for all wounds. There are 5 major interrelated and overlapping components to the healing process. They are:

Inflammation, Cellular proliferation,

Connective tissue formation, Wound contraction, and Wound remodeling.

Each component is dependent on the prior one for healing to occur and each component must be clearly understood by the care provider to allow wound healing to progress.[14-17] All phases require energy, protein, and an anabolic stimulus.

Acute Wound Healing

There are a number of overlapping phases or stages that occur during the acute healing process.

Inflammatory Phase (Immediate Onset)[16-18]

Components. The initial phase of healing (Table 7) requires the onset of wound inflammation. This process begins with the activation of clotting to seal bleeding vessels and increased vessel permeability to allow for antibodies and fibrin to enter the tissues. Increased blood flow then occurs through vasodilatation, as does an accumulation of neutrophils in the wound within minutes of injury. This helps prevent invasive infection.

Table 7. Inflammatory Phase

Inflammatory Phase

Abnormalities:

Clotting of bleeders (1-5 minutes) Increased blood flow (20-30 minutes) Increased oxygen in wound Antibodies released in wound Increased neutrophils (bacterial killing) Increased macrophages

Process suppressed, inadequate O2 for host defenses, corticosteroids stopping the

process Process accentuated, tissue damage, excessive inflammation

Neutrophils require oxygen to kill bacteria, so early defenses are dependent on blood flow delivering oxygen to the wound (Figure 4). Activation of inflammation sends out chemical messages, attracting macrophages to the wound. These long-lived cells, with a lifespan of weeks, orchestrate the remaining phases of wound healing through the release of a variety of polypeptides known as growth factors, which produce the various wound healing messages.

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Figure 4. Increased numbers of neutrophils and a protein exudate in the tissues result from altered permeability.

Cellular Proliferation Phase (Components)[18-21]

Cellular proliferation involves 3 key processes: angiogenesis, fibroblast proliferation, and epithelial proliferation. As with all processes, these require energy, protein synthesis, and anabolism. Angiogenesis. The wound surface or edge is relatively ischemic, and healing cannot effectively proceed until sufficient blood flow is restored to allow delivery of nutrients. Macrophages secrete a substance known as angiogenesis factor, which is believed to be a chemoattractant for mesothelial and vascular endothelial cells. The process of neovascularization or angiogenesis begins in the first several days, although the process is delayed if a thick layer of surface necrosis is present (Figure 5). Endothelial cells proliferate and form capillary buds at the wound surface. The buds form a network of loops, which fuse with other buds to form a new capillary bed. If the wound edges are approximated, the capillaries can bridge the wound (Figure 6).

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Figure 5. Angiogenesis on surface with new capillary formation.

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Figure 6. New blood vessels seen revascularizing an open wound. This process is impaired by excess inflammation, surface dead tissue, wound exudates, decreased perfusion, and corticosteroids Fibroblast proliferation. Fibroblasts begin to appear in the wound about 2 days after injury. The initial cells on the scene appear to migrate from nearby connective tissue. The stimuli for subsequent fibroblast proliferation and subsequent collagen synthesis appear to be growth factors from platelets and macrophages. The fibroblasts migrate into the wound along local fibrin strands from the initial wound coagulation as well as any remaining collagen strands. The fibroblasts, which are metabolically active, depend on the adequacy of locally available oxygen and the adequacy of neovascularization for continued proliferation. This process is impaired by decreased perfusion, inadequate nutrients, decreased anabolic activity, and corticosteroids. Epithelialization. The epidermal lining of skin is in a continual state of proliferation and desquamation, unlike the more dormant mesenchymal tissues. With loss of the epidermis, adjacent cells become reprogrammed. They detach from their basement membrane, divide, and migrate toward and across the wound, first forming a single cell layer. Various EGFs released from macrophages and platelets initiate the response. This process, however, is quite limited and any dead tissue on the surface will retard epithelialization. In addition, the cell distance traveled is limited to about 3 centimeters from the wound edge. The re-epithelialization process can be rapid, 3 to 5 days in a superficial injury, or several months, depending on the size of the defect, the nutrient supply, the number of remaining basal cells, and the wound environment. Once a single layer develops, additional layers form from mitotic division (Figure 7, Figure 8, and Figure 9).[11,16-20]

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Figure 7. Fibroblast proliferation of wound interstitium.

Figure 8. Healing wound, as evidenced by the fibroblasts, new collagen, and matrix in the gray area in the middle.

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Figure 9. Epithelial cell proliferation and migration across the wound surface. The new layer is also very vulnerable to dessication or destruction due to the release of neutrophil protease as a result of a surface infection and/or a new focus of inflammation.

Connective Tissue Formation

This phase is characterized by protein synthesis with both collagen and matrix formation. The fibroblasts have now been activated to produce protein by growth factors. Collagen production.[21,22] The stimulus for collagen production is the fibroblast-stimulating growth factors released from macrophages and platelets (Figure 10). The rate of production of collagen is dependent on a number of factors, the most important being the adequacy of perfusion and nutrients for energy and protein synthesis. Adequate nutrients, especially amino acids, as well as ferrous iron, ascorbic acid, vitamin A, zinc, and copper, are also specifically required for protein synthesis. Adequate molecular oxygen (O2) is essential for a number of key steps in collagen metabolism. Vitamin A maintains and restores (in the case of corticosteroids) the inflammatory stimulus required to

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generate the healing factors. Zinc is a cofactor in a number of enzyme systems, including new protein production.

Figure 10. Photomicrograph of collagen deposition in wound. The rate of collagen synthesis is maximal in the first 1 to 2 weeks, and collagen deposition is at its peak at 3 to 4 weeks. Interstitial matrix synthesis. The interstitial matrix, also produced by fibroblasts and other mesenchymal cells, influences the architectural structure and strength of the collagen fibers. Proteoglycans, which are composed of a protein core enclosed by GAGs, are a major component. The end result is a firm, nonpliable wound as the collagen fibers become bound into the more rigid matrix. With gradual scar maturation and remodeling, the proteoglycan content decreases (Figure 11).

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Figure 11. All components require energy, protein synthesis, and an anabolic stimulus. Impairment results when a decrease in tissue blood flow limits the available energy, which is needed by the now metabolically active fibroblast. Poor nutrition will clearly impair collagen synthesis and matrix synthesis. Wound contraction.[6,23] Wound contraction, illustrated by Figure 12, is the process whereby open wounds close by movement of the wound edges (not just epithelium) toward the center. The mechanism of the contraction, which shrinks the wound, is the generation of forces in the contractile elements of the fibroblasts toward the center of the wound. With fibroblast contraction, collagen and proteoglycan are secreted, locking the new tissue in place. Contraction is inhibited by malnutrition and decreased perfusion.

Figure 12. Wound contraction. Wound remodeling (scar maturation).[16,17] The remodeling process officially begins about 3 weeks after the injury and persists for months to years (Figure 13). The wound remodeling is the result of the following:

and

Increasing collagen crosslinking, resulting in increased strength; Action of collagenase to begin breaking down excess collagen accumulation; Regression of the lush network of surface capillaries as metabolic demands diminish; Decreasing proteoglycan and, in turn, wound water content.

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The loss of wound blood flow or the addition of infection, however, can lead to a net increase in collagen loss, resulting in a weakened wound. In general, wound strength continues to increase even beyond a year. Skin and fascia never regain full strength. The excessive deposition of scar can occur, leading to hypertrophic or excessive scar formation, which will impede movements of the tissue and usually result in a friable wound with pain on movement. A keloid is an excess in connective tissue formation.

Figure 13. Remodeling is characterized by removal of excess collagen and decreasing blood flow.

Evolution of Wound Care[23]

The predominant approach to the management of wounds throughout history has been to alter the wound surface in an attempt to improve healing.[23-28] This approach was based on the theories of the time, and it appears quite unusual to us now. Table 8 outlines the approaches to wound care over time. It is important to recognize that our current understanding of wound healing has evolved only recently and continues to grow. The concept that nutritional status dramatically affects healing is a relatively new but now proven concept.[29-32]

Table 8. Approaches To Wound Care

Era Method

Ancient Greece Cleanse, apply animal fat, and wrap Roman Empire Cleanse; apply ashes, oil, and herbs; then wrap Middle Ages 1800s Early 1900s Wax plus herbs or boiling oil Heat or ice Expose wound, apply tannic acid or variety of pigments to dry wound

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1950s to present 1960s to present

Use of topical antibiotics using the exposure or the closed dressing method Moist wound healing approach for acute and chronic wounds using a variety of products and techniques Rapid wound closure with surgery using skin or skin substitutes

1990s to present

Strong emphasis on nutritional status to prevent or correct protein-energy malnutrition Use of anabolic agents

A fluid layer on the wound surface increases not only the rate of re-epithelialization, but also improves all aspects of healing (Table 9; Figure 14). Surface dessication impairs re-epithelialization and decreases all phases of healing (Figure 15).

Table 9. Components of Healing Improved by Moisture[33-35]

Epithelialization

Keratinocyte proliferation Keratinocyte migration Keratinocyte differentiation Fibroplasia

Angiogenesis

Fibroblast proliferation Collagen matrix synthesis

Endothelial cell proliferation New blood vessel formation

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Figure 14. Moist healing. Fluid layer on wound surface increases not only the rate of reepithelialization, but also all aspects of healing.

Figure 15. Exposure method. Surface dessication impairs re-epithelialization and decreases all phases of healing.

Factors Impeding Healing

There are local factors, systemic factors, and systemic effects relating to an open wound that can impair healing.

Local Factors Impeding Healing

Table 10 outlines the local factors that impede healing.

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Table 10. Local Factors That Impede Healing[30,35-43]

Inadequate nutrients Inadequate energy Inadequate protein Inadequate anabolic stimulus Tissue hypoxia Low blood flow Eschar or exudates Consumption of O2 Tissue desiccation Occurs with open wound Impedes epithelial migration Risk of wound conversion Wound exudates Release of proteases Injury of new tissue Use of wound oxygen Wound infection Due to impaired local defense Exposure to microbes in the environment Increased inflammation-induced injury Wound trauma Environmental insult Use of toxic chemicals Traumatic dressing changes Inadequate nutrients.[30,36] No aspect of healing can proceed if there is inadequate energy to perform the metabolic reactions such as protein synthesis. In turn, protein synthesis cannot occur if there is insufficient protein substrate available to produce new tissue. Tissue hypoxia.[37] Because all phases of healing are oxygen dependent, a local decrease in wound tissue oxygen tension is the major impediment to proper healing. The most common causes of tissue hypoxia are:

A decrease in systemic blood volume and O2 delivery, A decrease in O2 saturation of hemoglobin, Eschar on the wound surface, and Surface exudates or infection consuming local oxygen.

Local infection.[39,40] There is a distinction made between surface wound colonization and wound infection. Colonization itself should not impede healing unless exudate buildup occurs. Infection by microbial tissue invasion destroys new tissue growth and accentuates inflammation. The infection is controlled with local wound antibiotics and, if systemic symptoms are present, with systemic antibiotics. Of concern is that many local antibiotics retard healing.

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Wound exudates.[38] The presence of surface inflammation and/or infection will result in buildup of exudates, which are mainly dead and dying white blood cells and their contents, all of which are toxic to new tissue growth. The increased release of proteinases on the wound retards the formation of new proteins, especially collagen. In addition, the excess surface of white blood cells can consume immense amounts of oxygen, depriving new tissue cells of O2, which in turn retards healing. Treatment is focused on preventing and removing exudates. Wound trauma.[41-43] This component covers everything from the use of toxic antibiotics or cleansing solutions, which injure tissue, to mechanical trauma caused by dressing changes. Wound dessication.[35] A dry wound surface impairs epithelial migration, decreases local wound defenses, and can lead to further surface necrosis. A thin moisture layer is needed to optimize the wound surface environment.

Systemic Factors Impeding Healing[44-50]

The systemic factors that can impair healing are highlighted in Table 11.

Table 11. Systemic Factors That Impair Healing

Inadequate wound blood volume and oxygen delivery Loss of body protein (lean body mass) Hypovolemia Dehydration Caused by ongoing catabolism Caused by decreased anabolism Caused by inadequate protein intake Decreased amino acids in the wound Inadequate nutrition Inadequate energy to wound for protein synthesis Inadequate amino acids for healing Systemic infection Increases catabolism Blood shunted from wound Collagenolysis Uncontrolled stress response Inadequate energy due to hypermetabolism Catabolism Excess generalized inflammation Inadequate wound blood volume and oxygen delivery.[44,45] The most important components of wound blood flow are adequate blood volume and cardiac output. These components are needed to deliver adequate amounts of oxygen. Neutrophils require oxygen for bacterial killing, fibroblasts require oxygen for collagen deposition and matrix deposition, and epithelial cells require oxygen for

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proliferation and wound contradiction. Acute or chronically injured patients are commonly dehydrated and/or hypovolemic, and adequate hydration is critical to maintain wound oxygenation. Loss of body protein.[47-51] Protein is found in muscle, but protein also makes up collagen and all the elements involved in healing, including growth factors. More than half the weight loss occurring with illness or injury is muscle, with the breakdown of other critical proteins, including those involved with immune defenses. The wound requires protein to heal and, in the malnourished patient, the amino acids must come from muscle and other stores. The body can deal with the increased demand until there is a loss of more than 15% of LBM. Beyond this point, there is competition for nutrients -- protein replacement vs wound healing -- with the net result being a decrease in wound healing rate. It is therefore critical that a patient who has lost significant weight regains the muscle component as quickly as possible. Optimum nutrition and resistance exercise is essential to increase anabolism. The addition of an anabolic agent will markedly accelerate restoration of lost weight. Maintaining body weight and protein (muscle mass) is an essential aspect of the wound healing management plan. Inadequate nutrition.[30,36,48-50] The wound consumes large amounts of energy (calories), amino acids (protein), and key macro- and micronutrients, as described in the first section on basic wound healing concepts. Because the wound is often present with other injuries or illness, the amount of nutrition needed exceeds normal levels by as much as 50%. Systemic infection.[45] A systemic infection is a drain on all the metabolic processes and will adversely affect local wound healing. Distant infection decreases all of the wound-healing processes, which depend on anabolic or protein synthesis. Blood flow is often shunted away from the wound to the core or visceral organs. And increased generalized collagenolytic activity decreases the collagen already deposited in the wound. Uncontrolled stress response.[47,52] The stress response to injury or illness increases catecholamine release and peripheral vasoconstriction. Any process that increases the release of catecholamines will further decrease wound blood flow. This includes pain and anxiety, reinforcing the need for adequate pain and anxiety management.

Systemic Effects of the Open Wound[47,53]

The systemic response to any open wound is the development of both local wound and systemic inflammation and the development of the "stress response" with increased metabolic demands and a catabolic stimulus. This process is magnified by other characteristics of the wound, pain, and local infection, which can lead to an invasive infection, sepsis, and heat loss. Both acute and chronic wounds (present longer than 3 months without healing) cause a systemic response.

Cutaneous Wounds and Involuntary Weight Loss

Defining the Terminology

Involuntary weight loss is the loss of 10% or more of body weight in 6 months, or 5% in 30 days.

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Protein-energy malnutrition (PEM) is the most common form of malnutrition in people with wounds. This pathologic state occurs when the intake of energy and protein is inadequate to meet the body's needs. It is frequently associated with significant involuntary weight loss. The loss of body weight, muscle wasting, poor healing, and the development of chronic wounds along with chronic infections, are due to PEM. Catabolism is defined as tissue breakdown. Anabolism is defined as tissue synthesis. A cutaneous wound is a wound that involves the skin and potentially the underlying soft tissue.[54,55] Cutaneous wound healing is a dynamic interactive process whereby tissue injury is repaired. Acute wounds are wounds that heal rapidly and uneventfully, wounds that heal by the normal healing process, or wounds that are traumatic or accidental in origin or electively produced such as the acute surgical wound (Figure 16 and Figure 17).[49,50] Chronic wounds are those that result in the failure of the normal healing process, lack of any significant healing for a 3-month period despite appropriate local care, chronic inflammation, or bacterial colonization (Table 12; Figure 18).[56,57] Pressure ulcers are localized areas of soft tissue necrosis that tend to develop when soft tissue is compressed between a bony prominence and an external surface for a prolonged period of time (Figure 19 and Figure 20).[58-61] The stages of pressure ulcers are:

dermis.

Stage 1: nonblanchable erythema of intact skin indicative of early skin ulceration. Stage 2: partial-thickness skin loss involving epidermis and variable portions of Stage 3: full-thickness skin loss also involving damage to subcutaneous tissue. Stage 4: full-thickness skin loss with extensive necrosis of underlying fat, muscle, and

bone.

Venous ulcers are full-thickness wounds found on the lower extremities usually over the malleolus (Figure 21).[62-64] They are caused by venous insufficiency, local stasis, edema, and ischemia. Diabetic ulcers are poorly healing ulcers usually on the feet, caused by a combination of diabetic foot neuropathy, bone prominences, and vascular disease leading to ischemia in the soft tissues when compressed against a hard surface (Figure 22).[65,66]

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Figure 16. An acute wound. Healing deep partial thickness burn to the back.

Figure 17. An acute wound. Healing crush injury to leg.

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Table 12. Chronic Wound Characteristics

Local Poor healing in all phases Increased surface inflammation Colonization with microbes Increased surface metalloproteinase activity Decreased growth factor activity Systemic Correlation with PEM and involuntary weight loss and the presence of diabetes PEM, protein-energy malnutrition

Figure 18. Nonhealing amputation site in malnourished patient (local and systemic problem).

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Figure 19. Chronic and progressive stage III-IV pressure ulcer in a patient with severe protein-energy malnutrition.

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Figure 20. Necrotic pressure ulcer on buttocks, likely stage III-IV.

Figure 21. Chronic venous ulcer. Note the characteristic chronic granulation tissue with surrounding thick fibrous tissue.

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Figure 22. Diabetic foot ulcer. Note the callous buildup on edges and pale opposing wound.

Pressure Ulcers: Often a Nonhealing Wound[58-61,67-71]

Historically, the term decubitus ulcer had been used instead of pressure sore. However, decubitus implies bedridden, and many types of wounds with the same pressure-induced etiology occur in nonbedridden patients; thus, the more appropriate term is pressure sore or pressure ulcer.

Pathophysiology

Pressure ulcers are initiated by excessive compression of soft tissues, which decreases blood flow and leads to tissue ischemia, followed by necrosis. A secondary infection is very common, accelerating tissue damage. Invariably, 1 or more comorbid factors are present, which increases the probability of

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continued wound breakdown. Other factors that increase the risk of developing pressure sores are increasing age, skin thinning, weight loss, and vascular insufficiency. The pathogenesis of pressure ulcers consists of more than simply pressure-related necrosis. Skin is usually resistant to this type of destruction, yet these ulcers evolve to include the skin. Once skin destruction occurs, it proceeds rapidly at a pace suggestive of bacterial enzymatic digestion. Bacteria allow many pressure sores to become deeper by further inducing the inflammatory response and resultant enzymatic digestion of normal tissue. Denervated tissue also appears to be much more susceptible to bacterial infection. Lack of adequate nutrition, with significant weight loss, plays a critical role in the development of pressure sores. Patients with weight loss who are malnourished have edema, and skin breakdown occurs readily. They are at higher risk for infection as well as nonhealing ulcers. More than 95% of pressure sores occur below the umbilicus. For supine patients, pressure sores occur over the sacrum and posterior heel. Patients positioned on their side commonly develop ischial pressure sores, and ambulatory patients with diabetes develop pressure ulcerations over their metatarsal.

Management

The most effective way to prevent tissue necrosis is by the intermittent relief of the pressure points for 5 minutes every hour. Maintenance of adequate perfusion in the absence of pressure is a key element in treating ulcers. Restoration of good blood volume and hydration is essential. If healing is impaired in the presence of adequate volume and cardiac output, an assessment of local blood flow is indicated. Peripheral vascular disease or venous stasis will lead to poor healing. Correction of the vascular insufficiency will be necessary for healing to occur. For infected wounds, the goal of treatment is to decrease the bacterial count of the wound tissue. Systemic antibiotics are useful for the treatment of cellulites surrounding a wound, and they may be indicated in the immunocompromised host to prevent cellulites and sepsis. For the wound itself, topical treatment is much more effective at lowering the bacterial count. The most common operative procedure to treat pressure sores is wide debridement. This may include debriding any exposed bone and eliminating dead space using tissue flaps, including myocutaneous and fasciocutaneous flaps. A carefully executed operation can rapidly close many pressure sores, eliminating time consuming dressing changes and metabolic losses inherent in the healing of a large open wound. Neurosensory flaps can be a useful technique in the paraplegic patient if the patient has functioning intercostal nerves. Although these operations do not appear technically difficult, appropriate patient selection is key. Residual comorbid factors such as severe weight loss will result in increased failure. Many patients with pressure sores have had major weight loss and are protein-energy malnourished, resulting in impaired healing. Decreased endogenous anabolism is also present. Anabolic agents have

30

been used with success in these patients. Good nutrition, along with anabolic agents, will accelerate the return of LBM, which in turn will increase the healing of pressure sores (Figure 23 and Figure 24).

Figure 23. The nonhealing wound.

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Figure 24. The healing wound.

PEM and Impaired Wound Healing

There are a number of conditions associated with the development of PEM (Table 13), including catabolic illness such as trauma, surgery, or wounds, involuntary weight loss, chronic illness, increased nutritional losses, and intestinal tract diseases.

Table 13. Conditions Associated With Development of Protein-Energy Malnutrition

Catabolic illness: the stress response (eg, trauma, surgery, wounds, infection, corticosteroids) Involuntary weight loss from any cause (exceeding 10% of ideal body weight) Chronic illness (eg, diabetes, cancer, renal failure)

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Increased nutritional losses from intestinal disease, surgery Intestinal tract diseases impairing absorption

PEM-Induced Altered Body Composition

To understand the impact of the erosion of LBM and the normal or abnormal use of protein and fat for fuel, a general understanding of normal body composition is required. Body composition is divided into fat and fat-free components. Body protein is present in the fat-free or LBM compartment. Fat mass is usually about 20% to 30% of the total. LBM is highly active metabolically and physiologically, and body mass is genetically determined. The LBM is protein and makes up 75% of body weight. There is no real protein store, as every protein molecule has a role in maintaining homeostasis. Loss of any body protein is deleterious. The majority of the protein in the LBM is in the skeletal muscle mass. LBM is 50% to 60% muscle mass by weight, the rest is bone and tendon. Protein makes up the critical cell structure in muscle, viscera, red blood cells, and connective tissue. Enzymes that direct metabolism and antibodies that maintain immune functions are also proteins. It is the loss of body protein accompanying the injury, not fat loss, that produces the complications of malnutrition.[72-74] Fat mass is stored and biologically inactive. Its only role is as a reservoir for calories (Figure 25). The morbidity related to involuntary weight loss is proportional to the loss of LBM as a proportion of the total (assuming the starting point is normal body composition) (Figure 26).[74]

33

Figure 25. What is lean mass and its importance?

34

Figure 26. Complications relative to loss of lean body mass. The extent of LBM loss indicates the morbidity and mortality that can be expected. A decrease of over 10% of total results in impaired immune function and increased infection risk. A decrease exceeding 15% is manifested by further infection risk, obvious evidence of weakness, and a decrease in the rate of wound healing. A decrease in LBM approaching 25% is manifested by profound weakness, infections, and lack of healing. In fact, the development of new wounds or breakdown of prior healed wounds is evident. Further decreases in LBM lead to life threatening infections and a high mortality rate. With a loss of LBM less than 10%, healing of the wound takes priority, using available protein substrate. As LBM is decreased, more consumed protein is used to restore LBM with less being available to the wound. The wound healing rate then decreases until LBM is restored (Figure 27). With a loss of LBM exceeding 20% of total, spontaneous wounds can develop due to the thinning of skin from lost collagen.[73-75]

Figure 27. Priority for protein intake vs percentage of loss of lean tissue. With a loss of lean mass less than 10%, healing of the wound takes priority, using available protein substrate. The impairment of cutaneous wound healing is also proportional to the amount of lost LBM. The wound has priority for protein substrate for healing with an LBM loss of up to 10% of total. With progressive losses, the restoration of LBM increasingly competes with available protein substrate to restore itself. This self-preservation process is aimed at avoiding further morbidity with lost LBM. As the skin protein decreases throughout the body, new wounds will develop and old wounds will reopen.

High-Risk Population for PEM and Impaired Healing

Catabolic Illness-Induced PEM: The "Stress Response"[47,53,76-81]

35

The most common precipitating cause of PEM is an acute injury or illness leading to a "stress response" with resulting hypermetabolism and increased catabolism.[82] This abnormal metabolic response is aggravated by an increase in catecholamines, cortisol and glucagons and a decrease in anabolic hormones, testosterone, and growth hormone. The magnitude of the systemic inflammation is dependent not only on the degree and persistence of the initial insult, but also on the patient's preprogrammed genetic response to a bodily insult (Table 14).[78-81,83-86]

Table 14. Conditions Associated With PEM, Weight Loss, and Impaired Healing[76-79,82,84,87-89]
Patient Population Cause

Severe trauma, infection Catabolic response to the insult is characteristic of this degree of insult Spinal cord injury Acute losses caused by response to injury and immobility; Chronic losses caused by ongoing catabolism and decreased anabolism Chronic care Weight loss is often the reason for lost nontreated PEM; Comorbid factors increase risk of PEM Wound presence often further increases the risk factor Chronic wounds Wound will increase catabolic activity and increase the degree of PEM; Have ongoing needs for increased energy, protein; Often have chronic wound due to PEM

PEM, protein-energy malnutrition Increased local metabolic activity and cellular work is required at the site of injury. The host must reabsorb damaged and devitalized tissue and then the tissues must be repaired. The wound consumes large quantities of energy during the healing process both by the large population of inflammatory cells and by the fibroblasts' production of collagen and matrix. The metabolic and catabolic response is both prolonged in degree and also in time course, lasting weeks to months as opposed to days to weeks with most other results.[79-81,83,84] Of major concern is when the adaptive response to preserve LBM (as seen with starvation) is overridden by the maladaptive hormonal environment, leading to a rapid loss of protein. Under these circumstances, both increased energy and protein production are required. However, the energy production is pathologically altered such that nutrient use to make energy becomes very inefficient. Substrates, mainly pyruvate and fatty acids, recycle back to glucose and fat instead of being metabolized to CO2 and H2O. This results in less adenosine triphosphate, and a wasted increase of energy in the form of heat production.[78-81] More calories in the form of nutrients are needed to keep up with needs, or an energy deficit results. The protein synthesis pathway is inefficient, due to anabolic activity, which results in 20% to 30% of

36

consumed amino acids being used for energy production instead of protein. Decreased endogenous anabolic activity is also responsible for the increased losses of amino acids in the urine.[84]

Persistent PEM and Lost LBM Into the Recovery Phase

A catabolic insult (eg, a hip fracture) results in the "stress response" being activated. The rate of LBM loss can reach 1 to 2 pounds a day, depending on the degree of catabolism and nutritional support. The recovery phase is entered when the catabolic insult has resolved and the metabolic rate is returning to normal. The high net catabolism during the acute phase is not matched by an excess endogenous anabolic stimulus during recovery. In fact, endogenous anabolic hormonal activity may remain low (Figure 28).
[79,86,90,91]

Figure 28. Maladaptive hormonal response.[78-81,83-85] The rate of recovery of LBM and therefore wound healing, if a wound is present, is 5 to 10 times slower than the rate of loss in spite of optimum nutritional support[86,92] unless an exogenous anabolic agent is added to accelerate protein synthesis.[92-96]

Chronic Illness and PEM[96,97]

The presence of a chronic illness (Table 15) can rapidly lead to PEM that continues to worsen, especially in the presence of a wound. Reversal of the process requires optimum nutrition (often supplements) and a resistance exercise program. An anabolic agent may also be beneficial (Figure 29).

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Table 15. Chronic Illness Leading to PEM and Impaired Wound Healing
Cardiovascular disease Chronic obstructive pulmonary disease Diabetes Renal dysfunction Morbid obesity Alcoholism, substance abuse Chronic infection Chronic musculoskeletal problems (eg, osteoporosis) Age-related frailty

PEM, protein-energy malnutrition

Figure 29. Result of adding an anabolic stimulus.

Elderly Patient Population[73,98,99]

With increasing age, there is often a gradual decrease in body muscle mass and a thinning of the dermis layer of the skin due to protein loss. This process is called degenerative aging and is usually found in those 70 years of age and older. The thinning of skin and lost muscle puts the elderly at increased risk for pressure sores. The lost tissue protein is due to a combination of poor nutrition, muscle inactivity, and decreased anabolic activity. However, the degenerative aging process can be controlled with good nutrition and exercise.

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Diabetes Mellitus[65,100,101]

This disease process prevents wound healing through a number of mechanisms:

Increased blood sugar, Decreased activity with LBM loss, PEM, and Impaired local immune defenses.

Progressive loss of LBM and replacement of fat mass is a common problem for people with diabetes. The resulting complications of impaired healing result. In addition, the diabetic person has specific wound healing problems related to the underlying disease. Impaired healing and the diabetic foot ulcer is a common problem. Uncontrolled blood glucose impairs blood flow through the critical small vessels at the wound surface by impeding red blood cell permeability. The increased glucose makes the cell wall rigid, thereby impeding flow. In addition, the hemoglobin release of oxygen is impaired, resulting in an oxygen and nutrient deficit in the healing wound. The diabetes-induced foot neuropathy and resulting vascular ischemia in pressure breakdown are typical. Wound healing now requires close attention to both local and systemic factors. Controlling blood glucose (often more difficult in an injured patient) is essential. PEM is commonly seen in diabetics. Endogenous anabolic activity provided by human growth hormone and insulin are also decreased. Impaired local immune defenses are due to decreased blood flow and decreased neutrophil killing, both secondary to high glucose levels. The treatment for both is increasing muscle mass and controlling blood sugar. The increased muscle mass will more effectively control the blood sugar, decrease fat deposition, and increase endogenous anabolism, which will help the wound healing process. Table 16 summarizes the categories of patients who are at high risk for developing PEM.

Table 16. Summary of High-risk Patients

Acutely Injured or Infected Patient
Cause Treatment

Marked hypermetabolism with energy deficit, stress-induced metabolism leading to rapid lean mass loss, or micronutrient depletion Inactivity leading to muscle loss Decreased endogenous anabolic activity Age-Related Frailty
Cause

Early aggressive initiation of nutrition support (preferably oral) of high-protein, high-energy, micronutrient-rich diet; Nutrient supplements may be required Early initiation of physical rehabilitation and appropriate nitrogen and caloric intake Use of anabolic agents to decrease lean mass loss and more rapidly restore lean mass

Treatment

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Poor nutrition due to disability, chewing and swallowing problems, and significant psychosocial issues Inactivity leading to muscle loss and further inactivity ("cycle of inactivity") Decreased endogenous anabolic activity

Aggressive restoration of high-protein, high-energy, micronutrient-rich diet; early use of ancillary support services Resistance exercise program Use of anabolic agents to restore lost weight and lean mass

Immobility (bedridden or wheelchair-bound individuals)

Cause Treatment

Poor nutrition due to disability, chewing and swallowing difficulties, and significant psychosocial issues Inactivity leading to muscle loss and further inactivity ("cycle of inactivity") Decreased endogenous anabolic activity Diabetes Mellitus
Cause

Aggressive restoration of high-protein, high-energy, micronutrient-rich diet Appropriate physical rehabilitation Use of anabolic agents to restore lost weight and lean mass, as indicated

Treatment

Decreased capillary blood flow from elevated glucose

Careful monitoring and control of glucose; education

Protein malnutrition and decreased muscle mass Increase protein intake to 1.5 g/kg per day Decreased insulin and anabolic hormones Increase exercise; provide adequate insulin; use anabolic agents

Diagnosis of PEM and Involuntary Weight Loss

PEM is defined as inadequate intake of energy and protein to meet bodily needs. The prevalence of PEM in hospitals and chronic care facilities ranges from 20% to 50%, with an even higher incidence in those patients who also have a chronic nonhealing wound. Therefore, a nutritional assessment is essential to determine which patients are at risk for or have PEM. All care providers must play a key role in determining which patients are malnourished or have potential nutritional deficiencies.[73,75,82,98,99,102-107] Because PEM is a metabolic disorder, diagnosis depends on a combination of findings, including the history and physical exam as well as biochemical markers. The latter are often the more sensitive measures. Because this assessment is not an exact science, there are a variety of different scales used for defining the degree of malnutrition.

Physical Examination[73,98,99,102-105]

The routine physical examination should note signs suggesting nutritional deficiencies, including muscle wasting or weakness, dermatitis, ulceration of mucous membranes, delayed wound healing, central nervous system depression, glossitis, and congestive heart failure. However, impaired wound healing is often the first and most predictive diagnostic finding.

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Biochemical Data[99,102-106]

These data are useful, objective, and usually readily available. They are, however, affected by the stress response to injury of infection or other medical conditions. Serum albumin is a common indicator of the patient's protein stores. But because albumin has a halflife of about 20 days, and large amounts are stored in the body, a patient may already be malnourished before serum albumin levels drop. Serum albumin below 3.5 g/dL is considered low and a level below 2.5 g/dL indicates a seriously deficient protein store. Serum transferrin is a more accurate indicator of protein stores. It responds more readily than serum albumin to acute changes in protein status. Serum transferrin has a shorter half-life (8 to 10 days) and smaller body stores than albumin. A serum transferrin level below 200 mg/dL is considered low and below 100 mg/dL is considered severe depletion of protein stores. Serum prealbumin, with a half-life of 2 days, is also a valuable marker. Total lymphocyte cell count is decreased with PEM, as revealed by loss of cutaneous energy or the ability to respond to skin testing. Biochemical data defining severity of PEM are outlined in Table 17.

Table 17. Biochemical Markers of PEM Defining Severity

Index Mild Moderate Severe

Albumin (g/dL)* Transferrin (mg/dL)

2.8-3.5 151-200

2.1-2.7 100-150

< 2.1 < 100

Total lymphocyte count (per mm3) 1200-1500 800-1199 < 800 *Not an early marker of PEM; PEM, protein-energy malnutrition

Involuntary Weight Loss[99,102-108]

One of the most common markers for PEM is unintentional weight loss (Table 18). Defined as 5% loss of body weight in 30 days, 7% loss in 3 months, or 10% loss in 6 months, this amount of weight loss may produce a significant health risk. Assessment should be based on a patient's "normal" weight, not weight just prior to being a wound patient, as weight loss could and likely has already occurred.

Table 18. Unintentional Weight Loss (> 10% in 6 months)

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Patient Population

Incidence

Major burns and trauma 80% Spinal cord injury Chronic care Chronic wounds 50% 25% plus 50% plus

Impaired Healing Caused by PEM With LBM Loss[94,95,103,107-109]

Involuntary weight loss and PEM are correlated with impaired healing of acute and chronic wounds. If severe PEM is present, wounds will spontaneously develop due to loss of skin integrity. The type of wounds and impaired healing often correspond to the degree of PEM and amount of weight loss. Immobility, age, cognitive function, and chronic illness are major contributors. However, a key component is the physical status of these populations and the degree to which impaired healing relates to their nutritional status, body composition, and activity. Therefore, the systemic component of involuntary weight loss and PEM is a common denominator in the impaired healing of all the at-risk populations. In acute wounds, the healing rate will be impaired when losses of LBM exceed 10% of the total. Healing will nearly cease with LBM losses approaching 20%. The acute wound then becomes a nonhealing wound. Other comorbid factors, such as age, immobility, diabetes, and cancer, will further amplify the problem. Chronic wounds, mainly pressure sores, begin to develop as a result of involuntary weight and LBM losses exceeding 20% of total (moderate-severe PEM). As collagen and other proteins in skin decrease with LBM and muscle weakness decreases mobility, wounds begin to develop. These wounds by definition will be nonhealing until sufficient LBM is regained. As weight gain increases, more energy and protein substrate becomes available to the wound (Figure 30, Figure 31, Figure 32, and Figure 33).

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Figure 30. The slow healing cutaneous wound resulting in the presence of involuntary weight loss of moderate severity.

43

Figure 31. A nonhealing cutaneous wound resulting from protein-energy malnutrition of moderate severity.

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Figure 32. Spontaneous skin breakdown in presence of protein-energy malnutrition and progressive loss of lean mass.

45

Figure 33. Severe involuntary weight loss (> 25%) and protein-energy malnutrition resulting in an enlarging pressure ulcer with infection.

Principles of Nutritional Support and Correction of Impaired Healing

The correction of PEM and altered healing is a multifactorial process.[103,104,109-112] The objectives are to:

Control the catabolic state; Restore sufficient nutrient intake to meet current energy and protein needs; Increase energy or calorie intake to about 50% above daily needs to begin the process of weight and LBM gain; Maintain protein intake at 1.5 g/kg per day to allow for restoration of lost LBM; Increase anabolic stimulation (which is abnormally low with PEM) to direct the protein intake into protein synthesis (and restore normal nutrient partitioning); Avoid replacement of lost LBM with fat gain; Use exercise (mainly resistance exercise) to increase the body's anabolic drive; and Consider use of exogenous anabolic hormones to increase net protein synthesis.
Maintaining Efficient Nutrient Use

The processing of nutrients through normal metabolic pathways is categorized into energy production and protein synthesis to replace daily protein losses, thereby maintaining LBM (Figure 34).[79,80,113] The macronutrients are carbohydrates, fat, and protein. The micronutrients are vitamins and minerals. The

46

majority of the calorie or energy needs (the energy compartment) come from the absorption and breakdown of carbohydrates and fat. Excess carbohydrates and fat are converted to fat as a reserve depot. Protein consumed is used mainly for protein synthesis.

Figure 34. Maintaining nutrient use. Protein consumed is digested and absorbed as peptides and amino acids to be used mainly for protein synthesis, thereby restoring and maintaining the LBM compartment (ie, muscle, skin, the immune system, and wound healing). The elderly break down more protein daily and therefore need more protein to be available for the added protein synthesis needed to keep up with losses. Consumed protein is diverted to the LBM compartment by the endogenous anabolic activity of the body, which includes hormones such as testosterone and growth hormone and muscle activity. Only about 5% of protein intake is used for energy or fat (unless there is a very low endogenous anabolic activity, in which more protein will be used for calories). As previously described, 20% to 30% of body protein is used for gluconeogenesis during the "stress response," leading to a rapid loss of LBM. More protein is required, as is more anabolic activity, to control the degree of protein loss.

Assessment of Nutritional Needs[104-107,114]

The assessment of nutritional needs can be divided into several components:

Energy or caloric requirements Protein requirements Micronutrient requirements

47

Degree of PEM

Calculation of energy needs.[83,104-108,115] Daily energy expenditures can be calculated or directly measured. Calculation is usually the preferred approach for the outpatient as the requirement for direct measurement is often available only in an acute care facility. Direct measurement using the method of indirect calorimetry is the most precise approach. The first step in calculating energy expenditure is to determine the basal metabolic rate (BMR) using predictive equations. There are a number of standard equations and tables that predict BMR. The BMR is the amount of energy expended at complete rest, shortly after awakening and in a fasting state for 12 to 18 hours. The second step is to adjust BMR for the added energy caused by the "stress" from injury, wounds, or disease. The metabolic rate (energy demand) increases 20% after elective surgery and 100% after a severe burn. A wound, infection, or traumatic injury will fall between these 2 extremes. One simple formula for defining the stress factor is described below. The stress factor is the multiplier of the BMR (Table 19). To calculate energy expenditure:

Determine BMR Determine activity level as a fractional increase from BMR Estimate stress factor (physiologic factors best defined) Energy expenditure = BMR x activity factor x stress factor

Table 19. Stress Factors Relative to Injury

Stress Stress Factors

Minor injury Minor surgery Clean wound Bone fracture

1.2 1.2 1.2 1.3

Infected wound 1.3 Malignancy Major trauma Major infection Severe burn 1.5 1.5 1.5 2.0

The third step is to determine the physical activity level of the patient. Physical activity is added by multiplying by an activity factor. For example, for ambulatory patients, use a factor of 1.2, and use 1.5 or more for active exercisers. For bedridden nonactive patients, the value would be 1.0.

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Thus, the energy requirements can be calculated as follows: Energy Expenditure = (BMR) x (stress factor) x (activity factor). Malnourished patients who already have a deficit require a 50% increase over calculated maintenance calories (energy). The reference standard for measuring energy expenditure in the clinical setting is indirect calorimetry. [109-111] Indirect calorimetry is a technique that measures oxygen consumption and carbon dioxide production to calculate resting energy expenditure.

Protein Requirements[85,103-109]

After determining caloric (energy) requirements, protein requirements are assessed (Table 20). A healthy adult requires about 0.8 g of protein per kg of body weight per day or about 60 to 70 g of protein to maintain homeostasis (ie, tissue synthesis equals tissue breakdown). Stressed patients need more protein, in the range of 1.5 g to 2.0 g of protein per kg of body weight per day. The increased needs stem from both increased demands for protein synthesis and increased losses of amino acids from the abnormal protein synthesis channeling where a substitute is used for fuel. Urinary nitrogen losses increase after injury and illness with an increase in the degree of stress. Nitrogen content is used as a marker for protein (6.25 g of protein is equal to 1 g of nitrogen). Nitrogen balance studies, such as a 24-hour urinary urea nitrogen measurement, which compare nitrogen intake with nitrogen excretion can be helpful in determining needs by at least matching losses with intake. Nutritionally depleted but nonstressed patients also require at least 1.5 g/kg per day to restore lost body protein. Stressed, depleted patients usually cannot metabolize much more than 2 g/kg per day of protein unless an anabolic agent is added (Table 20). Agents such as oxandrolone and growth hormone will improve net nitrogen balance.[116,117]

Table 20. Protein Requirements

Condition Daily Needs

Stress response

1.5 g/kg to 2 g/kg per day

Correct protein-energy malnutrition 1.5 g/kg per day Presence of wound Restore lost weight Elderly 1.5 g/kg per day 1.5 g/kg per day 1.2 g/kg to 1.5g/kg per day

Micronutrient Support[118,119]

Micronutrients are compounds found in small quantities in all tissues. They are essential for cellular function and, therefore, for survival. Marked deficiencies in key micronutrients occur with severe stress as a result of increased losses, increased consumption during metabolism, and inadequate replacement.

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Because micronutrients are essential for cellular function, a deficiency as seen in PEM further amplifies stress, metabolic derangements, and ongoing catabolism. The micronutrients include organic compounds (vitamins) and inorganic compounds (trace minerals). These compounds are both used and excreted at a more rapid rate after injury, leading to welldocumented deficiencies. However, because measuring levels of micronutrients is difficult, prevention of a deficiency is accomplished only by providing increased intake. Although the doses of micronutrients required to correct PEM are not well defined, a dose 5 to 10 times the recommended daily allowance is usually suggested until the PEM is corrected (Table 21).

Table 21. Vitamins and Minerals Needed to Reverse PEM

Vitamins Vitamin A Vitamin C Minerals Zinc Copper Cofactor for collagen and other wound protein synthesis Cofactor for connective tissue production; collagen cross-linking Stimulant for onset of wound-healing process; stimulant of epithelialization and fibroblast deposition of collagen Necessary for collagen synthesis

Manganese Collagen and ground substance synthesis

Degree of PEM[103,109,110]

The degree of PEM should also be estimated, as this assessment will help to define the appropriate treatment (Table 22 and Table 23) as well as the magnitude of impaired wound healing.

Table 22. Treatment of Mild to Moderate Protein-Energy Malnutrition (weight loss < 15%)
Replacement of an existing loss requires a protein intake of 1.5 gm/kg per day Caloric requirements about 30 kcal/kg per day Begin with multiple small meals using combination of easy-to-digest food and highenergy, high-protein liquid supplements Carbohydrates should make up 55% to 60% of calories, some simple sugar but mostly complex carbohydrates Fat should make up 25% of calories Protein should make up 20% of calories; use proteins of high biologic value, such as milk, eggs, fish, and meat Water: need at least 1 mL of water per calorie

Consider additional use of anabolic hormone to assist in restoring lean body mass

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rather than gaining fat

Table 23. Treatment of Severe PEM (weight loss 20%)

Because of disability, anorexia, and high morbidity risk, enteral +/- parenteral nutrition is indicated Use of tube feeding is preferred until PEM is beginning to resolve Intravenous feedings, if needed Energy requirements and protein requirements are the same as moderate PEM, as patient cannot process any more nutrients until the recovery process is underway

Consider anabolic agent once patient is tolerating nutrient intake goal

PEM, protein-energy malnutrition

Providing Nutritional Support

Table 24 illustrates the method of providing early optimum nutrition to control catabolic illness.

Table 24. Early Provision of Optimum Nutrition

Provide adequate energy and nutrient profile Provide adequate protein Provide necessary micronutrients Use anabolic agents, if needed, to increase the rate of anabolic

activity Provide exercise stimulus to muscles

Macronutrients.[112-115] Understanding of the metabolic changes that occur helps determine the appropriate mix of macronutrients (carbohydrates, fat, and protein) needed to treat PEM. Carbohydrates. Because hormonal imbalance favors excessive glucose production, there is a welldefined limit as to the quantity of carbohydrates that can be effectively metabolized. That value appears to be 7 g/kg to 8 g/kg per day, or 55% to 60% of kcals provided, preferably in the form of complex carbohydrates, using the enteral route. Because of intense anti-insulin activity, insulin is often required. If severe hyperglycemia persists, glucose intake needs to be decreased. Fat. Fat or fatty acids are used to a limited degree, especially when compared with starvation. In addition, certain fatty acids (linoleic, arachidonic) produce immunosuppressive byproducts. No more than 25% of kcals should be provided as lipids. Excess fats will only be stored and can cause a fatty liver.

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Protein. Protein should make up 20% to 25% of kcals because amino acids are used at an excessive rate for fuel and also required for increased protein synthesis. Obviously, not all the protein provided will be used for energy, but 25% of total kcals assures sufficient amino acid availability for both energy and protein synthesis. Micronutrients must be provided as well. Timing. It is essential to initiate nutrient support as soon as possible after a catabolic insult or with evidence of a malnourished state. Nutritional support should begin within 48 hours. A gradual restoration of optimum nutrition is necessary with evidence of severe PEM to avoid a refeeding syndrome. Route. The optimum route is the enteral route either using food and a nutrient supplement or the use of nasogastric tube feeding. The parenteral route is used if the enteral approach does not adequately meet needs (Table 25).

Table 25. Choices for Route of Nutrient Delivery

Route Enteral (first choice) Advantage Route Parenteral (second choice) Advantage Improves nutrient use, especially

protein Protects gut mucosa

Can initiate nutrition if gut not functional Does not require patient cooperation Disadvantage

Disadvantage

Timing

Aspiration Impaired absorption Requires patient cooperation Timing

High infection risk (line sepsis) Other catheter complications

As soon as possible to avoid gut function problems

Postresuscitation (usually day

3) If needed to supplement enteral

route Approach Approach Eating plus nutrient supplements Tube feeding

Central line through nonburn

area Peripheral line for more dilute

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Nutrient Supplements[112,120-124]

It is well recognized that the voluntary intake of food alone is usually insufficient for the increased energy and protein demands of the wound population, especially if PEM is present. This concept is evident in the burn patient; the addition of protein supplements to maintain intake at 1.5 g/kg to 2.0 g/kg per day significantly increased healing rates. Many high-protein supplements were not palatable and only used for tube feeding. There are now flavorful high-protein formulations available. However, not all protein formulations are considered equal. Some proteins and their peptides have a higher biologic value (ie, increased nitrogen retention) based on their structure and composition. In addition, specific peptides can act like growth factors or added anabolic stimuli. Table 26 suggests criteria for choosing nutrient supplements.

Table 26. Nutrient Supplement Selection Criteria

Sufficient protein content Sufficient caloric content Quality of the contained nutrients Route of administration (ie, taken orally or by feeding Palatability (which equates with compliance) Complications

tube)

Water Intake

Water is an essential element for survival and a deficiency leads to a variety of complications.[125,126] Patients with PEM have a greater risk of inadequate water intake due to a variety of reasons. The factors associated with dehydration in PEM are as follows:

Reduced thirst sensation Reduced intake throughout the day Limited access Increased kidney loss due to the aging kidney Lack of replacement after increased gastrointestinal losses Losses from medications, especially diuretics

Recommendations for daily fluid intake are as follows:

25 mL to 30 mL per kg body weight minimum of 1500 mL

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1 mL to 1.5 mL per calorie consumed Replacement of added losses from disease or medications

Dehydration is the most common cause of fluid and electrolyte disturbances.

Anabolic Strategy
The Rationale for the Use of Anabolic Hormones[127-131]

The successful correction of LBM loss and prevention of a severe protein deficiency in the presence of catabolic illness requires an increase in overall anabolism, especially in the presence of a wound to optimize healing. Table 27 and Table 28 highlight the roles and actions of anabolic hormones.

Table 27. Role of Anabolic Hormones

To attenuate the catabolic stimulus during stress To restore lean mass loss more rapidly

To restore normal nutrient partitioning such that protein consumed is not converted to energy and weight gained is not fat mass

Table 28. Actions of Anabolic Hormones

Anticatabolic by decreasing loss of amino acids from the protein synthesis

pathway Anabolic by increasing the rate of protein synthesis

Even in the recovery phase, endogenous anabolic activity remains depressed. This frequently occurs after a severe insult in elderly patients, those with chronic illness, or patients who already have involuntary weight loss (Figure 35 and Figure 36). Adequacy of substrate (1.5 g/kg per day protein) may not be sufficient to jump-start restoration of LBM. However, the body is capable of a very rapid rate of protein synthesis that is not age-dependent if stimulated by anabolic agents. Any patient with PEM and a wound would benefit from a more rapid rate of protein synthesis.[132,133] Body composition studies conducted on patients with PEM demonstrate that a significant portion of weight gain after unintentional weight loss from catabolic disease is fat and extracellular fluid, not added protein mass. Inadequate anabolic stimulation is the cause.

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Figure 35. Energy use from lean body mass.

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Figure 36. Energy demands in the catabolic state. The action of all anabolic agents currently in clinical use is 2-fold. First, amino acids are driven into the protein synthesis channel in the cell through action of cell surface receptors in the LBM compartment. The metabolic pathways used by different anabolic agents to achieve protein synthesis may be different, but the final result is increased body protein. The second action is anticatabolic. All anabolic agents appear to decrease protein degradation, possibly by blocking cell cortisol receptors.[128-133] The negative wound healing effects of cortisol have now been shown to be reversed using an anabolic steroid in corticosteroid dependent wound patients.[132] Anabolic hormones are being used with increasing frequency in populations with LBM loss or existing PEM, along with optimal nutrition and the added anabolic stimulus of resistance exercise (Figure 37).

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Figure 37. The rate of wound healing increased in all patients only after regaining lost lean muscle, using nutrition and an anabolic hormone. [128]

Specific Anabolic Hormones

A number of approaches to increasing anabolic activity are currently available. Several are effective for increasing protein synthesis during both the stress and recovery phases of burn injury. The most promising agents are discussed here. Human growth hormone (HGH).[116,129,131-135] HGH is normally produced by the pituitary gland (0.8 mg per day) and is a potent endogenous anabolic hormone. It is found in highest concentrations in childhood during the growth spurt and gradually decreases with age or chronic illness. HGH binds to specific cell receptors, leading to a host of metabolic effects, some due to direct hormone activity on tissues, especially in the liver. Other effects are due to the release of insulin-like growth factor-1, which has potent wound-healing effects. A number of studies have demonstrated improved wound healing with HGH with a catabolic insult. The metabolic effects of HGH, illustrated in Table 29, spare protein while increasing fat for fuel. Major complications of HGH use are its anti-insulin effect and hyperglycemia (Table 30).

Table 29. Metabolic Effects of HGH

Increased nitrogen retention, protein synthesis

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Increased cell amino acid influx, decreased Decreased urea formation Increased insulin-like growth factor-1 levels Increased fat oxidation, decreased catabolism Increased metabolic rate (10%) Insulin resistance, hyperglycemia

efflux

Table 30. Potential Complications of HGH

Insulin resistance (hyperglycemia) Fluid retention (usually self-limiting) Hypermetabolism

Increased mortality rate in certain critical care population However, HGH is only approved by the US Food and Drug Administration (FDA) for use in shortstature children and needs to be used off-label for PEM. Testosterone.[133,136] In the 1940s, testosterone was found to increase protein synthesis and aided in the production of red blood cells. Testosterone levels fall after severe trauma or critical illness, decreasing anabolic activity during this period of catabolism. Exogenously administered (oral or parenteral) testosterone is rapidly metabolized in the liver, resulting in a half-life of approximately 10 minutes, which is not practical for clinical use. Slow-release testosterone can be injected, but androgenic effects, such as hirsutism, hypersexualism, and mood changes, may occur. Anabolic activity is only modest compared with the testosterone analogs and it is currently not being used to treat PEM or improve healing. Testosterone analogs. Anabolic steroids refer to the parent hormone testosterone or its derivatives. Modifications in the steroid molecule produced a testosterone analog, resulting in increased activity time and anabolic potency. A 17 alpha methyl configuration for oral drugs and a 17 beta ester modification for parenteral agents are the now standard modifications.[137-139] The quality of a testosterone analog is based on the ratio of androgenic to anabolic activity -- the lower, the better. A low value indicates very little masculinizing effects compared with a very potent anabolic effect. A number of studies have documented the beneficial effects of testosterone analogs (mainly use of oxandrolone) on restoring LBM and improving wound healing. The negative effects are high androgenic activity and hepatotoxicity; all the testosterone analogs except oxandrolone are cleared by the liver.[138-144] Table 31 outlines the comparison of androgenic-anabolic activity as well as degree of hepatotoxicity for FDA-approved anabolic steroids.

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Table 31. Anabolic Activity of 17 Methyl Derivatives

Agent Androgenic Anabolic Activity Indications Hepatotoxicity

Testosterone Nandrolone

1:1 1:4-1:25

Hypogonadism Anemia Anemia Loss of body weight from injury or infection Moderate to severe Severe Mild, rare

Oxymetholone 1:3 Oxandrolone 1:3-1:13

Oxandrolone.[129,132,138-144] Oxandrolone is a 17 beta-hydroxy-17 alpha-methyl ester of testosterone, which is cleared primarily by the kidney. Hepatotoxicity is minimal, even at doses higher than the 20 mg per day recommended by the FDA. Oxandrolone is the only steroid in which a carbon atom within the phenanthrene nucleus has been replaced by oxygen. This alteration appears to be responsible for its potent anabolic activity, which is 5 to 10 times that of methyltestosterone. In addition, its androgenic effect is considerably less than testosterone, minimizing this complication common to other testosterone derivatives. The increased anabolic activity and decreased androgenic (masculinizing) activity markedly increases its clinical value. Oxandrolone is given orally, with 99% bioavailability. It is protein-bound in plasma with a biologic life of 9 hours. Its metabolic effects are comparable to HGH in that protein synthesis increases. However, the receptor used is an androgenic receptor found on most cells, especially the cutaneous fibroblast and the myocyte. Also, there are no anti-insulin effects as are often seen with HGH. Contraindications include the presence of hypercalcemia or the presence of a tumor with androgenic receptors, prostate cancer, or male breast cancer.[139] Oxandrolone is the only oral anabolic steroid that is FDA approved for restoration of weight loss after severe trauma, major surgical procedures, or infections. Weight gain is primarily LBM. Clinical trials conducted on a variety of patient populations, including patients with chronic hepatitis, AIDS, and severe burns, have demonstrated a significant weight gain, mainly muscle. LBM gain has been shown to be 4 times that seen with optimum nutrition alone. Oxandrolone has been shown to markedly attenuate postinjury catabolism and has no adverse hepatic effects. As with other anabolic agents, adequate calorie and protein intake is necessary for an optimum effect. The anabolic effect is dosedependent, with a 20-mg daily dose being about 5 to 10 times more potent than 2.5 mg per day. The primary contraindications for oxandrolone use are the presence of carcinoma of the male breast or prostate, as these tumors have androgenic receptors.

Resistance Exercise[145-150]

Resistance exercise, defined as muscle movement against a resistance such as weight lifting, is a potent anabolic stimulus. The mechanism remains unclear but is likely the result of local muscle effects and an overall systemic response. When initiated in the catabolic state, resistance exercise diminishes the degree of protein loss. Increasing LBM in the elderly and chronically ill population by this approach

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can markedly decrease disability. Large-muscle exercise should be given priority, because this training can significantly reduce muscle loss and accelerate gain. In a wound patient population in whom catabolism is pronounced, an aggressive, early program of resistance exercise that continues through the recovery phase is of major importance as an additional anabolic stimulus. In turn, lack of resistance exercise, as occurs with bed rest, a fixed splint, or general inactivity, will lead to muscle atrophy (net catabolism) in addition to that caused by a wound.

Summary
The patient population with wounds, especially chronic wounds, remains a challenge to healthcare providers. The presence of involuntary weight loss and PEM continues to be a major cause of poor wound healing. Recognition and treatment of an underlying systemic nutritional deficiency is essential to decrease the incidence of poor wound healing. The focus of this program was to educate healthcare professionals by describing the normal healing process and the abnormalities produced by undiagnosed PEM. The second objective was to address the loss of LBM, as it is this loss of body protein that affects healing. Also described are the patient populations and disease processes at highest risk for LBM loss. Not only will decreased LBM decrease healing, but also, with further weight loss, wounds will actually develop. The third objective was to discuss the diagnosis and treatment of PEM. The goal is to restore local nutritional weight, restore lost LBM, and improve wound healing. Finally, the rationale for the addition of anabolic agents is to correct LBM loss more rapidly and improve healing. This information should improve the care of the high-risk patient populations with wounds by giving the health professional the information to make a more rapid diagnosis, resulting in better treatment of any underlying nutritional deficiencies.

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Contents of Protein-Energy Malnutrition, and the Nonhealing Cutaneous Wound [http://cme.medscape.com/viewprogram/714]

1.

Protein-Energy Malnutrition, and the Nonhealing Cutaneous Wound [http://cme.medscape.com/viewarticle/418377] 2. The Anabolic Steroid, Oxandrolone, Reverses the Wound Healing Impairment in Corticosteroid-Dependent Burn and Wound Patients [http://www.medscape.com/viewarticle/423228]

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