Chapter 3, Examination and Evaluation of the Patient with a Wound, presented the two questions that need to be answered in order to successfully treat a patient with a wound: (1) Why does the patient have a wound? and (2) Why is the wound not healing? Once a wound diagnosis has been determined and standard care has been initiated, the wound should progress through the stages of wound healing discussed in Chapter 2, Healing Response in Acute and Chronic Wounds. When progress is not observed, the second question—Why is the wound not healing?—becomes even more imperative to answer. Sometimes the wound will respond initially and make measureable progress, then stall again for no apparent reason. This chapter focuses on those factors that are known to impede wound healing, some more obvious than others, and provides suggestions on how to identify and minimize the effect on the healing process. The factors are categorized into infection, medications, nutritional deficits, comorbidities, and extrinsic/psychosocial behaviors.

TABLE 11-1 provides laboratory values, always a good starting place for solving the conundrum, with normal values, trends that are typical when a patient does not have the normal healing response, and clinical presentations that accompany abnormal lab values. CASE STUDY

INTRODUCTION

Mr RG is a 45-year-old male with a 3+ year history of a non-healing wound on the right anterior leg (FIGURE 11-1). His medical history includes the following:

• 
  

  History of HIV for more than 15 years

  
  
• 
  

  History of Kaposi sarcoma on the right anterior leg at the site of the current wound, treated with radiation and chemotherapy (doxol or doxorubicin)

  
  
• 
  

  History of recurrent cellulitis, treated with both IV vancomycin and oral Xyvox

FIGURE 11-1

Case study at the time of initial evaluation Non-healing wound on the lower extremity of a patient with multiple factors that impede wound healing.

His HIV status is controlled with medication; he has an undetectable viral load and a low white count (≤3).

DISCUSSION QUESTIONS

1. 
   

   What subjective information is needed to determine the factors that have prevented this wound from healing?

   
   
2. 
   

   What questions would be helpful in obtaining this information?

   
   
3. 
   

   What tests and measures are indicated in order to establish a plan of care?

Definition of Terms

Pathogens, defined as any microorganism that can cause disease in its host, can either damage or infect any wound tissue, or they can adhere to and colonize the wound surface. One distinguishing feature of pathogenic (vs nonpathogenic) microorganisms is their ability to evade the host innate and adaptive immune defenses. Pathogens have developed a variety of strategies to avoid immediate destruction by the host, including covering themselves in a thick polysaccharide capsule termed biofilm,^1,2 or in the case of mycobacterium (eg, Mycobacterium leprae, Mycobacterium tuberculosis), growing inside the macrophage phagosomes while inhibiting the phagosomal acidification and subsequent fusion with lysosomes.³ Bactericidal agents (eg, toxic oxygen-derived products, nitric oxide, AMPs, and enzymes) are released by the phagocytic cells and are intended to render the invader harmless; however, these agents have consequences—they damage the surrounding host tissue and may potentiate the chronic proinflammatory state observed in chronic wounds (see FIGURES 11-2 and 11-3).

Just as the skin is known to have certain flora residing on the surface, so the wound bed has a variable amount of microbial presence that is defined as contaminated, colonized, critically colonized, or infected (see TABLE 11-2). The effect of the microbes on the wound bed is dependent on the type of bacteria, the number of colony-forming units (CFUs) per gram of tissue, and the host immune system. Colonization and critical colonization may respond to topical antimicrobials (see Chapter 13, Wound Dressings)²; infection and sepsis require that the patient receive systemic antibiotics specific to the invading microbe.

Bacterial Infection

The innate immune response is initiated with the engagement of primary host cells and conserved bacterial components, defined as the repetitive arrays of carbohydrates, lipids, and proteins that are contained in the bacteria cell walls. These repetitive arrays are termed pathogen-associated molecular patterns (PAMPs) and the receptors that recognize them are termed pattern recognition receptors (PRRs). Host cells (eg, macrophages) constitutively express PRRs that recognize essential and highly conserved microbial components. The PRRs recognize the microbe by contact with its living extracellular components or its phagocytosed components after it has been ingested. Although the PRRs have a limited degree of specificity, they are specific enough to engage the host innate immune system.

Gram-positive bacteria carry a number of proinflammatory cell wall components including peptidoglycan (PGN), teichoic acid, lipoteichoic acid, and other surface proteins. Gram-negative organisms express an extremely potent proinflammatory lipopolysaccharide (LPS). As a result, the evolution of the host innate immune system includes separate and distinct, although sometimes overlapping, sets of sensors to detect the components of both gram-positive and gram-negative organisms. The detection of the organism then sets into motion a cascading proinflammatory response from resident macrophages and leukocytes.¹ Bacteria are further characterized as aerobic (needing oxygen to survive) and anaerobic (able to survive without oxygen), and can coexist in chronic wounds, especially if there is necrotic tissue present.⁴ TABLE 11-3 provides a list of bacteria most commonly found in chronic wounds.

Biofilms

Colonizing pathogens establish an attachment to the host epithelium or wound surface that is composed of an exopolymeric matrix of polysaccharides, proteins, and DNA synthesized by the bacteria.⁴ The substance is adherent to the wound bed, providing an environment for the bacteria to live and replicate, and thus it is not easily removed by mechanical force or competing bacteria. Studies indicate that the first microorganism to establish host attachment has an advantage over subsequent colonizers even though competition of bacteria often occurs at the level of attachment to host receptors.⁵ The biofilm can sometimes resemble a layer of slough on the wound surface, or it can be invisible (FIGURE 11-4). In order for the wound to progress from chronic to healing, the biofilm must be removed, preferably with sharp debridement as most antimicrobial dressings will not penetrate the biofilm to kill the bacteria although they can suppress biofilm formation.²

Fungus Infections

Fungus infections are an increasing problem, especially among patients who are immunosuppressed or have transplants. Recent studies indicate that the fungal response to phagocytosis actively modulates the host immune cell function. Fungal pathogens avoid detection by masking PAMPs (such as cell wall carbohydrates), and by down-regulating the complement cascade. Once detected, various species of fungi actually interfere with phagocytosis and can repress production of antimicrobial substances like NO. Some fungi successfully replicate while inside the host macrophage. It is becoming readily apparent that fungi manipulate the host–pathogen interaction to their advantage (FIGURE 11-5).⁶

In the wound care clinic, they are sometimes observed in conjunction with compression therapy, especially if using dressings and systems that stay in place up to 7 days. The moisture of both wound drainage and perspiration creates an environment where fungi thrive. The infection can usually be managed with a topical antifungal medication, adequate absorbent dressings to manage the wound fluid, and more frequent dressing changes.

Identification of an infected wound is not always easy for even the most astute clinician. The most common signs are persistent periwound erythema, drainage, epidermal sloughing, odor, and failure to respond to standard care. Friable granulation tissue in a previously progressing wound bed is another sign of infection. Specific to the diabetic foot ulcer, erythema that extends more than 2 cm from the edge of the wound is highly correlated with infection; and if the wound can be probed to bone, there is a possibility of osteomyelitis.⁷ Accurate identification of any bacteria or fungi that is impeding wound healing is necessary for effective treatment, and effective treatment is necessary for wound healing to progress. A recent study found that swabs and biopsies yield the same culture results when taken from the same location, suggesting that biopsies are indicated only when needed for a pathological diagnosis, not for bacteria identification.⁸

Steroids

Anti-inflammatory steroids, including glucocorticosteroids, are known to significantly affect many aspects of wound healing. When steroids have been part of the patient’s medication regime prior to wounding, the elevated corticosteroid levels delay the appearance of inflammatory cells and fibroblasts; decrease the deposition of ground substances and collagen; and inhibit angiogenesis, wound contraction, and epithelial migration (FIGURE 11-6A, B).^9,10 The effect of steroid-mediated, delayed healing has been demonstrated to occur largely through the down-regulation of TGF-β and ILGF-1 and is apparent in all phases of wound healing. The effects of TGF-β on ECM formation are more profound than any other growth factor, and in the absence of TGF-β, matrix deposition and angiogenesis are impaired.¹¹ Specifically TGF-β is mitogenic for fibroblasts and stimulates the production of fibronectin and collagen. Insulin-like growth factor (ILGF-1) is a major regulator of wound healing. Wounds deprived of 90% of their IGFs demonstrate impairment in cell replication and deposition of collagen and a constitutive decrease in wound macrophage numbers. ILGF-1 also directly engages fibroblasts, endothelial and epithelial cells.^12,13 CASE STUDY

The following subjective information was obtained at the time of the evaluation:

• 
  

  Works as a landscape artist

  
  
• 
  

  Spends a lot of time standing and walking

  
  
• 
  

  Is compliant with all medications, takes vitamins

  
  
• 
  

  Works out at the gym 3–4 days a week

  
  
• 
  

  Eats a healthy diet

  
  
• 
  

  Has no history of smoking; occasional alcohol

  
  
• 
  

  Has no history of drug abuse

The following objective information was obtained:

• 
  

  Wound size: 2 × 2 cm

  
  
• 
  

  Friable granulation tissue that bled very easily

  
  
• 
  

  Periwound erythema

  
  
• 
  

  Moderate serous drainage

  
  
• 
  

  Moderate pitting edema with severe venous reflux

  
  
• 
  

  2–3/10 pain with touch or prolonged standing

  
  
• 
  

  3+ dorsalis pedis and posterior tibialis pulses

  
  
• 
  

  No hair growth on the periwound skin

DISCUSSION QUESTIONS

1. 
   

   What red flags indicate that critical colonization or infection may be present?

   
   
2. 
   

   What risk factors does the patient have that make him susceptible to infection?

   
   
3. 
   

   Are referrals to a medical specialist indicated? Which ones?

The wound healing trajectory is affected in several ways in patients who have been or are currently taking steroids. Decreased leukocyte infiltration, delayed insufficient inflammatory response to injury, and reduced autolysis of necrotic tissue are characteristics of a dampened response early in the healing process. The healing process and clearance of the debris and/or pathogen are inhibited secondary to decreased macrophage recruitment and proliferation. In the proliferative phase of healing the effects of steroids can be observed in the formation of less ground substance, decreased angiogenesis, and diminished fibroblast function, which directly decrease the amount of collagen synthesis. Fibroblasts do not differentiate into myofibroblasts, thus decreasing wound contraction and overall tensile strength. The effects of steroids on each phase of wound healing may lead to vulnerability for ulcer recurrence.¹⁴

Numerous studies have looked at the results of orthopedic surgery on patients (specifically with rheumatoid arthritis) who are on anti-inflammatory medications, either steroidal or disease-modifying antirheumatic drugs (DMARDs) such as methotrexate. A study on adverse events with craniovertebral junction fusion concluded that prednisone dosages <7.5 mg and/or methotrexate were safe with no effect on outcomes, whereas daily prednisone dosages >7.5 mg may impact clinical outcomes, as measured by the Nurick score.¹⁵ Three studies on postoperative complications (surgical site infections and delayed wound healing) on patients taking DMARDs found no statistically significant difference in wound healing in those patients taking the medications.^16–18 In their review of perioperative use of DMARDs on patients undergoing plastic surgery, Tsai and Borah¹⁹ suggest that in younger patients who have been placed on the medications recently, “it is reasonable to withhold therapy based on 3–5 half-lives of the specific agent,” whereas in older patients with more advanced disease, discontinuing therapy must be carefully considered by the patient and the rheumatologist. However, a conflicting case study reported failure of a skin graft on a patient taking methotrexate.²⁰

Two specific guidelines were issued by the British Society for Rheumatology: (1) methotrexate is unlikely to increase the risk of surgical complications if continued,²¹ and (2) anti-TNFα drugs (infliximab, etanercept, adalimumab) “should be withheld for 2–4 weeks prior to major surgical procedures” and resumed when wound healing is satisfactory.²² The decisions regarding steroid management for patients with chronic wounds demand careful consideration and observation from all the medical providers involved in their care.

Another potential side effect of long-term corticosteroid use that may affect wound healing is the development of drug-induced diabetes. This condition may not be diagnosed initially; therefore, if a patient receiving corticosteroid therapy has poor wound healing, monitoring blood glucose levels is advised. In addition, patients on steroids develop thin fragile skin that is at risk for skin tears (FIGURE 11-7).

Nonsteroidal Anti-Inflammatory Drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to treat both autoimmune diseases and acute injuries because of their ability to decrease inflammation, prevent disease progression, and mitigate pain. (See TABLE 11-4 for a list of commonly used NSAIDs.) These medications work by inhibiting both COX-1 and COX-2 enzymes, thereby decreasing the production of prostaglandins and leukotrienes.²³ The positive therapeutic effects of decreased production of prostaglandins are well known; however, the negative effects on wound healing are especially evident when given long-term and in higher doses.^24,25 The mechanisms through which wound healing may be impeded include the following:

• 
  

  Decreased production of thromboxane A₂, which decreases platelet aggregation and increases the propensity for bleeding and hematoma formation, especially postoperatively²⁶

  
  
• 
  

  Inhibition of hyaluronic acid production with less granulation formation during the proliferative phase of healing

  
  
• 
  

  Decreased neutrophil migration to the wound site with increased risk of infection

  
  
• 
  

  Decreased collagen synthesis with decreased tensile strength of new tissue

The results of several studies have led to the recommendation that NSAIDs be discontinued 1–4 weeks before surgery, depending on the half-life of the drug being taken by the patient, and some suggest that they should be withheld after surgery until the incision has healed.^14,27,28 Many of the studies are based on animal models and results are sometimes inconsistent, so the decision to discontinue their use before surgery needs to be weighed against the effects on the patient’s pain and disease progression.

Some of the clinical signs that may be observed if the NSAIDs are affecting wound healing include failure to progress through inflammation to the proliferative phase, tissue that bleeds easily, poor-quality granulation tissue that will not support re-epithelialization, tendency to develop infections, and vulnerability to break down during the remodeling phase (FIGURE 11-8). Patients who are taking NSAIDs for pain relief and not for anti-inflammatory effects may have better healing by substituting acetaminophen, especially if the NSAID dosage is high. If patients are on high doses of any anti-inflammatory medications, it is advised that they be tapered off in order to avoid side effects of sudden withdrawal.

Anticoagulants

Anticoagulants (eg, warfarin, apixaban, rivaroxaban, and dabigatran) inhibit the coagulation cascade and thereby may prevent fibrin deposition and delay the healing process.^24,29 Two patient populations that were found to have significantly higher rates of postoperative wound and bleeding complications were women who received anticoagulation during pregnancy and required Cesarean delivery³⁰ and patients who were female and/or received oral anticoagulation and had lower extremity bypass surgery for critical limb ischemia. This does not undermine the importance of continuing anticoagulation therapy for those patients who require it for cardiac or thrombosis reasons. For any patient undergoing surgery and on anticoagulation therapy, the decision to continue medication during the perioperative period requires careful consultation between the surgeon and the prescribing physician to consider benefits and potential complications.

Cutaneous reactions to anticoagulation that have been reported are heparin-induced bullous hemorrhagic dermatosis, hematomas, ecchymoses, erythematous plaques, nodules, contact dermatitis, and urticarial,³¹ as well as warfarin-induced skin necrosis (FIGURE 11-9). Although these conditions are rare, they are differential diagnoses to be ruled out in patients who develop skin necrosis, especially within 2 weeks of initiating therapy.³²

Antirejection Medications

The hallmark of successful organ transplantation is suppressing the immune system so that the host does not activate the immune cells to a level sufficient to reject the allograft. TABLE 11-5 provides a list of commonly used antirejection medications; most of which act by interfering with “discrete sites in the T- and B-cell cascades.”³³ Specifically, the actions include inhibition of cytokine transcription, inhibition of nucleotide synthesis, inhibition of growth factor signal transduction, inhibition of the stimulation of T-cell interleukin (IL)-2 receptor sites, and diminished chemotaxis.^33,34 In addition, the effects of the corticosteroids include decreased counts of lymphocytes, monocytes (thus decreased macrophages), and basophils while increasing the number of senescent cells.³⁵ These altered cellular functions are known to impede wound healing, resulting in frequent dehiscence of the transplant surgical incision (FIGURE 11-10).

Acute adverse effects of the antirejection medications may include increased risk of infection; nausea, vomiting, and diarrhea; and loss of appetite, all of which result in a diminished nutritional state with subsequent insufficient calories, proteins, and vitamins needed for incisional healing (FIGURE 11-11).

Because antirejection medications are required for the life of the recipient, the effects on wound healing are long term and may result in chronic wounds. This is especially a problem if the patient develops drug-induced diabetes. Another long-term effect of the medications is a significantly higher rate of aggressive squamous cell carcinoma (SCC), a malignant skin cancer linked to the increased number of senescent cells,³⁵ and an oxidative environment.^36,37 Careful skin inspections are advised in order to detect SCC in the early stages and to increase survival rates.

Diabetes

Diabetes has multiple inhibitory effects on wound healing, including neuropathic, macrovascular, and microvascular changes, as well as altering cytokine and growth factor signaling. Regardless of the etiology of the wound (surgical, neuropathic, pressure, venous, arterial, acute, or chronic) the patient with diabetes or routinely uncontrolled blood glucose levels is at risk for delayed healing. At the cellular level, diabetes is associated with decreased PDGF receptor expression³⁸ on epithelial and endothelial cells, thereby altering the wound healing process at the initial phase of hemostasis. In addition, patients with diabetes exhibit a prolonged inflammatory phase attributed to the following: CLINICAL CONSIDERATION

Even though they are acting as a foreign body, the blue sutures in a transplant incision cannot be removed because they are anchoring the deep fascial layers. Discussion with the surgeon will give the clinician direction on when and if sutures can be removed.

1. 
   

   A disproportionate expression of vascular cell adhesion molecules by endothelial cells, which increases extravasation and inflammatory cell accumulation at the wound site.

   
   
2. 
   

   The presence and increased infiltration of wound-activated macrophages (WAMs), which contribute to an increased and prolonged expression of inflammatory cytokines.^39,40

   
   
3. 
   

   Higher levels of neutrophil-formed extracellular traps (termed NETs⁴¹).

In the proliferative phase, diabetic wounds exhibit the following characteristics:

1. 
   

   Increased accumulation of fibrotic ECM at wound edges results in stalled keratinocyte migration (FIGURE 11-12).⁴²

   
   
2. 
   

   Impaired fibroblast signaling (FGF—FGFR) further contributing to poor granulation tissue formation.^43,44

   
   
3. 
   

   Glycation of the ECM, which causes ECM instability and disrupts matrix assembly and interactions between collagen and proteoglycans.⁴⁵ The ECM instability is compounded by the fact that high glucose levels stimulate MMP production by fibroblasts, macrophages, and endothelial cells.⁴⁶

   
   
4. 
   

   Poor ECM maturation secondary to elevated MMPs and reactive oxygen species (ROS) from inflammatory cells. Early cell senescence diminishes the effectiveness of newly arriving progenitor cells and biases the local cellular environment toward one of oxidation and proinflammation.³⁵ The triad of early cell senescence, diminished cell proliferation, and impaired cellular migration escalates the challenge of wound healing in the patient with diabetes.⁴⁷

Finally, there is an altered sensitivity to VEGF⁴⁸ resulting in decreased endothelial progenitor cell numbers and recruitment in response to injured tissue, thereby leading to poor revascularization. The impact of these cell signaling defects by wound healing phase is illustrated in FIGURE 11-13.

The American Diabetes Association (ADA) and the American College of Endocrinology (ACE) have established guidelines for blood glucose and hemoglobin A1C levels for patients with diabetes in order to minimize complications (TABLE 11-6). The ACE recommends that postoperative blood glucose levels be maintained at less than 180 mg/dL and further states that patients with hyperglycemia have higher infection rates.⁴⁹ Clinically, patients with diabetic foot ulcers who have A1C levels less than 7.1% have shorter healing times than those who have higher levels, and patients with higher A1C levels had more frequent ulcer recurrence.⁵⁰ Another review recommended that pre-surgical glucose levels be maintained in the 100–180 mg/dL range in order to prevent infection, decrease the risk of hypoglycemia, and prevent dehydration as a result of osmotic diuresis.⁵¹

An extensive review of diabetes and diabetic foot wounds is found in Chapter 7. However, the effect of diabetes, sometimes undiagnosed, on poor wound healing regardless of the wound etiology is a factor that always needs to be considered, especially if the patient has a known or suspected risk for diabetes or has a family history of diabetes.

Obesity

The health consequences of obesity include a range of negative outcomes, including cardiovascular disease,⁵² diabetes,^53,54 physical limitations,⁵⁵ and decreased mobility.⁵⁶ Excess body weight influences the onset and progression of chronic illness through multiple pathways.⁵¹ Adipose tissue is active, releasing nonesterified fatty acids, hormones (including leptin, glycerol, proinflammatory cytokines, eg, tumor necrosis factor-α), interleukin-6, and chemokines (including monocyte chemotactic protein-1), as well as other bioactive mediators.^57,58 In overweight or obese individuals, the increased number of adipocytes results in higher levels of all of these factors, thereby changing the regulation of basic physiologic processes at a systemic level,⁵⁷ and supposedly at the local level of the wound environment as well. CASE STUDY

As treatment continued on the lower extremity wound of Mr RG, it was noted that the wound was granulated but not epithelializing. The patient had not reported diabetes at the time of evaluation, and did not have the bodybuild or diet to indicate he was high risk for diabetes. However, in exploring every possible cause of poor healing, in addition to the radiated tissue, the patient reported that his grandmother had diabetes with lower extremity complications that led to amputation. He agreed to have his fasting blood glucose levels tested and did indeed have type 2 diabetes. He initially tried to control his blood glucose levels with diet and exercise; however, when he developed other medical issues including a gastrointestinal bleed, he required oral medication.

DISCUSSION QUESTIONS

1. 
   

   What are the mechanisms by which diabetes impedes wound healing?

   
   
2. 
   

   What are the visible signs that would indicate a wound is not healing because of diabetes?

   
   
3. 
   

   What risk factors does this patient have for diabetes?

There is now evidence that obesity also contributes to delayed wound healing by creating an aberrant low-level inflammatory state.⁵⁹ In addition, studies have shown that obese patients have higher risks for surgical site infections, wound dehiscence, and delayed wound healing.^60–62 This may be in part due to the decreased vascularity of adipose tissue with relative decreased oxygen tension, resulting in decreased collagen synthesis, decreased immunity to infection, overall decreased ability to support the processes of wound healing, and increased tissue necrosis (FIGURE 11-14).⁶³ The decreased vascularity may be inherent (with chronic low-grade inflammation and increased glucocorticoids that suppress angiogenesis) or acquired (as a result of surgical and trauma tissue injury that disrupts the adipose tissue); however, either mechanism can disrupt the normal healing process.⁶³ The heightened inflammatory state can also result in part from chronic venous insufficiency and thereby affect wound healing, especially in the lower extremities. The specific mechanisms involved in the chronic low-grade inflammatory process have been studied primarily in obese mice studies and have consistently shown increased proinflammatory cytokine production resulting from the activation of invariant natural killer T cells by the excess lipid.⁶³ Other inflammatory mediators that have been shown to increase with obesity include angiotensinogen, tumor necrosis factor alpha, leptin, interleukin 6, and transforming growth factor beta.^59,64 In addition, decreased adiponectin concentration (which occurs with obesity even though it is produced by adipocytes) impairs adequate profusion and wound epithelialization.⁶³ Other factors that may cause wounds or impede wound healing in the obese population are the prevalent comorbidities, non-adherence to treatment plans, poor nutrition, increased risk of friction/shear with resulting pressure ulcers, and confirmed infection.⁶⁵ Most strategies to address poor wound healing in the obese have concentrated on maintaining blood glucose levels, proper nutrition for optimal healing, preventing infections, and meticulous wound care. However, one animal study using obese mice suggests that physical exercise may help improve cutaneous healing in obese individuals.⁵⁹ Research on both cellular causes and interventions and holistic treatments such as exercise is still investigational but much needed, given the increased prevalence of obesity in our society.

Protein Energy Malnutrition

Healing a wound without protein is like building a house without bricks and lumber—amino acids are the building blocks needed for growth of new tissue, as was so exquisitely detailed in Chapter 2. Ingested proteins are metabolized into amino acids and peptides that serve as enzymes, hormones, cytokines, growth factors, and components of antibodies, all of which play a very important role in tissue maintenance and wound healing. Patient populations who are known to be at risk for protein energy malnutrition (PEM), defined as inadequate energy and protein intake to meet bodily demands, include the elderly,⁶⁶ HIV-positive patients,⁶⁷ and liver/cirrhosis patients (FIGURE 11-15).⁶⁸ TABLE 11-7 lists the protein requirements for wound healing, and when these proteins are not available from daily nutrition, they are taken from the skeletal muscle stores.

The normal body is 75% lean body mass (protein and water) and 25% fat (the calorie reservoir). If there is loss of lean body mass, the host takes precedent over the wound and healing will not occur (FIGURE 11-16).⁶⁹ TABLE 11-8 provides the relationship between loss of lean body mass and wound formation and/or healing. Laboratory values used to detect or measure PEM are given in TABLE 11-1, and include albumin, prealbumin, transferrin, and retinal binding protein. Albumin is commonly measured especially as an indicator for chronic malnutrition; however, it has the disadvantage of having a long half-life (20 days) and may not accurately reflect the protein substrates available for healing if the patient is acutely ill, dehydrated, or in hepatic or renal failure.⁷⁰ Advantages of prealbumin include the following: has a short half-life (48–72 hours), is not affected by dehydration or renal failure, does not increase with stress, decreases with sepsis and stress, and is easily monitored. Therefore, it is considered a more accurate reflection of a patient’s nutritional status.⁶⁹ Transferrin is a glycoprotein that binds and transports iron, and its level decreases with inflammation and malnutrition. However, it is less reliable (may increase with iron deficiency) and more expensive, thus not used as frequently as the other measures.^71,72 Retinal binding protein levels have been shown to decrease with protein malnutrition and vitamin A deficiency, and it is especially sensitive in patients with acute stress, inflammation, and infection, as well as in women and children.⁷³

Recent literature discusses the limitations in using these values to determine malnutrition because the inflammatory process can affect these levels in almost all chronic conditions, terming the values “negative acute-phase reactants” and, thus, no longer valid to use alone as a basis for providing nutritional interventions.^74,75 In 2012 the Academy of Nutrition and Dietetics (Academy) and the American Society for Parenteral and Enteral Nutrition (ASPEN) released a joint consensus statement that proposes a three-pronged etiology-based definition of malnutrition (TABLE 11-9), as well as the following six characteristics for the diagnosis:

• 
  

  insufficient energy intake

  
  
• 
  

  weight loss

  
  
• 
  

  loss of muscle mass

  
  
• 
  

  loss of subcutaneous fat

  
  
• 
  

  localized or generalized fluid accumulation that may sometimes mask weight loss

  
  
• 
  

  diminished functional status as measured by hand-grip strength.⁷⁵

Guidelines state that the presence of two or more of these criteria constitutes a diagnosis of malnutrition. Thus, one of the most important aspects of diagnosing malnutrition is the subjective patient history (including recent food intake, unintentional loss of body weight, medications), physical examination, and functional assessment. CLINICAL CONSIDERATION

For very active patients, for example, runners, who are having difficulty with wound healing, assessing the caloric intake with the energy expenditures during exercise may be helpful, in which case limiting the exercise until wound healing is completed may be the solution.