Nutrition, Anabolism, and the Wound Healing Process: An Overview

Robert H. Demling, MD

ePlasty. 2009;9:65-94.

Abstract and Introduction

Abstract

Objective:To develop a clear, concise, and up-to-date treatise on the role of anabolism from nutrition in wound healing. Special emphasis was to be placed on the effect of the stress response to wounding and its effect.
Methods: A compilation of both the most important and most recent reports in the literature was used to also develop the review. The review was divided into sections to emphasize specific nutrition concepts of importance.
Results: General and specific concepts were developed from this material. Topics included body composition and lean body mass, principles of macronutritional utilization, the stress response to wounding, nutritional assessment, nutritional support, and use of anabolic agents.
Conclusions: We found that nutrition is a critical component in all the wound healing processes. The stress response to injury and any preexistent protein-energy malnutrition will alter this response, impeding healing and leading to potential severe morbidity. A decrease in lean body mass is of particular concern as this component is responsible for all protein synthesis necessary for healing. Nutritional assessment and support needs to be well orchestrated and precise. The use of anabolic agents can significantly increase overall lean mass synthesis and directly or indirectly improves healing by increasing protein synthesis.

Introduction

Optimum nutrition is well recognized to be a key factor in maintaining all phases of wound healing. There are 2 processes that can complicate healing. One is activation of the stress response to injury, and the second is the development of any protein-energy malnutrition (PEM).

Any significant wound leads to a hypermetabolic and catabolic state, and nutritional needs are significantly increased. The healing wound depends on adequate nutrient flow (Fig 1). Of particular concern is the presence of any PEM, PEM being defined as a deficiency of energy and protein intake to meet bodily demands. PEM in the presence of a wound leads to the loss of lean body mass (LBM) or protein stores, which will in and of itself impede the healing process. Early aggressive nutrient and micronutritional feeding is essential to control and prevent this process from developing. PEM is commonly seen in the chronic wound population, especially the elderly, disabled, or chronically ill populations where chronic wounds tend to develop.^[1–5]

(Enlarge Image)

Figure 1.

Balance between adequacy of macronutrients and net anabolism and catabolism and its impact on wound healing.

Hunter, in 1954, followed by Culbertson and Moore, identified the fact that a wound being a threat to human existence takes preference for the available nutrients to heal, especially amino acids, at the expense of the host LBM.^[6–8] This process leads to an autocannibalism of available LBM to obtain the necessary amino acids for the required protein synthesis in the wound. If inadequate intake is present to keep up with needs, then PEM can develop. If inadequate glucose is available for the healing wound, proteins will break down into amino acids and through the alanine shunt lead to glucose synthesis by the liver. However, with severe losses of LBM, the host takes preference over the wound.^[9–13]

This entire process is the result of the activation of the "stress response" to injury or wounding with its hormonal imbalance favoring body protein catabolism for substrate, needed for protein synthesis. There is also increased metabolic or calorie demand.^[9–13]

There is a fundamental difference between the adequate intake seen in the unstressed patient and one where trauma or infection has activated the host stress response.^[14,15] Starvation alone produces a self-protective hormonal environment, which spares LBM with more than 90% of calories obtained from fat.^[14–16]

To optimize healing, a substrate that is more dependent on intake than on the bodily breakdown of protein needs to be available. Chronic wounds are more complicated because the biology of the healing process is significantly altered. However, a stress response is activated with any wound and any existing PEM will accentuate the already poor healing process.^[17–19] For the above reasons, one cannot dissociate the normal process of healing from the nutritional status.

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Table 1. Conditions associated with development of protein-energy malnutrition
Catabolic illness, "the stress response," eg, trauma, surgery, wounds, infection, corticosteroids
Involuntary weight loss exceeding 10% of ideal, for any reason
Chronic illnesses, eg, diabetes, cancer, mental impairment, arthritis, renal failure
Wounds, especially chronic
Increase in nutritional losses; open wounds, enteral fistulas
Intestinal-tract diseases impairing absorption

Table 2. What maintains lean mass
Intense genetic drive to maintain essential protein stores
Anabolic hormones that stimulate protein synthesis
Resistance exercise
Adequate protein intake to meet the demands

Table 3. Methods routinely available to assess body composition
Method	Description	Advantage	Disadvantage	Precision (coefficient of variation), %
Measurement of skin-fold thickness	Thickness of subcutaneous	Easily performed with portable equipment	Possibility of error and interobserver variability in measurement	5–10
Bioimpedance analysis	Low-level current is introduced, and measurements of impedance are used to calculate fat and fat-free mass	Easily performed with portable equipment, used to calculate body cell mass	Results will be affected by hydration	< 5
Nitrogen balance	Measurement of nitrogen intake minus urinary nitrogen loss to determine net nitrogen gain or loss	Easy to perform, indicates a real time evaluation of lean body mass	Not totally reliable, as there are other nitrogen losses besides urine	10–15

Table 4. Complications relative to loss of lean body mass*
Lean body mass (% loss of total)*	Complications (related to lost lean mass)	Associated, mortality, %
10	Impaired immunity, increased infection	10
20	Decreased healing, weakness, infection, thinning of skin	30
30	Too weak to sit, pressure sores develop pneumonia, no healing	50
40	Death, usually from pneumonia	100

*Assuming no preexisting loss.

Table 5. Major metabolic abnormalities with response to injury "stress response"
Increased catabolic hormones (cortisol and catechols)
Decreased anabolic hormones (human growth hormone and testosterone)
Marked increase in metabolic rate
Sustained increase in body temperature
Marked increase in glucose demands and liver gluconeogenesis
Rapid skeletal muscle breakdown with amino acid use as an energy source (counter to normal nutrient channeling)
Lack of ketosis, indicating that fat is not the major calorie source
Unresponsiveness of catabolism to nutrient intake

Table 6. Weight versus basal metabolic requirement
Body weight, kg	50	55	60	65	70	75	80
Normal basal metabolic rate, kcal/d	1310	1410	1600	1600	1700	1780	1870

Table 7. Objectives of nutritional assessment
Control the catabolic state
Restore sufficient macronutrient intake to meet current energy and protein needs
Increase energy intake to about 50% above daily needs, restore adequate calories to respond to wounding or to begin the process of weight and lean mass gain
Increase protein intake to 2 times the recommended daily allowance (0.8 g/kg/d), ie, to 1.5 g/kg/d to allow for restoration of wound healing and any lost lean body mass
Increase anabolic stimulation to direct the substrate from protein intake into protein synthesis
Avoid replacement of lost lean mass with fat gain
Utilize exercise (mainly resistance exercise) to increase the bodies anabolic drive to maintain and more rapidly regain lean mass
Consider use of exogenous anabolic hormones to increase net protein synthesis

Table 8. Calculation of energy expenditure (calories)
Determine BMR
Determine activity level as a fractional increase from BMR
Estimate stress factor (caused by wound)
Energy = BMR × stress factor × activity factor

BMR indicates basal metabolic rate.

Table 9. Calculation of stress factors
Stress insult	Stress factor
Minor injury	1.2
Minor surgery	1.2
Clean wound	1.2
Bone fracture
Infected wound	1.5
Major trauma
Severe burn

Table 10. Protein requirements
Condition	Daily needs, g/kg/d
Normal	0.8
Stress Response	1.5–2
Correct protein-energy malnutrition	1.5
Presence of wound	1.5
Restore lost weight	1.5
Elderly	1.2–1.5

Table 11. Essential micronutrients for wound healing
Vitamins
Vitamin A	Stimulant for onset of wound healing process
Vitamin A	Stimulant of epithelialization and fibroblast deposition of collagen
Vitamin C	Necessary for collagen synthesis
Minerals
Zinc	Cofactor for collagen and other wound protein synthesis
Copper	Cofacter for connective tissue production
Copper	Collagen cross-linking
Manganese	Collagen and ground substance synthesis

Table 12. Carbohydrate role in the wound
Energy production
Lubricant matrix
Transport
Immunologic
Hormonal
Enzymatic

Table 13. Properties of glutamine
1. Anabolic, anticatabolic
2. Stimulates human growth hormone release
3. Acts as Antioxidant
4. Direct fuel for rapidly dividing cells
5. Immune stimulant
6. Shuttle for ammonia
7. Synthesis for purine and pyrimidines

Table 14. Zinc properties
Cofactor for many protein synthesis pathways and DNA synthesis collagen production
Stimulates reepithelialization
Cofactor matrix metalloproteinase activity
Cofactor superoxide dismutase and glutathione with antioxidant activity
Augments immune function

Table 15. Arginine effects
Precursor of proline in collagen
Precursor for nitric oxide
Increases hydroxy proline production
Stimulates release of wound anabolic hormones insulin, insulin like growth factors, and human growth factors
Local immune stimulant for lymphocytes
A conditionally essential amino acid

Table 16. Anticatabolic and anabolic micronutrient support
Amino acids
Glutamine	Decreases net nitrogen loss
	Increases net muscle protein synthesis
	Nitrogen carrier
	Stimulates human growth hormone release
Arginine	Decreases net nitrogen loss
Antioxidants
Vitamins A, C, E, B; carotene, Zn, Cu, Se	Decreases net oxidant-induced protein degradation
Protein synthesis cofactors
Zn, Cu, Mg, vitamin B complex	Improve protein synthesis pathways

Table 17. Micronutrient support of the hypermetabolic state: energy production
Vitamin B complex		Daily dose
Thiamine	Oxidation reduction reactions	10–100 mg
Riboflavin	Oxidative phosphorylation for adenosine triphosphate production	10 mg
Niacin	Electron transfer reactions for energy production	150 mg
Vitamin B₆	Transamination for glucose production and breakdown	10–15 mg
Folate	One carbon transfer reaction required for all macronutrient metabolism	0.4–1 mg
Vitamin B₁₂	Coenzyme A reactions for all nutrient use	50 μg
Vitamin C	Carnitine production for fatty acid metabolism	500 mg to 2 g
Minerals
Selenium	Cofactor for fat metabolism	100–150 μg
Copper	Cofactor for cytochrome oxidase for energy production	1–2 mg
Zinc	Cofactor for DNA, RNA, and polymerase for protein synthesis	4–10 μg
Amino acids
Glutamine	Nitrogen shuttle for glucose amino acid breakdown, urea production, direct source of cell energy	10–20 g

Table 18. Anabolic hormone activity
Increased anabolism	Direct wound effect
Insulin	Yes	Unclear
Human growth hormone	Yes	Unclear
Insulin-like growth factor-1	Yes	Yes
Testosterone	Yes	No
Anabolic steroids	Yes	Yes

Table 19. Metabolic effects of human growth hormone
Increases cell uptake of amino acids
Increases nitrogen retention
Increases protein synthesis
Decreases cortisol receptor activity
Increases releases of Insulin-like growth factor-1
Increases insulin requirements
Increases fat oxidation for fuel, decreasing fat stores
Increases metabolic rate (10%–15%)
Produces insulin resistance, often leading to hyperglycemia

Table 20. Clinical effect of anabolic steroids
Attenuate the catabolic stimulus during the "stress response"
More rapid restoration of lost lean mass
Restore normal nutrient partitioning
Improved healing of chronic wounds with restoration of lost lean mass

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