Nutrition in Wound Healing for Adults with Diabetes: A Practice Update

Definitions

An ulcer present for more than three months is defined as a chronic ulcer⁶, while a chronic wound is defined as one which persists for more than six weeks or recurs frequently⁷.

The Wound Healing Society classifies ulcers into four groups: pressure ulcer, diabetic ulcer, venous ulcer and arterial insufficiency ulcer⁸. Alternatively, ulcers can be classified  based on their cause including vascular (venous, arterial or mixed), neuropathic (diabetes, tabes, syringomyelia), metabolic (diabetes, gout, prolidase deficiency), trauma-related (pressure, injury, burns), infection-related (bacterial, fungal, protozoan), tumours (basal or squamous cell carcinomas); haemotological; pyoderma, panniculitis and hypertensive ulcers⁶.

Pressure ulcers occur when capillary blood flow is cut off from the tissue, from inside to outside⁹. They are directly caused by pressure, friction, shear, immobility, loss of sensation or combined pathology¹⁰. Indirect causes include poor nutrition, mobility problems, health conditions (e.g. diabetes, renal or cardiovascular disease, incontinence, ageing skin and mental health conditions)¹⁰. They generally occur in the coccyx, scapula, greater trocanter, occiput, elbows, heels and knees^{9, 10}.

Diabetes-related foot ulcers generally occur on the plantar surface of the foot. They are caused by suboptimally managed diabetes, arterial insufficiency, peripheral neuropathy or when the calf-pump mechanism fails due to obstruction (Deep Vein Thrombosis (DVT) or extraluminal masses), regurgitation (valve weakness), venous incompetence (proximal DVT), vein weakness (primary varicose vein syndrome) or muscle failure (ankle trauma or surgical fusion)^11-13.

Venous leg ulcers, the most common type of leg ulceration in the lower limb, occur as a result of venous insufficiency, venous hypertension and/or valve and calf muscle pump failures^{6, 12, 13}. These are usually chronic and differ from neuropathic and arterial ulcers¹⁴.

Arterial ulcers are the second most common type of lower extremity ulcers and develop as a result of insufficient perfusion and oxygenation to the dermis or due to arterial ischaemia/occlusion which can likely result in limb loss^{12, 13}.

Neurotrophic foot ulcers are due to peripheral neuropathy resulting in loss of sensation^{12, 15}. Inadequate care (not wearing footwear/inappropriate footwear, not inspecting feet for dryness, cracks, injuries, calluses, not keeping the feet clean) in diabetic neuropathy can trigger new wounds due to loss of sensation/pain^{12, 13, 16}.

Factors affecting wound management

There are several intrinsic and extrinsic factors that affect wound management^{17, 18}. They include:

• type and location of wound¹
• duration of the wound¹⁹
• the type of tissue involved¹
• whether or not there is inflammation or infection¹
• the level of moisture/hydration of the wound¹
• person associated factors such as weight, hydration and nutrition status, exercise, glycaemic management, smoking^{1, 20}
• other metabolic management and psycho-social support²¹

Figure 1. Reproduced with permission from Pressure ulcers, JAMA, January 8, 2003: Vol 289, No.2

The relationship between nutritional status and wound healing has been well researched, but it is not commonly considered in practice. Ongoing chronic wounds deplete lean body mass and affect mobility, pain and quality of life, particularly in the elderly²². Most published studies do not provide details of populations studied, the nature of the wounds (aetiology, stage of wound, etc), anthropometry or details of diet or nutrient intake^{23, 24}. While a number of studies use oral nutrition supplements, enteral or parenteral nutrition, they appear to consider them as a single nutrition entity rather than the combined complex nutritional therapy that they can provide^23-25. Moisture, mobility, sensory perception and activity are potential confounders in these studies²³.

Nutrition in wound care is multifaceted as it involves different nutrients in various roles and stages of wound healing^{16, 26, 27}. Immune function, wound tensile strength, and collagen synthesis are all influenced by nutrition^{26, 27}. Some nutrients are required only in situations of deficiency, while others are conditionally essential^{16, 27, 28}. Adequate quantities of all nutrients are necessary and have a therapeutic role at the cellular/extracellular level^{25, 27}.  There is an important place for a complete diet in wound care, with all nutrients being considered^{14, 27}.

Phases of wound healing

The wound healing process involves different nutrients in different phases of wound healing^{16, 26, 28}. The first phase is haemostasis which starts at the time of injury and lasts several hours^{26, 28, 29}. During this phase there is formation of platelet plug and coagulation through vascular spasm^{18, 26, 29}. The inflammatory phase begins at the time of injury and may last up to six days, when there is proliferation of metabolic mediators and a fibrin clot forms as a protective barrier for haemostasis^{16, 18, 26, 28-30}. The next phase is the proliferative phase which starts three to five days after injury and may last up to three weeks^{16, 18, 26-29}. During this phase fibroblast formation, angiogenesis, epithelialisation and collagen cross linking result in wound contraction^{16, 18, 26-31}. This is followed by the remodelling phase approximately two weeks post injury, which can last up to two years^{18, 26-29}. Collagen maturation and stabilisation during this phase results in wound tensile strength and scar formation^26-30.

Figure 2. The NPUAP of pressure ulcer stages

Reproduced with permission from Ovid: How to assess pressure ulcers. Nursing Made Incredibly Easy!.7(6):20-25, November/December 2009. DOI:10.1097/01.NME.0000363319.70905.96

Role of nutrition in wound healing

The protracted nature of the wound healing process underscores the need for wound prevention, preparation (as in surgical) and treatment of acute and chronic wounds^{16, 30}. Nutritional risk factors that delay/impair wound healing include malnutrition (which could include under-nutrition, over-nutrition and nutrient deficiencies)^{14, 25-28, 32-34}, loss of appetite, dysgeusia, anosmia, inability to feed oneself, poor dental health, inadequate or excessive intake of macro and micronutrients and poor hydration^{16, 25-27, 30}. In addition, delayed treatment, advancing age, stress, memory impairment, alcoholism and smoking, medication side effects, medical, psychological, physiological, physical, social and economic difficulties can often compound the problem^{16, 25-30}.

Clinical markers are more commonly used than diagnostic markers in determining malnutrition³². Diagnostic markers of malnutrition are confounded by chronic infection or inflammation, other protein losing enteropathies, altered hepatic function and altered fluid status/shifts^{16, 26-28, 33}.  Checking Body Mass Index, C-reactive protein, albumin and pre-albumin levels have been suggested to monitor malnutrition status in people with wounds^{26-28, 33, 35}.

Nutrition interventions should be individualised based on current body weight, age, multi-morbidities, activity level, stage of wound, severity, and number of wounds^{16, 26-28, 30}. Nutrition support in wound healing should meet the increased energy and protein needs^{27, 33}. Macronutrients such as carbohydrates, proteins, fats and their distribution; micronutrients such as vitamins A,D,E,K and C, minerals such as iron and zinc, and hydration all play a vital role in wound healing^{16, 25-28, 30, 33-36}.

Role of nutrients

There is an increased need for energy in wound healing to promote anabolism and reverse catabolism³⁵. Energy requirements for adults are around 30-35kcals/kg or 40cals/kg if underweight¹⁶, while older Australians need around 20-25kcals/kg ²².

Carbohydrates are an essential component of immunological, hormonal, enzymatic function and cell structure^{16, 22}. They trigger insulin production which is useful in the proliferative phase as it is anabolic¹⁶. However, hyperglycaemia due to excess intake of carbohydrates (in diabetes) increases the risk of infectious complications and decreases granulocyte function¹⁶. Besides diabetes-induced hyperglycaemia, blood glucose can be elevated due to use of steroids, antibiotics, dextrose infusion in people without diabetes, infections and other physiological stressors increasing cortisol levels¹⁶. A diet with lower glycaemic index carbohydrate choices helps to manage blood glucose levels, but this is also dependent on its distribution across the day, meal combinations and several other factors. A meal plan with 40-50% carbohydrates is recommended^{22, 26, 32}. Grains, starchy vegetables, fruit and legumes are the main sources of carbohydrates in the diet^{28, 35}.

Proteins are essential for tissue growth, repair and regeneration thus vital for wound healing. Proteins provide amino acids and inadequate intake results in lean body mass degradation, increased skin fragility, decreased immune function and decreased reserve capacity due to microangiopathy, thus delaying wound healing and recovery^{16, 18, 22, 25-28, 30, 32-35}. Essential amino acids are building blocks of cells, extracellular matrix and granulation tissue proteins³⁷. If plasma proteins such as albumin is lost in the urine (proteinuria), this results in reduced oncotic pressure, increased capillary filtration and excess fluid build-up (peripheral oedema) in the tissues which delays venous wound healing¹⁶. Deficiency of proteins impairs fibroblast proliferation and collagen synthesis during the proliferative phase¹⁶. Protein requirements are around 1-1.5g/kg body weight for wounds without exudates and up to 2g/kg body weight for wounds with exudate²². More than 2g/kg of body weight is known to increase oncotic pressure¹⁶ affecting hydration and delaying wound healing²². Meal plans should contain 20-25% protein²² from animals sources (meat, fish, chicken, eggs, dairy, etc.), and/or vegetarian sources (legumes, nuts, soy products²⁸, etc.), whey or plant based protein powders and protein isolates³⁵. In some studies, certain amino acids, such as Arginine and Glutamine, have been shown to enhance wound healing^{16, 18, 24, 28, 33}, leading to some wound specific oral nutrition supplements containing these nutrients^{18, 22, 24, 33, 35}.

People with impaired renal function like acute kidney injury (AKI), chronic kidney disease (CKD) and end stage renal disease (ESRD) are pre-disposed to several types of wounds³⁸. The risk factors for poor wound healing in this group among others include suboptimally managed diabetes, ageing, trauma, burns, vasculitis, pharmacotoxicity, chronic venous insufficiency, neuropathy and peripheral arterial/vascular disease. In ESRD, uraemia, uraemic pruritus and calciphylaxis impair wound healing. Researchers report that people on haemodialysis lose 6-8g of protein/procedure while those on peritoneal dialysis lose 8-20g/day from the peritoneal cavity³⁸ adversely affecting wound healing. Hence nutrition supplementation is important and needs to be monitored carefully. Proteins along with fat-soluble vitamins (A, D, E, K), water-soluble vitamins (B, C) and minerals (potassium, phosphorous, zinc, selenium, iron) are altered during the process of dialysis and need to be replenished/maintained at adequate levels for optimal wound healing³⁸. In CKD stage 1 and 2 proteins are not usually restricted for wound healing and is the same as in healthy individuals with chronic wounds³⁹. While in CKD stage 3 and 4 recommendations vary from 0.6-0.75g/kg of body weight to limit urea accumulation in the body³⁹.

Fats provide signalling molecules and energy thus sparing proteins for wound healing and structural functions during tissue growth^{16, 22, 26-28}. They assist with absorption of fat-soluble vitamins, which produce important precursors in the inflammatory phase¹⁶.  Higher intakes of monounsaturated fats and omega-6 fatty acids are thought to promote wound healing due to the presence of essential fatty acids²². While omega-3 supplementation in some studies has been shown to decrease wound tensile strength^{16, 33}, it has also been shown to decrease pressure ulcer progression, when combined with omega-6 fatty acids^{16, 37}. Total intake of fat per meal should be 25-30% of total energy, with the majority of fats coming from polyunsaturated and monounsaturated sources. Deep sea fish, avocado, nuts and oilseeds are excellent sources of these fats³⁵.

Vitamins and minerals have a range of functions including maintaining epithelial mucosal cells, stimulating collagen synthesis, facilitating immune function and improving wound healing and oxygenation. Micronutrient deficiencies delay wound healing^{16, 18, 22, 25-28, 33-35}. In people with renal impairment the renal mechanisms to prevent hypervitaminosis is affected, therefore it is necessary to use caution during supplementation³⁸.

Vitamin A stimulates epithelial growth, fibroblasts, and ground substance, increases monocytes and macrophages in the inflammatory phase, facilitates epithelial cell differentiation and has an anti-inflammatory effect on open wounds^{16, 33}.  Deficiency of vitamin A alters B and T-cell function and, antibody production in the inflammatory phase, while also impairing collagen synthesis in the remodelling phase^{16, 18, 28}.

B-group vitamins act as coenzymes in the production of energy from macronutrients, maintain and support metabolic rate, maintain healthy muscle and skin tone, support immune and nerve function^{28, 34, 35}. Folate and vitamin B6 are required in the production of red blood cells, while riboflavin and thiamine are needed for collagen formation and cross-linking^{18, 28, 34, 35}. Meat, fish, dairy, some grains, vegetables and brewer’s yeast are good sources of vitamin B³⁴.

Vitamin C influences collagen formation, antioxidant function and immuno-modulation in wound healing^{16, 18, 28, 33, 34}. Deficiency of this vitamin impairs the immune response in the inflammatory phase, reduces collagen tensile strength and synthesis, and increases capillary fragility in the proliferative and remodelling phases^{16, 18, 28}. For wound healing there is a recommendation to provide 500-1000mg vitamin C daily in divided doses and up to 2g/day in severe wounds (burns)¹⁶.

Vitamin D is involved in inhibiting secretion of calcitonin and parathyroid hormones (which increases calcium uptake and metabolism). These hormones are involved in neuromuscular and immune function, bone and cartilage remodelling necessary for wound healing³⁴. Vitamin D also induces an anti-microbial peptide cathelicidin which promotes wound healing¹⁶, and vitamin D’s receptor signalling modulates structural integrity in addition to epithelial barrier transport function in wound repair^{16, 28}. Fatty fish, beef liver, eggs³⁴ and certain mushrooms⁴⁰contain vitamin D.

Vitamin E is an antioxidant needed for fat metabolism and collagenation^{18, 35}. It also stabilises cellular membrane integrity^{28, 33}.

Vitamin K is needed for coagulation and bone metabolism during the haemostasis phase of wound healing³⁴. Meat, dairy, eggs, avocado, green leafy vegetables, parsley and kiwi fruit are rich sources³⁴.

Minerals like zinc, selenium and iron may have a role in wound healing:^{18, 32, 33} as anti-oxidants and cell replication modulators, tissue repair and growth promotors and in nucleic acid metabolism^{16, 18, 28, 33}. All phases of wound healing are affected by zinc deficiency: in the inflammatory phase, higher susceptibility to infections and lower immunity; in proliferative phase, impaired wound tensile strength and collagen formation; and in the remodelling phase, reduced fibroblast proliferation, epithelialisation and collagen production¹⁶. Current recommendation for zinc supplementation, if deficient, is 40-220mg/day in divided doses for two weeks^{16, 34}. Excess supplementation interferes with iron and copper absorption^{16, 18}. Selenium has some antioxidant function which is beneficial in wound healing^{16, 34}. Iron as a co-factor in collagen synthesis is thought to have a beneficial effect in wound healing^{16, 18} but supplementation has not shown any benefit. In people with iron deficiency anaemia (known to impair wound healing) there is tissue hypoxia and supplementation increases oxygen transport to proliferating tissues^{16, 34}.

In CKD, sodium, potassium and phosphorous may need to be limited as these affect the kidneys and also delay wound healing^{38, 39}.  Supplemental nutrients are only recommended if there is a clinically diagnosed deficiency. Both overfeeding and underfeeding micronutrients (by supplementation) can deter wound healing^{23, 38}. It is, however, important to ensure that a nutrient dense diet including wholegrains, proteins, dairy, vegetables and fruits provide these essential vitamins and minerals.

Hydration is very important in wound healing²⁸ as fluids maintain skin turgor³² and promote tissue perfusion and oxygenation¹⁶. Blood flow and nutrient supply to the wound is affected by poor hydration thus slowing the progress of wound healing. Both over-hydration and dehydration can affect wound healing negatively³⁵. There are three types of hydration issues: hypotonic, hypertonic and isotonic³⁵. Water acts as a carrier solvent to transport nutrients and other molecules in and out of cells³⁵. Recommendations are 35ml/kg of body weight of water for adults and 30ml/kg of body weight for people over 55 years, with a minimum of 1.5-2L/day²². In certain clinical states such as cardiac or renal conditions, fever, diarrhoea³², vomiting and diuresis¹⁶ there are individual variations, while with extensive exudates, fluid requirements could be higher^{22, 32}. Generally for hydration water is preferred to other fluids¹⁶ except in under/malnourished states.

In cases of chronic alcohol consumption or alcoholic cirrhosis, liver and serum have depleted zinc and selenium levels, and supplementation improves nutrient levels and wound healing¹⁶. Narcotic use (prescription/recreational) can result in glycaemic variations, inadequate oral intake, constipation, nausea and anorexia, leading to increased nutritional deficiencies and delayed wound healing¹⁶.

The impact of nutrition on wound healing highlights the need for nutrition assessment and intervention to be part of standard practice in all phases of wound care to support optimal wound healing^{16, 22, 25-28, 30, 32-35}. A detailed nutrition assessment conducted by a dietitian^{16, 28, 35} will identify the needs of an individual requiring nutritional support for wound care (including requirements for normal function, tissue regeneration, tissue repair and replacement of nutrients lost in wound exudates)^{23, 26}. Measurement of nutrient losses is based on wound size and exudate volume¹⁴. Regular monitoring of nutrition is also valuable to prevent a decline in nutrition status, which can delay wound healing, affect quality of life and increase costs for both the client and the health system^{26, 27}.