Definition

A Diabetic foot ulcer (DFU) is a non‐healing or poorly healing, partial or full thickness wound below the ankle, in an individual with diabetes (Lavery 2008; Sanders 2011).

Etiology

Foot ulcers in people with diabetes are diagnosed by taking a history and a physical examination combined with monofilament testing for neuropathy and non‐invasive testing for arterial insufficiency (Armstrong 1998; Kruse 2006). People with diabetes may have either neuropathic, arterial or venous components to their ulcer, or a combination of all three (Nelzen 1993). Neuropathy is a disease affecting nerves, with the symptoms dependent on whether motor, sensory or autonomic nerves are affected (Marcovitch 2006). Long standing hyperglycaemia results in nerve damage associated with autonomic, sensory and motor neuropathy. All three categories of neuropathy can be found in people with diabetes: sensory neuropathy causes a loss of pain sensation; autonomic neuropathy can cause either anhydrosis (dry skin) or hyperhidrosis (excessive sweat), both of which affect skin quality; and motor neuropathy causes weakness of muscles and structural changes to the foot (Merriman 1995).

Peripheral vascular disease (PVD) is the narrowing of the vessels (arteries and veins) in the legs and is common in people with diabetes, with atherosclerosis caused by hypertension being the most common cause of PVD (Marcovitch 2006). Atherosclerosis is an accumulation of cholesterol plaques on the artery walls, or the degeneration of the artery walls caused by hypertension and high cholesterol (Marcovitch 2006; Tortora 2006). Bilateral macro‐ (large vessel) and micro‐ (small vessel) vascular insufficiency is common in people with diabetes due to the prevalence of atherosclerosis.

In people with diabetes, a combination of PVD and neuropathy dramatically increases the likelihood of the development of a DFU. Indeed, the United Kingdom Prospective Diabetes Survey (UK PDS 1998) found in their large, multicentre study of people with newly diagnosed type 2 diabetes that 10% had some level of neuropathy and vascular disease on diagnosis, however it was not stated as to whether this is common in the general population or is specifically related to those with diabetes.

Neuropathic DFUs can be caused by acute mechanical or thermal trauma or from repetitively or continuously applied mechanical stress, whereas ischaemic foot ulcers in people with diabetes are often caused by a single mechanical damage to poorly perfused (and often friable) tissues (Cavanagh 2005). Therefore ischaemic foot ulcers are often caused by a single trauma to poor quality skin and are slow to heal as a result of poor blood supply to the wound, whereas neuropathic DFUs are due to reoccurring pressure and shearing forces and, due to their lack of pain sensation, the person is often not aware of any potential problems until an ulcer has actually formed. Inappropriate footwear and walking barefoot or in sandals are common causes of DFUs (Boulton 2004).

Foot ulcers in people with diabetes can occur regardless of the type of diabetes: type 1 diabetes is caused by an absolute deficiency of insulin secretion; and type 2 is caused by a combination of resistance to insulin action and an inadequate compensatory insulin secretory response (ADA 2008). Several studies have found that the incidence of a foot ulcer is around 82% to 87% more common in people with type 2 diabetes than people with type 1 diabetes; (Jeffcoate 2006; Oyibo 2001b; Piaggesi 1998). Interestingly it has been noted that both type and duration of diabetes has no effect on ulcer outcomes (Abbott 1998; Oyibo 2001b).

Prevalence

Prevalence gives an indication of the total number of cases of disease present at any one time, and includes both old and new cases of the disease (Marcovitch 2006). Prevalence is important as it gives an overall picture of the current disease situation whereas incidence, the number of new cases that occur during a particular timeframe (Marcovitch 2006), is useful when planning for the future and when comparing and contrasting clinical outcomes and auditing care delivery.

Wild 2004 estimates that the global prevalence of diabetes in 2002 was 2.8% or 171 million persons, furthermore, this rate is projected to rise to 4.4% or 366 million persons by 2030. The projected rise in prevalence is based on demographic changes alone and thus is a conservative assumption as it does not include other risk factors such as obesity and reduced physical activity. The International Diabetes Federation (IDF 2012) released less conservative global prevalence estimates of 8.3% or 371,329 persons for the year 2012 and a projected estimate of 9.9% or 551,870 persons by 2030. From an individual country perspective, Diabetes UK estimate that the prevalence in the UK in 2006 was 3.5% and increased to 4.6% in 2012 (Diabetes UK 2006; Diabetes UK 2012). In Ireland, conservative estimates suggest that in 2008, 141,063 or 4.7% of adults had diabetes and in Ireland it is predicted that by 2015, 193,944 or 5.6% of adults will have diabetes (Balanda 2010). The prevalence of diabetes in Canada is also rising from 5.9% or 1.65 million in 2008 to 6.5% or 1.9 million in 2012 (Statistics Canada 2010; Statistics Canada 2013). In 2000, the prevalence of diabetes in Australia was 7.5% (Dunstan 2001). However, the Australian National Health Survey estimates more conservative figures; in 1995 it estimated 2.4% which rose to 3.8% in 2007‐2008 (ABS 2012). The American Diabetes Association (ADA) notes that in 2010, diabetes affected 25.8 million people or 8.3% of the US population, however these statistics are estimates as they include diagnosed and undiagnosed diabetes (ADA 2011). Unlike many countries, incidence and prevalence of diabetes in Scotland is collected on a national level. In 2011, the incidence of diabetes in Scotland was 258,570 or 4.9% of the population (NHS Scotland 2012). In 2011, the European prevalence rate was 8.1% or 52.8 million people (IDF 2012). The European region country with the highest rate of diabetes was Russia with 10% or 12.6 million people; in contrast, Moldova had the lowest rate of just 2.8% (IDF 2012). In 2011, the island nation of Kiribati was the country with the highest world wide diabetes prevalence of 25.7% (IDF 2012).

Diabetic peripheral neuropathy is one of the most common predisposing factors leading to foot ulceration; indeed, people with diabetes are 50 times more likely to develop a foot ulcer than their non‐diabetic counterparts (Tyrell 1999). The prevalence of DFUs in the diabetic population is suggested to range from 3% to 10% (Borssen 1990; NICE 2004; SIGN 2010). However, Singh 2005 argues that rates are much higher, suggesting that the life time risk of a person with diabetes developing a foot ulcer is as high as 25%. Recurrence rates of DFUs post‐healing are very high, at rates of 60.5% and 66% (Hunt 2009; Peters 2007). Furthermore, diabetes is the leading cause of non‐traumatic limb amputation in the world (Tyrell 1999). Within 18 months following amputation, almost 50% of people will develop a DFU on the other limb, and of these people, 58% have further amputations within three to five years. It is worthy of note that the three‐year mortality rate after the first amputation is between 20% and 50% (Boulton 2005; Mulder 2003).

Incidence

The ADA found that 1.9 million new cases of diabetes were diagnosed in people aged 20 years and older in 2010 (ADA 2011). The Scotish incidence of diabetes, across all ages, was 18,985 in 2012 (NHS Scotland 2012). The annual incidence of DFUs is 2.5% to 10.7% in resource‐rich countries (e.g. Australia, Finland and the US) (Hunt 2009). The incidence of lower limb amputation in Scotland was 1359 or 0.6%, however 13,091 or 5.1% of people with either type 1 or type 2 diabetes were recorded to have had a DFU (NHS Scotland 2012).

Health‐related quality of life

DFUs are associated with disability and reduction in health‐related quality of life (HRQoL) (Nabuurs‐Frassen 2005; Ragnarson Tennvall 2000; Siersma 2013). Indeed, the presence of a DFU has been shown to have an independent effect on HRQoL of both patients and carers. The largest impact on HRQoL for patients is related to mobility, with the largest impact on carers being emotional (Nabuurs‐Frassen 2005). Indeed, frequent hospital visits, the need for wound care, and the fear of amputation were among the factors responsible for the impact on carers' HRQoL. For the individual, the longer the DFU is present the greater the burden, with Nabuurs‐Frassen 2005 noting a moderate improvement in HRQoL once the DFU is healed and a further improvement three months post‐healing. Interestingly, Ragnarson Tennvall 2000 identified that patients who healed post‐major amputation have a lower HRQoL than those who heal without the need for an amputation, indicating that the method of healing has an influence on post‐DFU HRQoL. Thus, owing to the negative influences on HRQoL related to the presence of a DFU and its associated treatments, Siersma 2013 argues that to improve HRQoL, treatment should not be only focused on DFU healing, but rather on all aspects of quality of life. This emphasises the importance of adopting a multidisciplinary approach to the prevention and management of the DFU, in order that the needs of the person with diabetes are adequately addressed.

Cost

It is estimated that in 2001, DFUs, excluding amputations, cost the US healthcare system USD 10.9 billion (EUR 8.09 billion) (Gordois 2003a; Shearer 2003), whereas, in the UK, in the same year, Gordois 2003b estimated that GBP 252 million (EUR 300 million) was spent on DFUs. A large European, multicentre, prospective study, averaged the cost of treating a DFU at approximately EUR 10,000, however these costs vary between different outcome group, furthermore, the data were derived from seven countries including both low and high cost countries (Prompers 2008). In general, however, it is suggested that the costs attributed to the diabetic foot in the US and Europe are as high as 20% (7% to 20%) of total diabetes expenditure (Apelqvist 1994; Girod 2003; Gordois 2003a; Gordois 2003b; Harrington 2000; Saar 2005; Sedory‐Holzer 1998; Shearer 2003; Van Acker 2000; Van Houtum 1995; Vozar 1997).

Duration of DFU influences the cost of overall treatment, and Apelqvist 1994 noted that 54% of people with a DFU heal within two months, 19% heal in three to four months and 27% heal in more than five months. A more recent prospective study (Zimny 2002) found the average DFU duration was 133 days for ischaemic wounds, 123 days for neuroischaemic wounds and 77 days for neuropathic wounds. Furthermore, the costs rise markedly with DFU severity (Gordois 2003a). For example, a retrospective cost analysis (Sedory‐Holzer 1998) noted an incremental cost increase related to the progression of DFU from Wagner grade 1 to Wagner grade 5. Management of Wagner grade 1 or 2 averaged at USD 1929 (EUR 1426.25) compared to Wagner grade 5 which averaged at USD 15,792 (EUR 11,683.93). A more recent study (Stockl 2004) also found a correlation between costing's and Wagner grade where the cost of Wagner grade 1 averaged at USD 1892 (EUR 1399) and Wagner grade 5 averaged USD 27,721 (EUR 20,509). Furthermore, Reiber 1995 noted that the cost for a major amputation doubles that of a minor amputation USD 12,879 compared to USD 26,940.

Eighty per cent of people with diabetes live in low and middle income countries (IDF 2013). Amputation and death are common outcomes of ulceration in Tanzania where treatment is inaccessible or unavailable to many (Abbas 2005). The availability of diabetes treatments and care in developing countries is a broad subject but perhaps low tech approaches such as nutritional intervention could be of particular benefit in these settings.

Classification

DFU status is recorded and monitored using a classification system (Oyibo 2001a). There are several different systems in use currently, however none is universally accepted and different centres use different systems (Schaper 2004). Despite this, Oyibo 2001a highlights the Wagner Wound Classification (Wagner 1981) and the University of Texas (UT) Diabetic Wound Classification system (Lavery 1996) as two of the most widely used and well established classification systems available. Detailed scoring systems, such as the UT system, offer a valuable method for comparison of data from different diabetic foot centres, however simplistic scoring systems, such as the Wagner system, may be used in clinical practice (Karthikesalingam 2010).

Pillars of diabetic wound healing

HbA_1c is an index of the average blood glucose concentration over approximately the preceding six weeks (Kumar 2005). Control of HbA_1c is paramount in wound healing, and poor metabolic control has long been associated with non–healing wounds (Boyko 1999; Greenhalgh 2005). In addition to HbA_1c control offloading, debridement (the mechanical removal of foreign material and damaged tissue from a wound (Marcovitch 2006)) and infection control are seen as the corner stones to foot ulcer treatment in people with diabetes. Other supplementary interventions are also used in the treatment of DFUs such as hyperbaric oxygen therapy (Abidia 2003; Faglia 1996), growth factors (Tsang 2003) and tissue‐engineered skin (Marston 2003). The role of nutrition in the treatment of DFUs has largely been under researched, as the focus of nutrition has tended to be on achieving tight control of HbA_1c.

Oral nutritional support

NICE 2006 lists fortified food, additional snacks and sip feeds as methods of oral nutritional support (ONS). Some ONS products are nutritionally complete and can be taken to supplement the diet, or as a sole source of nutrition, however others only contain certain nutrients and are designed to supplement the diet (Bowling 2004). Standard ONS includes polymeric‐, peptide‐, or amino acid‐based (types of protein) supplements and also those where novel substrates have been added, such as glutamine (an amino acid synthesised within the body from glutamic acid and used in preventing immunosuppression after exercise and as an aid in recovery after a critical illness (Marcovitch 2006)), fish oils, arginine or antioxidants. We will include nutrient‐based novel substrate in this review. We will exclude prebiotics, probiotics and synbiotics as they are not nutrients. Schrezenmeir 2001 describes prebiotics, probiotics and synbiotics as non‐digestible food ingredients.

Enteral

Enteral tube feeding is the delivery of a nutritionally complete feed via a tube into the stomach, duodenum or jejunum (NICE 2006). NICE 2006 recommend enteral tube feeding for those requiring long‐term (four weeks or more) nutritional support.

Parenteral

Parenteral nutrition is the method of providing nutritional support to an individual whose gastrointestinal tract is not functioning or is inaccessible (BDA 2001). Nutrients are delivered directly into the circulatory system via a dedicated peripherally inserted central catheter (BDA 2001). NICE 2006 suggests that micronutrients, trace elements, electrolytes and nutrients can be added to parenteral feeds to meet the patient's individual needs. Parenteral nutrition is considered a short‐term method of nutritional support (less than 14 days), however in very special considerations it may be used as a long‐term method (NICE 2006).

NICE 2006 advises the use of oral, enteral and parenteral nutrition alone, or in combination, for people who are either malnourished or at risk of malnutrition. However, Gottschlich 2001 argues that enteral nutrition is superior to parenteral nutrition, particularly during the early phase of wound healing.