DIABETES COMPLICATIONS

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CHAPTER 5 DIABETES COMPLICATIONS

Erectile dysfunction 155

Injection sites 160

Vascular emergencies 160

OVERVIEW

NSF

In this section, specific complications associated with diabetes are discussed. Most of the mechanisms are vascular and the interventions will include components that reduce cardiovascular risk or improve glycaemic control. The assessment and interventions should be structured and follow agreed pathways.

EYES

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RATIONALE

Diabetes has long been associated with eye problems, including retinopathy, cataracts and glaucoma. Individually or collectively, these problems can lead to visual loss. Diabetic retinopathy is a specific vascular complication of diabetes and is the most common cause of newly registered cases of blindness (12%) in those aged 20 to 64 years in the UK (Evans et al 1991). In type 2 diabetics, glaucoma and cataracts are a more frequent cause of visual loss than retinopathy, but the latter is already present at diagnosis in one-fifth of patients (Macleod et al 1994) and its prevalence relates directly to the duration of diabetes.

Among the risk factors associated with the development and progression of diabetic retinal disease in type 2 diabetics are: raised blood pressure (UKPDS 1998c), increased duration of diabetes (Klein et al 1984), and the presence of microalbuminuria (Savage et al 1996).

The St Vincent Declaration of 1989 set a target to reduce new blindness caused by diabetes by one-third or more (Krans et al 1995). Regular accurate screening for diabetic eye disease can improve the prognosis by detecting abnormalities earlier in their natural history. Active management of microangiopathy affecting the retina has been possible since the development of laser photocoagulation. Cataract surgery and other surgical techniques that may benefit patients with diabetic eye disease are now available.

TARGETS

The aims of a screening and management programme for diabetic eye disease should be to:

• Prevent or delay the onset of diabetic retinopathy

• Detect at the earliest opportunity any treatable abnormalities in the lens and/or retina by population-based, high-quality screening

• Treat effectively any diabetic eye disease present

• Preserve visual function.

SCREENING

INTERVENTIONS

The appropriate management of diabetic retinopathy should follow the pathway outlined in Table 5.1.

TABLE 5.1 Management pathways following eye assessment (NICE 2002a, UK National Screening Committee 2004)

Suitable interventions that can be undertaken in primary care include:

• Modification of risk factors (tighter glycaemic and blood pressure control). It is advisable to stabilise sight-threatening retinal disease first, as rapid improvement in glycaemic control can result in the short-term worsening of diabetic retinal disease. However, tight blood glucose control has been shown to reduce the progression of diabetic retinopathy (requiring retinal photocoagulation) and the deterioration of visual acuity in type 2 diabetics (Stratton et al 2000). Aspirin use, in the absence of contraindications, should be considered.

• Appropriate referral to secondary care, depending upon the degree of retinopathy found or whether cataracts interfere with vision.

• Rehabilitation may involve community support, low-vision aids and training in their use for patients with visual impairment.

Secondary-care interventions may include the following:

• Laser photocoagulation for high-risk retinopathy (moderately proliferative or worse) and CSMO (focal or modified grid laser)

• Vitrectomy may be considered in type 2 diabetics who have a vitreous haemorrhage too severe to allow laser photocoagulation

• Cataract extraction, the outcome of which is closely linked to age and severity of retinopathy present before surgery

• Intravitreal steroids, which is not without risks

• A potential new treatment is Ruboxistaurin, an oral protein kinase C inhibitor, which is showing promise in trials in patients with CSMO.

NEPHROPATHY

RATIONALE

Diabetic nephropathy is one of the more serious complications of diabetes. It occurs in 20–40% of patients with diabetes and its prevalence is increasing. Indo-Asian and Afro-Caribbean type 2 diabetics are at a greater risk of developing diabetic nephropathy than whites. In England, the rates for initiating treatment for end-stage renal disease were reported as 4.2 and 3.7 times higher in Afro-Caribbeans and Indo-Asians, respectively, than in whites (Roderick et al 1996).

Persistent albumin excretion greater than 300 mg/day, termed macroalbuminuria, in the absence of infection, marks the onset of diabetic nephropathy, and is also associated with increased mortality, particularly from vascular causes (Macleod et al 1995). The natural history of overt diabetic nephropathy is to progress to end-stage renal failure. The presence of lesser amounts of urinary albumin (less than 300 mg/day), termed microalbuminuria, indicates early renal damage. This is a risk factor for cardiovascular morbidity and mortality in type 2 diabetics (Dinneen & Gerstein 1997). About half of diabetics develop microalbuminuria at some stage. Of these (the study’s subjects were on insulin) 30–50% will progress to macroalbuminuria, but 30–50% will revert to normal albumin excretion and 20–30% will continue to have microalbuminuria (Laing et al 2003). If retinopathy is also present, then diabetes-related renal disease is the likely cause of the albuminuria. If retinopathy is absent, other causes of renal disease should be considered (NICE 2002b).

Prompt and effective interventions, particularly at an early stage, may both prevent end-stage renal failure and reduce the high risk of cardiovascular disease. The management of chronic kidney disease is now the subject of an NSF published in 2005 (DH Renal NSF Team 2006).

AIM

The overriding aim is to identify and manage patients at increased risk of premature vascular disease and of diabetic nephropathy, and to reduce their risk of progressing to end-stage renal failure.

SCREENING

Screening for diabetic nephropathy should check at least annually two parameters:

1. Urinary albumin excretion

2. Estimated glomerular filtration rate (eGFR) or serum creatinine from a blood sample.

Urinary albumin (including microalbuminuria)

The categorisation of levels of albumin excretion is explained in Table 5.2.

TABLE 5.2 Levels of urinary albumin excretion

Category	Spot collection (ng/ml creatinine)
Normal	< 30
Microalbuminuria	30–299
Macro- (clinical) albuminuria	300 or more

The “gold standard” for the measurement of urinary albumin excretion is a timed urine sample (either over 24 hours, enabling simultaneous measurement of creatinine clearance, or 4 hours), but this is not a practical screening procedure for widespread use in the community.

Sending an early morning urine sample (also referred to as a “spot check”) to a chemical pathology laboratory to measure the albumin:creatinine ratio (ACR) is both more practical and the preferred method recommended by the ADA. ACR levels equal to or greater than 2.5 mg/mmol in males or 3.5 mg/mmol in females indicate microalbuminuria. The test needs to be repeated for confirmation, as microalbuminuria can be transient. One of the authors completed a study in which the prevalence of microalbuminuria in diabetics in an ethnically mixed UK community was 19.3%. The characteristics independently associated with a higher prevalence of microalbuminuria were current insulin use, current smoking, older age, higher systolic blood pressure and poorer metabolic control, but there was no significant association with either increasing duration or gender. Unfortunately, the sample size was not large enough to determine whether there was an association between microalbuminuria and Indo-Asian ethnicity (Levene et al 2004).

Estimated glomerular filtration rate

From 2006 the reporting of estimated glomerular filtration rate (eGFR) has replaced the measurement of serum creatinine as standard in most laboratories. This change follows the recommendation of the Renal NSF. Serum creatinine levels may be affected by several factors, including age, gender, ethnicity, muscle mass, diet and some medications. Although not perfect, the eGFR is believed to be a better measure of renal function and easier for patients to understand than a serum creatinine result.

The glomerular filtration rate can be calculated using a formula and has been proposed as a more accurate, but logistically feasible, estimation of renal function. The 4-variable Modification of Diet and Renal Disease (MDRD) (Levey et al 1999) formula uses the patient’s creatinine, age (valid only between 18 and 70 years), sex and race:

GFR (ml/min/1.73 m²) = 175 × (S_cr/88.4)^−1.154 × (age)^−0.203 × (0.742 if female) × (1.210 if black), where S_cr is the plasma creatinine expressed in μmol/l (SI units)

Pathology laboratories have started reporting eGFR automatically (with white ethnicity as default) using the MDRD formula: the result must be multiplied by 1.21 if the patient is black African. If the laboratory does not provide an eGFR result or if looking at a historical creatinine result, then eGFR can be calculated using a readily available online calculator: http://www.kidney.org/professionals/kdoqi/gfr_calculator.cfm.

Since glomerular filtration rate is affected by the body’s surface area and the eGFR’s calculation does not include this, an eGFR result can underestimate renal function in large people and underestimate it in slim small people.

The Renal NSF classifies those with kidney disease into 5 stages, based upon eGFR and the presence of urinary albumin (see Table 5.3).

TABLE 5.3 Classification into CKD stages 1 to 5, based upon estimated glomerular filtration ratio (eGFR)

Stage	eGFR (ml/min)	Other
1	≥ 90	Haematuria or proteinuria must be present
2	60–89	Haematuria or proteinuria must be present
3	30–59
4	15–29
5	≤ 15 or renal replacement therapy

MANAGEMENT

A number of interventions have been shown to delay the progression of diabetic nephropathy.

Management can be divided into nonpharmacological and pharmacological:

Nonpharmacological

Smoking cessation

This also reduces CVD risk.

Optimising glycaemic control

The UKPDS found that intensive diabetes management with the goal of achieving near normoglycemia delayed the onset of microalbuminuria and the progression of micro- to macroalbuminuria in type 2 diabetics (UKPDS 1998a, b).

Dietary protein restriction

There are “no RCTs evaluating the effects of protein restriction in people with type 2 diabetes and … nephropathy on the outcomes of all cause mortality, incidence of end stage renal disease, or incidence of cardiovascular events” (Clinical Evidence online).

Pharmacological

Lowering blood pressure

Tight blood pressure control is the most important intervention for delaying the development of diabetic nephropathy (UKPDS 1998c). The target is a diastolic blood pressure below 75 mmHg in “normotensive insulin-dependent” or 90 mmHg in “hypertensive non-insulin-dependent” (BNF).

There is strong evidence for the reno-protective effect of ACE inhibitors/ARBs which have a greater effect upon urinary albumin excretion, a stronger marker for renal disease and cardiovascular health, than other blood-pressure-lowering drug classes. A Cochrane review suggests that ACE inhibitors are the best drug class to prevent microalbuminuria and nephropathy (Strippoli et al 2005). One randomised controlled trial (RCT), whose subjects were people with type 2 diabetes, hypertension, and microalbuminuria, reported that, compared with placebo, an ARB (irbesartan) reduced progression from early to late nephropathy over 2 years (Parving et al 2001). Another RCT, whose subjects were people with type 2 diabetes and early nephropathy found no significant difference in glomerular filtration rate change, mortality, or cardiovascular disease (CVD) events between an ARB (telmisartan) and an ACE inhibitor (enalapril) over 5 years (Barnett et al 2004). Other studies have found ARBs to be reno-protective in patients with type 2 diabetes and overt nephropathy (Brenner et al 2001, Lewis et al 2001).

However, effective blood pressure control is paramount, and non-DCCBs, β-blockers, or diuretics should be used in combination with or, if ACE inhibitor/ARB is contraindicated or not tolerated, as alternatives to inhibition of the renin-angiotensin-aldosterone system (Black et al 2003, Pepine et al 2003).

Low-dose aspirin

Unless contraindicated, low-dose aspirin (75 mg per day) should be taken by patients with diabetic nephropathy to reduce cardiovascular risk.

Improving lipid profile

Prescribing a statin reduces cardiovascular risk in patients with diabetic nephropathy.

The small Danish Steno-2 study compared the effect of a targeted, intensified, multifactorial (both lifestyle and pharmacological) intervention with that of conventional treatment on modifiable risk factors for CVD in type 2 diabetics and microalbuminuria, showing significantly reduced hazard ratios for the development of both macro- and microvascular complications in type 2 diabetics with microalbuminuria (Gaede et al 2003).

Monitoring serum potassium

Abnormal potassium levels can occur for a variety of reasons in patients with diabetes, and with or without nephropathy. Hyperkalaemia (serum potassium above the upper reference limit, usually 5.5 mEq/l) can result from ACE inhibitors, ARBs or potassium-sparing diuretics, and may occur in renal impairment. Hypokalaemia (serum potassium below the lower reference limit, usually 3.5 mEq/l) can result from long-term thiazide treatment without potassium-sparing medication or supplement. Treatment aims to restore normokalaemia.

Referral

If renal function deteriorates in patients with diabetic nephropathy (particularly to CKD Stages 4 or 5), then referral to a specialist nephropathy team may be appropriate for the following reasons:

1. Optimising medical management

2. Determining if a component of renovascular disease is present. Angioplasty to improve renal perfusion may preserve renal function

3. Preparing patients for dialysis (usually chronic ambulatory peritoneal dialysis), which is increasing performed in diabetics.

Patients with CKD stage 3 may need referral, depending on the presence of other morbidities or failure to respond to the interventions described above.

FEET

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RATIONALE

Definition

WHO has defined the diabetic foot as a group of syndromes in which neuropathy, ischaemia and infection lead to tissue breakdown, resulting in morbidity and possible amputation (Krans et al 1995).

Pathological processes

Peripheral neuropathy causes lost sensation and autonomic dysfunction. Peripheral vascular disease (atherosclerosis of large and/or small leg vessels) causes ischaemia. Trauma (which may involve altered pressure-loading and be unnoticed by the patient) followed by infection complicates neuropathy and ischaemia to cause significant tissue damage, such as ulceration.

There are two main pathological pathways in diabetic feet:

• Neuropathic feet have good circulation (pulses are present) and are warm, dry, numb and usually painless. The two main complications are neuropathic ulcers (commonly on the soles) and neuropathic (Charcot) joints. Rapidly spreading infection can result in massive tissue destruction, the main indication for amputation in neuropathic feet.

• Neuro-ischaemic feet are also numb, but cool, and the pulses are absent. In addition to the above neuropathic complications, pain at rest, ulcers at the edges, which result from trauma such as pressure damage, and gangrene may occur.

In both groups, the sequence of minor trauma, cutaneous ulceration and finally failure of the wound to heal can eventually lead to amputation, particularly if infection sets in, and rapid and significant tissue destruction occurs.

In diabetics attending dedicated foot clinics, approximately 50% have neuropathic feet and 50% have neuro-ischaemic feet (Edmonds et al 1986).

The burden of diabetic foot problems

A UK population-based study in type 2 patients gave a prevalence of 1.4% for foot ulcers, but the prevalence of the risk factors that give rise to ulcers was 41.6% (Kumar et al 1994). Once a limb has been amputated the prognosis for the contralateral limb is poor (Ebskov & Josephsen 1980). Foot ulcers occur more frequently in whites than in Indo-Asians or Afro-Caribbeans, and are associated with adverse social circumstances such as deprivation and isolation (Boulton 1997), poor glycaemic control, the presence of other vascular risk factors (e.g. smoking) and increased duration of diabetes.

Up to 50% of foot ulcers and amputations could be prevented by patient education and effective intervention (Boulton 1997). Diabetes complications consume considerable resource (both health and social costs). There are no current UK estimates for the costs of treating diabetic foot problems.

AIMS

Diabetic foot care must seek to prevent foot ulcers and gangrene (leading to amputation). However, this aim can be subdivided into:

1. Provision of suitable health education that increases the patient’s ability to self-manage effectively with prompt appropriate illness-seeking behaviour in the presence of suspected pathology.

2. Identifying patients who have either a high risk (presence of neuropathy and/or peripheral vascular disease) of developing, or the presence of, lower-limb complications (e.g. foot ulcer, gangrene).

3. Optimal management of these patients to minimise morbidity, especially amputation.

ASSESSMENT

Assessment should be undertaken regularly by suitably trained professionals. The assessment process needs to be systematic with the aim of identifying the level of risk to the foot and, thus, ensuring that the appropriate management can be undertaken to prevent or minimise complications. Information gathering involves both a history and an examination.

History

The professional should also look for factors that may affect the patient’s ability to self-manage. The following may be useful to elicit:

• Any sensory symptoms, such as pain, numbness, coldness, or tingling

• Any associated physical problems, such as poor visual acuity or mobility that can adversely affect self care

• Concurrent diabetes complications (nephropathy, retinopathy – hopefully apparent from the rest of the review or medical records) and risk factors (smoking, alcohol)

• A previous history of increased or high-risk diabetic foot (such as infection or foot ulcer), which may be documented in the medical records

• The patient’s understanding of preventive foot care

• The patient’s social circumstances.

Examination

The four main components of a routine structured foot examination of a person with diabetes are:

1. Testing of foot sensation.

Neuropathy can be identified either by testing sensation threshold using a 10 g monofilament (light, easy to use and cheap – use on 10 patients before allowing 24 hours for filament to recover) or by testing vibration threshold using either a calibrated tuning fork or a biothesiometer (requires a power source and costs about £ 400).

2. Palpation of foot pulses

However, it should be remembered that pulse assessment in an oedematous, ulcerated foot may be impossible, and infection of foot ulcers due to neuropathy often masks the subtle signs of arterial insufficiency, e.g. skin colour changes associated with elevation or lowering of the foot. Measuring the ankle-brachial pressure ratio (ABPR) in diabetics with Doppler may be misleading, due to calcification: it should be undertaken only in specialist clinics

3. Inspection of any foot deformity

4. Inspection of footwear (McIntosh et al 2003).

More details of each of these examination components are given in Table 5.4.

TABLE 5.4 Examination of the diabetic foot

Inspect footwear for suitability and for evidence of excessive wear or pressure loading. Inspect distal lower limbs, looking for:

• Foot deformity, callus formation at pressure areas (increased risk of trauma)

• Distended foot veins (associated with autonomic neuropathy)

• Small muscle wasting (associated with somatic neuropathy)

• Oedema (associated with impaired circulation)

• Hair loss (associated with impaired circulation)

• Colour changes (pallor associated with ischaemia; erythema associated with cellulitis)

• Ulcerative lesions (neuropathic more likely on the sole; ischaemic more likely on the toe tips and/or dorsum)

• Other serious lesions, such as abscess, osteomyelitis or gangrene

Check for evidence of neuropathy:

• Decreased vibration sensation using a 128 Hz tuning fork, or a biothesiometer (if available)

• Decreased skin pressure perception threshold using a 10 g (5.07) monofilament, which is pushed perpendicularly against the skin on the sole of the foot until it buckles; inability to feel the filament applied in this way indicates a greater risk of developing a foot ulcer (McIntosh et al 2003)

• Decreased ankle reflexes

• Dry and warm skin may indicate autonomic neuropathy

Check for evidence of impaired circulation:

• Reduced or absent pulses: in proximal disease femoral pulses are weak and more distal pulses are absent; in distal disease, which occurs more often in diabetics, femoral and popliteal pulses are normal, but foot pulses are absent

• Decreased skin temperature

• Foot whitens when held elevated for 30 seconds

• If available, Doppler can be used to quantify the extent of arterial obstruction by measuring blood pressure in the lower limb

Check for evidence of musculoskeletal abnormalities:

• Is the range of movement of ankle joint and foot normal?

• Analysis of gait and stance abnormalities may suggest trauma and/or tissue damage

A range of risk factors are associated with the development of diabetic foot disease or ulcers. These include:

• Peripheral vascular disease (including previous vascular surgery)

• Physical disability (e.g. cardiovascular accident, gross obesity).

Ideally, the examination will correctly identify:

• The presence of neuropathy, circulatory impairment or abnormal pressure that puts the foot “at risk”

• A serious diabetic foot problem, such as ulcer, infection (cellulitis, abscess and/or osteomyelitis) or gangrene.

Critical ischaemia is characterised by rest or night pain or pale/mottled foot or dependent rubor or ischaemic ulceration or gangrene. Severe infection is characterised by the presence of abscess or cellulitis.

Charcot osteoarthropathy

Charcot osteoarthropathy is a progressive condition, associated with neuropathy in diabetics. It is characterised by dislocation of joints, fractures and destruction of the bony architecture. In diabetics, the arch of the foot is most frequently affected. Trauma (even through simple weight bearing) in a severely neuropathic limb is thought to trigger Charcot’s osteoarthropathy. Although not particularly common, it is a major risk factor for foot ulceration and amputation. If suspected, the patient should be referred promptly to the multidisciplinary foot care management team, where the management includes immobilisation of the affected joint and long-term off-loading to prevent ulceration (McIntosh et al 2003).

Categorisation of level of risk

Based upon the information acquired from the history and examination, the level of current risk to the diabetic foot of developing a foot disease or ulcer can be determined. NICE in 2003 has defined the features and management at each level of risk (McIntosh et al 2003). A fifth level (number 5) is added to this categorisation.

The levels of risk are:

1. In a foot at low risk, all of the following are present: normal sensation, palpable pulses, no deformity, no skin lesions. Also there is no previous history of diabetic foot ulcer.

2. In a foot at increased risk, one of the following is present: neuropathy or absent pulses (or previous vascular surgery) or a risk factor.

3. In a foot at high risk, neuropathy or absent pulses plus skin changes or deformity or previous ulcer (caused by neuropathy and/or ischaemia) are present. A history of previous amputation can also be considered as an indicator of a high-risk foot.

4. In a foot with active disease, either an active foot ulcer or difficult to control painful neuropathy or a Charcot osteoarthropathy is present.

5. An emergency foot problem is when either critical ischaemia or severe infection is present.

The severity of a foot ulcer is classified according to the Wagner system, summarised in Table 5.5 (Wagner 1983).

TABLE 5.5 Wagner classification of foot ulceration (Wagner 1983)

Grade	Description
0	High-risk foot; no ulcers
1	Superficial ulcer (skin deep), not clinically infected
2	Deeper ulcer, often with cellulitis; no abscess or bony involvement
3	Deep ulcer with abscess or bony involvement (osteomyelitis)
4	Localised gangrene (involving toe, forefoot or heel)
5	Gangrene of the entire foot

MANAGEMENT

The level of risk to the diabetic foot determines the optimal management pathway, summarised in Table 5.6.

TABLE 5.6 Summary of management pathways for diabetic feet

Level of risk	Management
Low risk	Agree management plan, including footcare education
	Trained patient undertakes own nail care
	Arrange recall and annual review as part of ongoing care
Increased risk	Surveillance by podiatrist or practice nurse with increased training
Increased risk	Recall and review every 3 to 6 months
High risk	Refer to podiatrist with special interest in diabetes or to local hospital-based specialist diabetes team
High risk	Recall and review every 1 to 3 months
Active foot disease	Refer urgently to multidisciplinary footcare team (within 24 hours)
Emergency foot problem	Admission for in-patient care

(modified from Mclntosh 2003 foot care guidelines)

Management options in primary care

Even when the patient is under active specialist care, there are a number of appropriate interventions that can and should be undertaken in a primary care setting.

Health education

This is an essential component and needs to be ongoing, whatever the level of risk. Table 5.7 lists the important health education messages concerning foot care that need to be delivered to diabetics. This can be given by the GP or practice nurse (if suitably trained) or by the podiatrist.

TABLE 5.7 Health education guidelines for foot care in diabetics (Leicestershire Health 1996)

Hygiene
Good hygiene is essential: at least twice-weekly bathing and gentle dryings socks or stockings should be changed daily, the foot inspected carefully for infection talc avoided

How to avoid problems

Do not wear constricting footwear

Do not walk bare foot, sit by an open fire or use hot water bottles

Do not wear garters; these can reduce blood supply to the feet

Do not self-treat corns or callosities; go to a state-registered podiatrist

Cut nails straight across and not too short

Do not cut toenails yourself if you have difficulty in managing

Examine feet regularly for possible injuries, using a mirror to inspect the soles

Shoes should be inspected before and after putting them on; ensure no grit or other objects are in the shoe; avoid wear of lining, insoles and heels

Proper fitting and selection are essential when buying new shoes:

measure feet when standing; uppers should be of soft leather

ensure enough room across the ball of the foot and around the toes to enable wiggling there should be some sort of fastening mechanism; soles should be of rubber or microcellular type

avoid excessively high heels

high-quality cushioned-sole trainers reduce plantar pressure more than ordinary shoes, but less than custom-built shoes

Keep feet warm in winter: natural fibre cotton and/or wool hosiery is better than nylon

Seek advice from podiatrist or doctor if you notice:

any foot injuries

any swelling or throbbing pain in any part of feet

any colour changes in any part of feet

any discharge of coloured fluid from your feet, especially from corns, calluses or beneath toenails

undue numbness or prickling sensation in feet

Optimising glycaemic control

Poor glycaemic control is associated with a greater risk of microvascular complications (UKPDS 1998b).

Improved management of other cardiovascular risk factors

The interventions may include low-dose aspirin, lowering blood pressure, encouraging smoking cessation, and improving the lipid profile. Patients with peripheral vascular disease probably have widespread atheroma and, therefore, are also at a higher risk of developing cardiovascular disease.

Debridement

Patients with neuropathic ulcers require frequent removal of any dead skin or callus, unless revascularisation is required. This should be carried out only by a suitably qualified podiatrist. There should be a very low threshold here for referral to secondary care, since “ordinary” podiatrists who are unfamiliar with diabetes care often do not debride ulcers effectively enough.

Analgesia

Neuropathic pain often does not respond to conventional analgesia. Tricyclic antidepressants, the anticonvulsant carbamazepine, and topical capsaicin can be effective in reducing pain. Gabapentin and pregabalin are anticonvulsants that increasingly are being used successfully by pain management experts.

Antibiotics

Patients with foot infections require prompt and aggressive treatment with one or more broad-spectrum antibiotics. Ideally, the choice of antibiotic should be guided by culture and sensitivity results (where available) and response to treatment. Unfortunately, surface swabs have been shown to be unreliable for determining the nature of infection and the more reliable method of tissue biopsy is not available in primary care (O’Meara et al 2006).

A longer duration and higher dose of antibiotic is usually required because of the poorer tissue perfusion and delayed healing that occurs in diabetics. NICE found insufficient data to support recommending any particular antibiotic regimen (McIntosh et al 1993).

Rational prescribing

In patients with peripheral vascular disease, certain drug classes may be less safe, such as β-blockers and ACE/ARB (increased risk of renal artery stenosis).

Earlier review

Depending upon the nature of the problem, recall for an earlier review is indicated to prevent progression.

Referral

High-risk patients, with an active foot disease or with an emergency diabetic foot require a timely and appropriate referral to secondary care to reduce the risk of progression to a higher-level lesion and, ultimately and tragically, amputation.

Secondary care interventions

In addition to the above, the following interventions are available in secondary care:

Orthotics

Custom-built footwear or orthotic insoles should be used to reduce plantar callus thickness and the incidence of foot ulcer relapse in high-risk diabetic feet.

Dressings and topical agents

When a foot ulcer is not infected, protective bandaging may be appropriate. A good dressing needs to be effective within the closed environment of footwear without causing problems, such as plugging the wound, failing due to pressures of walking, preventing ulcer inspection and occupying too much space. A variety of dressings are available: NICE recommends that the choice should “match clinical experience, patient preference, and the site of the wound” with consideration of costs (McIntosh et al 1993).

Intravenous antibiotics

These are indicated in severe cellulitis.

Vascular surgery

Patients with tissue loss and arterial disease should be considered for arterial reconstruction or angioplasty by a vascular surgeon. These are more likely to succeed if proximal disease is present rather than the more common distal disease.

Off-loading

Redistribution of weight, using casts, is also known as off-loading. It may be used to protect the vulnerable foot, such as in Charcot’s osteoarthropathy, unless there is severe ischaemia.

Other treatments

NICE’s most recent footcare guidelines cited a current lack of trial evidence for not recommending the use of other available interventions in treatment of foot ulcers.

Following a patient’s discharge from hospital, the GP and/or practice nurse should monitor closely these patients and continue to undertake the above-stated primary care interventions.

NEUROPATHY

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RATIONALE

It is thought that 30–50% of diabetics will develop chronic peripheral neuropathy over their lifetime, with 10–20% having severe symptoms (Tesfaye & Kempler 2005). Diabetic neuropathy is not a single homogeneous condition: its clinical manifestations are diverse. These can be either focal or diffuse, and can cause considerable morbidity and may contribute to premature mortality. The two most frequent presentations are:

1. Distal symmetric polyneuropathy (DPN)

and

2. Autonomic neuropathy.

Neuropathies result from microangiopathy of the vasa nervorum. The development of diabetic neuropathy starts with intraneural biochemical abnormalities, which lead to decreased nerve conduction velocity, then to clinical neuropathy and end with end-stage complications caused by major irreversible derangements of the nerve structure and function. Autonomic neuropathy can affect every organ system in the body. Often the pathogenic process does not progress through all of the stages, and only the latter two stages are clinically apparent.

The early recognition and appropriate management of diabetic neuropathies may be important for the following reasons:

• Up to 50% of patients with distal symmetric polyneuropathy may be asymptomatic: therefore, at increased risk of inadvertent injury to insensate feet.

• Cardiovascular autonomic neuropathy does cause substantial morbidity and mortality.

• Treatable nondiabetic neuropathies may be present.

• There are several interventions available for symptomatic relief of DPN and autonomic neuropathy (see below).

AIMS

The aims of screening and prompt appropriate interventions are to prevent or delay the onset of further neuropathy, and to alleviate symptoms (e.g. pain), and to reduce the risk of sudden death or disability from cardiac autonomic neuropathy.

SCREENING

The diagnosis of diabetic neuropathy is mainly clinical. More details of the features of the various manifestations of diabetic neuropathy can be found in Table 5.8. Before attributing the neuropathy found to diabetes, nondiabetic causes of neuropathy should be considered, including uraemia, deficiencies (B12), alcohol, neoplasia, paraproteinaemia, Guillain-Barré syndrome and drugs such as nitrofurantoin. Nausea, vomiting and diarrhoea can be caused by infection.

TABLE 5.8 Classification and features of diabetic neuropathies

Type of neuropathy	Features include
Distal symmetric polyneuropathy or peripheral sensorimotor	(Acute or chronic) symmetrical; mainly sensory
	Pain is sharp, stabbing or burning
	Paraesthesia of soles or hyperaesthesia
	Often has a stocking-glove distribution
Autonomic:
Orthostasis	Dizziness; drop of > 20 mmHg systolic BP when standing
Resting tachycardia	Pulse > 100 beats/min at rest
Gustatory sweating	Abnormal facial sweating while eating
Gastroparesis	Nausea and vomiting
Change in bowel frequency	Diarrhoea (often nocturnal) or constipation
Bladder dysfunction	Recurrent UTI, incontinence, palpable bladder
Erectile dysfunction (see below also)	Loss of penile erection and/or retrograde ejaculation
Mononeuropathy:	Median carpal tunnel syndrome
Mononeuropathy:	Cranial nerves (III, IV, VI, VII)
External nerve pressure	Radial, ulnar and peroneal nerve palsies associated with pain
Proximal motor	Severe pain, associated with poor control
	Paraesthesiae in the proximal lower limbs
	Muscle wasting

(modified from Macleod 1997)

History

The history should elicit the presence of neuropathic symptoms, such as pain, weakness, sensory dysfunction. There may be features that suggest a nondiabetic cause. The symptoms of autonomic dysfunction may be elicited during a review of systems, involving the skin, pupils, heart, or gastrointestinal and genitourinary systems.

A potentially worrying symptom of autonomic neuropathy can be loss of the warning symptoms of impending hypoglycaemia.

Examination

The extent and type of examination is likely to be dictated by the history. If autonomic neuropathy is present, then distal symmetric polyneuropathy is also likely to be present.

For the assessment of distal symmetric polyneuropathy, a variety of tests can be used, such as pinprick sensation, temperature and vibration perception (using a 128-Hz tuning fork), 10-g monofilament pressure sensation at the dorsal surface of both great toes (just proximal to the nail bed), and ankle jerks (decrease or absence). If both loss of 10-g monofilament perception and reduced vibration perception are found, then a foot ulcer is more likely to develop. Although a minimum of one clinical test is used for screening, the use of two tests will lead to a more accurate diagnosis. To assess focal and multi-focal neuropathy, the clinical examination needs to be done in areas indicated by the neurological symptoms.

A decreased heart rate in response to the Valsalva manoeuvre and/or an unchanged heart rate variation during deep breathing is evidence of autonomic neuropathy. Erratic glycaemic control can be associated with gastroparesis. Cardiac autonomic neuropathy may be suggested by resting tachycardia (greater than 100 beats per minute), orthostatic hypotension (a fall in systolic blood pressure greater than 20 mmHg upon standing), or other disturbances in autonomic nervous system function.

Investigations

Specialised investigations are sometimes indicated. Structural abnormalities in the gastrointestinal tract may need to be excluded by either endoscopy or barium studies.

MANAGEMENT

The optimal management of diabetic neuropathy depends to some extent upon its type and presentation. Care should be taken to monitor any side effects of any medication used. Some neuropathies, such as cranial nerve mononeuropathy, can improve spontaneously within weeks to months.

The interventions available in primary care include:

Optimising glycaemic control

Maintaining optimal glycaemic control will not reverse neuropathy, but observational studies suggest that it may improve or delay worsening of neuropathy. It is also suggested that avoiding extreme blood glucose fluctuations may be helpful (ADA 2007).

Analgesia

Mild-to-moderate pain may respond to paracetamol or a nonsteroidal anti-inflammatory drug (if not contraindicated). However, more severe neuropathic pain may not respond to conventional analgesia.

Tricyclic antidepressants have been historically the drugs of choice (e.g. amitriptyline and nortriptyline) for neuropathic pain. A Cochrane systematic review found these drugs to be effective for a variety of neuropathic pains, with best evidence for amitriptyline (Saarto & Wiffen 2005), but tricyclic antidepressants are not currently licensed for the treatment of diabetic neuropathy in either the UK or USA. Proximal motor neuropathic pain may be relieved by amitriptyline. Tricyclics are generally inexpensive, but their use may be limited by their side effects; they may also exacerbate some autonomic symptoms such as gastroparesis. The 5-hydroxytryptamine and norepinephrine reuptake inhibitor duloxetine has a license for the treatment of diabetic peripheral neuropathic pain. There is limited evidence for the effectiveness of selective serotonin reuptake inhibitor antidepressant drugs (SSRIs). Further studies are needed to identify the most effective antidepressant.

The antiepileptic drug gabapentin is licensed for the treatment of neuropathic pain, and is being used as an alternative to a tricyclic antidepressant, particularly by those with an interest in pain management. Gabapentin should be started at low dose, then titrated over days to weeks to a dosage that is well tolerated and produces symptomatic relief (one regimen is 300 mg day one, 300 mg twice daily day 2, then 300 mg three times daily, with increases of 300 mg subsequently, as necessary). Pregabalin is structurally related to gabapentin, but is longer acting and has recently been confirmed to be useful in painful diabetic neuropathy in a randomised controlled trial. It too is licensed for the treatment of neuropathic pain. The antiepileptic drugs carbamazepine and phenytoin are unlicensed, but may be useful for the relief of shooting or stabbing pain: however, adverse effects (including nausea and vomiting, dizziness, headache and confusion) can occur frequently with these drugs.

Topical capsaicin cream (0.075%) is licensed for painful diabetic neuropathy and may bring some relief, but its use may be limited by the intense burning sensation it can produce when first used. A systematic review found that capsaicin “has poor to moderate efficacy in the treatment of chronic neuropathic … pain. However, it may be useful in people who are unresponsive to, or intolerant of other treatments” (Mason et al 2004).

In intermediate-term studies neuropathic pain has been shown to respond better to opioid analgesics, such as tramadol and oxycodone, than to placebo (Eisenberg et al 2006). These have a role when other treatments have failed, but more research is needed to determine their long-term efficacy and safety.