University of Toronto - Faculty of Medicine

 

• The chronic complications of diabetes mellitus are responsible for most of the morbidity and mortality associated with this disease.
• The prevention of the chronic complications of diabetes involves not only glucose control but also specific risk factor modification and treatment strategies aimed directly at the prevention and treatment of chronic complications.
• A detailed discussion of the pathogenesis of the chronic complications of diabetes is beyond the scope of these guidelines. What follows is a brief description of aspects of the prevention and management of diabetic complications.
• Diabetic complications are classified into:
  Macrovascular: Coronary artery disease, cerebrovascular disease, and peripheral arterial disease
  Microvascular: Retinopathy, nephropathy and neuropathy.

 

Author
The revision of this section was prepared by Lawrence Leiter, MD, FRCPC, FACP

• Atherosclerotic complications include coronary artery disease (CAD), cerebrovascular disease (CVD), and peripheral arterial disease (PAD).
• They account for more than 70% of deaths in persons with diabetes.
• Etiology of atherosclerosis is multifactorial and includes:
  • Quantitative lipid abnormalities-primarily increases in VLDL-cholesterol (triglycerides) and decreases in HDL-cholesterol
  • Qualitative lipid abnormalities-Increases in small, dense LDL-C as well as in glycated and oxidized LDL-C
  • Increased insulin resistance/hyperinsulinemia
  • Increased procoagulant and decreased anticoagulant factors
  • Hyperglycemia itself
  • Other risk factors e.g. hypertension, abdominal obesity

Coronary Artery Disease

• 2-3 fold more common in persons with DM
• Multiple and more diffuse atherosclerotic lesions
• Women with DM lose their usual premenopausal protection against atherosclerosis
• Increase in silent ischemia
• Worse prognosis following angioplasty/CABG

Peripheral Arterial Disease

• Peripheral arterial disease including intermittent claudication and gangrene is much more common in people with diabetes.
• The atherosclerosis tends to be more diffuse and involves small vessels.
• PAD, especially in conjunction with diabetic neuropathy, leads to an increased risk for foot ulcers and amputation in those with DM.

Cerebrovascular Disease

• Diabetes increases the risk of stoke.
• Strategies aimed at primary and secondary prevention of stroke are similar to those aimed at coronary artery disease.

Preventive Maneuvers to Decrease Macrovascular Disease in DM

All people with diabetes:

• Lifestyle modifications
  • Achievement and maintenance of a healthy body weight
  • Healthy Diet
  • Regular physical activity
  • Smoking cessation
• Optimal control of blood pressure <130/80 mm Hg
• Optimize glycemic control

People with diabetes considered at high risk of a CV event:

• ACE inhibitor or ARB therapy
• Antiplatelet therapy
• Lipid-lowering medication (primarily statins) with an aim of LDL-C<2.0 & TC/HDL-C<4

TABLE 16.1 People With Diabetes Considered at High Risk of a CV Event Reprinted with permission from Can J Diabetes, 2008;32 (suppl 1): S102.
Men aged ≥45 years, women aged ≥50 years Men <45 years and women <50 years with ≥ 1 of the following: Macrovascular disease (MI or ischemia, CAD, PAD, stroke, transient ischemic attack, cerebrovascular disease, evidence of silent MI or ischemia or PAD) Microvascular disease (especially nephropathy or retinopathy) Multiple additional risk factors, especially with a family history of premature coronary or cerebrovascular disease in a first degree relative Extreme level of a single risk factor (e.g. LDL-C >5.0 mmol/L, systolic BP >180 mm Hg) Duration of diabetes >15 years with age >30 years
BP = blood pressure CAD = coronary artery disease CV = cardiovascular	LDL-C = low-density lipoprotein cholesterol MI = myocardial infarction PAD = peripheral arterial disease

 

Author
The revision of this section was prepared by Michael H. Brent, MD, FRCSC

• Diabetes is the leading cause of blindness in North America in patients under the age of 60 years, and the second leading cause of blindness in patients over the age of 60 years.
• Although diabetic retinopathy itself cannot be prevented, in many cases its blinding complications can.
• In type 1 diabetes, retinopathy is rarely seen before 5 years from diagnosis, but in type 2 diabetes, some retinopathy is present in 17% of patients at the time of diagnosis.
• By 15 years, 98% of type 1 and 78% of type 2 diabetics have some retinopathy.

Classification of Diabetic Retinopathy

1. Non-proliferative (NPDR): Characterized by microaneurysms, dot & blot hemorrhages, hard exudates, and nerve fibre layer infarcts (NFLI).
2. Pre-proliferative (Severe NPDR): Characterized by increased NFLI and hemorrhages, presence of intraretinal microvascular abnormalities (IRMA), venous bleeding, and reduplication of vessels. 50% of patients will progress to proliferative disease within two years.
3. Proliferative (PDR): Characterized by neovascularization of the optic disc (NVD), or neovascularization of the retina elsewhere (NVE). Associated findings may include vitreous hemorrhage and/or tractional retinal detachment.

Prognosis

• In NPDR and Severe NPDR, visual loss can occur secondary to clinically significant macular edema (CSDME) and macular ischemia. While ischemia is irreversible, CSDME can be sometimes be treated with laser or intravitreal injections.
• In PDR, visual loss can occur similarly to NPDR, but can also occurs from vitreous hemorrhage or from tractional retinal detachment.

Screening

• Those with Type I DM of at least 5 years duration should have an annual eye examination by an ophthalmologist.
• Those with Type 2 DM should be examined by an ophthalmologist at the time of diagnosis, or shortly thereafter, and then annually.
• More frequent examinations may be required depending on severity of retinopathy, at the discretion of the ophthalmologist.
• In Pregnancy, a retinal examination should be performed in the first trimester and then every 3 months, or sooner if retinopathy is active.

Diagnosis

• Diabetic retinopathy is evaluated with visual acuity, slit lamp biomicroscopy, dilated retinal examination with binocular direct and indirect ophthalmoscopy.
• If significant retinopathy is present, fundus photography and fluorescein angiography may be indicated.
• Optical Coherence Tomography(OCT) is new technology that provides non-invasive crossectional imaging of the Retina, and is useful in detecting diabetic macular edema. Predominently clear media is necessary for this investigation.
• If media opacity is present precluding visual retinal examination, A and B scan ultrasonography can be extremely helpful in diagnosis.

Risk Factors

• Risk factors for diabetic retinopathy include duration of disease, elevated glycosylated hemoglobin, hypertension, hyperlipidemia, puberty, smoking, as well as a genetic predisposition for retinopathy.
• The DCCT and UKPDS have demonstrated a significant reduction in visual complications with tight control of blood sugar, blood pressure, and lipids.
• There may be an initial worsening of retinopathy when poorly controlled patients initiate intensive treatment protocols, but retinopathy usually improves within 2-3 years, and long-term benefits of tight control usually exceed the risk of initial deterioration.

Management

• An important part of managing diabetic retinopathy is informing patients of the natural history of the disease, and their current status with respect to severity.
• Risk factors should be reviewed, and patients should be encouraged to monitor and optimize controllable factors such as glycemic control, hypertension, lipid status, and smoking.
• The mainstay of treatment for CSDME in NPDR is focal or grid laser photocoagulation, as reported by the ETDRS.
• Investigational use of intravitreal injections of triamcinolone or anti-VEGF agents has shown promise in reducing macular edema that has extended beneath the fovea. A combination of laser and intravitreal injections may also prove to be effective in stabilizing central visual loss.
• The mainstay for PDR is panretinal photocoagulation (PRP), as reported by the DRS.
• Treatment of a non-clearing vitreous hemorrhage or traction retinal detachment may require a vitrectomy with possible endolaser enhancement.
• With timely application of each form of treatment, visual loss from diabetic retinopathy can be reduced significantly.
• People with DM should optimize their vision with appropriate visual aids such as spectacles or contact lenses.
• It is important to have stable glycemic control for at least 2 months prior to refraction to get an accurate result.
• Low vision aids, such as hand-held magnifiers, may be extremely helpful in patients with moderate to severe visual loss.
• Referral to the Canadian National Institute for the Blind (CNIB) forms an integral role in the support and management of patients with severe visual loss.

Other Diabetic Eye Complications

• Diabetes is also associated with increased prevalence of cataracts, and glaucoma.
• Best results from cataract surgery are achieved when diabetic retinopathy has been treated optimally pre-operatively to minimize macular edema and/or proliferative disease.
• Glaucoma must be managed aggressively, to minimize its contributory effects.
• Neuropathy affecting corneal sensation can affect the ability of the corneal epithelium to heal.
• Diabetic cranial nerve palsies can cause diplopia.
• Optic neuropathy can occur suddenly and severely decrease vision even though retinopathy may be quite mild. Optic Neuropathy is sometimes reversible in those under 50 years of age, if put on a course of high dose corticosteroid.

 

Author
The revision of this section was prepared by Sandra Donnelly, MDCM, FRCPC

• Diabetes is the leading cause of end stage renal disease in Canada, the USA and Europe accounting for 35-40% of incident cases. In patients, the development of diabetic renal disease is associated with a magnified risk of all the long-term complications of diabetes.
• In people with type 1 diabetes, 25-45% will develop clinical nephropathy (stage 4, see below).
• In people with type 2 diabetes, the risk of end-stage renal disease (ESRD) is less due to increased cardiac mortality at stage 4. However, in some sub-groups, such as the Pima Indians, the incidence of ESRD is similar to that in type 1 diabetes.
• In type 1 diabetes, nephropathy is rarely seen before 5 years, but in type 2 diabetes, microalbuminuria is often present at the time of diagnosis.
• Hypertension is extremely common affecting 20-60% of patients with diabetes. In type 2 diabetes, it is part of the metabolic syndrome and is often present at diagnosis of diabetes. In type 1 diabetes, blood pressure starts to rise early during the course of diabetes and may progress to reach hypertensive levels.

Diagnosis

• The earliest clinical evidence of nephropathy is the appearance of low levels of albumin in the urine (microalbuminuria).
• Overt diabetic nephropathy is present when there is >500 mg proteinuria/day.
• Urinalysis demonstrates a bland sediment (i.e. usually hematuria is not present).
• Renal function is evaluated with a serum creatinine. The estimated Glomerular Filtration Rate (eGFR) is derived from the serum creatinine and accounting for the subjects age and sex if calculated with the abbreviated Modification of Diet in Renal Disease (MDRD) equation.
• 90% of patients with clinical nephropathy have diabetic retinopathy.
• Although the 'gold standard' for diabetic nephropathy is renal histology, when the clinical course and the above noted features are present, a renal biopsy is not generally necessary to make the diagnosis.
• Chronic kidney disease in diabetes may be due to disease other than diabetes. In subjects with diabetes and renal dysfunction, as many as 50% may not have diabetic nephropathy per se, but have renal disease due to nephrosclerosis or to renovascular disease ie. part of the diffuse macrovascular disease that can be seen in patients with diabetes.

Stages of Disease

• Functional changes at the onset of diabetes are marked by hyperfiltration and transient microalbuminuria. These changes may be reversed or attenuated with improved glycemic control.
• Clinically silent - though pathological changes of diabetic renal disease are evolving.
• Incipient nephropathy-persistent microalbuminuria of 30-300 mg albumin/day or 20-200 µg/min or an albumin:creatinine ratio (ACR) of 2.0-20mg/mmol (male), 2.8-28mg/mmol (female) demonstrated in 2 out of 3 samples collected over a 6-month period. Urine samples must be collected when other causes of elevated microalbuminuria are absent (see Screening).
• Overt nephropathy-macroalbuminuria with a decline in glomerular filtration rate with or without hypertension. This is the stage classically referred to as 'diabetic nephropathy'.
• End-stage renal disease requiring renal replacement therapy with dialysis or kidney transplantation.

Risk Factors

• Hypertension: Increased risk of nephropathy with increased systolic blood pressures.
• Glomerular filtration rate: GFR > 150 mls/min associated with a greater risk of developing diabetic nephropathy
• Glycemic Control: In both type 1 and type 2 diabetes, improved glycemic control is associated with a reduced risk of developing stage 3 or stage 4 disease as demonstrated in the DCCT and the UKPDS studies, respectively.
• Genetics and Race: Risk increased in aboriginal people, blacks (4-6 fold compared to Caucasians) and people of Hispanic descent.

Screening
As renal disease in diabetes may be due to diabetic nephropathy per se marked by albuminuria or vascular disease marked by decreased renal function, screening requires the assessment of both proteinuria and renal function.

• Type 1: Annual screen for microalbuminuria and eGFR in patients >15 years of age and after 5 years duration of diabetes.
• Type 2: Screen for microalbuminuria and eGFR at diagnosis and annually thereafter.
• Spot collection or first morning void should be assessed for albumin/creatinine ratio (ACR) as a screening test.
• Screening tests should be scheduled when other causes of transient increases in microalbuminuria are not present (i.e. transient loss of glycemic control, intercurrent febrile illness, urinary tract infections, heart failure, marked hypertension and vigorous exercise). Except for exercise, allow 4-6 weeks for their effects on albumin excretion or renal function to abate.
• If the eGFR <60mls/min or ACR is elevated, repeat the eGFR in 3 months and the ACR twice within 3 months. If eGFR is <60mls/min or 2 out of 3 ACRs are elevated, check urinalysis to assess possibility of other causes of renal disease. Treat diabetic nephropathy or investigate other causes accordingly.

Treatment
The emphasis of management is on prevention of progressive disease through screening and early detection and on aggressive targets for glycemic, lipemic and blood pressure control, dietary protein and the modifiable cardiovascular risk factors.

• Glycemic control: Best possible glucose control. In light of the emerging appreciation for the reversibility of diabetic nephropathy, the importance of glycemic control at any stage of the disease cannot be overstated.
• Blood pressure: Target of <130/80 in all patients or <125/75 in patients with greater than 1 gram/day of proteinuria. Lifestyle modifications are introduced for mild hypertension (<140/90). Use of multiple antihypertensive medications is often required. Initial therapy with an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin II receptor blocker (ARB) followed by the addition of a diuretic (indapamide or low dose hydrochlothiazide, up to 25 mg) often achieves the target. Other drug classes including β-blockers and calcium channel blockers (CCBs) should be added and guided by the presence of comorbid conditions. The dihydropyridine CCBs are suggested as additions to ACEi and β-blockers whereas the non-dihydropyridine CCBs may reduce proteinuria per se.
• Renal protection: Interrupting the renin-angiotensin-aldserterone system (RAAS), in addition to lowering blood pressure, has vascular and renal protective effects. Hence, the addition of an ACEi or an ARB is associated with improved renal and vascular outcomes. The combination of and ACEi and ARB, while potentially decreasing proteinuria more than either alone, may be associated with adverse outcomes. They are contraindicated in pregnancy and this requires emphasis in women of childbearing potential.
  • Angiotensin-converting enzyme inhibitors (ACEi)*: In type 1 diabetes to delay the progression of incipient or clinical nephropathy and in type 2 diabetes to delay the progression of nephropathy and proteinuria.
  • Angiotensin II receptor blockers*: If ACEi are not tolerated in type 1 diabetes. They may be used as first line in type 2 diabetes to prevent the development of albuminuria or to slow the progression of nephropathy.
  • Direct renin inhibitors: dual blockade with ARB and direct renin inhibition in type 2 diabetic nephropathy can further reduce proteinuria, but the long term effects on hard clinical outcomes are not yet defined.
• Lipid control: Target levels as in the presence of cardiovascular disease.
• Dietary protein restriction: A dietary protein intake of .8-1.0g/kg/day of protein in the presence of clinical nephropathy or if hyperfiltration (creatinine clearance >130 mls/min) seems reasonable although the added benefit of protein restriction currently with the aggressive BP targets and RAAS inhibition is not known. Further, the challenges of compliance for patients who already have fat and carbohydrate restrictions is acknowledged.
• Smoking cessation

*Note of Caution: check the serum potassium and creatinine at 1-2 weeks after starting these medications or after adjusting the dosage upwards.

• Refer to a nephrologist: if BP of ACR targets are not achievable due to hyperkalemia or >30% increase in serum creatinine after starting RAS inhibition OR there is a progressive loss of renal function to 50% of normal or an absolute eGFR of <30mls/min for timely planning of renal replacement therapy and management of the other features of progressive renal insufficiency including anemia. Pre-emptive living renal transplantation followed by pancreas transplantation or simultaneous cadaveric kidney-pancreas transplantation is the treatment of choice for type 1 diabetes ESRD.

Patient Education
An important part of managing diabetic nephropathy is educating patients about the natural history of the disease and treatment options for end-stage renal disease.

• Risk factors should be reviewed, and patients should be encouraged to be vigilant with controllable factors such as glycemic control, hypertension, lipid status, and smoking. Importance of lifestyle factors for control of hypertension requires emphasis as therapies that partner with the medications.
• Referral to the Kidney Foundation of Canada for information and peer support surrounding the needs of renal replacement therapy by dialysis or transplantation is encouraged.

 

Author
The revision of this section was prepared by Bruce Perkins, MD, MPH, FRCPC

• Diabetic neuropathy refers to a set of clinical conditions in patients with diabetes that share as a common feature abnormality in the structure and the function of peripheral nerves. However, the term "diabetic neuropathy" is often reserved for the most common form of diffuse peripheral nerve damage, diabetic sensorimotor polyneuropathy.
• The metabolic derangement in diabetes leads to generalized subclinical nerve injury that may itself progress to clinical disease, or, in the setting of nerve entrapment (as in the carpal tunnel, for example), this underlying injury may increase the likelihood of clinical mononeuropathies.
• Diabetic Neuropathy may affect sensory, motor, and autonomic neurons of the peripheral nervous system.
• Injury to peripheral nerves may represent direct injury to nerve axons or injury to the endothelial cells within the nerve's vascular supply. Hyperglycemia-induced overproduction of superoxide by the mitochondrial electron-transport chain serves to inhibit a critical glycolytic step, thereby diverting upstream metabolites from glycolysis into pathways of glucose overutilization: the polyol pathway, the hexosamine pathway, non-enzymatic glycation of proteins (advanced glycation endproduct formation), and inappropriate activation of protein kinase C.
• The most common form of neuropathy is "diabetic sensorimotor polyneuropathy", affecting up to 50% of patients. It is an insidious, progressive, and diffuse process that eventually involves all nerve types and for which the pathological severity is poorly linked with the development of symptoms. It is the cause of extreme morbidity and health care costs arising from pain, sensory ataxia, deformity, and the late stage sequelae of infection, ulceration and amputation. Consequently, diabetic polyneuropathy necessitates routine screening in the clinic.

• Although several classification schemes exist, the most broadly accepted one considers all diabetic neuropathies as being categorized as diffuse (anatomically symmetrical) or focal (anatomically asymmetrical).
• While diffuse and focal neuropathies may involve any nerve fiber type, involvement of the autonomic nervous system is often classified separately.

Diffuse (Symmetrical)

• Diabetic Sensorimotor Polyneuropathy (by far the most common form of diabetic neuropathy)
• Small fiber polyneuropathy associated with weight loss and cachexia.
• Hypoglycemic polyneuropathy.
• Chronic Inflammatory Demyelinating Polyneuropathy (although not thought to be caused by the metabolic abnormalities in diabetes, this condition is more frequently seen in the diabetes population. It differs from the other diffuse forms in that motor nerve involvement occurs earlier an outweighs sensory nerve dysfunction).

Focal (Asymmetrical)

• Proximal diabetic neuropathy (the so-called "diabetic amyotrophy")
• Truncal Radiculoneuropathy
• Limb mononeuropathies
  • Median neuropathy ("Carpal Tunnel Syndrome")
  • Ulnar neuropathy
  • Brachial plexus neuropathy
  • Peroneal neuropathy
• Cranial neuropathies
  • Ocular neuropathies (Third and Sixth Cranial Nerves)

Autonomic Neuropathies

• Cardiac Autonomic Neuropathy
• Gastropathy/Enteropathy
• Cystopathy
• Sexual Dysfunction
• Sweating irregularities (sudomotor neuropathy)
• Hypoglycemia-associated autonomic failure
• Although involvement of the autonomic nervous system is generally diffuse (as in diabetic pandysautonomia listed above), symptoms may be confined to a single target organ or organ system.

• The Diabetes Control and Complications Trial demonstrated a dramatic 5-year risk reduction (57-69%) in the onset of diabetic polyneuropathy in those free of this complication at baseline.
• Furthermore, the United Kingdom Prospective Diabetes Study in patients with type 2 diabetes showed that a policy of intensive glycemic control compared with more standard therapy maintained for 9 years resulted in improved markers of diabetic polyneuropathy.
• Glycemic control is the only proven modality for the prevention of the onset and the progression of diabetic polyneuropathy. Clinical trial evidence for therapy against the other forms of diabetic neuropathy does not exist.

Diabetic Sensorimotor Polyneuropathy
The natural history of diabetic sensorimotor polyneuropathy is described in Figure 16.1. Clinically, this presents as progressive sensory loss (diabetic sensory polyneuropathy) in a stocking-and-glove distribution often associated with pain, and eventually complicated by motor impairment (diabetic sensorimotor polyneuropathy) and the late-stage sequelae of infection, ulceration, deformity, amputation, and Charcot deformity. Autonomic dysfunction frequently accompanies late-stage polyneuropathy.

FIGURE 16.1 Diabetic Sensorimotor Polyneuropathy: Classical Features
Generalized asymptomatic dysfunction of peripheral nerve fibers Detectable by NCS, heartbeat deep-breathing and valsalva abnormality Decrease or loss of vibration sensation at the great toes Panmodality sensory loss of the toes, feet, distal legs Abnormal tendon reflexes Autonomic abnormalities Weakness of small foot muscles and of ankle dorsiflexion

• Given the latency phase seen in Figure 16.1, screening is important for the identification of diabetic sensorimotor polyneuropathy, for intervention with improved glycemic control, and for institution of foot care programs to prevent the late-stage complications.
• In atypical presentations, neuropathies due to uremia, toxins, nutritional deficiencies, neoplasia, drugs, autoimmune and genetic factors should be considered.
• Charcot deformity is a condition that occurs in patients with advanced polyneuropathy and leads to damage of the joint's architecture. A team approach (orthopaedic surgeon, chiropodist, endocrinologist and diabetes educators) is required for successful management.
• At present, the only proven disease-modifying therapy for polyneuropathy is glycemic control.

Truncal Radiculoneuopathy and Proximal Neuropathy

• Truncal radiculoneuropathy presents with pain in the distribution of a nerve root on the torso of the body.
• Proximal neuropathy presents with marked pain and muscle wasting of the thighs.
• Both conditions are hypothesized to have an inflammatory and/or ischemic etiology.
• These occur primarily in older men with type 2 diabetes, and do not appear to accompany other complications.
• In striking contrast to diabetic polyneuropathy, these conditions have a relatively acute onset, run a clearly-defined course with remission occurring within 6-18 months, generally without further recurrence.
• Treatment is supportive and aimed at optimization of glycemic control.

Limb and Cranial Mononeuropathies

• The most common upper limb mononeuropathy is median nerve impairment (the "carpal tunnel syndrome").
• Entrapment of a susceptible nerve, as a result of underlying subclinical diffuse nerve injury, likely explains the increased incidence in diabetes patients.
• Treatment includes a trial of conservative measures (splints), and surgical release when conservative measures fail.
• Third nerve cranial mononeuropathy typically presents with diplopia and ptosis (and sparing of pupillary responses) occurring with acute onset usually over hours and associated with ipsilateral headache.
• Therapy is aimed at optimization of glycemic control and eye patch for suppressing diplopia during the recovery phase.

Autonomic Neuropathy

• Cardiac autonomic neuropathy often accompanies diabetic sensorimotor polyneuropathy, and results in abnormalities in heart rate control and vascular dynamics. These are manifested by exercise intolerance, intra-operative cardiovascular lability, orthostatic hypotension, and silent myocardial ischemia.
• Further clinical manifestations of autonomic neuropathy include gustatory sweating, gastroparesis, diarrhea, fecal incontinence, urinary retention, retrograde ejaculation, and impotence.
• Hypoglycemia associated autonomic failure (HAAF) is characterized by defective glucose counter-regulation and hypoglycemia unawareness.

• Screening for diabetic sensorimotor polyneuropathy should be carried out annually to identify those at high risk of developing foot ulcers.
• Screening for diabetic sensorimotor polyneuropathy should be done by assessing loss of sensitivity to the 10-g monofilament at the great toe or loss of sensitivity to vibration at the great toe. A protocol for these screening maneuvers can be found in Perkins et al. 2002, cited below.
• People with type 1 and type 2 diabetes should be treated with intensive glycemic control management to delay the onset and slow the progression of polyneuropathy.
• Antidepressants, anticonvulasants, opioid analgesics, topical isosorbide dinitrate, or topical capsaicin should be considered alone or in combination for relief of pain associated with diabetic sensorimotor polyneuropathy, particularly when it interferes with sleep.
• Examples of commonly used therapy:
  • Amitriptyline, initiated at 10 mg po qhs, increased weekly by 10 mg/day to a maximum of 150 mg/day.
  • Gabapentin, initiated at 300 mg po tid, increased weekly by 300 mg/d to a maximum of 3600 mg/day.
  • Pregabalin 75 mg po bid, double weekly to a maximum dose of 300 mg po bid.
  • Sustained-release oxycodone, initiated at 10 mg po bid, increased every three days by 10 mg to a maximum of 60 mg po bid. Combination with gabapentin has proven clinical trial efficacy.
• People with clinically significant autonomic dysfunction should be appropriately assessed and referred to a specialist experienced in managing the affected body system.

 

Author
The initial draft of this section was prepared by prepared by Laura Teague, RN, MN, APN and
Ann-Marie McLaren, DCh, BSc, MClScWH

• Diabetic foot ulceration is the most common diabetes complication requiring admission to hospital. Diabetic foot infection is the most common precipitant of non traumatic amputation. The 30-day peri-operative mortality rates are poor with reports ranging from 10.2-11.1 % in some studies. A strategy to prevent lower limb amputation should be developed by each diabetes team.
• An interdisciplinary network is required to assess, prevent and manage diabetes foot complications.
  Core team members should include:
  • Family Practitioner, Diabetes Specialist or Nurse Practitioner
  • Chiropodist/Podiatrist
  • Diabetes Educators
  • Orthotist/Pedorthist
  • Orthopedic or Vascular Surgeon were required

Prevention

• All patients with diabetes should be screened for foot complication risk; according to a systematic approach using validated risk assessment tool. Refer to Reference 5 for section 16.5 and Table 16.2.
• Loss of protective sensation occurs with significant peripheral polyneuropathy. Sensation is abnormal if there is loss of sensitivity to the 10-g monofilament at the great toe or loss of sensitivity to vibration at the great toe. See section 16.4 Diabetic Neuropathy.
• Paramount to preventing foot complications is patient education.
• Patients should be made aware of their risk of ulceration and infection.
• Encourage frequent self-inspection of feet to detect injury, minor ulcers, or abrasion.
• Risk factors for the development of diabetic foot ulcers and amputations include peripheral neuropathy, peripheral vascular disease, abnormal plantar pressure load and infection, abnormal gait.
• For those at moderate/high risk for foot complications, or for those unable to perform safe routine foot care due to vision or dexterity problems, foot care by a registered foot specialist (chiropody/podiatry) should be implemented.
• Properly fitted and protective footwear (socks and shoes) is recommended for those at increased risk by appropriately trained fitters.
• Particular attention should be made to the prevention foot injury (e.g. trauma, foreign body, friction, shear) and management of increased plantar pressures.
• Patients with foot deformities with or without neuropathy may benefit from specialized corrective footwear and accommodative insoles as prescribed and closely monitored by a trained healthcare professional.
• Patients with foot deformities and ulceration, pressure offloading techniques and/or devices (e.g. removable walking cast, total contact cast) should be implemented and closely monitored.

Treatment

• Patients who develop diabetic foot ulcers are at very high risk for infection and subsequent amputation.
• Patients with diabetic foot ulcers require lifestyle (activity, smoking, alcohol, diet) and co-morbidity (metabolic control, depression) management concurrently if wound healing is the goal.
• The use of a validated grading system allows health care professionals to consistently document and monitor progress of wound healing trajectories.
• Standing AP/Lat foot and ankle plain radiographs are helpful in establishing a baseline, ruling out foreign body, bony deformity and Charcot arthropathy.
• Vascular assessment includes asking about claudication symptoms, palpation for distal pulses, and ankle brachial index measurements to determine macrovascular involvement.
• Further investigations should be considered if the above assessments suggest peripheral vascular disease.
• Transcutaneous oxygen measurements are useful in determining healing potential at skin level in the absence of acute infection.
• Consultation with vascular surgeon is recommended if the patient has ulceration, gangrene or abnormal findings in the vascular assessment.
• Infection must be ruled out. The most reliable method for obtaining a wound culture is using Levine's technique. Tissue and bone cultures are recommended for deep ulcers that probe to bone.
• Hospitalization is recommended for close monitoring if limb threatening infection is present.
• Antimicrobial therapy should begin with clinical signs of infection AFTER wound cultures are obtained. Gram negative, gram positive and anaerobic bacteria may be responsible for infection.
• In the absence of limb ischemia, local wound care should included sharp debridement, local bacterial burden and moisture management.
• Pressure offloading to the affected foot is paramount for healing. Options for offloading include casts, removable cast walkers, canes, crutches, wheelchair. Choice of devices for this purpose are patient specific. Patients who fail to progress towards wound closure (wound should be measurably smaller by 30% at 4 weeks) should be completely reassessed.

TABLE 16.2 Diabetic Foot Classification System Categories 0-6: Risk Factors for Amputation Adapted with permission from the Journal of the American Podiatric Medical Association, 86(7), 311-316,1996.5
Category 0: No Pathology	Category 1: Neuropathy, No Deformity
Patient diagnosed with Diabetes Mellitus Protective sensation intact (normal neuropathy screen*) Ankle Brachial Index (ABI) > 0.80 and toe systolic pressure >45 mmHg Foot deformity may be present No history of ulceration POSSIBLE TREATMENT FOR CATEGORY 0 Two to three visits a year to assess neurovascular status, dermal thermometry, and foci of stress Possible shoe accommodations Patient education	Protective sensation absent (abnormal neuropathy screen*) Ankle Brachial Index (ABI) > 0.80 and toe systolic pressure >45 mmHg No history of ulceration No history of diabetic neuropathic osteoarthropathy (Charcot's Joint) No foot deformity POSSIBLE TREATMENT FOR CATEGORY 1 Same as Category 0 plus Possible shoe gear accommodation (pedorthic/orthotist consultation) Quarterly visits to assess shoe gear and monitor for signs of irritation
Category 2: Neuropathy with Deformity	Category 3: History of Pathology
Protective sensation absent (abnormal neuropathy screen*) Ankle Brachial Index (ABI) >0.80 and toe systolic pressure >45 mmHg No History of neuropathic ulceration No History of Charcot's joint Foot deformity present (focus of stress) POSSIBLE TREATMENT FOR CATEGORY 2 Same as Category 1 plus: Pedorthic/orthotist consultation for possible custom molded/extra depth shoe accommodation Possible prophylactic surgery to alleviate focus of stress (e.g., correction of hammer toe or bunion deformity)	Protective sensation absent (abnormal neuropathy screen*) Ankle Brachial Index (ABI) >0.80 and toe systolic pressure >45 mmHg History of neuropathic ulceration History of Charcot's joint Foot deformity present (focus of stress) POSSIBLE TREATMENT OF CATEGORY 3 Same as Category 2 plus: Pedorthic/orthotist consultation for custom molded/extra depth shoe accommodation Possible prophylactic surgery to alleviate the focus of stress (e.g., correction of bunion or hammer toe) More frequent visits may be indicated for monitoring
Category 4A: Neuropathic Wound	Category 4B: Acute Charcot's Joint
Protective sensation absent Ankle Brachial Index (ABI) > 0.80 and toe systolic pressure >45 mmHg Foot deformity normally present Non-infected neuropathic ulceration (ALL UT* STAGE A wounds) No acute diabetic neuropathic osteoarthorpathy (Charcot's Joint) present POSSIBLE TREATMENT FOR CATEGORY 4A Same as Category 3 plus: Pressure reduction program instituted Wound care program instituted	Protective sensation absent Ankle Brachial Index (ABI) > 0.80 and toe systolic pressure >45 mmHg Non-infected neuropathic ulceration may be present Diabetic neuropathic osteoarthropathy (Charcot's Joint) present POSSIBLE TREATMENT FOR CATEGORY 4B Same as Category 0 plus Pressure reduction program instituted Thermometric and radiographic monitoring If ulcer is present, treatment same as Category 4A
Category 5: The Infected Diabetic Foot	Category 6: The Ischemic Limb
Protective sensation may or may not be present Infected wound Charcot's Joint may be present ALL UT* STAGE B wounds POSSIBLE TREATMENT FOR CATEGORY 5 Debridement of infected, necrotic tissue and/or bone, as indicated Possible hospitalization, antibiotic treatment regimen Medical management	Protective sensation may or may not be present Ankle Brachial Index (ABI) <0.80 and toe systolic pressure <45 mmHg or Pedal Transcutaneous Oxygen Tension < 40 mmHg Ulceration may be present ALL UT* STAGE C AND D wounds POSSIBLE TREATMENT OF CATEGORY 6 Vascular consult, possible revascularization If infection present, treatment same for Category 5. Vascular consultation concomitant with control of sepsis.
* Section 16.5 author's modification to table.

 

TABLE 16.4 Levine's Technique (90% sensitivity & 57% specificity) Gardner et al. 2006.12
Cleanse wound with normal saline Moisten swab with culture medium Area near centre of wound free of necrotic tissue, debris and purulent exudate Rotate swab over a 1 cm2 area for 5 seconds applying pressure to extract fluid

TABLE 16.5 Diabetic Wound Classification System Adapted from Diabetes Care, 21(5), 855-859, 1998.4
Stage	Grades
	0	1	2	3
A	Pre-or post-ulcerative lesion	Superficial wound, not involving tendon, capsule, or bone	Wound penetrating to tendon or capsule	Wound penetrating to bone or joint
B	Pre- or post-ulcerative lesion, completely epithelialized with infection	Superficial wound, not involving tendon, capsule, or bone with infection	Wound penetrating to tendon or capsule with infection	Wound penetrating to bone or join with infection
C	Pre- or post-ulcerative lesion, completely epithelialized with ischemia	Superficial wound, not involving tendon, capsule, or bone with ischemia	Wound penetrating to tendon or capsule with ischemia	Wound penetrating to bone or joint with ischemia
D	Pre- or post-ulcerative lesion, completely epithelialized with infection and ischemia	Superficial wound, not involving tendon, capsule, or bone with infection and ischemia	Wound penetrating to tendon or capsule with infection and ischemia	Wound penetrating to bone or joint with infection and ischemia

Figure 16.2 - Physician's Orders - Diabetic Foot Infection (Click for Larger Version)

References for section 16.1 Macrovascular Complications

1. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2008 Clinical practice guidelines for the prevention and management of diabetes in Canada. Can J Diabetes 2008;32(suppl 1): S95-S65
2. Colhoun HM et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): Multicentre, randomised, placebo-controlled trial. Lancet 2004; 364:685-96.

References for Section 16.2 Diabetic Retinopathy

1. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema. ETDRS report number 1. Arch Ohpthalmol.1985;103:1796-1806
2. Early Treatment Diabetic Retinopathy Study Research Group. Grading diabetic retinopathy from stereoscopic color fundus photographs - an extension of the modified Airlic House classification. ETDRS ETDRS report number 10. Ophthalmology. 1991;98:786-806.
3. The Diabetic Retinopathy Study Research Group. Photocoagulation treatment of proliferative diabetic retinopathy: the second report of Diabetic Retinopathy Study findings. Ophthalmology. 1978;85:82-106.
4. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin dependant diabetes mellitus. N Engl J Med 1993;329:977-986.
5. The Diabetes Control and Complications Trial Research Group. The effect of intensive diabetes treatment on the progression of diabetic retinopathy in insulin-dependent diabetes mellitus. Arch Ophthalmol. 1995;113:36-51.
6. The Diabetes Control and Complications Trial Research Group. Early worsening of diabetic retinopathy in the Diabetes Control and Complications Trial. Arch Ophthalmol. 1998;116:874-886.
7. The Diabetic Retinopathy Vitrectomy Study Research Group. Early vitrectomy for severe vitreous hemorrhage in diabetic retinopathy. Four-year results of a randomized trial: Diabetic Retinopathy Study report 5. Arch Ophthalmol. 1990;108:958-964.
8. The Diabetic Retinopathy Vitrectomy Study Research Group. Early vitrectomy for severe proliferative diabetic retinopathy in eyes with useful vision. Results of a randomized trial - Diabetic retinopathy Vitrectomy Study report 3. Ophthalmology. 1988;95:1307-1320.
9. Cunningham ET Jr, Adamis A, Altweel M, et al. A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema. Oththalmology. 2005;112:1747-1757.
10. Grover D, Li J, Chong CW. Intravitreal steroid for macular edema in diabetes. Cochrane Database Syst Rev. 2008;(1):CD005656

References for Section 16.3 Diabetic Nephropathy

1. Canadian Institute for Health Information. Canadian Organ Replacement Registry (CORR): 2001 Annual Report, Ottawa, On. CIHI, 2001
2. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new predication equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 130:461, 1999
3. Middleton RJ, Foley RN, Hegarty J, et al. The unrecognized prevalence of chronic kidney disease in diabetes. Nephrol Dial Transplant 21:88, 2006
4. Fioretto P, Mauer SM, Bilous RW et al. Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl J Med 339:69,1998
5. Wang PH, Lau J, Chalmers TC. Meta-analysis of effects of intensive blood-glucose control on late complications of type I diabetes. Lancet 341:1306, 1993
6. Sowers JR, Epstein M, Frohlich ED. Diabetes, hypertension, and cardiovascular disease: an update. Hypertension 37:1053, 2001
7. Mann JFE, Schmieder RE, McQueen M, et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomized, double-blind, controlled trial. Lancet 372:547, 2008
8. Viberti G, Mogensen CE, Groop LC, et al Effect of captopril on progression to clinical proteinuria in patients with insulin-dependent diabetes mellitus and microalbuminuria JAMA 271:275, 1994
9. Captopril reduces the risk of nephropathy in IDDM patients with microalbuminuria. The Microalbuminuria Captopril Study Group. Diabetologia 39:587, 1996
10. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting enzyme inhibition on diabetic nephropathy N Engl J MED 329:1456, 1993
11. Kaplan NM. Vascular outcome in type 2 diabetes: an ADVANCE? Lancet 370:804, 2007
12. Parving HH et al. Aliskiren combined with losartan in type 2 diabetes and nephropathy N Engl J Med 358:2433, 2008
13. Hansen HP, Tauber-Lassen E, Jensen BR, Parving HH. Effect of dietary protein restriction on prognosis in patients with diabetic nephropathy, Kidney Int 62:220, 2002

References for section 16.4 Diabetic Neuropathy

1. Backonja M, Beydoun A, Edwards KR, et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA.1998;280:1831-1836.
2. Dogra S, Beydoun S, Mazzola J, et al. Oxcarbazepine in painful diabetic neuropathy: a randomized, placebo-controlled study. Eur J Pain. 2005;9:543-554.
3. Gilron I, Bailey JM, Tu D, et al. Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med. 2005;352:1324-1334.
4. Gimbel JS, Richards P, Portenoy RK. Controlled-release oxycodone for pain in diabetic neuropathy: a randomized controlled trial. Neurology 2003;60:927-934
5. Gomez-Perez FJ, Rull JA, Dies H, et al. Nortriptyline and fluphenazine in the symptomatic treatment of diabetic neuropathy. A double-blind cross-over study. Pain. 1985;23:395-400.
6. Harati Y, Gooch C, Swenson M, et al. Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology. 1998;50:1842-1846.
7. Herman WH, Kennedy L. Underdiagnosis of peripheral neuropathy in type 2 diabetes. Diabetes Care. 2005;28:1480-1481.
8. Low PA, Opfer-Gehrking TL, Dyck PJ, et al. Double-blind, placebo-controlled study of the application of capsaicin cream in chronic distal painful polyneuropathy. Pain. 1995;62:163-168.
9. Max MB, Culnane M, Schafer SC, et al. Amitriptyline relieves diabetic neuropathy pain in patients with normal or depressed mood. Neurology. 1987;37:589-596.
10. Max MB, Lynch SA, Muir J, et al. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med. 1992;326:1250-1256.
11. McQuay H, Carroll D, Jadad AR, et al. Anticonvulsant drugs for management of pain: a systematic review. BMJ. 1995; 311:1047-1052.
12. Partanen J, Niskanen L, Lehtinen J, et al. Natural history of peripheral neuropathy in patients with non-insulin-dependent diabetes mellitus. N Engl J Med. 1995;333:89-94.
13. Perkins BA, Olaleye D, Bril V. Carpal tunnel syndrome in patients with diabetic polyneuropathy. Diabetes Care. 2002; 25:565-569.
14. Perkins BA, Olaleye D, Zinman B, et al. Simple screening tests for peripheral neuropathy in the diabetes clinic. Diabetes Care. 2001;24:250-256.
15. Rahman M, Griffin SJ, Rathmann W, et al. How should peripheral neuropathy be assessed in people with diabetes in primary care? A population-based comparison of four measures. Diabet Med. 2003;20:368-374.
16. Raskin J, Smith TR, Wong K, et al. Duloxetine versus routine care in the long-term management of diabetic peripheral neuropathic pain. J Palliat Med. 2006;9:29-40.
17. Raskin P, Donofrio PD, Rosenthal NR, et al. Topiramate vs placebo in painful diabetic neuropathy: analgesic and metabolic effects. Neurology. 2004;63:865-873.
18. Reichard P, Berglund B, Britz A, et al. Intensified conventional insulin treatment retards the microvascular complications of insulin-dependent diabetes mellitus (IDDM): the Stockholm Diabetes Intervention Study (SDIS) after 5 years. J Intern Med. 1991;230:101-108.
19. Richter RW, Portenoy R, Sharma U, et al. Relief of painful diabetic peripheral neuropathy with pregabalin: a randomized, placebo-controlled trial. J Pain. 2005;6:253-260.
20. Rith-Najarian SJ, Stolusky T, Gohdes DM. Identifying diabetic patients at high risk for lower-extremity amputation in a primary health care setting. A prospective evaluation of simple screening criteria. Diabetes Care. 1992;15:1386-1389..
21. Rowbotham MC, Goli V, Kunz NR, et al. Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study. Pain. 2004;110:697-706.
22. Stracke H, Meyer UE, Schumacher HE, et al. Mexiletine in the treatment of diabetic neuropathy. Diabetes Care. 1992;15:1550-1555.
23. Tesfaye S, Chaturvedi N, Eaton SE, et al. Vascular risk factors and diabetic neuropathy. N Engl J Med. 2005;352:341-350.
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25. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993; 329:977-986.
26. The Diabetes Control and Complications Trial Research Group. The effect of intensive diabetes therapy on the development and progression of neuropathy. Ann Intern Med. 1995;122:561-568.
27. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837-853.
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References for section 16.5 The Diabetic Foot

1. Registered Nurses Association of Ontario (2005). Assessment and management of foot ulcers for people with diabetes. Toronto, Canada: Registered Nurses Association of Ontario.
2. Frykberg, R.G., Zgonis, T., Armstrong, D.G., Driver, V.R., Giurini, J.M., Kravitz, S.R., Landsman, A.S., Lavery, L.A., Moore, J.C., Schuberth, J.M., Wukich, D.K., Andersen, C. & Vanore, J.V. Diabetic foot disorders: A clinical practice guideline (2006 revision), Foot & Ankle Surgery, 2006, 45(5), S1-S66.
3. Andros, G. Diagnostic and therapeutic arterial interventions in the ulcerated diabetic foot. Diabetes Metab Res Rev 2004, 20(Sup[;1), S29-33
4. Armstrong, D., Lavery, L. A. & Harkless, L. B. (1998). Validation of a diabetic wound classification system: The contribution of depth, infection and ischemia to risk of amputation. Diabetes Care, 21(5), 855-859.
5. Armstrong, D. G., Lavery, L. A., & Harkless, L. B. (1996). Treatment-based classification system for assessment and care of diabetic feet. Journal of the American Podiatric Medical Association, 86(7), 311-316
6. Armstrong, DG, Lavery, LA, Nixon, BP & Boulton, AJM. It's not what you put on, but what you take off: Techniques for debriding and off-loading the diabetic foot wound. Clinical Infectious Diseases, 2004, 39, S92-9.
7. Armstrong DG, Nguyen HC, Lavery LA, van Schie CHM, Boulton AJM, Harkless LB. Off-loading the diabetic foot wound. Diabetes Care, 2001, 1019-1022.
8. Pellizzer, G., Strazzabosco, M., Presi, S., Furlan, F., Lora, L., Bendetti, P., Monato, M., Erle, G., & de Lalla, R. Deep tissue biopsy vs. Superficial swab culture monitoring in the microbiological assessment of limb-threatening diabetic foot infection. Diabetic Medicine 2001, 18, 822-827.
9. Grayson, M.L., Gibbons, G.W., Balogh, K., Levin, E., Karchmer, A.W. Probing to bone in infected pedal ulcers. JAMA 1995, 273(9), 721-723.
10. Levin, M. E. (2001). Pathogenesis and general management of foot lesions in the diabetic patient. In J. H. Bowker & M. A. Pfeifer (Eds.), Levin and O'Nea'ls The Diabetic Foot. 6th ed. (pp.222). St. Louis, MO: Mosby, Inc.
11. Sheehan, P., Jones, P., Caselli, A., Giurini, J.M. & Veves, A. Percent change in wound area of diabetic foot ulcer over a 4-week period is a robust predictor of complete healing in a 12-week prospective trial. Diabetes Care 2003, 26(6), 1879-1882.
12. Gardner, SE, Frantz, RA, Saltzman, CL, Hillis, SL, Park, J, Scherubel, M. Diagnostic validity of three swab techniques for identifying chronic wound infection. Wound Repair and Regeneration, 2006, 14, 548-557.
13. Sella, EJ, Grosser, DM. Imaging modalities of the diabetic foot. Clinic Podiatr Med Surg, 2003, 20, 729-740.
14. Sibbald, G., Williamson, D., Orsted, H., Campbell, K., Krasner, D., Sibbald, D. Preparing the Wound Bed-Debridement, Bacterial Balance, and Moisture Balance. Ostomy/Wound Management, 2000, 46(44):14-35.
15. Sibbald RG, Orsted HL, Coutts PM, Keast DH. Best practice recommendations for preparing the wound bed: update 2006. Advances in Skin & Wound Care, 2007, 390-405.
16. Subramaniam, B., Pomposelli, F., Talmor, D. & Park, KW. Perioperative and long-term morbidity and mortality after above-knee and below-knee amputations in diabetics and nondiabetics. Anesthesia & Analgesia, 2005, 100, 1241-1247.
17. Peng, C.W. & Tan, S.G. Perioperative and rehabilitative outcomes after amputation for ischemic leg gangrene. Ann Acad Med Singapore, 2000, 29, 168-72.
18. Margolis, D., Allen-Taylor, L., Hoffstad, O., Berlin, J., (2005). Diabetic neuropathic foot ulcers and amputation. Wound Repair and Regeneration, 13, 230-236.
19. Bus, S.A., van Deursen, R.W., Armstrong, D.G., Caravaggi, C., Hlavacek, P., Bakker, K. & Cavanagh, P.R. The effectiveness of footwear and offloading interventions to prevent and heal foot ulcers and reduce plantar pressure in diabetes: A systematic review. Diabetes/Metabolism Research and Reviews, 2008, 24 (Suppl 1):S162-S180.
20. Bus, S.A., van Deursen, R.W., Armstrong, D.G., Caravaggi, C., Hlavacek, P., Bakker, K. & Cavanagh, P.R. Specific guidelines on footwear and offloading. Diabetes/Metabolism Research and Reviews, 2008, 24 (Suppl 1):S192-S193.
21. Royal Melbourne Hospital (2002). Evidence based guidelines for the inpatient management of acute diabetes related foot complications. Melbourne Health [Electronic version]. Available: http://www.mh.org.au/ClinicalEpidemiology/new_files/Foot%20guideline%20supporting.pdf
22. Butalia, S, Palda, VA, Sargeant, RJ, Detsky, AS & Mourad, O. (2008) Does this patient with diabetes have osteomyelitis of the lower extremity? JAMA, 299(7), 806-813.
23. Canadian Diabetes Association, website, http://www.diabetes.ca
24. Senneville, E, Melliez, H, Beltrand, E, Legout, L, Valette, M, Cazaubiel, M, Cordonnier, M, Caillaux, M, Yazdanpanah, Y & Mouton, Y. Culture of percutaneous bone biopsy specimens for diagnosis of diabetic foot osteomyelitis. Clin Infect Dis 2006, 1:42(1), 57-62.
25. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2008 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J of Diabetes 2008; 32(Suppl 1): S32-36, S168-180.