Diabetes mellitus is associated with more than half of all non-traumatic lower limb amputations. The major pathophysiological factors are ischaemia, neuropathy, infection and wound healing factor. They operate concurrently and sequentially, enhancing the risk for amputation fifteen-fold in diabetic subjects compared to non-diabetics. Since the `diabetic foot’ is the sequel of interaction of a multitude of factors, intervention must be directed towards correction of all the causative factors.
FACTORS OPERATIVE IN THE CAUSATION OF DIABETIC FOOT
Diabetes mellitus is associated with structural changes in large as well as small blood vessels, resulting in ischaemia. The atherosclerotic process in a diabetic occurs more frequently and at an early age and advances more rapidly compared to non-diabetics, and is devoid of the normal sex difference seen in the latter. The frequently associated risk factors for diabetic vascular disease include smoking, hypertension, hyperlipidaemia and insulin resistance with compensatory hyperinsulinaemia, besides the severity and duration of diabetes, age and genetic factors. Smoking enhances the risk of peripheral vascular disease more than one hundred times compared to non-diabetic non-smokers. However, cessation of smoking has been associated with a decrease in the progression of atherosclerosis.
Hypertension is twice as common in diabetics as compared to non-diabetics; roughly one-third to one-half of diabetics have hypertension. Systolic hypertension has been linked with disease of proximal blood vessels. A significant association of hypertension with above knee and bilateral amputations has been observed.
Numerous studies allude to the strong association of hyperlipidaemia with peripheral vascular disease. The ratio of LDL-cholesterol to HDL-cholesterol probably assumes greater significance in the diabetic population because the protective effect of a high HDL-cholesterol is nullified by a concomitant increase in LDL-cholesterol fraction.
Loss of pain and thermal sensation renders the foot vulnerable to trauma due to mechanical, chemical and thermal factors, leading to ulcerations. Loss of proprioception and muscle atrophy due to motor neuropathy result in foot deformities. The resultant alteration in the configuration with new pressure points leads to callous formation and subsequent ulceration. Autonomic neuropathy with absent sweating and dry, fissured skin offering portals of entry for infection are important contributory factors for foot ulcer. The association of autonomic neuropathy with foot ulcer is almost 100%.
Combination of neuropathy and trauma results in tissue breakdown. The atrophy of the intrinsic muscle of the foot, predominantly plantar flexars of the toes alters the flexar / extensor balance at the metatorso phalangeal joints and causes clawing of the toes and prominence of the metatorsal heads. Alterations of foot shape results in increased plantar pressure. A majority of wounds on insensitive foot are not caused by accidental injury or ischemia but from continous pressure. Often moderate stress as occurring during locomotion on the same part of the insensitive foot leads to calus formation and ulcer. The presence of calus may exacerbate the problem both acting as a foreign body and by increasing the plantar pressure.
Limited joint mobility (LJM) is yet another factor contributing to elevated plantar pressure. Glycosylation of collagen results in thickening and cross-linking of collagen bundles. This result in restriction of joint movements particularly sub talar joint and alters the mechanism of walking. Limited joint mobility also occurs in the hands.
Haematocrit, plasma viscosity, platelet activity and red blood cell (RBC) aggregation constitute macrovessel haemorrheology while microvessel haemorrheology involves RBC and white blood cell (WBC) deformability. All these components are unfavorably altered in diabetic subjects, accentuating the ischaemic process due to structural changes of large and small blood vessels.
Frequent and severe infection in diabetic subjects is facilitated by vascular insufficiency. A normal individual responds to infection by increasing the blood supply to the site, as blood supply has to be increased 12-15 times to maintain the viability of the skin If this increased demand cannot be met, the skin breaks down and tissue necrosis results. Necrosed tissue is a good nidus for organisms to thrive.
Most of the diabetic foot infections are caused by multiple organisms, including anaerobes. Bacteriodes are the commonest group of pathogens isolated in culture. Soft tissue gas formation has been encountered in diabetic subjects and the capacity for gas formation is exhibited not only by the coliform group (aerobic and anaerobic gram negative rods) but also by streptococci and staphylococci. Osteomyelitis is observed in some of the diabetic foot lesions.
The neuropathy and the pathophysiology of the diabetic foot is depicted in the Fig – 1.
Fig – 1
Neuropathy and Pathophysiology of the diabetic foot
The peripheral vascular disease occurring in diabetic subjects is multi-segmental with a predilection for vessels below the level of the popliteal artery; often the pathology is bilateral. These features are in marked contrast to those encountered in the non-diabetic population. Not uncommonly, the collateral vessels are also involved, with the result that gangrene occurs in patchy areas of the foot and toes, in contrast to the extensive gangrene occurring in the non-diabetic subjects.
Patients may present with intermittent claudication, nocturnal pain and rest pain, the latter two being relieved by dependency. Nocturnal pain is a form of ischaemic neuritis that precede rest pain. During sleep, the circulation predominantly caters to that splanchnic area, resulting in diminished perfusion of the lower extremities; the consequent ischaemic neuritis becomes intense and disturbs and patient from his sleep. The patient attempts to gain relief by standing, dangling the feet or occasionally walking a few steps; the resultant increase in cardiac output improves tissue perfusion, affording relief from pain. Failure of intervention at the stages of nocturnal and rest pain ultimately results in tissue necrosis and gangrene, necessitating amputation.
On examination of an ischaemic limb, the feet are cold with absent pulses, blanching on elevation with delayed venous filling. The skin appears shiny with loss of hair and thickened nails(Table – 1). On the other hand, the neuropathic foot will be warm and veins will be prominent on the dorsum of the foot due to arterio-venous shunts resulting from autonomic neuropathy(Table-2).
Table – 1
Features of the Ischemic foot
– Painful lesions: dry black gangrene either confined to a toe or the heel, or extensive and superinfected
– Cold feet that become pale on elevation and cyanosed on depression
– Thin atrophic feet; thickened nails; sparse hair
– Peripheral pulses weak or absent
– Slow venous filling
– Vascular investigations: ischemia
– Normal or slightly reduced reflexes and sensation.
Table – 2
Features of the neuropathic foot
– Disproportion between lesions and absence of pain.
– Keratosis, cracks, ulcers and plantar ulcers.
– Deformity of foot and toes; amyotrophy
– Loss of sense of touch, pain and vibration; loss of tendon reflexes
– Warm dry feet; venous congestion; edema
– Pulses present; no evidence of ischemia on investigation.
The vascular laboratory provides essential additional information which serves to initiate measures in the management of peripheral vascular disease. The ankle and toe pressures, ankle-brachial systolic pressure ratio (ischemic index), the wave pattern of flow, are some of the indices routinely used in the assessment. An ankle pressure of less than 70 mm Hg is associated with poor healing of ulcers while a pressure of more than 100 mm Hg is associated with good prognosis. Similarly, a toe pressure of less than 20 mm Hg has been found to be associated with increased failure of distal amputation, while more than 40 mm Hg is associated with good prognosis. An ischemic index of 0.45 with pulsatile flow indicates healing in 93% of subjects, while subjects with an index below 0.45 have to be evaluated for vascular reconstruction.
However, the outcome of non-invasive vascular studies should not be allowed to influence clinical judgment on site selection for amputation, because falsely high segmental systolic pressures could be obtained with a rigid calcified lower extremity artery. In fact, the importance of pulsatile wave forms on arterial impedance Plethysmography are more reliable parameters of prevailing vascularity.
Sophisticated techniques are now available for vascular assessment in predicting healing of amputation and ulcers. Skin blood flow calculated from xenon-133 clearance, a micro-invasive procedure and transcutaneous oxymetry are some of those techniques. Cutaneous blood flow of more than 2.6 ml/100 g/min has been associated with good healing. However, all the above indices may fail to predict healing accurately because the state of the local wound dominates the outcome. For example, a seven infection can dampen the beneficial effects of the marginal blood flow or occasionally even a good blood flow.
The classical peripheral neuropathy of diabetes mellitus is often bilateral and symmetrical. The sensory component predominates, with patients complaining of pan and paraesthesia while on objective examination there is blunting of pain and temperature sensation – `the painful painless leg’. The sensory disturbances generally appear early in the distal portions of the lower extremities, eventually progressing to a stock and glove distribution. Involvement of large sensory and motor fibres impairs light touch and propioception and causes weakness of intrinsic muscles of the feet with alteration of pressure points (Fig – 2).
Fig – 2
Prediction of foot ulcers vs. Neuroarthropathy
Neuropathy can be assessed by clinical examination and conduction studies. Autonomic neuropathy with its important contribution towards the propagation and maintenance of foot ulcer can be assessed at the bedside by a battery of tests. Since the peripheral nerve is the common pathway for neural flow, severe peripheral neuropathy is manifested by autonomic disturbances in the periphery.
Repetitive Moderate Stress
In a normal as well as in insensitive feet, walking briskly is accompanied by progressive hyperemia over points of maximum stress. Thermography helps to outline the temperature contrast of progressive inflammation from such a process. In subjects with insensitive feet, the thermo graphic pattern shows hyperemia at sites of old scar, thereby inferring that these subjects have been stressing that particular area more than optimally, due to absence of pain and as a result of motor neuropathy. Similarly, in-shoe foot prints help to detect the points of persistent and maximum stress on the feet which probably could be alleviated by proper footwear.
Many diabetic foot ulcers tend to be neglected because patients are asymptotic. Osteomyeitis should be suspected when a non-healing ulcer overlies a bony prominence. It should however be distinguished from diabetic osteopathy, occurring as a result of denervation(Fig-2). The radiological hallmark of diabetic osteopathy is the characteristically pointed distal metatarsal called `the peppermint stick sign’. The distribution of diabetic osteopathy is multifocal and bilateral; besides, the condition is associated with normal leukocyte count and ESR. However, the distinction between osteomyelitis and osteopathy is often made on clinical grounds.
The Wagner Classification of foot ulcer is given in Table-3.
Table – 3
Grading of diabetic foot lesions*
Grade 0 Intact skin. Possible bony deformities such as bunions, claw toes, depressed metatarsal heads and charcot break down with bony prominences. Possible hyperkeratotic lesions around or under bone deformities.
Grade 1 Superficial ulcer. The base may be necrotic or viable with early granulation tissue.
Grade 2 Deeper lesion extending to bone, ligament, tendon, joint capsule or deep fascia. No abscess or osteomyelitis as yet.
Grade 3 Deep abscess, osteitis, or osteomyelitis. The exact extent of the lesion is difficult to determine from superficial examination.
Grade 4 Moist or dry gangrene of some portion of the topes or forefoot.
Grade 5 Such complete involvement that no foot healing or local procedure is possible.
The essential factors for healing of diabetic foot ulcer are 1) ensuring adequate blood supply, 2) redistribution of body pressure over the entire foot and 3) debridement of necrotic and infected tissues, besides good metabolic control and appropriate antibiotics(Fig-3).
Fig – 3
Clinical Features and Management of diabetic foot disease
An ischemic ulcer is an extremely painful, yellow, punched out, necrotic ulcer with sharp margins. There is scanty bleeding from the central aspect on debridement, while the periphery bleeds for less than a minute. In contrast to ischemic ulcers, the neuropathic ulcer is relatively painless, is located over a weight-bearing area, and has pink granulation tissue with a white fibrotic rim surrounded by hyperkeratotic tissue. Additionally, the changes occurring in the tarsal and metatarsal joints of the diabetic foot lead to `charcot’s joint’ with loss of the longitudinal arch of the foot and resultant abnormal configuration; this results in new pressure points with callous formation and subsequent ulceration. Hemorrhage into a callous, mimicking infection, may be a preulcerative lesion. Debridement of necrotic tissue and meticulous wound care forms the treatment of choice for a foot ulcer devoid of infection.
Vascular surgery if feasible forms the only means of improving blood circulation in a diabetic with peripheral vascular disease. Foot ulcers and infections not responding to conventional management, impending gangrene, and rest pain and nocturnal pain are some of the indications for surgery. Arteriography is mandatory for locating the block and for ascertaining the feasibility of surgery. Conventional arteriography does not satisfactorily outline the vessels primarily involved in diabetic peripheral vascular disease. The recent technique of femoral balloon occlusion arteriography by occluding the femoral artery enables the dye to reach the periphery, thereby providing a satisfactory outline of the vasculature. Another recent investigative procedure for vascular assessment, digital subtraction angiography, requires a very small mount of contrast material, with the result that the risk of contrast-induced renal damage is substantially reduced.
Strict glycemic control has bee found to improve motor conduction velocities, and drugs like tricyclic antidepressants and anticonvulsants afford symptomatic relief from the disabling paraesthetic symptoms. The loss of pain and temperature sensation, the major pathophysiological factor in the etiology of diabetic foot ulcer, is seldom alleviated. Hence, inspection of the foot atleast once daily by the patient and during clinical visits must be strongly advocated. Likewise, ill-fitting shoes with pressure effects have to be replaced with ones that suit individual needs with extra cushioning over areas of altered pressure points as evidenced by callous formation or as outlined b thermography. Repetitive moderate stress in the insensitive feet must be eliminated as much as possible with micocellular footwear.
Fibrinolytic agents (streptokinase), calcium channel antagonists (cinnarazine) acting presumably by decreasing the RBC calcium content and thereby enhancing its deformability, and anti platelet aggregating agents (aspirin, dipyridamole) have been routinely used to ameliorate the unfavorable haemorrheological status of diabetic subjects. Pentoxyfylline, a methylxanthine derivative, has been found to increase the RBC deformability by increasing ATP levels; in addition, it decreases platelet aggregation and improves WBC deformability. Clinical studies have documented the beneficial effects of pentoxyfylline in subjects with intermittent claudication. Cilastozole a recently introduced drug is also beneficial.
Medical management of diabetic foot infection includes a combination of antimicrobial agents which are likely to be effective, based on factors like bacterial culture and sensitivity testing, clinical appearance of lesions, history of recent progression and general condition of the patient. A high percentage of foot ulcers in diabetics harbor anaerobic bacteria. Mixed anaerobic infections are foul-smelling and are associated with gas in the soft tissues. Derivatives of penicillin like ticarcillin or cloxacillin or cephalosporins like cefoxitin should be administered initially. In the presence of history of allergic reaction to penicillin, non beta-lactam antibiotics such as chloramphenicol may be used. Since many foot lesions in diabetics are caused by aerobic gram-negative rods or a combination of these organisms with others, aminoglycosides are frequently required for therapy. Metronidazole is frequently used in conjunction with other drugs for combating anaerobes, especially bacteroides. Quinolone derivatives like ciprofloxacin have a wide antimicrobial spectrum and are found to be quite effective in the treatment of foot lesions. Tropical quinolines are also useful.
Debridement and Amputation
Aggressive wound debridement is essential in the management of diabetic foot ulcer. Debridement should include not only the necrotic tissue which serves as an excellent culture medium and a barrier to new granulation tissue but also the second zone of viable but severely infected tissues. Clinically, one has to distinguish a superficially infected wound from an invasive ulcer. A superficially infected ulcer has a fibropurulent covering without erythema, edema or lymphatic streaking; usually the patient is afebrile and without significant hyperglycemia. On the other hand, the invasive ulcer is associated with erythema, edema or lymphatic streaking around the wound; subjects have constitutional symptoms like fever with frequently elevated blood sugar levels.
If conservative measures of management fail to yield results, one has to contemplate amputation. The site and timing of amputation are influenced by factors like the duration and severity of the foot lesion, the general condition of the patient, the vasculature of the limbs and associated diseases. However, surgeons have recognized that below knee amputations can be performed with favorable outcome for wound healing even in the absence of a popliteal pulse. Post amputation surveillance and rehabilitation with prosthesis are equally important. The stumps should be inspected daily for skin problems. Fungal infections and blockage of the sweat glands and secondary infections may be encountered. Stump pain, painful neuromas, phantom pain and phantom sensations are also observed.
One must be familiar with these causes of patient morbidity following amputation and suitable remedial measures must be instituted.
Following amputation, the patient must be physically and mentally prepared for accepting a prosthesis. The contraindications for prosthesis include
1) chronic mental deterioration that renders successful training impossible, and 2) neurological disorders like stroke and severe parkinsonism medical disorders like unstable angina and congestive cardiac failure, and lastly inability of the patient to walk even before amputation.
Thus, the evaluation and treatment of diabetic subjects with non healing foot ulcer should include the following steps: 1) detailed medical history, physical examination and clinical assessment; 2) non-invasive vascular testing; 3) arteriography when indicated; 4) aggressive ulcer debridement; 5) suitable vigorous antibiotic therapy; 6) vascular reconstruction when indicated; and 7) amputation and rehabilitation. These steps have to be implemented in conjunction with a well organized diabetic education program. Adequate emphasis must be laid on advising patients to examine their feet daily. About one-sixth of diabetic subjects may require amputation. Organized foot care clinics with sincere efforts toward imparting patient education have a positive effect on lessening the number of amputations and also increasing the awareness in the diabetic population regarding the potential risk and associated morbidity and mortality.
Charcot foot or neuroarthropathy is defined as a relative painless, progressive degenerative arthropathy of single or multiple joints caused by underlying neuropathy. Charcot neuroarthropathy is characterized by simultaneous presence of bones and joint destruction, fragmentation and remodeling. Diabetes is the commonest cause of charcot foot and most patients have a dense neuropathy but good circulation. Walking on an insensitive foot leads to excessive and repetitive stress to bone causing micro fracture and finally bone and joint destruction. Diabetic neuropathy and the presence of autosmpathectomy leads to peripheral vasodilation (Warm foot). A significant arteriovenous shunting takes place leading to abnormal bone cell activity (osteoclastic) and eventual resorption and weakening of bone. Ultimately the foot shape is deformed and turns into a ‘bag of bones’. Ultimately there may be considerable deformities, including collapse of the foot arches leading to a ‘rocker bottom foot’ and disruption of ankle joints. The sequence of events resulting in charcot foot is given in fig – 4.
Fig – 4
Development of Charcot foot
Plain X- ray of the foot will show demineralization, bone destruction and periosteal reaction. Marked osseous resorption of bone results in ‘pencil pointing’ and ‘sucked candy’ deformities of the metatorsal heads and shafts. In the largest joints of the foot there will be destruction of bone and new bone formation.
The treatment is conservative, mainly immobilization either by total contact cast or the diabetic air cast walker with inflatable air cells. There is some evidence now that biphosphanate drugs given intravenously in the acute phase may shorten the duration of the acute phase presumably by reducing the bone turnover directly and also slowing down the process which weakens the bone and renders it susceptible for foot fracture and fragmentation.
It is a dictum that ‘a warm swollen foot in a diabetic with neuropathy without local and systemic signs of infection, charcot foot must be considered until proven otherwise’.
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