abc of arterial and venous disease www[1].forumakademi.org

ABC of arterial and venous diseaseNoninvasive methods of arterial and venous assessmentRichard Donnelly, David Hinwood, Nick J M London

Although diagnostic and therapeutic decisions in patients withvascular disease are guided primarily by the history andphysical examination, the use of noninvasive investigations hasincreased significantly in recent years, mainly as a result oftechnological advances in ultrasonography. This articledescribes the main investigative techniques.

Principles of vascularultrasonographyIn the simplest form of ultrasonography, ultrasound istransmitted as a continuous beam from a probe that containstwo piezoelectric crystals. The transmitting crystal producesultrasound at a fixed frequency (set by the operator accordingto the depth of the vessel being examined), and the receivingcrystal vibrates in response to reflected waves and produces anoutput voltage. Conventional B mode (brightness mode)ultrasonography records the ultrasound waves reflected fromtissue interfaces, and a two dimensional picture is built upaccording to the reflective properties of the tissues.

Doppler ultrasonographyUltrasound signals reflected off stationary surfaces retain thesame frequency with which they were transmitted, but theprinciple underlying Doppler ultrasonography is that thefrequency of signals reflected from moving objects such as redblood cells shifts in proportion to the velocity of the target. Theoutput from a continuous wave Doppler ultrasonograph isusually presented as an audible signal, so that a sound is heardwhenever there is movement of blood in the vessel beingexamined.

Pulsed ultrasonographyContinuous wave ultrasonography provides little scope forrestricting the area of tissue that is being examined because anysound waves that are intercepted by the receiving crystal willproduce an output signal. The solution is to use pulsedultrasonography. The investigator can focus on a specific tissueplane by transmitting a pulse of ultrasound and closing thereceiver except when signals from a predetermined depth arereturning. This allows, for example, the centre of an artery andthe areas close to the vessel wall to be examined in turn.

Duplex scannersAn important advance in vascular ultrasonography has beenthe development of spectral analysis, which delineates thecomplete spectrum of frequencies (that is, blood flow velocities)found in the arterial waveform during a single cardiac cycle.The normal (“triphasic”) Doppler velocity waveform is made upof three components which correspond to different phases ofarterial flow: rapid antegrade flow reaching a peak duringsystole, transient reversal of flow during early diastole, and slowantegrade flow during late diastole.

Doppler examination of an artery distal to a stenosis willshow characteristic changes in the velocity profile: the rate ofrise is delayed, the amplitude decreased, and the transient flowreversal in early diastole is lost. In severe disease, the Doppler

Handheld pencil Doppler being used to measure ankle brachial pressureindex

Left: Doppler velocity waveforms: (a) triphasic waveform in normal artery;(b) biphasic waveform, with increased velocity, through a mild stenosis; (c)monophasic waveform, with greatly increased velocity, through tight stenosis;and (d) dampened monophasic waveform, with reduced velocity, recordeddistal to tight stenosis. Right: Anatomical chart used to record position ofstenoses, showing three stenoses with velocity increases of 7×, 4×, and 3×compared with adjacent unaffected arteries

Tight 7x

Significant 3x

4x

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waveform flattens; in critical limb ischaemia it may beundetectable.

Examination of an arterial stenosis shows an increase inblood velocity through the area of narrowing. The site(s) of anystenotic lesions can be identified by serial placement of theDoppler probe along the extremities. The criteria used to definea stenosis vary between laboratories, but a twofold increase inpeak systolic velocity compared with the velocity in an adjacentsegment of the artery usually signifies a stenosis of 50% ormore.

By combining the pulsed Doppler system with real time Bmode ultrasound imaging of vessels, it is possible to examineDoppler flow patterns in a precisely defined area within thevessel lumen. This combination of real time B mode soundimaging with pulsed Doppler ultrasonography is called duplexscanning. The addition of colour frequency mapping (so calledcolour duplex or triplex scanners) makes the identification ofarterial stenoses even easier and reduces the scanning time.

Investigations of arterial diseaseAnkle brachial pressure indexUnder normal conditions, systolic blood pressure in the legs isequal to or slightly greater than the systolic pressure in theupper limbs. In the presence of an arterial stenosis, a reductionin pressure occurs distal to the lesion. The ankle brachialpressure index, which is calculated from the ratio of ankle tobrachial systolic pressure, is a sensitive marker of arterialinsufficiency.

The highest pressure measured in any ankle artery is usedas the numerator in the calculation of the index; a value >1.0 isnormal and a value < 0.9 is abnormal. Patients withclaudication tend to have ankle brachial pressure indexes in therange 0.50.9, whereas those with critical ischaemia usually havean index of < 0.5. The index also has prognostic significancebecause of the association with arterial disease elsewhere,especially coronary heart disease.

Diabetic limbsSystolic blood pressure in the lower limbs cannot be measuredreliably when the vessels are calcified and incompressible—forexample, in patients with diabetes—as this can result in falselyhigh ankle pressures. An alternative approach is to use eitherthe pole test or measurement of toe pressures. Normal toesystolic pressure ranges from 90100 mm Hg and is 8090% ofbrachial systolic pressure. A toe systolic pressure < 30 mm Hgindicates critical ischaemia.

Spectral analysis of blood velocity in a stenosis, andunaffected area of proximal superficial femoral artery. Thevelocity increases from 150 to 300 m/s across the stenosis

Colour duplex scanning of blood flow through stenosis of superficialfemoral artery. Colour assignment (red or blue) depends on direction ofblood flow and colour saturation reflects velocity of blood flow. Lesssaturation indicates regions of higher blood flow and deeper coloursindicate slower flow; the absence of flow is coded as black

Years

Pat

ien

t su

rviv

al (

%)

108642020

60

800

100ABPI > 0.85ABPI 0.4-0.85ABPI < 0.4

40

Patient survival according to measurements of ankle brachial pressure index(adapted from McKenna et al, Atherosclerosis 1991;87:11928)

Pole test for measurement of ankle pressures in patients with calcifiedvessels: the Doppler probe is placed over a patent pedal artery and the footraised against a pole that is calibrated in mm Hg. The point at which thepedal signal disappears is taken as the ankle pressure

Relation between increased blood velocity and degree ofstenosis

Diameter ofstenosis (%)

Peak sytolicvelocity* (m/s)

Peak diastolicvelocity* (m/s)

Internal: commoncarotid arteryvelocity ratio†

039 < 1.1 < 0.45 < 1.8

459 1.11.49 < 0.45 < 1.8

6079 1.52.49 0.451.4 1.83.7

8099 2.56.1 > 1.4 > 3.7

> 99 (critical) Extremely low NA NA

*Measured in lower part of internal carotid artery†Ratio of peak systolic velocity in internal carotid artery stenosisrelative to proximal measurement in common carotid artery

Clinical review

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Walk testExercise testing will assess the functional limitations of arterialstenoses and differentiate occlusive arterial disease from othercauses of exercise induced lower limb symptoms—for example,neurogenic claudication secondary to spinal stenosis. A limitedinflow of blood in a limb with occlusive arterial disease resultsin a fall in ankle systolic blood pressure during exercise inducedperipheral vasodilatation.

The walk test is performed by exercising the patient for 5minutes, ideally on a treadmill, but walking the patient in thesurgery or marking time on the spot are adequate. The anklebrachial pressure index is measured before and after exercise. Apressure drop of 20% or more indicates significant arterialdisease. If there is no drop in ankle systolic pressure after a 5minute brisk walk, the patient does not have occlusive arterialdisease proximal to the ankle in that limb.

Duplex scanningDuplex ultrasonography has a sensitivity of 80% and aspecificity of 90100% for detecting femoral and poplitealdisease compared with angiography, but it is less reliable forassessing the severity of stenoses in the tibial and peronealarteries. Duplex scanning is especially useful for assessing thecarotid arteries and for surveillance of infrainguinal bypassgrafts where sites of stenosis can be identified before completegraft occlusion occurs and before there is a fall in ankle brachialpressure index. The normal velocity within a graft conduit is50120 cm/s. As with native arteries, a twofold increase in peaksystolic velocity indicates a stenosis of 50% or more. A peakvelocity < 45 cm/s occurs in grafts at high risk of failure.

Identification of distal vessels for arterial bypass graftingIn critically ischaemic limbs, where occlusive disease tends to bepresent at multiple levels, arteriography often fails to showpatent calf or pedal vessels as potential outflows forfemorodistal bypass grafting. Alternative noninvasiveapproaches have been developed for preoperative assessment,including pulse generated run off and dependent Dopplerassessment.

Transcranial Doppler ultrasonographyLower frequency Doppler probes (12 MHz) can be used toobtain information about blood flow in arteries comprising thecircle of Willis and its principal branches. Mean flow velocities> 80 cm/s in the middle cerebral artery, or > 70 cm/s in theposterior and basilar arteries, indicate a serious stenosis.Transcranial Doppler scanning has several applications but isespecially useful for intraoperative and postoperativemonitoring of patients having carotid endarterectomy.

Helical or spiral computed tomographySpiral computed tomography is a new, minimally invasivetechnique for vascular imaging that is made possible bycombining two recent advances: slip ring computedtomography (which allows the x ray tube detector apparatus torotate continuously) and computerised three dimensionalreconstruction. A helical scan can cover the entire region ofinterest (for example, the abdominal aorta from the diaphragmto the iliac bifurcation) in one 3040 second exposure, usually ina single breath hold. This minimises motion artefact and allowsall the scan data to be collected during the first pass of anintravenous bolus of contrast through the arterial tree—that isduring the time of maximal arterial opacification. A largenumber of finely spaced slices from one scan can then bereconstructed to produce high quality two or three dimensionalimages of the contrast enhanced vessels.

Uses of colour duplex scanning

Arterialx Identify obstructive

atherosclerotic disease:CarotidRenal

x Surveillance ofinfrainguinal bypass grafts

x Surveillance of lower limbarteries after angioplasty

Venousx Diagnosis of deep vein thrombosis

above the kneex Assessing competence of valves in

deep veinsx Superficial venous reflux:

Assessing patient with recurrentvaricose veinsIdentify and locate reflux atsaphenopopliteal junction

x Preoperative mapping of saphenousvein

Clinical use of transcranial Doppler scanning in adults

x Intraoperative monitoring during carotid endarterctomy:Shunt functionCerebral perfusion

x Postoperative montoring after carotid endarterectomy:Detection of emboliFormation of carotid thrombus

x Detection of intracranial vasospasm after subarachnoidhaemorrhage

x Detection of middle cerebral artery diseasex Evaluation of collateral circulation in patients with carotid diseasex Evaluation of arteriovenous malformations of the brain

Min after exercise

An

kle

bra

chia

l pre

ssu

re in

dex

101 205Rest00

0.2

0.3

0.4

0.5

0.6

0.7

0.80.9

1

Normal

0.1Intermittent claudication

Fall in ankle brachial pressure index with exercise in patient withintermittent claudication and normal subject (adapted from Creager, Vasc

Med 1997;2:2317)

Spiral computed tomogram of both carotid systems showing a tight stenosisin the proximal segment of left internal carotid artery

Clinical review



Magnetic resonance angiographyMagnetic resonance angiography has developed rapidly overthe past five years. It has the advantage of imaging a movingcolumn of blood and does not require ionising radiation oriodinated contrast, but the technique has obvious drawbacks interms of cost efficiency and accessibility to scanners. A variety ofimaging sequences are used depending on the vessels beingstudied and the field strength of the machine. The mostcommonly used techniques include time of flight, two and threedimensional angiography and phase contrast.

Use of a magnetic resonance imaging scanner with a highfield strength (which allows rapid acquisition of data) and acarefully timed bolus of gadolinium contrast enables highquality angiographic images to be obtained in a single breathhold. Magnetic resonance angiography is well established forexamining the cerebral vessels and the carotid arteries, and itsrole in other territories is being extended.

Investigations of venous diseaseVenous thrombosisColour Duplex scanning is both sensitive and specific (90100%in most series) for detecting proximal deep vein thrombosis.Deep veins and arteries lie together in the leg, and the normalvein appears as an echofree channel and is usually larger thanthe accompanying artery.

Venous ultrasonography is a very accurate method ofidentifying deep vein thrombi from the level of the commonfemoral vein at the groin crease to the popliteal vein but is lessreliable for diagnosing calf vein thrombosis.

Venous refluxColour duplex scanning has revolutionised the investigation ofthe lower limb venous system because it allows instantvisualisation of blood flow and its direction. Thus, reflux at thesaphenofemoral junction, saphenopopliteal junction, andwithin the deep venous system, including the popliteal veinbeneath the knee and the gastrocnemius veins, can be detectedwithout invasive techniques. Although venous reflux can beassessed with a pencil Doppler, this technique misses 12% ofsaphenofemoral and 20% of saphenopopliteal junction refluxcompared with colour duplex scanning.

We thank Jean Clarke for expert secretarial assistance; Frances Ryan andTim Hartshorne (vascular technicians) and colleagues in the vascular laboratories at Derbyshire Royal Infirmary and Leicester Royal Infirmary; KenCallum and Roddy Nash (vascular surgeons) for helpful input to themanuscript and illustrations; and Jane Wain and staff of the audiovisualdepartment at Derbyshire Royal Infirmary.

David Hinwood is consultant vascular radiologist, Derbyshire RoyalInfirmary, Derby.

The ABC of arterial and venous disease is edited by RichardDonnelly, professor of vascular medicine, University of Nottinghamand Southern Derbyshire Acute Hospitals NHS Trust(richard.donnelly@ nottingham.ac.uk) and Nick J M London,professor of surgery, University of Leicester, Leicester([email protected]). It will be published as a book laterthis year.

BMJ 2000;320:698701

Magnetic resonance angiogram using an intravenous bolus ofgadolinium contrast showing normal renal arteries

ArteryArtery Artery

Vein

Vein Vein

Ultrasound detection of deep vein thrombosis. The probe is held lightly onthe skin and advanced along the course of the vein (left). Pressure is appliedevery few centimetres by compressing the transducer head against the skin.The vein collapses during compression if no thrombus is present (middle)but not if a deep vein thrombus is present (right)

Colour duplex scanning of saphenopopliteal junction. The calf muscles aremanually compressed producing upward flow in the vein (top), whichappears as a blue colour for flow towards the heart (panel A). Suddenrelease of the distal compression causes reflux, seen as a red colourindicating flow away from the heart (panel B)

Criteria for diagnosis of deep vein thrombosis

x Failure of vein to collapse on direct compressionx Visualisation of thrombus within lumenx Absent or abnormal venous pulsation on Doppler scanning

Clinical review



ABC of arterial and venous diseaseAcute limb ischaemiaKen Callum, Andrew Bradbury

Limb ischaemia is classified on the basis of onset and severity.Complete acute ischaemia will lead to extensive tissue necrosiswithin six hours unless the limb is surgically revascularised.Incomplete acute ischaemia can usually be treated medically inthe first instance. Patients with irreversible ischaemia requireurgent amputation unless it is too extensive or the patient too illto survive.

Clinical featuresApart from paralysis (inability to wiggle toes or fingers) andanaesthesia (loss of light touch over the dorsum of the foot orhand), the symptoms and signs of acute ischaemia arenonspecific or inconsistently related to its completeness. Painon squeezing the calf indicates muscle infarction andimpending irreversible ischaemia.

Acute arterial occlusion is associated with intense spasm inthe distal arterial tree, and initially the limb will appear “marble”white. Over the next few hours, the spasm relaxes and the skinfills with deoxygenated blood leading to mottling that is lightblue or purple, has a fine reticular pattern, and blanches onpressure. At this stage the limb is still salvageable. However, asischaemia progresses, stagnant blood coagulates leading tomottling that is darker in colour, coarser in pattern, and doesnot blanch. Finally, large patches of fixed staining progress toblistering and liquefaction. Attempts to revascularise such alimb are futile and will lead to life threatening reperfusioninjury. In cases of real doubt the muscle can be examined atsurgery through a small fasciotomy incision. It is usuallyobvious when the muscle is dead.

AetiologyAcute limb ischaemia is most commonly caused by acutethrombotic occlusion of a preexisting stenotic arterial segment(60% of cases) or by embolus (30%). Distinguishing these twoconditions is important because treatment and prognosis aredifferent. Other causes are trauma, iatrogenic injury, poplitealaneurysm, and aortic dissection.

More than 80% of peripheral emboli arise from the leftatrial appendage in association with atrial fibrillation. They mayalso arise from the left ventricle, heart valves, prosthetic bypassgrafts, aneurysmal disease, paradoxical embolism, and atrialmyxoma (rare). In 15% of cases the source of embolus isobscure. Thrombosis in situ may arise from acute plaquerupture, hypovolaemia, or pump failure (see below).

Management

General measuresWhen a patient is suspected to have an acutely ischaemic limbthe case must be discussed immediately with a vascular surgeon.A few hours can make the difference between death oramputation and complete recovery of limb function. If there areno contraindications (acute aortic dissection or multiple trauma,particularly serious head injury) give an intravenous bolus ofheparin to limit propagation of thrombus and protect thecollateral circulation.

Classification of limb ischaemia

Terminology

Onset:AcuteAcute on chronic

ChronicSeverity (acute, acute on chronic):

IncompleteCompleteIrreversible

Definition or comment

Ischaemia < 14 daysWorsening symptoms and

signs ( < 14 days)Ischaemia stable for > 14 days

Limb not threatenedLimb threatenedLimb nonviable

Symptoms and signs of acute limb ischaemia

Symptoms or signs

PainPallorPulselessPerishing cold

Paraesthesia*

Paralysis*

Comment

Occasionally absent in complete ischaemiaAlso present in chronic ischaemiaAlso present in chronic ischaemiaUnreliable as ischaemic limb takes on ambient

temperatureLeading to anaesthesia (unable to feel touchon foot or hand)Unable to wiggle toes or fingers

*Anaesthesia and paralysis are the key to diagnosing complete ischaemiathat requires emergency surgical treatment

Differentiation of embolus and acute arterial thrombosis(thrombosis in situ)

Clinical features

Severity

OnsetLimb affectedMultiple sitesEmbolic source

Previous claudicationPalpation of arteryBruitsContralateral leg

pulsesDiagnosisTreatment

Embolus

Complete (nocollaterals)

Seconds or minutesLeg 3:1 armUp to 15%Present (usually atrial

fibrillation)AbsentSoft, tenderAbsentPresent

ClinicalEmbolectomy,

warfarin

Thrombosis

Incomplete(collaterals)

Hours or daysLeg 10:1 armRareAbsent

PresentHard, calcifiedPresentAbsent

AngiographyMedical, bypass,

thrombolysis

Marble white foot (left of picture) inpatient with acute ischaemia

Clinical review



Is angiography required?If ischaemia is complete, the patient must be taken directly tothe operating theatre because angiography will introduce delay,thrombolysis is not an option, and lack of collateral flow willprevent visualisation of the distal vasculature. If ischaemia isincomplete the patient should have preoperative angiographysince simple embolectomy or thrombectomy is unlikely to besuccessful, thrombolysis may be an option, and the surgeonrequires a “road map” for distal bypass.

Acute embolusEmbolic occlusion of the brachial artery is not usually limbthreatening, and in elderly people nonoperative treatment isreasonable. Younger patients should have embolectomy toprevent subsequent claudication, especially if the dominant armis affected.

A leg affected by embolus is nearly always threatened andrequires immediate surgical revascularisation. Emboli usuallylodge at the common femoral bifurcation or, less commonly,the popliteal trifurcation. Femoral embolus is associated withprofound ischaemia to the level of the upper thigh because thedeep femoral artery is also affected. A femoral pulse does notexclude the diagnosis. Embolectomy can be done under local,regional, or general anaesthetic.

The adequacy of embolectomy should be confirmed byangiography while the patient is on the operating table.Ontable thrombolysis should be considered if mechanicalclearance has been unsuccessful. If the embolus has occurred inan area of longstanding atherosclerotic disease, surgical bypassmay be necessary.

Postoperatively the patient should continue to receiveheparin to prevent formation of further emboli. Many surgeonspostpone heparin for six hours after surgery to reduce the riskof a haematoma forming. Warfarin reduces the risk of recurrentembolism, and unless contraindicated, should be prescribed toall patients long term. Patients should not be given warfarinwithout first being on heparin for 48 hours since warfarin canproduce a transient procoagulant state due to inhibition of thevitamin K dependent anticoagulant proteins C and S.

Opinions differ about how thorough you should be inestablishing the source of emboli. Transthoracicechocardiography is poor at detecting a thrombus in patientswith atrial fibrillation, and a negative result does not exclude thediagnosis. Transoesophageal echocardiography providesexcellent views of the left atrium but is moderately invasive andnot universally available. In patients with suspected paroxysmaltachyarrhythmias, 24 hour electrocardiographic monitoringshould be considered. Even if no source of embolism is found,anticoagulation should continue long term.

Although immediate loss of a limb after correctly managedacute embolus is unusual, many series report a 1020%inhospital mortality from heart failure or recurrent embolism,particularly stroke.

Saddle embolusPatients with acute embolic occlusion of the aortic bifurcationhave femoral pulses and appear marble white or mottled to thewaist. They may also present with paraplegia due to ischaemiaof the cauda equina, which can be irreversible. Immediatebilateral embolectomy restores lower limb perfusion, but manypatients subsequently die from reperfusion injury.

Popliteal aneurysmA popliteal aneurysm can initiate acute ischaemia by forming athrombus or acting as a source of emboli. Thrombolysis is oftenthe best treatment as simple embolectomy or thrombectomy

Factors predisposing to acute thrombosis

Cause

DehydrationHypotension

Unusual posture oractivity

MalignancyHyperviscosityThrombophilia

Comment

Hot weather, diabetes, infection, gastroenteritisMyocardial infarction, arrhythmia, heart failure,

gastrointestinal haemorrhage, septic shock,multiple organ failure

Prolonged sitting, kneeling

Solid and haematologicalPolycythaemia, thrombocytosisProtein C or S and antithrombin III

deficiencies; activated protein C resistance;factor V Leiden; antiphospholipid syndrome

Embolus at popliteal trifurcation

Ontable angiograms showingincomplete clearance of embolus

Aortic occlusion

Clinical review



usually leads to early rethrombosis and surgical bypass is oftenprecluded by obliteration of the distal runoff. Once thecirculation is restored, a bypass should be performed to excludethe aneurysm.

AtheroembolismCholesterol emboli are shed from a complex, often acutelyruptured, atherosclerotic plaque. Distal pulses are usuallypresent. The patient characteristically presents with the blue toe(finger) syndrome, which may mimic Raynaud’s phenomenon. Ifthe blue toe syndrome is not recognised patients maydeteriorate rapidly and require amputation.

Thrombosis in situLimbs affected by stable chronic ischaemia do not usuallysuddenly deteriorate without a reason—for example, silentmyocardial infarction or underlying, hitherto asymptomatic,malignancy. Septicaemia, particularly pneumococcal andmeningococcal, may be associated with widespread thrombosis.

TraumaThe commonest causes of noniatrogenic injury are limbfractures and dislocations (supracondylar fractures of thehumerus in children, tibial fractures in adults), blunt injuriesoccurring in road traffic accidents, and stab wounds. In theUnited Kingdom, acute traumatic limb ischaemia is ofteniatrogenic, being caused by arterial cannulation (coronaryangioplasty, aortic balloon pump), vascular and orthopaedicprocedures on the limb (especially if exsanguinatingtourniquets are used), or pelvic surgery (cystectomy, anteriorresection) in patients with subclinical aortoiliac disease in whomthe ligated pelvic collaterals form the main blood supply to thelegs. Postoperative assessment of lower limb ischaemia may beconfused by the presence of epidural or spinal anaesthesia.

The presence of distal pulses does not exclude seriousarterial injury. Pulse oximetry, Doppler signals, andmeasurement of the ankle brachial pressure index may behelpful, but in cases of doubt, proceed to angiography.

Intraarterial drug administrationIntraarterial drug administration leads to intense spasm andmicrovascular thrombosis. The leg is mottled and digitalgangrene is common, but pedal pulses are usually palpable. Themainstay of treatment is supportive care, hydration to minimiserenal failure secondary to rhabdomyolysis, and fullheparinisation. Vascular reconstruction is almost neverindicated, but fasciotomy may be required to prevent acompartment syndrome.

Venous gangreneVenous gangrene can be mistaken for acute limb ischaemia.However, the leg is invariably swollen and the superficial veinsfull. Oedema may make it impossible to palpate pedal pulses,but Doppler examination will show normal distal waveformsand pressures. Management includes elevation, heparinisation,thrombolysis, and treatment of the underlying cause (usuallypelvic or abdominal malignancy).

Aortic dissectionThis may cause upper and lower limb ischaemia due topinching of the ostia of the relevant arteries by the false lumen.

Thoracic outlet syndromePressure on the subclavian artery from a cervical rib orabnormal soft tissue band may lead to a poststenotic dilatationlined with thrombus, which predisposes to occlusion or

Initial management of acute limb ischaemia

Sensation and movement absentx Intravenous heparinx Rapid resuscitation to best medical conditionx Intravenous fluids, catheter, and good urine outputx Urgent surgery—embolectomy or bypass

Sensation and movement presentx Optimise patient to best medical conditionx Admit to hospitalx Intravenous heparinx Observe limb for signs of deterioration (and act if it occurs)x Arteriogram when convenient

Blue toe syndrome must be promptly identified

Compound fracture of tibia with ischaemia

Ischaemia after intraarterial drug administration

Venous gangrene

Clinical review



embolisation. The distal circulation may be chronicallyobliterated and digital ischaemia advanced before the thoracicoutlet syndrome is diagnosed. The diagnosis is based on theresults of duplex ultrasonography or angiography, or both.Treatment options include thrombolysis, thrombectomy orembolectomy, excision of the cervical rib, and repair of theaneurysmal segment.

ThrombolysisIn thrombolysis a cannula is embedded into the distal extent ofthe thrombus and streptokinase or, preferably, recombinanttissue plasminogen activator is infused. The technique cannotbe used in patients with complete ischaemia because thrombusdissolution takes several hours. It is also relatively ineffectiveagainst the organised thrombus present in most peripheralemboli and is associated with an appreciable minor (20%,mainly groin haematoma) and major (5%, serious haemorrhageand stroke) complication rate. Thrombolysis should beundertaken only in an environment where experienced nursingand medical staff can closely monitor the patient.

Postischaemic syndromes

Reperfusion injuryThe reintroduction of oxygenated blood after a period ofischaemia causes more damage than the ischaemia alone.Generation of highly reactive, oxygen free radicals is greatlyincreased, and these activate neutrophils which migrate into thereperfused tissue causing injury. For vascular injury to occurneutrophils must be present and must adhere to theendothelium. The damaged endothelial cells become morepermeable.

Effects of reperfusion syndromeLocal—Limb swelling due to increased capillary permeabilitycauses a compartment syndrome, impaired muscle function dueto ischaemia, and subsequent muscle contracture if the muscleinfarcts.

General—Acidosis and hyperkalaemia occur due to leakagefrom the damaged cells, causing cardiac arrhythmias andmyoglobinaemia, which can result in acute tubular necrosis.Acute respiratory distress syndrome may also develop, andgastrointestinal endothelial oedema may lead to increasedgastrointestinal vascular permeability and endotoxic shock.

Compartment syndromeIncreased capillary permeability and oedema on reperfusion inthe calf, where muscles are confined within tight fascialboundaries, causes an increase in interstitial pressure leading tomuscle necrosis despite apparently adequate inflow—compartment syndrome. There is swelling and pain onsqueezing the calf muscle or moving the ankle. Palpable pedalpulses do not exclude the syndrome. The key to management isprevention through expeditious revascularisation and a lowthreshold for fasciotomy. (If in doubt—do it.)

Chronic pain syndromesAcute complete ischaemia can lead to peripheral nerve injurythat manifests as the chronic pain syndrome, also referred to ascausalgia, reflex sympathetic dystrophy, and many other terms.If the syndrome is recognised and treated early then manypatients gain prolonged relief from drugs or chemical orsurgical sympathectomy.

We thank Professor C V Ruckley, Mr A Jenkins, and Mr J A Murie forhelp with the illustrations.

Digital gangrene due to pressure on subclavian artery from cervical rib

Haematoma due to thrombolysis

Fasciotomy

Ken Callum is consultant surgeon, Derbyshire Royal Infirmary, Derby,and Andrew Bradbury is professor of surgery, University ofBirmingham, Birmingham Heartlands Hospital, Birmingham.

The ABC of arterial and venous disease is edited by Richard Donnelly,professor of vascular medicine, University of Nottingham andSouthern Derbyshire Acute Hospitals NHS Trust([email protected]) and Nick J M London, professorof surgery, University of Leicester, Leicester ([email protected]). Itwill be published as a book later this year.

BMJ 2000;320:7647

Clinical review



ABC of arterial and venous diseaseChronic lower limb ischaemiaJonathan D Beard

Peripheral vascular disease commonly affects the arteriessupplying the leg and is mostly caused by atherosclerosis.Restriction of blood flow, due to arterial stenosis or occlusion,often leads patients to complain of muscle pain on walking(intermittent claudication). Any further reduction in blood flowcauses ischaemic pain at rest, which affects the foot. Ulcerationand gangrene may then supervene and can result in loss of thelimb if not treated. The Fontaine score is useful when classifyingthe severity of ischaemia.

Although many patients with claudication remain stable,about 150200 per million of the population progress to criticallimb ischaemia (Fontaine III or IV) each year. Many patientswith critical limb ischaemia can undergo revascularisation,which has a reasonable chance of saving the limb. A recentaudit by the Vascular Surgical Society found a success rate ofover 70% for these patients. However, many patients still requiremajor amputation. Rehabilitation of elderly patients afteramputation can prove difficult, with high community costs.Critical limb ischaemia has been estimated to cost over £200ma year in the United Kingdom.

Intermittent claudication

History and examinationA history of muscular, cramplike pain on walking that israpidly relieved by resting, together with absent pulses, stronglysupports the diagnosis of intermittent claudication. Disease ofthe superficial femoral artery in the thigh results in absentpopliteal and foot pulses and often causes calf claudication.Disease of the aorta or iliac artery results in a weak or absentfemoral pulse, often associated with a femoral bruit. Disease atthis level may cause calf, thigh, or buttock claudication.

The dorsalis pedis artery lies superficially on the dorsum ofthe foot, although its position varies considerably. The posteriortibial artery lies deeper behind the medial malleolus. Manyhealthy people have only one foot pulse. The popliteal pulsecan be difficult to palpate in muscular patients. A prominentpopliteal pulse suggests the possibility of a popliteal aneurysm.

Fontaine classification of chronic leg ischaemia

Stage I AsymptomaticStage II Intermittent claudicationStage III Ischaemic rest painStage IV Ulceration or gangrene, or both

Angiogram showing bilateral occlusions of superficial femoralarteries in thighs. Collaterals arising from the profunda femorisartery can functionally bypass this occlusion

Method of palpating dorsalis pedis (left) and posterior tibial (right) pulses.Examine pulses from the foot of the bed, keeping the fingers flat for thedorsalis pedis and using the fingertips for the posterior tibial, while applyingcounterpressure with the thumb

Method of palpating popliteal artery with patient’s knee slightly flexed. Usethumbs to apply counterpressure while palpating the artery, which lies deepin popliteal fossa, with fingers

Method of palpating femoral pulse in skin crease of groin. Counterpressureon the lower abdomen pushes the skin crease towards the inguinal ligamentand reduces the risk of missing the pulse

Clinical review



Differential diagnosisThe pain of nerve root compression can be mistaken forvascular claudication. A careful history can usually distinguishnerve root compression, especially sciatica due to compressionof the lumbosacral root. However, compression of the caudaequina due to spinal stenosis can be more difficult to diagnose.This condition usually causes pain that radiates down both legs.Although the pain is made worse by walking, it also comes onafter prolonged standing and is not rapidly relieved by rest,unlike vascular claudication.

InvestigationThere are many causes of leg pain that can occur in thepresence of asymptomatic peripheral vascular disease.Therefore, the absence of pulses does not necessarily imply acausal link. Furthermore, the presence of pulses at rest does notexclude symptomatic peripheral vascular disease. A goodhistory together with an ankle brachial systolic pressure indexof less than 0.9 confirms the diagnosis.

Exercise testing provides an objective measurement ofwalking distance, and highlights other exercise limitingconditions such as arthritis and breathlessness. However,exercise testing takes time, and many patients find it difficult orimpossible to walk on a treadmill. Only those with a goodhistory of claudication and normal resting ankle brachialsystolic pressure indexes require an exercise test.

Duplex ultrasound scanning is useful for delineating theanatomical site of disease in the lower limb. Many hospitals stilluse arteriography for this purpose or when the results ofduplex scanning are equivocal. This invasive and expensiveinvestigation should not be requested unless there is a plan toproceed with revascularisation, if possible.

Principles of treatmentIntermittent claudication seems a relatively benign condition,although severe claudication may preclude patients from manualwork. The risk of generalised vascular disease is probably moreimportant. Patients with claudication have a three times higherrisk of death compared with age matched controls. Modificationof risk factors is therefore vital to reduce death from myocardialinfarction and stroke. All patients should be advised to stopsmoking and take regular exercise. They should also be screenedfor hyperlipidaemia and diabetes. Patients with peripheralvascular disease benefit from regular chiropody, and those withdiabetes should attend a foot clinic. Obesity reduces exercisecapacity, and losing weight will improve the walking distance.

Drug treatmentAll patients with peripheral vascular disease benefit fromaspirin (75300 mg/day) because this reduces the risk ofcardiovascular events. Patients who are intolerant of aspirinshould take dipyridamole (200 mg, twice daily) or clopidogrel(75 mg/day). Naftidrofuryl may improve the walking distance ofpatients with moderate claudication (less than 500 m), but it isnot known if it affects the outcome of the disease. The evidenceto support naftidrofuryl is controversial, and patients prescribedit should be reassessed after three to six months.

Exercise programmesA recent metaanalysis of 21 supervised exercise programmesshowed that training for at least six months, by walking to nearmaximum pain tolerance, significantly improved pain free andmaximum walking distances. The only controlled trialcomparing an exercise programme with percutaneoustransluminal angioplasty found that exercise was better.Exercise programmes are cheaper than percutaneous

Factors which may influence the decision to treatclaudication

For Against

Severe symptoms Short historyJob affected Continued smokingNo better after exercise training Severe angina or chronic

obstructive airways diseaseStenosis or short occlusion Long occlusionProximal disease Distal diseaseUnilateral disease Multilevel disease

Leg pain

? claudication

Resting ankle brachial

pressure index

Normal

Poor history Good history

Not vascular Exercise test

No fall in

pressures

Fall in

pressures

Vascular

claudication

Poor history Good history

Reduced

Algorithm for investigation of suspected intermittent claudication

Non-invasive

assessment

Modification of risk

factors

Warrants

intervention

Bypass or

endarterectomyAngioplasty

Intervention

not justified

Arteriography

or duplex scanning

Claudication

WorseStable or

improved

Exercise

programme

Algorithm for treatment of intermittent claudication

Treadmills can be used forobjective measurement of walkingdistance and for exercise training

Clinical review



transluminal angioplasty or surgery, although long termcompliance seems poor.

Endovascular techniquesThe number of percutaneous transluminal angioplastiesperformed for claudication has risen steeply in recent years. Insome situations endovascular techniques have virtually replacedconventional surgery. Percutaneous transluminal angioplastyseems best suited for stenoses or short occlusions of the iliacand superficial femoral vessels, with one year patency rates of90% and 80% respectively. Angioplasty carries a small butdefinite risk of losing the limb because of thrombosis orembolisation, and patients should be informed of this risk.

Metallic stents push back the atheroma and improve on theinitial lumen gain after angioplasty alone. The indications foriliac stents include a residual stenosis or dissection afterangioplasty and long occlusions, but there seems little evidenceto justify their routine use. Deployment of stents more distallyhas produced disappointing results due to high restenosis rates.

SurgeryThe role of bypass for longer arterial occlusions remains poorlydefined because of a lack of proper trials comparing it withpercutaneous transluminal angioplasty and conservativetreatment. Polyester (Dacron) aortobifemoral bypass grafts havefive year patency rates of over 90% but are associated with amortality of up to 5%. Complications include graft infectionand postoperative impotence. Femoropopliteal bypass grafting,using autologous long saphenous vein, polyester, orpolytetrafluoroethylene (Goretex) yields patency rates of lessthan 70% at five years. The early patency of prosthetic graftsseems similar to that of vein grafts, although the long termresults seem less good. Femoropopliteal bypass grafts shouldrarely be used for patients with claudication.

Critical limb ischaemia

History and examinationPatients with critical limb ischaemia often describe a history ofdeteriorating claudication, progressing to nocturnal rest pain.Ulceration or gangrene commonly results from minor trauma.Nocturnal rest pain often occurs just after the patient has fallenasleep when the systemic blood pressure falls, further reducingperfusion to the foot. Hanging the foot out of bed increasesperfusion and produces the typical dusky red hue due to loss ofcapillary tone. Elevation causes pallor and venous guttering.Inspect the foot carefully for ulceration under the heel andbetween the toes. Swelling suggests deep infection. If you canpalpate foot pulses consider an alternative cause of pain, suchas gout. Patients with critical limb ischaemia require urgentreferral to a vascular surgeon.

InvestigationThe ankle brachial systolic pressure index is usually less than0.5. Arterial calcification may result in falsely increasedpressures, and caution is needed when relying on Dopplerpressures alone, especially in diabetic patients. All patients withcritical limb ischaemia should ideally have arteriography with aview to endovascular treatment, if feasible. Duplex scanningmay be used instead of angiography and for mapping of thelong saphenous vein before distal bypass surgery. DependentDoppler or pulse generated runoff can help to determine themost suitable artery to receive a distal bypass graft if thesecannot be identified by angiography.

Short occlusion of left popliteal artery (left) treated by percutaneoustransluminal angioplasty. The balloon catheter is passed through theocclusion over a guide wire and inflated (middle). Appearance afterangioplasty is shown on right

Occlusion of the right common iliac artery before (left) and after (right)insertion of stent

Critically ischaemic foot displaying typical duskyred hue on dependency (ischaemic rubor)

Clinical review



Principles of treatmentThe same principles and techniques used to treat claudicationalso apply to critical limb ischaemia. However, critical limbischaemia is usually caused by multilevel disease, which meansthat success rates are lower. Treatment focuses on saving thelimb, although modification of risk factors remains important.

Endovascular treatmentPercutaneous transluminal angioplasty or stenting of proximaldisease may relieve ischaemic rest pain, but healing ofulceration or gangrene usually requires restoration of footpulses. This may necessitate extensive angioplasty of thesuperficial femoral, popliteal, and tibial arteries. Good resultshave been reported with subintimal angioplasty. Endovasculartreatment can also reduce the magnitude of subsequentsurgery.

SurgeryPatients with a pattern of arterial disease considered unsuitablefor endovascular treatment will usually require surgery. Fitpatients with proximal disease benefit greatly fromaortobifemoral bypass grafting. In unfit patients the optionsinclude crossfemoral bypass for unilateral disease oraxillobifemoral bypass for bilateral disease. Theseextraanatomic procedures have lower patency rates. Manypatients with distal disease will require bypass grafting to thepopliteal or crural arteries below the knee. Autologous veingrafts give the best patency rates (70% at one year).Postoperative duplex surveillance may improve patency bypermitting the detection and treatment of vein graft stenosesbefore occlusion occurs.

AmputationPatients with unreconstructable peripheral vascular disease,fixed flexion deformities, or extensive tissue loss usually requirea major amputation. Preservation of the knee joint hasenormous advantages for wearing artificial limbs andsubsequent mobility. However, there is little point in risking anonhealing, below knee amputation if the patient seemsunlikely to walk again. Similarly, a patient with good prospectsof wearing an artificial limb will fare better with an above kneeamputation, if below knee amputation seems unachievable.Local amputation of ulcerated or gangrenous toes will not healwithout revascularisation.

Pain reliefCritical limb ischaemia causes severe pain that requires narcoticanalgesia to provide relief. A slow release opiate such asmorphine seems a good option. Opiates can be supplementedby nonsteroidal antiinflammatory drugs if these are notcontraindicated. Apart from rehydration, adequate analgesiaalone may be the best treatment for patients with dementia orother severe comorbidity. If opiate analgesia remainsinadequate, then lumbar sympathectomy (surgical or chemical)or spinal cord stimulation may help.

About 2030% of patients with critical limb ischaemia haveunreconstructable disease. A metaanalysis of six randomisedtrials of Iloprost, a stable prostacyclin analogue, found thatinfusion of this drug reduced the death and amputation rate.Phantom limb pain may complicate major amputation.Amitryptyline, carbamazepine, transcutaneous nervestimulation, and acupuncture can help in this situation.

Methods of pain relief for critical limb ischaemia

x Slow release opiate analgesia—for example, morphine sulphatex Prostacyclin analogues*—for example, Iloprost or prostaglandin E1

(alprostadil)x Chemical or surgical lumbar sympathectomyx Dorsal column spinal stimulation

*Not licensed in United Kingdom

Further reading

x Scottish Intercollegiate Guidelines Network. Drug therapy forperipheral vascular disease. SIGN 1998;27.x Joint British recommendations on the prevention of coronary heartdisease in clinical practice. Heart 1998;80(suppl):S129.x Leng GC, Fowler B, Ernst F. Exercise for intermittent claudication.In: Cochrane Library. Issue 4. Oxford: Update Software, 1999.x Davies AH, Beard JD, Wyatt MG. Essential vascular surgery. London;W B Saunders, 1999.

Critical limb ischaemia

Limb not

salvageable

Patient moribund Patient fit Arteriography or

duplex scanning

Analgesia Amputation

Non-healing Healing

Angioplasty Bypass or

endarterectomy

Limb

salvageable

Algorithm for treatment of critical limb ischaemia

Iliac occlusionIliac stenosis

Iliac angioplasty

and

crossover graft

Aortobifemoral

bypass graft

Axillobifemoral

bypass graft

Surgical treatment options for aortoiliac disease

Jonathan D Beard is consultant vascular surgeon at Sheffield VascularInstitute, Northern General Hospital, Sheffield.

BMJ 2000;320:8547

The ABC of arterial and venous disease is edited by Richard Donnelly,professor of vascular medicine, University of Nottingham andSouthern Derbyshire Acute Hospitals NHS Trust ([email protected]) and Nick J M London, professor of surgery,University of Leicester, Leicester ([email protected]). It will bepublished as a book later this year.

Clinical review



ABC of arterial and venous diseaseAcute strokePhilip M W Bath, Kennedy R Lees

Acute stroke is now a treatable condition that deserves urgentspecialist attention. Drug treatment and specialist care bothinfluence survival and recovery. This article considers theoptimal approaches to diagnosis and early management.

Stroke, a sudden neurological deficit of presumed vascularorigin, is a clinical syndrome rather than a single disease. It is acommon and devastating condition that causes death in onethird of patients at six months and leaves another thirdpermanently dependent on the help of others. Each year in theUnited Kingdom there are 110 000 first strokes and 30 000recurrent strokes; 10 000 strokes occur in people younger than65 and 60 000 people die of stroke. It is the largest cause ofdisability, and more than five per cent of NHS and socialservices resources are consumed by stroke patients. Correctmanagement relies on rapid diagnosis and treatment, thoroughinvestigation, and rehabilitation.

Assessing the patientPatients should be assessed at hospital immediately after a stroke.They may need to go straight to hospital rather than wait to seetheir general practitioner since hyperacute treatments such asthrombolysis must be administered within as little as three hoursafter stroke. Ambulance crews can be trained to apply simplescreening questions to identify likely stroke patients.

Stroke is a clinical diagnosis, but brain imaging is requiredto distinguish ischaemia from primary intracerebralhaemorrhage. The pattern of neurological signs, includingevidence of motor, sensory, or cortical dysfunction andhemianopia, can be used to diagnose certain clinical subtypesand thus to predict prognosis. Other signs also relate tooutcome and may help identify the cause. If neurologicalsymptoms resolve in less than 24 hours, the traditionaldiagnostic label is “transient ischaemic attack” rather thanstroke. However, not all transient ischaemic attacks aregenuinely ischaemic, and many are associated with permanentcerebral damage: a better term therefore is “ministroke.”

PathophysiologyFor practical purposes, there are two types of stroke aftersubarachnoid haemorrhage has been excluded. Ischaemiaaccounts for 85% of presentations and primary haemorrhagefor 15%. Haemorrhage causes direct neuronal injury, and thepressure effect causes adjacent ischaemia. Primary ischaemiaresults from atherothrombotic occlusion or an embolism. Theusual sources of embolism are the left atrium in patients withatrial fibrillation or the left ventricle in patients with myocardialinfarction or heart failure.

Vessel occlusion arises from atherosclerosis, typically in theinternal carotid artery just above the carotid bifurcation or fromsmall vessel disease deep within the brain. Ischaemia causesdirect injury from lack of oxygenation and nutritional supportand sets up a cascade of neurochemical events that lead tospreading damage. The ischaemia may be reversible ifreperfusion is obtained quickly (now proved in clinical trials),and the chemical injury may be interrupted by variousneuroprotective drugs (unproved in humans).

Conditions requiring referral to hospital

Admit to hospitalx Neurological deficit lasting 1 hour or morex Dependent patients—that is, moderate to severe strokex Transient ischaemic attack lasting 1 hour or morex More than one transient ischaemic attack within a weekx Transient ischaemic attack on anticoagulationx Patient presenting to hospitalx At request of general practitioner

Refer to cerebrovascular clinicx Independent patient more than 48 hours after stroke (withhold

aspirin)x Transient ischaemic attack lasting less than 1 hour (give aspirin)

Symptoms and signs of stroke

Anterior circulation strokesx Unilateral weaknessx Unilateral sensory loss or

inattentionx Isolated dysarthriax Dysphasiax Vision:

Homonymous hemianopiaMonocular blindnessVisual inattention

Posterior circulation strokesx Isolated homonymous

hemianopiax Diplopia and disconjugate eyesx Nausea and vomitingx Incoordination and unsteadinessx Unilateral or bilateral weakness

and/or sensory loss

Nonspecific signsx Dysphagiax Incontinencex Loss of consciousness

Characteristics of subtypes of stroke

Lacunar

Partialanteriorcirculation

Totalanteriorcirculation

Posteriorcirculation

Signs Motor orsensoryonly

2 of following:motor orsensory;cortical;hemianopia

All of:motor orsensory;cortical;hemianopia

Hemianopia;brain stem;cerebellar

% dead at1 year

10 20 60 20

% dependentat 1 year

25 30 35 20

Signs of stroke at clinical examination

x Conscious levelx Neurological signsx Blood pressurex Heart rate and rhythmx Heart murmursx Peripheral pulsesx Systemic signs of infection or neoplasm

Clinical review

920 BMJ VOLUME 320 1 APRIL 2000 bmj.com


Emergency managementWithin the first hours after onset of cerebral ischaemia part ofthe brain is under threat of death. The infarct core may bedensely ischaemic and will inevitably die, but there is also tissuewith a compromised blood supply balanced on a knife edgebetween death and recovery. At this stage, oxygenation andhaemodynamic and metabolic factors are crucial. Theemergency management of stroke requires medical stabilisationand assessment of factors that may lead to complications (suchas swallowing and hydration); thrombolysis may be considered(see below). An acute stroke unit concentrates patients,healthcare staff, resources, and expertise into one area, and suchunits may be associated with a better outcome.

InvestigationsPatients with acute stroke should have computed tomographyof the brain to distinguish ischaemic and haemorrhagic stroke.This separation is vital since subsequent investigations andtreatment differ for the two types. Neuroimaging will alsoidentify conditions mimicking stroke and can help predictoutcome. Ideally, imaging will be performed soon afteradmission. Magnetic resonance imaging of the brain mayeventually replace computed tomography since it not onlyidentifies stroke anatomy but can also assess blood flow andperfusion in the brain, detect whether lesions are new or old,and identify carotid artery stenosis.

The extent to which the cause of the stroke should beinvestigated depends on several factors, including the likelydegree of recovery, the presence of obvious risk factors, and theage of the patient; younger patients are more likely to have anidentifiable cause such as an inflammatory or clotting disorderwhich may require specific treatment. Although investigationsshould be restricted to tests that will inform clinicalmanagement, guidelines can be used to determine whichinvestigations are needed after stroke.

Swallowing and feedingDysphagia affects 35% of stroke patients. It is oftenunrecognised after mild stroke and is associated with a pooroutcome, partly because it predisposes to aspiration andpneumonia and partly because of the nutritional deficit.Presence of a gag reflex is a poor guide to safe swallowing, anda formal assessment by trained staff is essential. Fluids are moredifficult to swallow than semisolids. Dysphagic patients shouldbe fed through a nasogastric tube or percutaneous endoscopic

Death rate (percentage) 30 days, one year, and five years afterdifferent types of stroke

30 days 1 year 5 years

Ischaemic stroke 10 23 52

Intracerebral haemorrhage 52 62 70

Subarachnoid haemorrhage 45 48 52

Conditions that mimic stroke

Diagnosis Diagnostic features

Decompensation ofprevious stroke

Evidence of infection such as urinary orrespiratory tract; metabolicdisturbance

Cerebral neoplasm(primary or secondary)

Less abrupt onset; primary tumour orsecondary to, for example, lung orbreast cancer

Subdural haematoma Recent head injury

Epileptic seizure Possible previous episodes

Traumatic brain injury History of trauma

Migraine Less abrupt onset; followed byheadache; younger patients

Multiple sclerosis Less abrupt onset; possible previousepisodes

Cerebral abscess Infection

Investigation of stroke

All patientsx Computed tomography (or magnetic resonance imaging)x Electrocardiographyx Chest radiographyx Full blood countx Clotting screenx Electrolyte and creatinine concentrations

Subgroupsx Carotid duplex scanningx Echocardiographyx Thrombophilia screenx Immunology screenx Syphilis serologyx Cerebral angiography (rarely)

Computed tomogram showing ischaemic stroke Computed tomogram showing haemorrhagicstroke

Magnetic resonance angiogram showing middlecerebral artery occlusion

Clinical review

921BMJ VOLUME 320 1 APRIL 2000 bmj.com


feeding tube until it is safe to resume oral food and fluids. Mostdysphagic patients will not need enteral feeding beyond a fewweeks. However, when and how optimally to feed dysphagicpatients remains to be determined.

Acute interventionFirm evidence from two large trials has shown that aspirin(160300 mg daily by mouth, nasogastric tube, or rectum) startedwithin 48 hours of onset of acute ischaemic stroke reduces therisk of subsequent death and disability. However, the effect ofaspirin is small (number needed to treat (NNT) = 77) and isprincipally mediated through reducing the risk of earlyreinfarction. Neuroimaging is strongly recommended beforestarting aspirin. A large trial of unfractionated heparin in strokepatients found that heparin did not improve outcome, even inpatients with presumed embolic stroke. Heparin may still beuseful in certain groups of patients.

Thrombolysis with alteplase within three hours of onset ofstroke significantly increases the chance of a near completerecovery (NNT = 7) when administered by specialists. Treatmentup to six hours after stroke has been found less effective inmetaanalysis of randomised controlled trials (estimatedNNT = 12). Thrombolysis is currently licensed for stroke only inNorth America and New Zealand, and concerns remain aboutits safety.

Neuroprotectant drugs (which may protect neurones fromischaemia) have, to date, shown no benefit in ischaemic orhaemorrhagic stroke, although several trials are still in progress.

Patients with a large cerebellar infarct or bleed should bereferred for immediate neurosurgical evaluation to facilitateevacuation of the clot or infarct, or shunting for acutehydrocephalus, if required. Anticoagulants should be reversedin patients with primary intracerebral haemorrhage.

Complications of strokeStroke may be complicated by several conditions that can alteroutcome adversely. Hyperglycaemia, fever, and hypertension areeach associated with a poor prognosis. In the absence of trialevidence, raised glucose concentrations should be normalisedand paracetamol given for fever. In contrast, hypertensionshould not be treated for the first week since someantihypertensive drugs (notably calcium channel blockers) seemto worsen outcome, possibly by reducing regional cerebralblood flow. Large ischaemic strokes are often complicated byoedema, swelling, and herniation leading to death; no provedtreatment is available for these complications.

Venous thromboembolic disease (deep vein thrombosis,pulmonary embolism) develops in half of immobile patientsunless preventive measures are taken. Although compressionstockings reduce the risk of deep vein thrombosis in othergroups of high risk patients, this has not been confirmed instroke. A combination of stockings, early mobilisation, adequatehydration, and aspirin is considered good practice in patientswith ischaemic stroke. Early mobilisation may also reduce therisk of pressure sores, respiratory tract infections, and urinarytract infections. When possible, urinary catheters should beavoided to minimise the risk of infection.

RehabilitationThe principal aims of rehabilitation are to restore function andreduce the effect of the stroke on patients and their carers.Rehabilitation should start early during recovery withassessment and mobilisation while the patient is in the acute

Acute drug treatments for ischaemic stroke

Aspirinx Most patients

Heparin (unfractionated or low molecularweight):

Prophylacticx Previous venous thromboembolismx Morbid obesity

Therapeuticx Carotid artery dissectionx Embolic, recurrent transient ischaemic attacks

Complications of strokex Hyperglycaemiax Hypertensionx Feverx Infarct extension or rebleedingx Cerebral oedema, herniation, coningx Aspirationx Pneumoniax Urinary tract infectionx Cardiac dysrhythmiax Recurrencex Deep vein thrombosis, pulmonary embolism

Study Experimental

n/N

Control

n/N

0.5 0.7 1 1.5

Favours treatment Favours control

2

Peto odds ratio

(95% CI fixed)

Peto odds ratio

(95% CI fixed)

ATLANTIS A 1999

ATLANTIS B 1999

ECASS I 1995

ECASS II 1998

Mori 1992

NINDS 1995

Subtotal (95% CI)

χ2 =13.23 (df=5), Z=2.97

Total (95% CI)

χ2 =13.23 (df=5), Z=2.97

64/71

141/307

185/313

187/409

11/19

155/312

729/1431

729/1431

56/71

135/306

185/307

211/391

10/12

192/312

789/1399

789/1399

2.35 (0.95 to 5.82)

1.08 (0.78 to 1.48)

0.79 (0.58 to 1.09)

0.72 (0.55 to 0.95)

0.32 (0.07 to 1.48)

0.62 (0.45 to 0.85)

0.80 (0.69 to 0.93)

0.80 (0.69 to 0.93)

Metaanalysis shows that thrombolysis reduces combined death anddisability from stroke

Stroke patient receiving rehabilitation therapy

Clinical review



stroke unit. Once patients are medically stable, they should betransferred to a stroke rehabilitation unit if furtherrehabilitation is required. Formal rehabilitation in a stroke unitis associated with reduced death and disability (NNT = 12) and ashorter stay in hospital. Optimal care is multidisciplinary:doctors, nurses, physiotherapists, occupational therapists,speech and language therapists, dieticians, psychologists, andsocial workers all have a role.

Secondary preventionSecondary prevention (apart from blood pressure control)should start shortly after admission. All patients should beoffered lifestyle guidance, including advice to stop smoking,reduce saturated fat and salt consumption and alcohol intake,lose weight, and increase exercise. Aspirin started for thetreatment of acute ischaemic stroke should be continuedindefinitely for secondary prevention. The use of alternative oradditional antithrombotic drugs (dipyridamole, clopidogrel, andwarfarin), carotid endarterectomy, and management ofhypertension and hyperlipidaemia after stroke are discussed inthe next article in the series.

The futureStroke management is now supported by good qualityevidence, but many questions remain unanswered. Wheneverpossible, patients should be given the opportunity to enrol inrandomised trials of acute interventions, rehabilitation, orsecondary prevention.

The magnetic resonance image was provided by Professor Alan Moody,University of Nottingham. The data on thrombolysis were provided byDr Joanna Wardlaw, University of Edinburgh.

Healthcare professionals, patients, and carers can obtainfurther information about strokes from the StrokeAssociation (020 7566 0300), Chest, Heart and StrokeAssociation Scotland (0131 225 6963), Chest, Heart, andStroke Association Northern Ireland (01232 320184), orDifferent Strokes (01908 236033)

Further reading

x Bath PMW. The medical management of stroke. Int J Clin Pract1997;51:50410.

x Lees KR. If I had a stroke. . . . Lancet 1998;352 (suppl III):2830.x Royal College of Physicians. Stroke audit package. London: RCP,

1994.x Stroke Units Trialists’ Collaboration. Collaborative systematic review

of the randomised trials of organised inpatient (stroke unit) careafter stroke. BMJ 1997;314:11519.

Philip M W Bath is professor of stroke medicine, University ofNottingham, and Kennedy R Lees is professor of cerebrovascularmedicine, university department of medicine and therapeutics,Western Infirmary, Glasgow.


BMJ 2000;320:9203

My most valuable lesson

A full examination is always useful

It happened two weeks ago. One of the patients attending theunit that day was a man who had received an allogeneic stem celltransplant nine months earlier. He presented with a 24 hourhistory of right sided chest pain which seemed to be temporallyrelated to a recent bout of coughing.

The patient duly undressed to the waist and I performed arespiratory examination, starting with assessment of chestexpansion. My gaze fixed in the direction of my thumbs, Idetected no abnormality. Tracheal position central. Tactile vocalfremitus and percussion were normal over the anterior andlateral chest. Auscultation was unremarkable in these areas.Moving to the patient’s back there were no new chest signs to beelicited, although my attention was briefly drawn to a small groupof reddish papules in the skin overlying the vertebral process ofT8. Finally I discovered some local tenderness in the area of thepatient’s discomfort, blindly palpating his right lateral chest wall,and diagnosed an intercostal muscular strain secondary tocoughing. I told the consultant of my findings, and he came to seethe patient himself.

Courtesy dictated that I should remain in attendance while therepeat assessment took place. The patient’s shirt was once moreremoved whereupon my boss took a discernible step backwards(advice given to me repeatedly when I was preparing for mymembership examination) and then inspected the chest wall withthe patient’s right arm raised.

My pen almost fell out of my hand, poised as it was over thecase notes. There, in full view, was a narrow, intermittent row ofpapules, conforming to an arc extending between the patient’sback and right anterior axillary line.

My consultant turned back to me, directing a quizzical look inmy direction; I suspect it was met by my own open mouthed,disbelieving one. His words were spoken quietly and distinctly, butthey shook me like thunder:

“It’s zoster, isn’t it?”Alexander Pope wrote, “A man should never be ashamed to

own he has been in the wrong, which is but saying, in otherwords, that he is wiser today than he was yesterday.”

I now have proof, if I needed it, that clinical examinationtechnique has enormous relevance to our everyday practice.Furthermore, after the intense embarrassment I suffered on thatfateful day, I now find myself in the new, liberated position that, ifI am ever inclined or encouraged to criticise a colleague’s clinicaloversight in the future, I need only to bring to mind my patientwith his dermatomal eruption.

Richard J A Murrin specialist registrar in haematology, Birmingham

We welcome articles of up to 600 words on topics such asA memorable patient, A paper that changed my practice, My mostunfortunate mistake, or any other piece conveying instruction,pathos, or humour. If possible the article should be supplied on adisk. Permission is needed from the patient or a relative if anidentifiable patient is referred to. We also welcome contributionsfor “Endpieces,” consisting of quotations of up to 80 words (butmost are considerably shorter) from any source, ancient ormodern, which have appealed to the reader.

Clinical review



ABC of arterial and venous diseaseSecondary prevention of transient ischaemic attack and strokeKennedy R Lees, Philip M W Bath, A Ross Naylor

Stroke or transient ischaemic attack is common and likely to befatal or cause serious disability. A second stroke will notnecessarily be of the same type as the initial event, althoughhaemorrhages tend to recur. Patients with previous strokecommonly succumb to other vascular events, in particularmyocardial infarction. Effective secondary prevention dependson giving attention to all modifiable risk factors for stroke aswell as treating the causes of the initial stroke. Four questionsshould be answered:

Is it acute cerebrovascular disease?The key features of acute cerebrovascular disease are focalneurological deficit, sudden onset, and absence of an alternativeexplanation. Abrupt onset of a dense hemiparesis beforegradual improvement in a conscious patient rarely causesdoubt, but conditions which commonly mimic stroke must beconsidered (see previous article BMJ 2000;320:9203).

Is it ischaemic or haemorrhagicstroke?Neither clinical history nor examination can reliably distinguishinfarction from primary intracerebral haemorrhage. A smallbleed can produce transient symptoms, although these rarelyresolve within an hour.

Cerebral imaging is essential, and the choice and timing ofthe scan is important. Haemorrhage is immediately apparenton computed tomography, but its distinctive appearancebecomes indistinguishable from infarction over a few weeks; formajor symptoms, a computed tomogram taken within twoweeks should still be diagnostic, but a small bleed may bemissed after one week.

Magnetic resonance imaging has a greater sensitivity forbrain stem, cerebellar, and small ischaemic strokes of the brainthan computed tomography. It can also identify haemorrhagicstroke and remains diagnostic long after signs have becomeundetectable on computed tomography.

Risk of recurrence after stroke or transientischaemic attack

Strokex 8% a year

Transient ischaemic attackx 8% risk of stroke in first monthx 5% risk of stroke a year thereafterx 5% risk of myocardial infarction a year

Modifiable risk factors for strokex Hypertensionx Smokingx Diabetes mellitusx Diet: high salt and fats, low potassium and vitaminsx Excess alcohol intakex Morbid obesityx Low physical exercisex Low temperaturex Cholesterol concentration—at least in patients with coronary disease

Correct imaging techniques for patients with symptoms ofstroke

Symptoms for< 1 hour

Symptomsfor > 1 hour;onset < 2weeks

Symptomsfor > 1 hour;onset > 2weeks

Abrupt onset,typicalcerebrovascularsymptoms

Image only ifanticoagulationproposed

Computedtomography

Magneticresonanceimaging

Insidious onsetsuspicious oftumour

Not applicable Computedtomographywith contrast

Computedtomographywith contrast

Insidious onsetsuggestive ofmultiple sclerosis

Not applicable Magneticresonanceimaging

Magneticresonanceimaging

Computed tomograms on days 0 (left) and 8 (right) after left subcorticalhaemorrhage presenting as a transient ischaemic attack with symptomslasting 50 minutes. Note the resolution of diagnostic appearances at day 8

Magnetic resonance image of posteriorfossa of brain in patient with rightcerebellar infarction

T1 weighted magnetic resonanceimage of left subcorticalhaemorrhage (day 9 in samepatient as computed tomogramsabove)

Clinical review



Cardioembolic or vascular aetiology?Up to a quarter of ischaemic strokes are due to embolism fromthe heart or major vessels. In these patients, full anticoagulationshould be considered. Embolic stroke can affect any vascularterritory but can rarely be diagnosed conclusively. Certainfeatures should prompt a search for an embolic source.Transthoracic echocardiography is usually adequate, buttransoesophageal echocardiography is justified if the results areequivocal or the index of suspicion is high.

Anterior or posterior circulation?The vertebrobasilar arteries supply the brain stem, cerebellum,and occipital lobes; the cerebral hemispheres are suppliedthrough the carotid arteries. This distinction is important sincecarotid Doppler ultrasonography with a view to endarterectomyis justified in patients with severe carotid disease only ifsymptoms have arisen from the anterior circulation.

Hospital referralAlthough the approach to investigation of stroke is simple, fewgeneral practitioners will have open access to the necessaryfacilities or see sufficient cases to develop expertise ininterpretation of the results. Patients with suspected stroke needurgent telephone or fax referral to a “fast track” specialistcerebrovascular clinic or stroke unit because of the timelimitations on the diagnostic capability of computed tomographyand the limited availability of magnetic resonance imaging.

Management of risk factorsSmoking is an important correctable risk factor and should bestrongly discouraged. The risk of stroke of a smoker returns tothat of a nonsmoker within three to five years of stoppingsmoking.

Immediate reduction of blood pressure may be deleterious,but long term risk is inversely related to the blood pressureachieved. Treatment may therefore be justified even in patientswith “normal” blood pressures. Hypertension should be treatedone to two weeks after a stroke on the basis of BritishHypertension Society guidelines. Patients at high risk of afurther stroke (such as elderly people) derive the greatestbenefit from treatment.

The role of serum cholesterol concentration in thepathogenesis of stroke remains debatable. Nevertheless, statinshave been shown to reduce the risk of stroke in clinical trials ofpatients with coronary heart disease. Lowering cholesterolconcentrations with a statin after atherosclerotic stroke ortransient ischaemic attack probably reduces recurrent eventsand the risk of developing ischaemic heart disease. Since strokepatients represent such a high risk population, the cost oftreatment may be justified.

Diabetes confers a substantial disadvantage for survival andfunctional outcome on patients with acute stroke. Themechanism for this is unknown, but since it is a long term effect,attempts should be made to normalise blood glucoseconcentrations. Blood pressure targets are lower for diabeticthan nondiabetic patients.

Raised plasma homocysteine concentration is increasinglylinked to premature vascular disease and can be easily loweredthrough vitamin supplements (folate and pyridoxine). Althoughthe value of lowering homocysteine concentrations has notbeen proved, younger patients with raised plasma homocysteineconcentrations may benefit.

Embolic causes of stroke found on echocardiography

x Mitral stenosisx Left atrial enlargement ( > 4 cm)x Dyskinetic or akinetic left ventriclex Severe global left ventricular dysfunctionx Valvular vegetationx Left atrial or ventricular thrombusx Mitral valve calcificationx Calcific aortic valves or stenosis predispose to embolism but may

not justify anticoagulation

Justifications for echocardiography

x Atrial fibrillationx Heart failurex Myocardial infarction within

3 monthsx Electrocardiographic

abnormalities:Myocardial infarction orischaemiaBundle branch block

x Cardiac murmurx Peripheral embolismx Clinical events in >2 territories:

Right and left hemisphereAnterior and posteriorcirculation

x >2 cortical events (even insame territory) unless severeipsilateral carotid disease

Blood pressure targets (mm Hg) in nondiabetic and diabeticstroke patients

No diabetes Diabetes

Titrate to diastolic blood pressure <85 <80

Optimal blood pressure < 140/85 < 130/80

Suboptimal blood pressure >150/90 >140/85

Carotid Doppler ultrasonogram in patient with severe internal carotid arterystenosis. Upper panel shows angle of insonation (a) of internal carotid arteryand sampling window (b); the velocity of systolic blood flow at the point ofmaximal narrowing (c), is nearly 4 m/s (normal <1 m/s). Stenosis causes flowvelocity to increase and produces turbulence, which is seen as shadingwithin the Doppler spectrum (d)

≥ 200/110

Days or

weeksMonths Months

140-199/90-109 130-139/80-89

≥ 140/90 130-139/80-89

< 130/80

Treat Treat Reassess

annually

Reassess

in 5 years

Blood pressure thresholds (mm Hg) for treatment after stroke or transientischaemic attack (based on British Hypertension Society Guidelines 1999)

Clinical review



Antiplatelet therapy andanticoagulationPatients with atrial fibrillation should receive warfarin if theyhave no contraindications, aiming at an internationalnormalised ratio of 2.03.0. Patients with other importantsources of cardiac embolism also benefit from warfarin. Onlypatients with mechanical prosthetic heart valves require ahigher international normalised ratio target of 2.54.5, althoughthe exact value depends on the type of valve.

For all other patients with ischaemic stroke, antiplatelettherapy would be first line treatment. Aspirin is inexpensive andsimple to administer, and its benefits are conclusively proved.An initial dose of 300 mg followed by 75 mg daily is advised(higher doses have little advantage but increase gastrointestinalside effects and bleeding).

Modified release dipyridamole (200 mg twice daily) has anindependent and additive effect to low dose aspirin inpreventing further strokes but not coronary events or overallmortality. The routine addition of dipyridamole to aspirin forsecondary prevention of strokes may be cost effective.

Clopidogrel (75 mg daily), a new antiplatelet drug, is welltolerated and was slightly more effective than aspirin in a largetrial. However, it is not cost effective for initial treatment.Clopidogrel should be used in patients with true intolerance toaspirin (allergy or intractable side effects on low dose entericcoated aspirin with or without antiulcer drugs); dipyridamolealone does not prevent cardiac events.

Carotid surgery and angioplastyFirm evidence from two large trials has clarified the role ofcarotid endarterectomy in patients with ipsilateral severe carotidstenosis. Patients with severe disease benefit from surgery for upto 12 months after the most recent cerebral event. The benefitderived is inextricably linked to the operative risk (stroke ordeath within 30 days). In the randomised trials, the operativemortality in patients with severe disease was 1.0%, the risk ofdeath or disabling stroke < 4%, and the risk of death or anystroke < 7.5%. Surgical risk is inversely proportional to surgicalvolume, implying that patients should be referred to busycarotid endarterectomy centres. Surgeons must quote their ownrisks rather than results obtained in trials.

Any patient presenting with carotid territory symptomsshould be considered a potential candidate for carotidendarterectomy, and carotid Doppler ultrasonography shouldbe done if the patient is fit for surgery. The presence or absenceof a carotid bruit is irrelevant. An ongoing metaanalysis mayfurther refine the indications, particularly regarding themanagement of women and patients with isolated retinalsymptoms, who seem to have a lower overall risk of stroke.

A successful carotid endarterectomy is not a majorprocedure, and most patients can be discharged home the dayafter surgery. Neither clinical nor ultrasonographic surveillance

Main contraindications to long termwarfarin treatment

x Gastrointestinal bleedingx Active peptic ulcerationx Frequent fallsx Alcohol misusex History of intracranial haemorrhageAge, by itself, is not a contraindication

Summary of results from European carotid surgery trial

Stenosis(%)

Incidence of stroke (%) Absolute riskreduction (%)

Relative riskreduction(%)Surgery

armMedicalarm

030 11.8 6.2 − 5.6 at 3 years None

3169 16.0 15.0 − 1.0 at 5 years None

7099 12.3 21.9 9.6 at 3 years 44 at 3 years

Computed tomography

Aspirin 75-300 mgClopidogrel 75 mg

Aspirin intoleranceor contraindication

Haemorrhage excludedStart aspirin 150-300 mg

Aspirintolerant

1-2 weeks

Acuteprophylaxisof furthervascularevents

Aspirin intoleranceor contraindication

Dipyridamole intoleranceor contraindication

Continue longterm unless

contraindicationdevelops

Aspirin 75-300 mg andDipyridamole 200 mg

twice daily

Secondarypreventionof strokeand othervascularevents

Angiogram showing tight stenosis ofinternal carotid artery just distal tobifurcation

6

Years of follow up

Ris

k of

stro

ke (

%)

5 84321 70

10

15

20

90-99% (n=60)

Stenosis

5

80-89% (n=160)

70-79% (n=169)

50-69% (n=376)

0-49% (n=441)

Risk of stroke in patients not having surgery according to degree of stenosis.Data from European Carotid Surgery Trialists’ Collaborative Group, Lancet

1998;351:137987

Indications for carotid endarterectomy

Surgery not indicatedx Carotid territory symptoms and an ipsilateral 069% stenosisx Complete occlusion of the carotid artery

Surgery indicatedx Carotid territory symptoms within 6 months and an ipsilateral

7099% stenosisx Carotid territory symptoms within 12 months and an ipsilateral

8099% stenosis

Clinical review



prevents late stroke, and so most patients are discharged fromfollow up at six weeks with the proviso that they should bereferred immediately should further cerebral ischaemicevents occur.

In carotid angioplasty the stenosis is dilated by using aballoon catheter introduced percutaneously through thefemoral artery. The potential advantages of carotid angioplastyinclude reduced hospital stay, cranial nerve injury, woundcomplications, and other cardiovascular morbidity. The mainconcern about carotid angioplasty is the risk of embolic strokeat the time of the procedure and recurrent stenosis. Carotidangioplasty aids the management of fibromuscular dysplasia,radiation injury, and symptomatic restenosis after carotidendarterectomy. Otherwise, carotid angioplasty should notbe performed outside randomised trials and, as with carotidendarterectomy, outcomes in individual centres shouldbe audited.

Complex casesSecondary prevention of stroke is rightly the province ofgeneral practitioners and the preceding suggestions will covermost patients with recent stroke. However, patients withcomplex conditions will need access to specialist services,although definitive trial evidence justifying therapeuticdecisions in such cases is often absent. Patients should bemonitored for compliance with treatment and the developmentof complications such as renovascular disease, ischaemic heartdisease, and further cerebrovascular problems. Optimal dietary,smoking, lipid, and blood pressure management is alwaysrequired in addition to antithrombotic treatment.

G T McInnes and L Ramsay contributed towards the blood pressure guidelines.M R Walters supplied some of the pictures and J Overell supplied the antiplateletflow chart.

Kennedy R Lees is professor of cerebrovascular medicine, universitydepartment of medicine and therapeutics, Western Infirmary,Glasgow ([email protected]); Philip M W Bath is professor ofstroke medicine, University Hospital, Nottingham; and A Ross Nayloris senior lecturer, department of surgery, Leicester Royal Infirmary,Leicester.

Complex cases that may require hospital referral

Case Possible treatment

Recurrent stroke or transientischaemic attack despite antiplatelettreatment (treatment failure)

Consider higher doses ofaspirin, addition ofdipyridamole (if not alreadyprescribed), substitution oraddition of clopidogrel, orsubstitution or addition ofwarfarin

Recurrent embolic events despiteadequate anticoagulation withwarfarin

Consider adding low doseaspirin

Recurrent nonhaemodynamicsymptoms from inoperable severecarotid stenosis or seriousintracranial stenosis despiteantiplatelet treatment

Consider warfarin

Hypertension and inoperable severecarotid stenosis

Consider cerebral blood flowmonitoring (withultrasonography orradionucleotide perfusionscanning) beforeantihypertensive treatment


BMJ 2000;320:9914

Severe carotid stenosis before (left) and after carotid angioplasty andstenting (right)

Further reading

x Antiplatelet Trialists’ Collaboration. Collaborative overview ofrandomised trials of antiplatelet therapy. 1. Prevention of death,myocardial infarction, and stroke by prolonged antiplatelet therapyin various categories of patients. BMJ 1994;308:81106.

x EAFT (European Atrial Fibrillation Trial) Study Group. Secondaryprevention in nonrheumatic atrial fibrillation after TIA or minorstroke. Lancet 1993;342:125562.

x Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A,for the ESPS2 Working Group. European Stroke Prevention Study2. Dipyridamole and acetylsalicylic acid in the secondary preventionof stroke. J Neurol Sci 1996;143:113.

x CAPRIE Steering Committee. A randomised, blinded, trial ofclopidogrel versus aspirin in patients at risk of ischaemic events(CAPRIE). Lancet 1996;348:132939.

x European Carotid Surgery Trialists’ Collaborative Group.Randomised trial of endarterectomy for recently symptomaticcarotid stenosis. Final results of the MRC European carotid surgerytrial (ECST). Lancet 1998;351:137987.

Clinical review



ABC of arterial and venous diseaseVascular complications of diabetesRichard Donnelly, Alistair M EmslieSmith, Iain D Gardner, Andrew D Morris

Adults with diabetes have an annual mortality of about 5.4%(double the rate for nondiabetic adults), and their life expectancyis decreased on average by 510 years. Although the increaseddeath rate is mainly due to cardiovascular disease, deaths fromnoncardiovascular causes are also increased. A diagnosis ofdiabetes immediately increases the risk of developing variousclinical complications that are largely irreversible and due tomicrovascular or macrovascular disease. Duration of diabetes isan important factor in the pathogenesis of complications, butother risk factors—for example, hypertension, cigarette smoking,and hypercholesterolaemia—interact with diabetes to affect theclinical course of microangiopathy and macroangiopathy.

Microvascular complicationsA continuous relation exists between glycaemic control and theincidence and progression of microvascular complications.Hypertension and smoking also have an adverse effect onmicrovascular outcomes. In the diabetes control andcomplications trial—a landmark study in type 1 diabetes—thenumber of clinically important microvascular endpoints wasreduced by 3476% in patients allocated to intensive insulin(that is, a 10% mean reduction in glycated haemoglobin (HbA1c)concentration from 8.0% to 7.2%). However, these patients alsohad more hypoglycaemic episodes. Similarly, in the UKprospective diabetes study of patients with type 2 diabetes, anintensive glucose control policy that lowered glycatedhaemoglobin concentrations by an average of 0.9% comparedwith conventional treatment (median HbA1c 7.0% v 7.9%)resulted in a 25% reduction in the overall microvascularcomplication rate. It was estimated that for every 1% reductionin HbA1c concentration there is a 35% reduction inmicrovascular disease.

RetinopathyDiabetic retinopathy is a progressive disorder classifiedaccording to the presence of various clinical abnormalities. It isthe commonest cause of blindness in people aged 3069 years.Damage to the retina arises from a combination ofmicrovascular leakage and microvascular occlusion; thesechanges can be visualised in detail by fluorescein angiography.A fifth of patients with newly discovered type 2 diabetes haveretinopathy at the time of diagnosis. In type 1 diabetes, visionthreatening retinopathy almost never occurs in the first fiveyears after diagnosis or before puberty. After 15 years, however,

Risk of morbidity associated with all types of diabetes mellitus

Complication

BlindnessEnd stage renal diseaseAmputationMyocardial infarctionStroke*Compared with nondiabetic patients

Relative risk*

2025402523

Vascular complications of diabetes

MicrovascularRetinopathyNephropathyNeuropathy

MacrovascularIschaemic heart diseaseStrokePeripheral vascular disease

Classification and features of diabetic retinopathy

Grade Examination features Symptoms

I Backgroundretinopathy

MicroaneurysmsSmall blot haemorrhagesHard exudatesNot affecting macula

None

II Background withmaculopathy

Leakage in macular regionCapillary occlusionHard exudates

Central visualloss (such asreading difficulty)

III Preproliferativeretinopathy

Cotton wool spotsVenous abnormalitiesLarge blot haemorrhagesIntraretinal microvascularabnormalities

None

IV Proliferativeretinopathy

New vessels on disc orelsewhere on retina

None, butcomplicationscause visual loss

V Advanceddiabetic eye disease

Extensive fibrovascularproliferationRetinal detachmentVitreous haemorrhageThrombotic glaucoma

Severe visual loss

Glycated haemoglobin (%)Rat

e o

f p

rog

ress

ion

of

reti

no

pat

hy

(per

10

0 p

atie

nt-

year

s)

10.09.08.07.06.05.00

4

6

8

10

12

14

16

2

Glycated haemoglobin (%)

Rat

e o

f se

vere

hyp

og

lyca

emia

(p

er 1

00

pat

ien

t-ye

ars)

10.09.08.07.06.05.00

40

60

80

100

120

20

Relation between glycaemic control (HbA1c) and risk of progression ofmicrovascular complications (retinopathy) and severe hypoglycaemia inpatients with type 1 diabetes. Data from the diabetes control andcomplications trial. Dotted lines represent 95% confidence intervals

Background retinopathy showingmicroaneurysms and small blot haemorrhages

Clinical review



almost all patients with type 1 diabetes and two thirds of thosewith type 2 diabetes have background retinopathy.

Vision threatening retinopathy is usually due toneovascularisation in type 1 diabetes and maculopathy in type 2diabetes. Depending on the relative contribution of leakage orcapillary occlusion, maculopathy is divided into three types:exudative maculopathy (when hard exudates appear in theregion of the macula), ischaemic maculopathy (characterised bya predominance of capillary occlusion which results in clustersof haemorrhages), and oedematous maculopathy (extensiveleakage gives rise to macular oedema). Treatment ofmaculopathy and proliferative retinopathy with laserphotocoagulation prevents further loss of vision rather thanrestores diminished visual acuity.

NephropathyDiabetic nephropathy is characterised by proteinuria> 300 mg/24 h, increased blood pressure, and a progressivedecline in renal function. At its most severe, diabeticnephropathy results in end stage renal disease requiring dialysisor transplantation, but in the early stages overt disease ispreceded by a phase known as incipient nephropathy (ormicroalbuminuria), in which the urine contains trace quantitiesof protein (not detectable by traditional dipstick testing).Microalbuminuria is defined as an albumin excretion rate of20300 mg/24 h or 20200 ìg/min in a timed collection and ishighly predictive of overt diabetic nephropathy, especially intype 1 diabetes.

The rate of decline in glomerular filtration rate varies widelybetween individuals, but antihypertensive treatment greatlyslows the decline in renal function and improves survival inpatients with diabetic nephropathy.

In patients with type 1 diabetes complicated by diabeticnephropathy, angiotensin converting enzyme inhibitors haverenoprotective effects above those that can be attributed toreduced blood pressure; they are beneficial even in normotensivepatients and ameliorate other associated microvascularcomplications such as retinopathy. In patients with type 2diabetes, achieving good blood pressure control (which oftenrequires combination therapy) is more important than the choiceof antihypertensive drug, although angiotensin convertingenzyme inhibitors are the preferred first line treatment

The development of proteinuria is a marker of widespreadvascular damage and signifies an increased risk of subsequentend stage renal disease and macrovascular complications,especially coronary heart disease. Microproteinuria andproteinuria are strongly associated with decreased survival inboth type 1 and type 2 diabetes.

NeuropathyThe diabetic neuropathies present in several ways. Thecommonest form is a diffuse progressive polyneuropathyaffecting mainly the feet. It is predominantly sensory, oftenasymptomatic, and affects 4050% of all patients with diabetes.Reduced sensation can be detected with a monofilament, andpatients with sensory neuropathy as well as other high riskfeatures need advice on foot care to minimise the risk ofulceration. Neuropathic foot ulcers can be distinguished fromvascular ulcers, although a mixed aetiology is common.

Macrovascular complicationsAtherosclerotic disease accounts for most of the excessmortality in patients with diabetes. In the UK prospectivediabetes study, fatal cardiovascular events were 70 times morecommon than deaths from microvascular complications. The

Clinical features of “high risk” diabetic foot

x Impaired sensation (monofilament)x Past or current ulcerx Macerationx Fungal or gryphotic (thickened or horny) toenailsx Biomechanical problems (corns or callus)x Fissuresx Clawed toes

Clinical features that distinguish neuropathic and vascularfoot ulcers

Neuropathic Vascular

Painless PainfulLocated at points of high pressure Often located at the

extremities“Punched out” appearance surrounded by callusWarm foot Cool ischaemic footBounding foot pulses Absent foot pulses

Diabetic maculopathy

Years

Alb

um

inu

ria

(µg

/min

)-2 -1 0 1 2 3 4 5 6 7 8 9

750

1250

250M

ean

art

eria

lp

ress

ure

(mm

Hg

)

95

105

115

125Start of antihypertensive treatment

Glo

mer

ula

rfi

ltra

tio

n r

ate

(ml/

min

/1.7

3m

2)

45

65

75

85

95

105

55

Change in glomerular filtration rate

11.3 ml/min/year

3.5 ml/min/year

1.2 ml/min/year1.3 ml/min/year

Effect of antihypertensive treatment (â blockers and diuretics) on meanarterial pressure, glomerular filtration rate, and albuminuria in patients withtype 1 diabetes and nephropathy. Reproduced with permission fromMogensen, Diabetic Med 1995;12:7569.

Years of follow up from baseline

Su

rviv

al p

rob

abili

ty

161284 14106200

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0.1

Years of follow up from baseline

161284 1410620

Light

None

Heavy

Type 1 Type 2

Data from WHO multinational study of vascular disease in diabetes showingsurvival in patients with type 1 and type 2 diabetes according to degree ofproteinuria (none, slight, or heavy) at baseline. Reproduced with permissionfrom Stephenson et al, Diabetic Med 1995;12:14955

Clinical review



relation between glucose concentrations and macrovascularevents is less powerful than for microvascular disease; smoking,blood pressure, proteinuria, and cholesterol concentration aremore important risk factors for atheromatous large vesseldisease in patients with diabetes.

Hyperlipidaemia is no more common in patients with wellcontrolled type 1 diabetes than it is in the general population.In patients with type 2 diabetes, total and low densitylipoprotein cholesterol concentrations are also similar to thosefound in nondiabetic people, but type 2 diabetes is associatedwith a more atherogenic lipid profile, in particular lowconcentrations of high density lipoprotein cholesterol and highconcentrations of small, dense, low density lipoprotein particles.

Hypertension affects at least half of patients with diabetes. Inthe UK prospective diabetes study tight blood pressure control(mean 144/82 mm Hg) achieved significant reductions in therisk of stroke (44%), heart failure (56%), and diabetes relateddeaths (32%), as well as reductions in microvascularcomplications (for example, 34% reduction in progression ofretinopathy). One third of patients required three or moreantihypertensive drugs to maintain a target blood pressure< 150/85 mm Hg. In another recent study (hypertensionoptimal treatment study) rates of cardiovascular events inpatients with type 2 diabetes were reduced even further whencombination treatment was used to aim for target diastolicblood pressures < 80 mm Hg.

Coronary heart diseaseThe incidence and severity of coronary heart disease events arehigher in patients with diabetes, and several clinical features areworth noting. The diabetes subgroups in the major secondaryprevention studies of cholesterol reduction (Scandinavian

simvastatin survival study (4S) and cholesterol and recurrentevents (CARE) trial) show a beneficial effect of statins.

Peripheral vascular diseaseAtheromatous disease in the legs, as in the heart, tends to affectmore distal vessels—for example, the tibial arteries—producingmultiple, diffuse lesions that are less straightforward to bypassor dilate by angioplasty. Medial calcification of vessels(Mönckeberg’s sclerosis) is common and can result in falselyraised measurements of the ankle brachial pressure index. Thisindex is therefore less reliable as a screening test in patientswith diabetes and intermittent claudication.

StrokeRoughly 85% of acute strokes are atherothrombotic, and the restare haemorrhagic (10% primary intracerebral haemorrhage and5% subarachnoid haemorrhage). The risk of atherothromboticstroke is two to three times higher in patients with diabetes, butthe rates of haemorrhagic stroke and transient ischaemic attacksare similar to those of the nondiabetic population. Patients with

Predictors of cardiovascular mortality

Type 1 diabetes Type 2 diabetesx Overt nephropathy x Presence of coronary heart diseasex Hypertension x Overt proteinuriax Smoking x Glycated haemoglobinx Microalbuminuria x Hypertensionx AgeTaken from BMJ 1996:313:77984, Diabetes1995;44:13039

70Age (years)

Est

imat

ed h

azar

d r

atio

s

(95

% C

I)

6560555045400.4

1

3

Low density lipoprotein

cholesterol (mmol/l)

5.04.54.03.53.02.5High density lipoprotein

cholesterol (mmol/l)

1.31.21.11.00.9

Glycated haemoglobin (%)

Est

imat

ed h

azar

d r

atio

s

(95

% C

I)98765

0.4

1

3

Systolic blood pressure

(mm Hg)

160150140130120110 Currentsmokers

Formersmokers

Neversmokers

Estimated hazard ratios for significant risk factors for coronary heartdisease occurring in 335 out of 3055 patients with type 2 diabetes.Reproduced from Turner et al, BMJ 1998;316:8238.

Target diastolic blood pressure (mm Hg)

Eve

nts

per

10

00

pat

ien

t-ye

ars

0<80

(n=499)<85

(n=501)<90

(n=501)

10

15

20

25

P value for trend 0.005

30

5

Rates of serious cardiovascular events according to target diastolic bloodpressure in 1500 patients with hypertension and type 2 diabetes. Drawnfrom Hansson et al, Lancet 1998;351:175562.

Features of coronary heart disease in diabetic patients

Atherosclerosis Acute myocardial infarction Revascularisationx Prevalence of fatal and nonfatal coronaryheart disease events 220 × higher than fornondiabetics of similar agex Protective effect of female sex is lostx Higher incidence of diffuse, multivesseldiseasex Plaque rupture leading to unstable anginaand myocardial infarction is more commonx Superimposed thrombosis more likely

x Inhospital and 6 month mortality doublethat in nondiabeticsx Complications (eg, arrhythmias, heart failure,death) more commonx Reperfusion rates after thrombolysis aresimilar to those of nondiabetics, butreocclusion and reinfarction rates are higherx Mortality reduced by insulin glucose infusionimmediately after myocardial infarction

x 5 year survival rates after coronaryartery bypass graft or percutaneouscoronary angioplasty lower than fornondiabeticsx 5 year survival better after coronaryartery bypass graft than percutaneouscoronary angioplasty because of higherrestenosis rates with angioplasty (81% v66%)

Clinical review



diabetes are probably more prone to irreversible rather thanreversible ischaemic brain damage, and small lacunar infarcts arecommon. Stroke patients with diabetes have a higher death rateand a poorer neurological outcome with more severe disability.Maintaining good glycaemic control immediately after a stroke islikely to improve outcome, but the long term survival is reducedbecause of a high rate of recurrence. Antihypertensive treatmentis effective in preventing stroke.

Erectile dysfunctionErectile dysfunction is a common complication of diabetes,occurring in up to half of men aged over 50 years (comparedwith 1520% in age matched nondiabetic men), although theexact prevalance is unknown because of likely underreporting.The underlying pathogenesis is multifactorial, with autonomicneuropathy, vascular insufficiency, and psychological factorscontributing to the clinical picture. The condition causesappreciable social and psychological problems for many patients,and its importance should not be underestimated. The recentintroduction of sildenafil, which is reported to have a 5070%success rate in patients with diabetes, is an important advance.

Surveillance and management ingeneral practiceScreening for diabetesUp to half of people with type 2 diabetes have vascularcomplications at the time of diagnosis. Early detection ofdiabetes is therefore essential. Screening (by measuring fastingblood glucose concentration) should be considered for high riskpatients, especially those who are middle aged and obese, are ofAsian or AfroCaribbean origin, have a history of gestationaldiabetes, or have a family history of diabetes.

Eye screeningThe small number of patients with retinopathy in any onepractice (about 50 patients per 10 000 practice list) does notallow most general practitioners to develop and maintain theirfunduscopic skills. Innovative approaches, including the use oftrained community optometrists and mobile retinalphotography units that visit practices annually, can provide ahigh standard of retinal screening in the community.

Cardiovascular risk predictionIdentification of patients at highest risk of developingcardiovascular events allows efforts and resources to bechannelled most effectively. Coronary risk prediction chartsand computer programs such as that recently produced as

Recommendations on prevention of coronary heart disease in clinical practice

Glycaemic control Blood pressure control Lipid control

Target Glycated haemoglobin <7.0% Fastingblood glucose 47 mmol/l

<140/80 mm Hg without macrovasculardisease<130/80 mm Hg with macrovasculardisease

Serum cholesterol < 5.0 mmol/l in patientswith established coronary heart diseasePrimary prevention in those with > 30%risk of coronary heart disease over 10 years

Treatment(in additionto lifestyleand dietaryadvice)

Metformin (first line if body massindex > 25)SulphonylureaAcarboseGlitazones (not yet available in UnitedKingdom)InsulinCombination therapy

Angiotensin converting enzyme inhibitors:renoprotective but caution in renal arterystenosis (17% of hypertensive diabetics)Diureticsâ blockersá blockersLong acting calcium antagonists50% of patients will require >3 drugs foroptimum control

Statins (regular monitoring of liverfunction)

Years from randomisation

Pat

ien

ts w

ith

eve

nts

(%

)

543210 6 87 90

10

20Tight control <150/85 mm Hg

Less tight control <180/85 mm Hg

StrokeReduction in risk with tight control 44%(95% confidence interval 11% to 65%, P=0.013)

KaplanMeier plot of proportions of patients who developed fatal ornonfatal stroke, according to blood pressure control. Reproduced fromTurner et al, BMJ 1998;317:70313.

Normal renal function

• Glomerular hyperfiltration and hyperperfusion

• Glomerular hypertrophy

• Mesangial expansion

• Modest increase in blood pressure

Microalbuminuria

("incipient nephropathy")

Albumin excretion rate

20-300 mg/24 h

Macroproteinuria

("overt nephropathy")

Albumin excretion rate

>300 mg/24 h

Dipstick

negative

Dipstick

positive

End stage renal disease

(dialysis or transplantation)

• Increased albumin excretion rate

• Decreasing glomerular filtration rate

Ris

k o

f m

acro

vasc

ula

r ev

ents

, es

pec

ially

coro

nar

y h

eart

dis

ease

• Uraemia

• Fluid retention

• Increased blood pressure

Transition from normal renal function through to end stage renal diseaserequiring dialysis or transplantation. Increasing proteinuria and renalimpairment is associated with an increasing risk of fatal or nonfatalcoronary heart disease, especially in older patients with type 2 diabetes andother risk factors

Clinical review



part of the joint British recommendations on prevention ofcoronary heart disease in clinical practice will help generalpractitioners to implement the findings of recent majorclinical trials.

Annual complications assessmentAll patients with diabetes should be offered an annual clinicalassessment concentrating on the prevention, detection, andmanagement of macrovascular and microvascular complications.

Areas of debate in surveillance of diabetes complicationsThe value of routine measurements of microalbuminuria inpatients with type 2 diabetes is less clear than in type 1 diabetes.Arrangements to allow the testing of microalbuminuria ingeneral practice are not universally available.

The presence of left ventricular hypertrophy is a powerfulpredictor of the risk of a cardiovascular event, but screening byechocardiography or electrocardiography is often not includedas part of the routine annual assessment.

Unlike total cholesterol concentrations and the totalcholesterol to high density lipoprotein cholesterol ratio, theimportance of raised triglyceride concentrations in the riskprofile of patients with type 2 diabetes is unclear.

Team approach to integrated diabetic careThe ongoing care of patients with diabetes, in particular oncethey have developed vascular complications, includes a widespectrum of healthcare professionals. A systematic, integrated,and collaborative approach must be developed at a regionallevel, with clear lines of communication and the adoption oflocally agreed guidelines for treatment and referral based onnational guidelines—for example, those from the ScottishIntercollegiate Guideline Network (www.show.scot.nhs.UK/sign/home.htm).

Alistair M EmslieSmith is general practitioner, Tayside Centre forGeneral Practice, Dundee; Iain D Gardner is consultantophthalmologist, Derbyshire Royal Infirmary, Derby; and Andrew DMorris is senior lecturer in medicine and diabetes, Ninewells Hospitaland Medical School, Dundee.

BMJ 2000;320:10626

Annual complications assessment

Physical examinationx Body mass index calculation (weight (kg)/(height (m))2)x Blood pressure measurement with patient sitting and

appropriate sized cuffx Palpation of foot pulsesx Measurement of foot sensation by one or more of following:

10 g monofilament weight (not detected = impaired)Vibration of 128 Hz tuning fork over medial malleolus(perception for < 5 secs = impaired)Assessment of ankle jerk with tendon hammer (less reliablein elderly people)

x Inspection of feet for nail care, callosities, fissures, fungalinfection, blisters, ulcers, claw toes, prominent metatarsalheads, and Charcot arthropathy

x Visual acuity in corrected state, using standard 6 m (or 3 m)Snellen chart. Use pin hole if corrected acuity is >6/9

x Retinal examination by one of:Direct ophthalmoscopy through pupils dilated with 1%tropicamideCombination of direct ophthalmoscopy and slit lampbiomicroscopyRetinal photography through fixed site or mobilenonmydriatic fundus camera

Biochemical analysisx Dipstick urine analysis for proteinuriax Urine testing for microalbuminuria in type 1 diabetesx Blood testing of:

Glycated haemoglobinSerum creatinineSerum total cholesterol and high density lipoproteincholesterol

History, advice, and educationx Smoking historyx Education and reinforcement of advice on diet, aerobic

exercise, and lifestylex Review treatment, including side effects and compliancex Assess knowledge of diabetes and self management skills,

including warning signs for complications (intermittentclaudication, angina pectoris, foot problems)

x Review footwear provisionx Review need for contact with dietetics, chiropody, orthotics,

and diabetes specialist nurse supportx Advice on erectile dysfunction in menx Prepregnancy counselling, where appropriatex Calculate and discuss risk of coronary heart disease and

modification of risk factors

Neuropathic ulcer is acommon complication inpatients with diabetes

Use of monofilament to detect impairedsensation during annual assessment

Mobile eye screening unit


Clinical review



organism). Nine samples (8%) from five children (fourboys) grew > 105 coliforms/ml, suggesting infection.However, this was excluded by sterile samples collectedon the same day or on immediate repeat in hospital.

Parents found the pads and bags easy to use andpreferred them to clean catch collections (table) forboth sexes. The pad was considered comfortable,whereas the bag was distressing, particularly onremoval, often leaking and leaving red marks. Somefound extracting the urine from the pad or emptying itfrom the bag to be awkward. Most parents complainedthat clean catch collections were time consuming andoften messy; nine gave up after prolonged attempts.Five parents whose infants voided immediately rankedit best. The median collection time was 25 minutes foreach method, but parents resented constraining theirchildren this long for clean catch collections.

Comment

This is the first study of parents’ views of infant urinecollection methods. Pad, bag, and clean catch sampleswere equally effective at excluding an infection;variations in contamination rates balanced collectionfailures. Most parents disliked clean catch collections;their views should be heeded. Most preferred pads tobags, and they are cheaper. They also found inoculatingdipslides with swabsticks easy; this technique may havecontributed to their relatively low contamination rates.3 4

Since Kass suggested a diagnostic cut off of a singlebacterial species cultured at > 105/ml, it has been widelytaken as proof of a urine infection and assumed not tooccur from skin contamination, even though his study5

and others3 recorded similar false positive rates to ours.False positive results potentially lead to inappropriatetreatment and imaging. Suprapubic puncture is anunrealistic alternative in primary care. Although collecting multiple samples would reduce the false positiverate, it might delay antibiotic treatment.

We thank the parents for volunteering and their thoughtfulcomments and Dr Mohammad Raza for microbiological help.

Contributors: MGC had the original idea for the study and isthe guarantor. The study was designed, the data analysed, andthe paper written jointly by all the authors. LDTL carried outthe clinical aspects and DMN and SJP the laboratory aspects ofthe study.

Funding: None.Competing interests: The Children’s Kidney Fund of the

Newcastle University Hospitals special trustees receives royaltiesfrom Ontex UK from sales of Newcastle sterile urine collectionpacks.

1 Jadresic L, Cartwright K, Cowie N, Witcombe B, Stevens D. Investigationof urinary tract infection in childhood. BMJ 1993;307:7614.

2 Vernon S, Foo CK, Coulthard MG. General practice management of children with urinary tract infection: an audit in the former Northern region.Br J Gen Pract 1997;47:297300.

3 Hardy JD, Furnell PM, Brumfitt W. Comparison of sterile bag, clean catchand suprapubic aspiration in the diagnosis of urinary infection in earlychildhood. Br J Urol 1976;48:27983.

4 Macfarlane PI, Houghton C, Hughes C. Pad urine collection for earlychildhood urinarytract infection. Lancet 1999;354:571.

5 Kass EH. Asymptomatic infections of the urinary tract. Trans Assoc AmPhys 1956;69:5663.

(Accepted 22 February 2000)

Corrections and clarifications

ABC of vascular disease: Vascular complications ofdiabetesAn error crept into a figure in this article byRichard Donnelly and colleagues (15 April,pp 10626). In the KaplanMeier plot at the top ofp 1065, the definition of less tight control shouldbe < 180/105 (not < 180/85) mm Hg.

MinervaMinerva slipped up on two names, one personaland one taxonomic, in the picture article in theissue of 18 March (p 814). The third author’s nameis R Whitfield; the culture grown was Mycobacteriummarinum.

Assessments by 44 parents of three methods of home urine

collection

Parents’ assessments

No of parents:

Pad Bag

Clean

catch

Preference order

First 21 18 5

Second 19 12 13

Third 4 14 26

Open comments

Positive

Easy, hygienic, or quick 25 24 8

Comfortable for child 10 3 0

Negative

Uncomfortable or distressing 1 26 3

Fiddly or messy 9 10 20

Impractical or time consuming 10 0 36

Difficult to get urine out of pad 8 — —

Red marks left on skin — 11 —

Too much trouble—gave up (boys) 1 (0) 4 (3) 9 (5)

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Papers

1313BMJ VOLUME 320 13 MAY 2000 bmj.com


ABC of arterial and venous diseaseRenal artery stenosisKevin McLaughlin, Alan G Jardine, Jon G Moss

Renal artery stenosis is becoming increasingly commonbecause of atherosclerosis in an ageing population. Patientsusually present with hypertension and varying degrees of renalimpairment, although silent renal artery stenosis may bepresent in many patients with vascular disease. Despiteimprovements in diagnostic and interventional techniques,controversy remains over whether, when, and how torevascularise the kidneys of patients with renal artery stenosis.

PathophysiologyThe pathophysiology of unilateral renal artery stenosis providesa clear example of how hypertension develops. Narrowing ofthe renal artery, due to atherosclerosis or, rarely, fibromusculardysplasia, leads to reduced renal perfusion. The consequentactivation of the reninangiotensin system causes hypertension(mediated by angiotensin II), hypokalaemia, and hyponatraemia(which are features of secondary hyperaldosteronism).Although these features may be reversed by correcting thestenosis, a classic presentation is uncommon, and hypertensionis rarely cured in patients with atheromatous renal arterystenosis. In addition, it is now known that renal artery stenosis isunderdiagnosed and may present as a spectrum of disease fromsecondary hypertension to end stage renal failure, reflectingvariation in the underlying disease process. Thus, the presenceof overt, or coincidental, renal artery stenosis usually reflectswidespread vascular disease, with the associated implications forcardiovascular risk and patient survival.

Clinical featuresAtheromatous renal artery stenosis typically occurs in malesmokers aged over 50 years with coexistent vascular diseaseelsewhere. It is underdiagnosed and may present with aspectrum of clinical manifestations. Although conventionallythought of as a cause of hypertension, atheromatous renalartery stenosis is not commonly associated with mild tomoderate hypertension. However, it is present in up to a thirdof patients with malignant or drug resistant hypertension. Renalartery stenosis is a cause of end stage renal failure, and patientscommonly present with chronic renal failure (with or withouthypertension). Typical patients have a bland urine sediment andnonnephrotic range proteinuria, although occasional patientsmay have heavy proteinuria with focal glomerulosclerosis onrenal biopsy. Patients may also present with acute renal failure,particularly those with bilateral renal artery stenosis (or stenosisof a single functioning kidney) who are taking drugs that blockthe reninangiotensin system.

Less common presentations include recurrent, rapid onset(“flash”) pulmonary oedema, which is probably a consequenceof fluid retention, and diastolic ventricular dysfunction, whichoften accompanies (bilateral) atheromatous renal arterystenosis. Biochemical abnormalities may also be present inpatients with modest or no serious renal impairment. Patientswith unilateral renal artery stenosis have raised circulatingconcentrations of renin and aldosterone and associatedhypokalaemia; in contrast to patients with primaryhyperaldosteronism, their plasma sodium concentration is

Characteristics of renal artery stenosis

Fibromuscular dysplasiax Young age groupx Predominantly affects womenx Presents as hypertensionx Rarely causes renal impairment

Atherosclerosisx Older age groupx More common in menx Affects smokersx Evidence of atherosclerosis elsewherex Causes hypertension—often treatment resistantx Often associated with renal impairment

Prevalence of atheromatous renal artery stenosis

x 27% of necropsiesx 25% of patients having routine coronary angiographyx 50% of patients having peripheral angiographyx 1620% of all patients starting renal dialysisx 2530% of patients aged over 60 years on dialysis programmes

Clinical features and pointers to diagnosis of renal arterydisease

x Young hypertensive patients with no family history (fibromusculardysplasia)

x Peripheral vascular diseasex Resistant hypertensionx Deteriorating blood pressure control in compliant, long standing

hypertensive patientsx Deterioration in renal function with angiotensin converting enzyme

inhibitionx Renal impairment with minimal proteinuriax “Flash” pulmonary oedemax > 1.5 cm difference in kidney size on ultrasonographyx Secondary hyperaldosteronism (low plasma sodium and potassium

concentrations)

Atheromatous lesions may affect different sized vessels within the kidney,and multiple lesions may exist. The site limits the potential forrevascularisation; only lesions within the large vessels are amenable. Thecommonest site, at the ostium of the renal artery, is more effectively treatedby stenting. Ulcerated atheromatous plaques may also generate cholesterolmicroemboli (particularly after vascular intervention)

Clinical review



normal or reduced. Patients with bilateral renal artery stenosiscommonly have impaired renal function.

Clinical examination often shows bruits over major vessels,including the abdominal aorta (a feature of widespreadatherosclerosis), although the classic finding of lateralisingbruits over the renal arteries is uncommon.

DiagnosisThe main differential diagnoses of atheromatous renal arterystenosis in patients with hypertension and renal impairment arebenign hypertensive nephrosclerosis and cholesterolmicroembolic disease. Differentiating between these conditionsmay be difficult, particularly as all three can occursimultaneously.

Angiography remains the standard test for diagnosingatheromatous renal artery stenosis and is widely available.However, it is not without risk and may worsen renal function.Noninvasive imaging techniques are beginning to replaceconventional angiography. Although acceptable results havebeen reported by single enthusiastic centres, it remains to beseen whether these can be reproduced. Each has its ownlimitation. Doppler ultrasonography is very operator sensitiveand is often impossible in obese patients. Spiral computedtomography requires the use of iodinated contrast media andradiation. Isotope renography (with or without captopril) hasthe advantage of providing information on renal function but isof little value in bilateral disease or when renal function isseriously impaired. Magnetic resonance angiography is themost promising imaging technique. It requires no contrast andpermits reconstruction of the image in different planes.However, use of this technique is limited by lack of access tomagnetic resonance imaging machines in the United Kingdom.

All the above noninvasive tests require variable degrees ofpatient cooperation, particularly the ability to hold a breath forup to 30 seconds for image acquisition. Moreover, none of theavailable imaging techniques identify the patients who willrespond to revascularisation. The aim of investigation is toestablish the diagnosis and whether revascularisation is possibleor appropriate. In practice we use ultrasonography to definerenal size and symmetry before proceeding to angiography todelineate the lesion. Magnetic resonance angiography isreserved for patients at high risk of angiographic complications.

PrognosisThe rate of progression of atheromatous renal artery stenosis isdifficult to evaluate accurately, and reports from large tertiaryreferral centres are likely to be biased by case mix as the studieshave followed selected cohorts. Moreover, follow up may belimited by the influence of concomitant vascular disease onsurvival. Most studies (over a variable follow up period) estimatethe risk of radiological progression of atheromatous renalartery stenosis to be about 50%, and risk is dependent on initialseverity of the lesion. The rate of occlusion of renal arteries withgreater than 60% stenosis is about 5% a year.

Patients who have bilateral atheromatous renal arterystenosis with an occluded renal artery are three times morelikely to reach end stage renal failure within two years thanpatients who have bilateral disease without occlusion (50% v18%). The rate of loss of functional renal tissue (implied by lossof renal size of >1 cm at one year after diagnosis) is about threetimes higher for patients with bilateral disease than for thosewith unilateral disease (43% v 13%).

Noninvasive imaging techniques

x Doppler ultrasonographyx Captopril renographyx Spiral computed tomographyx Magnetic resonance angiography

Angiogram of renal artery stenosis due to fibromuscular dysplasia of renalartery. Lesions typically affect the main renal artery, are beaded inappearance, and may have multiple stenoses

Gadolinium enhanced magnetic resonance angiogramshowing a tight stenosis at the origin of the right renalartery. The left renal artery is normal

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Effect of coexistent renal artery stenosis on survival among patients havingcoronary angiography

Clinical review



TreatmentTreatment of atheromatous renal artery stenosis must be tailoredto the individual and should be undertaken in the expectationthat revascularisation will prolong life. Hypertension in patientswith renal artery stenosis can be controlled by drugs alone inalmost 90% of cases. Angiotensin converting enzyme inhibitorsreduce the glomerular filtration rate in about one third of patientswith high grade bilateral atheromatous renal artery stenosis.Although this reduction is reversible in most cases, these drugsshould be used with utmost caution.

Angioplasty is the traditional revascularisation procedure.Technical advances have revolutionised angioplasty, but fewtrials have examined its effects in renal artery stenosis. Theavailable randomised controlled trials comparing drugtreatment with angioplasty have shown only a modest reductionin blood pressure or antihypertensive drug requirements afterangioplasty. Unlike treatment of fibromuscular dysplasia, cure ofatheromatous renal artery stenosis by angioplasty alone is rare.

Most atheromatous renal artery stenosis is due to aorticplaques encroaching on the ostium of the renal artery.Angioplasty is less than ideal in this situation because of theelastic recoil of the aortic plaques. The introduction of stentshas helped overcome this problem. A recent randomisedcontrolled trial comparing stent insertion to angioplasty alonein patients with ostial stenosis found a higher initial success rate(88% v 57%) and lower restenosis rate at six months (14% v48%) in patients who had a stent inserted. Apart from expensethere is little to argue against a policy of primary stenting forostial renal artery stenosis. Although the patency rates fromsurgical bypass are excellent, surgery should probably bereserved for patients in whom stenting fails or who developcomplications.

Benefits of revascularisationRenal function may improve greatly after vascular intervention,although it is difficult to identify which patients will benefit andthe potential of the kidney distal to the stenosis to recoverfunction. The available studies in patients with mild to moderaterenal impairment show that renal function improves in 25% ofpatients, remains stable in 50%, and deteriorates in 25% aftersurgical revascularisation or stenting. Renal length >8 cm onultrasonography and the presence of intact glomeruli on renalbiopsy have been suggested as good prognostic markers buthave not been formally studied. Patients in whom renal functiondeteriorates after vascular intervention have an extremely poorprognosis, with most requiring dialysis or dying within one year.

Treatment options for renal artery stenosis

x Drug treatment to reduce blood pressure (avoiding angiotensinconverting enzyme inhibitors if possible)

x Stop smokingx Lipid lowering treatmentx Preventive treatment for coexistent vascular disease, eg aspirinx Angioplasty for nonostial disease and fibromuscular dysplasiax Stent insertion for ostial atheromatous renal artery stenosisx Surgical bypass for failed endovascular procedures

Indications for revascularisation

x Resistant hypertensionx Deteriorating renal functionx Critical stenosis, or stenosis with deteriorating function, in single

functioning kidneyx Fibromuscular dysplasiax Associated heart failure (“flash” pulmonary oedema)

Complications of intervention

x Groin haematomax Femoral artery false aneurysmx Ischaemia distal to puncture sitex Contrast nephrotoxicityx Renal artery occlusion, dissection, or perforationx Cholesterol embolism syndrome

Occluded renal artery before (left) and after (right) successful stenting. It ispossible to revascularise an occluded renal artery provided there is distalreconstitution of the renal artery with collateral vessels maintaining viability.In this relatively unusual case, the patient required dialysis at presentationbut became dialysis independent after stenting

Endovascular treatment. In this ostial lesion (left) there is no improvement after angioplasty because of elastic recoil (middle). An excellentmorphological result is then achieved by stent placement (right)

Clinical review



Although a modest improvement in blood pressure or areduction in antihypertensive drug requirement may be thegoal of revascularisation, renal protection may emerge as amore important factor. Animal studies have shown that renaltissue distal to renal artery stenosis undergoes irreversibleischaemic change, tubular atrophy, interstitial fibrosis, andglomerulosclerosis despite antihypertensive treatment.Although similar evidence is not available in humans, insertionof a stent in patients with renal artery stenosis slowed the rate ofloss of renal function despite modest blood pressure benefits. Afinal reason to pursue revascularisation is the fact that patientswith atheromatous renal artery stenosis have a worse prognosisthan any other group on dialysis, with a median survival of 27months, and prevention of progression to end stage renalfailure may have greatest benefits in this group. The benefits ofrevascularisation, and the potential benefits of early intervention(for example, in patients with coincidental findings of renalartery stenosis) will need to be established by randomisedcontrolled trials before the burden of additional procedures isplaced on both radiologists and patients.

Special casesFibromuscular dysplasia is a much less common cause of renalartery stenosis. It principally occurs in young women, whopresent with unilateral disease, hypertension, and biochemicalabnormalities. The lesions are graded by their distribution. Incontrast to atheromatous renal artery stenosis, fibromusculardysplasia is often cured by intervention, and often byangioplasty alone.

Patients with renal transplants have acceleratedcardiovascular disease, one of the manifestations of which is thedevelopment of stenosis in the transplanted renal artery. Thisproduces hypertension, fluid retention, and renal impairmentsimilar to that found in patients with bilateral renal arterystenosis and is an indication for revascularisation.

Treatment recommendationsRecommending treatment for renal artery stenosis is difficultwith the quality of the evidence available and the paucity ofcontrolled trials. Surgical revascularisation is rarely indicatedbut may have a role in patients for whom angioplasty orstenting is not technically feasible or in patients with complexdisease having abdominal vascular surgery. Nephrectomy (byminimally invasive surgery) may be considered in patients withunilateral disease whose blood pressure cannot be controlledbecause of a small or poorly functioning kidney.

Whatever recommendations we suggest, there will bedisagreement. Firmly held, preconceived beliefs exist on thetreatment of renal artery stenosis despite the fact that therehave been few large outcome studies comparing treatmentstrategies. The ASTRAL (angioplasty and stent for renal arterylesions) study is a British randomised controlled trial that willcompare angioplasty with and without stenting against drugtreatment in 1000 patients with renal artery stenosis. Our futureapproach to the management of renal artery stenosis willdepend on the conduct of relevant controlled trials.

The picture of gadolinium enhanced magnetic resonance angiography wasprovided by D Wilcock, Leicester Royal Infirmary.

Kevin McLaughlin is assistant professor of nephrology, University ofCalgary, Canada; Alan G Jardine is senior lecturer and consultantnephrologist, department of medicine and therapeutics, WesternInfirmary, Glasgow ([email protected]); and Jon G Moss isconsultant interventional radiologist, Gartnavel General Hospital,Glasgow.

Further readingx Mailloux LU, Napolitano B, Bellucci AG, Vernance M, Wilkes BM,

Mossey RT. Renal vascular disease causing endstage renal disease:incidence, clinical correlates and outcomes: a 20year clinicalexperience. Am J Kidney Dis 1994;24:6229.

x Plouin PF, Chatellier G, Darne B, Raynaud A. Blood pressureoutcome of angioplasty in atherosclerotic renal artery stenosis: arandomized trial. Essai Multicentrique Medicaments vs Angioplastie(EMMA) Study Group. Hypertension 1998;31:8239.

x Van de Ven PJG, Kaatee R, Beutler JJ, Beek FJ, Woittiez AJ, BuskensE et al. Arterial stenting and balloon angioplasty in ostialatherosclerotic renovascular disease: a randomised trial. Lancet1999;353:2826.

x Textor SC. Revascularisation in atherosclerotic renal artery disease.Kidney Int 1998;53:799811.

x Conlon PJ, Athirakul K, Kovalik E, Schwab SJ, Crowley J, Stack R, etal. Survival in renovascular disease. J Am Soc Nephrol 1998;9:2526.

Recommendations for treatment

Patient characteristics Treatment

Controlled blood pressureMinimal renal impairment (creatinine< 150 mmol/l) MedicalRenal artery stenosis < 50% (unilateralor bilateral)

Advanced renal failure andRenal size < 8 cm orRenal artery occlusion (without distalrecanalisation) orNo evidence of renal function inaffected kidney or

No prospect of recoverywith intervention

Biopsy showing severe irreversiblechanges

Renal size > 8 cm and renal arterystenosis > 50% andPoorly controlled blood pressure orDeterioration in renal function withangiotensin converting enzymeinhibitors orProgressive renal impairment

Angioplasty for nonostiallesionsAngioplasty plus stent forostial disease


BMJ 2000;320:11247

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Effect of stent placement on rate of loss of renal function (expressed as slopeof serum creatinine concentration with time). Overall, a significant reductionoccurred in the rate of loss of renal function, although the individualresponse was variable

Clinical review



ABC of arterial and venous diseaseArterial aneurysmsM M Thompson, P R F Bell

True arterial aneurysms are defined as a 50% increase in thenormal diameter of the vessel. Clinical symptoms usually arisefrom the common complications that affect arterialaneurysms—namely, rupture, thrombosis, or distal embolisation.Although the aneurysmal process may affect any large ormedium sized artery, the most commonly affected vessels arethe aorta and iliac arteries, followed by the popliteal, femoral,and carotid vessels.

Abdominal aortic aneurysmsAneurysms of the infrarenal abdominal aorta and iliac arteriescoexist to such a degree that they may be considered a singleclinical entity. Abdominal aneurysms usually affect elderly men( > 65 years), with a prevalence of 5%. In England, abdominalaneurysm is responsible for over 11 000 hospital admissionsand 10 000 deaths a year. Interestingly, unlike otheratherosclerotic vascular disorders, the prevalence of abdominalaortic aneurysms is increasing rapidly, and aneurysmal ruptureis now the 13th commonest cause of death in the Westernworld.

Clinical presentationAlthough abdominal aneurysms may cause symptoms becauseof pressure on surrounding structures, about three quartersremain asymptomatic at initial diagnosis. With the exception ofvague abdominal pain, clinical symptoms usually result fromembolisation or rupture of the aneurysm.

The appearance of microembolic lower limb infarcts in apatient with easily palpable pedal pulses may suggest thepresence of either popliteal or abdominal aneurysms.Additionally, patients with embolisation of mural thrombusfrom an abdominal aneurysm may present with acute limbischaemia due to femoral or popliteal occlusion.

The diagnostic triad of hypovolaemic shock, pulsatileabdominal mass, and abdominal or back pain is encountered inonly a minority of patients with ruptured abdominal aneurysms.In general, ruptured abdominal aortic aneurysm should beconsidered in any patient with hypotension and atypicalabdominal symptoms. Similarly, the presence of abdominal painin a patient with a known aneurysm or pulsatile mass must beconsidered to represent a rapidly expanding or rupturedaneurysm and be treated accordingly. In the community setting,the death rate from ruptured abdominal aortic aneurysms isalmost 90%, as 80% of patients will die before reaching hospitaland about 50% die during surgery to repair the rupture.

Methods of diagnosisThe sensitivity of abdominal palpation to detect aorticaneurysms increases with the diameter of the aneurysm, butpalpation is not sufficiently reliable for routine diagnosis.Similarly, plain abdominal radiography shows a calcifiedaneurysmal aortic wall in only half of cases.

The simplest diagnostic test is B mode ultrasonography,which gives an accurate assessment of both the diameter andthe site of the aneurysm. If more accurate morphological dataare required to determine the exact relation of the aneurysm tothe visceral or renal arteries, detailed cross sectional imaging

Large infrarenal abdominal aortic aneurysm before surgical repair

Clinical picture of “trash foot.” The appearance is caused by multiplemicroscopic atheromatous emboli from a large infrarenal aorticaneurysm. The presence of digital infarcts in a patient with easilypalpable pulses may point to an aneurysmal source of emboli

Ruptured abdominal aneurysm. Rupture usually occurs posteriorly into theretroperitoneum, which produces a contained leak and allows the possibilityof surgical repair. Free anterior intraperitoneal rupture usually results inexsanguination

Clinical review



may be obtained by computed tomography or magneticresonance angiography.

The diagnosis of ruptured abdominal aortic aneurysms relieson clinical symptoms. Ultrasonography is used to confirm ananeurysm if it is difficult to palpate. Computed tomography has alow specificity (about 75%) for determining the presence of arupture and adds little information to routine clinical assessment.

Indications for surgery

Elective surgeryThe decision to operate on a patient with an asymptomaticabdominal aneurysm is based on an analysis of the risk ofaneurysmal rupture compared with the mortality of electivesurgical repair. The risk of rupture is related to many factors,but the diameter of the aortic aneurysm has historically beenused as the principal determinant.

Unfortunately, little information is available on the rupturerates of large abdominal aneurysms, but pooled analysis ofexisting data suggests that the risk of rupture increasesexponentially in aneurysms above 5560 mm. This has led to abroad surgical consensus that aneurysms exceeding 55 mm indiameter should be surgically repaired if there are noconfounding factors that would substantially increase the risk ofelective surgery.

The treatment for smaller aneurysms has recently beenclarified by the UK small aneurysm trial, which studied 1090patients with aneurysms of 4055 mm. The study found a 30 dayoperative mortality of 5.8%, mean risk of rupture for smallaneurysms of 1% a year, and no difference in survival betweentreatment groups at two, four, or six years. The cost for earlysurgery was higher than for surveillance, but early surgery wasassociated with improvement in some measures of quality of life.

Emergency treatmentPatients with suspected ruptured aneurysms should beconsidered for emergency surgical repair. Several studies havelooked at preoperative risk factors and survival after emergencyrepair of an aneurysm. Although there is no precise scoringsystem that will allow accurate prediction of survival, the presenceof several predictive factors (age > 80 years, unconsciousness, lowhaemoglobin concentration, cardiac arrest, severecardiorespiratory disease) can be used to determine patients inwhom the risk of dying during surgery approaches 100%.

Patients with symptomatic aneurysms should be treated asurgent cases and have the aneurysm repaired. The aetiology ofpain from abdominal aneurysms is not well understood,although it has been attributed to stretching of the aneurysmsac or severe inflammation within the aneurysm wall(inflammatory aneurysms, see below).

Conventional surgical repairTraditional surgical repair for asymptomatic abdominal aorticaneurysms involves exposure of the abdominal aorta, aortic andiliac clamping, and replacement of the aneurysmal segment witha prosthetic graft. Graft replacement is an effective, durableprocedure, and most centres report 30 day mortality of about 5%,although this varies with the volume of work and type of hospital.

The mortality associated with surgical repair of aneurysms isclosely related to the “fitness” of the patient for surgery; patientswith severe cardiorespiratory disease have a perioperativemortality approaching 40%, with most deaths caused by cardiacevents.

Endovascular repairOne of the major developments in vascular surgery over thepast five years has been the introduction of endovascular repair

Factors predisposing to rupture of abdominal aorticaneurysms

x Diameter of aneurysmx Diastolic blood pressurex Chronic obstructive pulmonary diseasex Smokingx Family history of ruptured aneurysmx Expansion ratex Intrinsic biology—inflammation within the aortic wallx Thrombusfree surface area of aneurysm sac

Computed tomogram showing large infrarenalabdominal aortic aneurysm

90 100

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Annual rupture rates of abdominal aortic aneurysmsaccording to size (based on pooled available data)

Conventional repair of abdominal aortic aneurysm. The aneurysmalsegment of the aortoiliac segment is replaced with a prosthetic vascular graft(usually Dacron or ePTFE), which is sutured to the normal arterial “cuffs”above and below the aneurysm

Clinical review



of aneurysms. This technique uses an endoprosthesis, which isdelivered through the femoral arteries, to exclude an aneurysmfrom the circulation. The endograft is secured to the normalcalibre aorta and iliac arteries using metallic expandable stentsand relies on subsequent thrombosis of the aneurysm to abolishthe risk of rupture.

Endovascular repair has several theoretical advantages overconventional surgery, and early evidence suggests thatendovascular surgery is better for patients with coexistentdisease, who would be high risk for conventional surgery.However, the long term durability of endovascular techniques isunknown, although experience so far shows that up to a quarterof patients undergoing endovascular aneurysm repair willrequire subsequent endovascular interventions to ensureregression of the aneurysm sac. A multicentre trial ofendovascular repair and conventional surgery has started in theUnited Kingdom.

Screening and medical treatmentUltrasonographybased screening programmes to detect andtreat asymptomatic aneurysms have been proposed as amechanism to reduce the mortality from ruptured abdominalaortic aneurysms. Screening studies report a 2.5% prevalence ofabdominal aortic aneurysms larger than 40 mm in men agedover 60 years.

Advocates of community screening have suggested that asingle abdominal scan in men aged 65 would exclude 90% ofthe population from future aneurysm rupture, and long termfollow up of screened and control populations in Chichestershowed an 85% reduction in rupture in the screened group. Amulticentre randomised trial is currently investigating thecosteffectiveness of community based aneurysm screening.

One of the problems with screening programmes is that itidentifies many people with small aneurysms. These patients arenot offered any form of treatment other than ultrasonographicsurveillance, which may have implications for quality of life.However, recent studies have begun to elucidate the molecularand biochemical mechanisms of aneurysm formation, andclinical trials of the effectiveness of several groups of drugs toreduce expansion of small aneurysms are likely. The mostpromising of these drugs in experimental studies have beeninhibitors of matrix metalloproteinases.

Variants of abdominal aneurysms

Inflammatory aneurysmsInflammatory aneurysms are characterised by a denseinflammatory infiltrate within the aneurysm wall. They aretypically white in appearance and may be densely adherent tosurrounding structures, which could account for the increasedoperative mortality in affected patients Patients typically presentwith fever, malaise, and abdominal pain.

Thoracoabdominal aneurysmsThoracoabdominal aneurysms extend to a variable degree fromthe thoracic aorta into the abdominal aorta. They typically

Endovascular aneurysm repair. The aneurysm sac is excluded by anendograft, which is introduced through a remote arteriotomy and anchoredabove and below the aneurysm sac

Aortoiliac aneurysm before and after exclusion by a bifurcated endovasculargraft

Inflammatory abdominal aneurysm. The aneurysm is typically white inappearance and densely adherent to surrounding structures. The duodenumis being mobilised from the aneurysm sac by sharp dissection

Computed tomogram of thoracoabdominal aneurysm

Potential advantages of endovascular repair overconventional surgery

x No need for abdominal incisionx Avoidance of aortic cross clampingx No retroperitoneal dissectionx Improved perioperative cardiorespiratory functionx Reduction in metabolic stress response to aortic aneurysm repairx Improved renal and gastrointestinal functionx Reduced hospital stay

Clinical review



affect the origins of the visceral and renal arteries, which mustbe reimplanted into the graft during repair of the aneurysm.Mortality from repair of thoracoabdominal aneurysms issignificantly higher than that for infrarenal surgery.

Peripheral aneurysmsPopliteal aneurysms comprise 80% of all peripheral aneurysmsand usually exceed 20 mm in diameter. They are associated withaortic aneurysms (40% of cases), and are frequently bilateral(50%). In contrast to abdominal aortic aneurysms, patients withpopliteal aneurysms usually present with acute limb ischaemiasecondary to aneurysm thrombosis or distal embolisation. Adiagnosis of popliteal aneurysms is suggested by easily palpablepopliteal pulses and confirmed by duplex ultrasonography.

Patients who develop acute limb ischaemia due to poplitealthrombosis or embolism have a relatively poor prognosis (15%amputation rate) because of occlusion of the run off vessels. Inthese cases patients should have saphenous vein bypass andligation of the popliteal aneurysm with clearance of the cruralvessels by balloon thrombectomy or thrombolysis. Theindications for elective surgery for asymptomatic poplitealaneurysms are based on suggestive evidence only, with mostclinicians opting for surgical treatment when the aneurysmexceeds 25 mm in diameter. Results of bypass of asymptomaticpopliteal aneurysms are excellent, with five year graft patency of80% and limb salvage of 98%.

Femoral artery aneurysms are the second commonestperipheral aneurysm. Patients present with local pressuresymptoms, thrombosis, or distal embolisation. Surgical treatmentof true femoral aneurysms relies on the principles of excludingthe aneurysm and restoration of blood flow in the limb.

M M Thompson is consultant vascular and endovascular surgeon,Leicester Royal Infirmary ([email protected]), and P R F Bell isprofessor of surgery, University of Leicester.

The ABC of arterial and venous disease is edited by RichardDonnelly, professor of vascular medicine, University of Nottinghamand Southern Derbyshire Acute Hospitals NHS Trust(richard.donnelly@ nottingham.ac.uk) and Nick J M London,professor of surgery, University of Leicester, Leicester([email protected]). It will be published as a book later this year.

Key references

x Thompson MM, Sayers RD. Arterial aneurysms. In: Beard JD,Gaines P, eds. Companion to specialist surgical practice. Vol VII. Arterialsurgery. London: W B Saunders, 1998.

x UK Small Aneurysm Trial Participants. Mortality results forrandomised controlled trial of early elective surgery orultrasonographic surveillance for small abdominal aorticaneurysms. Lancet 1998;352:164955.

x Scott RAP, Wilson NM, Ashton HA, Kay DM. Influence of screeningon the incidence of ruptured abdominal aortic aneurysm: 5yearresults of a randomised controlled study. Br J Surg 1995;82:106670.

BMJ 2000;320:11936

Arteriogram of patient with popliteal artery aneurysm showing typicalspiralling appearance of the superficial femoral and popliteal arteries

A memorable anaesthetic

“Shouldn’t we do something about the fire?”

Can this have happened only about 40 years ago? It would beunthinkable now, for many reasons. What makes it memorable isthe aspect of saving life; we all, in our disillusioned moments,make cynical jokes about saving life, but on this occasion I mayactually have saved several lives all in one go. I was a second yearclinical student, doing part of my obstetric attachment in Januaryin one of the colder parts of Britain.

Late one evening, the obstetric registrar asked me if I wouldlike to accompany him on a flying squad call; a parturient in aremote farmhouse some 18 miles away had a retained placenta.We set off in a taxi. The driver had only a vague idea of where wewere going, and needed to stop frequently at pubs to askdirections. After every stop his driving seemed to get more erratic.We eventually arrived at the house, where the farmer’s wife layunconcerned in bed, while the infant slept peacefully in a cot. Anopen fire burned merrily in the huge fireplace.

The GP, smart in tweed jacket and plus fours, radiated an air ofconfidence and competence, though he must have known therewas little he could do. I don’t remember seeing the farmer, but thepresence of the husband in the delivery room was not thenusually accepted. It was decided that the placenta should be

manually removed in the bed, under open ether anaesthesia.While preparations were being made for this, I had uneasymemories of accidents involving ether and flames in thechemistry laboratory at school.

Eventually, I plucked up courage to say, “Shouldn’t we dosomething about the fire?” This was agreed to be sensible, and wecarried out the blazing logs in buckets to a safe part of the frostbound farmyard. The ether was poured by the GP and theplacenta was delivered without loss of life and farmhouse.

The journey back to the hospital seemed shorter than theoutward journey; the pubs were closed by then. All had gone well,but I wonder what the Confidential Inquiry into MaternalMortality would have said if we had all gone up in flames.

Peter Young consultant anaesthetist, Gloucestershire

We welcome articles of up to 600 words on topics such asA memorable patient, A paper that changed my practice, My mostunfortunate mistake, or any other piece conveying instruction,pathos, or humour. If possible the article should be supplied on adisk. Permission is needed from the patient or a relative if anidentifiable patient is referred to.

Clinical review



ABC of arterial and vascular diseaseSecondary prevention of peripheral vascular diseaseSean Tierney, Fiona Fennessy, David Bouchier Hayes

Most patients with peripheral vascular disease may be reassuredthat, with respect to their legs, the condition usually runs abenign course. Less than one third of patients will require anysurgical or radiological intervention and only 5% will haveamputation. However, peripheral vascular disease is anindependent predictor of increased risk of cardiovascular death.Half of patients presenting with peripheral vascular diseasehave symptoms of coronary artery disease orelectrocardiographic abnormality, 90% have abnormalities oncoronary angiography, and 40% have duplex evidence ofcarotid artery disease.

Symptomatic peripheral vascular disease carries at least a30% risk of death within five years and almost 50% within 10years, primarily due to myocardial infarction (60%) or stroke(12%). The risks are more than doubled in patients with severedisease (requiring surgery), but even asymptomatic patients(ankle brachial pressure index < 0.9) have a twofold to fivefoldincreased risk of fatal or nonfatal cardiovascular events.

Although modification of risk factors has not been shown toprevent progression of peripheral vascular disease or loss oflimbs, detection of disease mandates an aggressive approach tomodifying risk factors in order to reduce the risk of fatal andnonfatal myocardial infarction and stroke. The approach torisk reduction in patients with peripheral vascular disease isbased on extrapolation from results of large studies of patientswith coronary artery disease.

Modification of risk factorsEffective reduction of the risk of cardiovascular disease dependson coordinated and stringent modification of identifiable riskfactors to prevent progression or new disease and the use ofdrugs to correct existing abnormalities. Stopping smoking,correction of hyperlipidaemia and hypertension, andoptimisation of diabetic control are the cornerstones ofsecondary prevention of cardiovascular disease. Lesser benefitsare also likely to accrue through weight reduction in obesepatients, the institution of regular exercise, and dietarymodification. Additional risk factors have been identified butare uncommon and their treatment is of unproved value.

Cigarette smokingCigarette smoking contributes to a third of all deaths fromcoronary artery disease, doubles the risk of stroke, and is almostubiquitous among patients with peripheral vascular disease.Synergy between smoking and other risk factors substantiallyincreases the risks of cardiovascular death associated with thesefactors. After a myocardial infarction or stroke, the risk ofrecurrence is reduced by 50% in those who stop smoking (evenamong long term heavy smokers). Firm evidence also exists thatstopping smoking increases walking distance by twofold tothreefold in 85% of patients with intermittent claudication.Furthermore, in patients requiring surgical bypass, patencyrates are better among those who successfully stop smoking.

Because as few as 4% of established smokers in the generalpopulation successfully stop smoking without assistance,measures to improve on this are essential in the secondary

All patients with peripheral vascular disease should havetheir risk factors for coronary artery disease assessed and,if appropriate, modified according to current guidelines

Risk factors for cardiovascular disease

x Cigarette smokingx Hyperlipidaemiax Hypertensionx Diabetes mellitusx Obesityx Physical inactivityx Diet high in saturated fatsx Hyperhomocysteinaemiax Raised Lp(a) lipoprotein concentrationsx Hypercoagulable states

Excised atherosclerotic plaque

Gum (46 studies)

χ2 = 54.5

Patch (30 studies)

χ2 = 34.33

Intranasal spray (46 studies)

χ2 = 1.22

Inhaler (4 studies)

χ2 = 1.34

Sublingual (2 studies)

χ2 = 0.1

1405/7235

1225/8929

107/448

84/490

49/243

1065/9247

458/7903

52/439

44/486

31/245

1.63 (1.48 to 1.78)

1.77 (1.58 to 1.97)

2.27 (1.61 to 3.20)

2.08 (1.43 to 3.04)

1.73 (1.07 to 2.80)

Study Experimental ControlPeto odds ratio

(95% CI)Peto odds ratio

Favours treatmentFavours control

0.1 0.2 1 5 10

Summary of results of metaanalysis of nicotine gum, patch, intranasal spray,and sublingual tablet versus control for stopping smoking. Maximum followup 612 months

Clinical review

1262 BMJ VOLUME 320 6 MAY 2000 bmj.com


prevention of cardiovascular disease. Modern smokers areclearly able to ignore punitive taxes and health warnings onpackaging. They respond better to short (510 minutes)counselling from doctors, particularly if they are recoveringfrom myocardial infarction (50% success rates). Rates ofstopping smoking have been increased to 70% by the additionof telephone based counselling.

Surprisingly, only half of current smokers in one study hadbeen encouraged to stop smoking, and fewer had beenspecifically counselled. Hospitals caring for patients withcardiovascular disease can help by offering supportprogrammes. The use of nicotine replacement (chewing gum orpatches), which is safe for patients with stable cardiovasculardisease, is effective when combined with counselling.

HyperlipidaemiaEpidemiological data clearly indicate an association betweentotal cholesterol concentration and the risk of cardiovasculardeath. Dietary measures may reduce serum cholesterol and lowdensity lipoprotein cholesterol concentrations by about 10%,but long term compliance is poor.

The use of statins (hydroxymethylglutaryl coenzyme Areductase inhibitors) to lower total and low density lipoproteincholesterol concentrations by 3040% reduces the risk ofcardiovascular death by up to 42% among patients youngerthan 70 years with established disease. The only statins licensedfor secondary prevention are simvastatin and pravastatin.Statins also reduce triglyceride concentrations. Patients withsevere dyslipidaemia require specialised treatment.

Although there are no published studies examining theeffect of lipid reduction in patients with isolated peripheralvascular disease, patients with peripheral disease are included asa subgroup in current large trials such as the heart protectionstudy and the Medical Research Council bezafibrate in patientswith lower extremity arterial disease (LEADER) trial study.Because of their high risk of ischaemic heart disease patientswith peripheral vascular disease who have a serum cholesterolconcentration over 5.5 mmol/l should be treated. All patientsshould therefore have their lipid concentrations measured evenif they do not require specific treatment for their peripheralvascular disease.

Diabetes mellitusThe adverse effect of diabetes on serum lipid concentrationsand the accelerated atheromatous process in diabetic patientsact synergistically with the result that 80% die of cardiovasculardisease. The atheromatous process particularly affects smallermore distal vessels, which makes surgical reconstruction moredifficult or impossible. Diabetic patients are therefore morelikely to require amputation than other patients with peripheralvascular disease. Modification of other risk factors is particularlyimportant in this population, and the absolute benefits ofreducing cholesterol concentration are likely to be greater indiabetic patients.

Poor glycaemic control in patients with type 2 diabetes isassociated with an increased risk of cardiovascularcomplications, but the value of tighter control in preventingmajor cardiac events remains unclear. However, tight glycaemiccontrol has beneficial effects on serum lipid concentrations, andthe DIGAMI (diabetes insulin glucose after myocardialinfarction) study showed that improved glycaemic controlbenefits patients after myocardial infarction. Careful attention to

Measures to encourage stopping smoking

x Public health educationx Taxesx Smoke free hospitals and workplacex Advice from doctorx Nurse case managersx Support groups and counsellingx Nicotine replacement therapy

Dietary modifications in hyperlipidaemia

x Reduce total fat intake ( < 30% of total energy)x Reduce saturated fat intake ( < 7% of energy) and substitute with

unsaturatesx Decrease dietary cholesterol intake ( < 200 mg/day)x Increase fibre intakex Moderate alcohol intakex Aim for ideal body mass index (2125)

Foot of diabetic patient with peripheral vascular disease

Clinical review



foot care is particularly important in diabetic patients withperipheral vascular disease.

HypertensionThe rationale for treating hypertension is largely based on itsadverse effects on the heart and cerebrovascular system.Conventional guidelines such as those produced by the secondworking party of the British Hypertension Society areapplicable to patients with peripheral vascular disease.Although it might seem preferable to use vasodilators inpatients with peripheral vascular disease, â blockers are safe ifthey are required to obtain adequate blood pressure control.

Specific therapeutic measures

DietObservational studies suggest that diets rich in fish, fruit,vegetables, and fibre but low in saturated fat may protect againstcardiovascular disease. Dietary supplementation with fish oil(which is rich in n3 polyunsaturated fatty acids) has recentlybeen shown to protect against cardiovascular death aftermyocardial infarction in a large trial, but other trials have failedto find such a benefit.

Vitamins and trace elements may also alter cardiovascularrisk through other mechanisms. Antioxidants (vitamins E andC) help prevent the oxidation of low density lipoproteincholesterol, which is a key step in the atherogenic process.Studies in patients with peripheral vascular disease have shownno specific benefits of antioxidants, but no large scale trials havebeen done.

Cardiovascular risk is independently related to plasmahomocysteine concentrations, and it has been proposed thatdietary supplementation with folic acid (which reduceshomocysteine concentrations) may aid in the primaryprevention of cardiovascular disease. However, no largeprospective trials have been done. Severehyperhomocysteinaemia ( > 10 ìmol/l), which may respond tovitamin supplementation, should be considered in patients withpremature atherosclerotic disease without other risk factors. Inthe absence of strong evidence for routine vitaminsupplementation, the most prudent approach is to recommenda balanced diet rich in fruit, vegetables, and whole grains.

ExercisePhysical rehabilitation programmes form an important part ofreducing the risk of cardiovascular disease. If no supervisedexercise programme is available, patients with intermittentclaudication should be advised to walk for an hour a day,pausing to rest whenever claudication pain develops. Thisresults in a 20200% improvement in walking distance.Although it has been suggested that repeatedischaemiareperfusion injury provoked by walking might havedeleterious systemic effects, regular exercise actually reducesconcentrations of serum inflammatory markers.

Antiplatelet therapyAspirin has been proved effective in the secondary preventionof cardiovascular events and death in patients with establishedatherosclerosis. Patients with peripheral vascular disease who donot have specific contraindications should receive 75 mg aspirindaily. The cost effectiveness of newer antiplatelet drugs remainsto be determined.

Further reading

x Bainton D, Sweetnam P, Baker I, Elwood P. Peripheral vasculardisease: consequence for survival and association with risk factors inthe Speedwell prospective heart disease study. Br Heart J1994;72:12832.

x Leng GC, Price JF, Jepson RG. Lipidlowering for lower limbatherosclerosis. In: Cochrane Library. Issue 4. Oxford: UpdateSoftware, 1999.

x Scottish Intercollegiate Guidelines Network. Lipids and the primaryprevention of coronary heart disease. SIGN 1999;40.

x Department of Health. Standing medical advisory statement on the useof statins. Leeds: DoH, 1997. (Circular EL (97) 41.)

x O’Brien E, Bouchier Hayes D, Fitzgerald D, Atkins N. The arterialorgan in cardiovascular disease: ADAPT (arterial diseaseassessment, prevention, and treatment) clinic. Lancet1998;352:17001.

x American Heart Association Writing Group. Optimal risk factormanagement in the patient after coronary revascularization.americanheart.org/Scientific/statements/1994/129401.html

x American Heart Association. Antioxidant consumption and risk ofcoronary heart disease: emphasis on vitamin C, vitamin E, and betacarotene. Circulation 1999; 99:5915.

A balanced diet rich in fruit, vegetables, and fish may protect againstcardiovascular disease

Clinical review



ConclusionAlthough individual specialties tend to treat arterial lesions inisolation, this approach ignores the real risk to patients from theeffects of the same disease on other vascular beds. Althoughsimple measures (diet, exercise, stopping smoking) may beadequate for some, the management of many patients iscomplex. Patients at high risk of cardiovascular disease are bestmanaged in an integrated fashion, and the concept of anarterial disease assessment, prevention, and treatment clinic toovercome the often haphazard management of risk factorsseems the best way forward. Precise risk can be determined byusing a computer program based on history, examination, andlaboratory results and a specific programme of modificationinstituted and monitored. This holistic approach to themanagement of cardiovascular disease is the best way tominimise the risk of disease progression and premature deathin patients with peripheral vascular disease.

The metaanalysis data on nicotine replacement therapy were takenfrom Silagy et al. Cochrane library. Issue 4. Oxford: Update Software,1999.

Sean Tierney is lecturer in surgery ([email protected]), Fiona Fennessyis a research fellow, and David Bouchier Hayes is professor of surgery,Beaumont Hospital, Dublin, Ireland.


BMJ 2000;320:12625

Prevention and treatment

Risk factor modification

Vascular surgeon Neurologist Ophthalmologist Cardiologist

Nephrologist Diabetologist Family doctor Hypertension clinic

Lipid clinic

ADAPT clinic

Risk factor assessmentLifestyle

Family history

Smoking

Alcohol

Salt intake

Obesity

Sedentary or active

Blood pressure

Urine analysis, fasting glucose and insulin

Fasting cholesterol, triglycerides, and high

and low density lipoprotein cholesterol

Thyroid function tests

Homocysteine*

Thrombophilia screen*

* Measure if peripheral vascular disease is

premature (patient under 50 years)

Target organ assessmentKidney

• Urine analysis (including microalbumin)

• Biochemistry (urea, creatinine,

electrolytes, urate)

• Haematology (haemoglobin, film, white

cell count)

Heart

• Electrocardiography (echocardiography,

stress test, and angiography selectively)

Brain

• Carotid duplex scan in symptomatic

patients

Arterial organ

• Funduscopy; when indicated, arterial

tonometry and biochemical analysis of

endothelial function

Arterial disease assessment, prevention, and treatment (ADAPT) clinics provide a common strategy for all patients with cardiovasculardisease regardless of target organ affected

The health benefits from collecting for Christian Aid

The World Health Organisation has defined health as a state ofphysical, mental, and social wellbeing, not merely the absence ofdisease. House to house collection of charity envelopes is aexercise that can be done in three health promoting rounds. Thefirst round is the mental health promotion exercise. Find andlocate the right roads and work out the shortest way to go roundthem. Should I do one side at a time or cross the road at strategicjunctions? Get the rules clear. Who does the corner house? Is itme or the unknown person who may be collecting from the otherroad? Should gates be left open or shut and what do I do aboutthose dogs? Then how do I respond to the little notice as I walk toa front door that says, “You are being photographed”? Should Ibrush my remaining hair and try to look suitably smart or covermy face and run past? The next brain teaser is searching for letterboxes, the variation in letter box locations is truly amazing. Idiscover that a doctor who I know professionally has no letterbox; it is a good way of avoiding unwanted junk mail or bills.

Next on the list is physical exercise. This combines the walkround with door bell hunting, door hammering, and being ableto beat a smart retreat when appropriate. It is also good exercisein being rejected, lectured at—“charity begins at home” or “ifthose lazy so and soes would do some work they would not needany charity”—or being welcomed by someone with a promptlyopened door, a smile, and the envelope ready. With a bit of luckthere is some weight lifting before the end as the collected

envelopes begin to weigh you down. A five pound note does notweigh too much but 2p coins and 20 large washers do.

Social exercise comes with the last round. It is part of the rulesof the game that envelopes should be opened and counted by atleast two people. A good neighbour comes across the road. Teaand talk as the piles of coins grow. Foreign coins and otherextraneous objects go to one side. Counting pennies into the littleplastic bags is a skill that should be easy, but even easier to getwrong. Counting done and the tea drunk. Was it worth it? Am Iany healthier as a result? I hope so, but it has informed me of thegreat generosity of many people who live in this area; and whatother form of exercise can be so beneficial for those namelessones far away whose health may depend on the money raised?

Martin Schweiger consultant in communicable disease control, Leeds


Clinical review



ABC of arterial and vascular diseaseVasculitisC O S Savage, L Harper, P Cockwell, D Adu, A J Howie

Vasculitis is inflammation of blood vessel walls. The clinical andpathological features are variable and depend on the site andtype of blood vessels that are affected. Diseases in whichvasculitis is a primary process are called primary systemicvasculitides.

The main types of vasculitides can be described usingclinical features and pathological findings according to theChapel Hill Consensus Conference. These names anddefinitions will be followed in this article. Definitive classificationof systemic vasculitis is unsatisfactory since aetiology andpathogenesis are rarely known, and clinical and histologicalfeatures overlap. Vasculitis may also occur as a secondaryfeature in other diseases, such as systemic lupus erythematosusand rheumatoid arthritis.

Fever, night sweats, malaise, myalgia, and arthralgia arecommon in all types of vasculitis. Active vasculitis is usuallyassociated with an acute phase response with an increase in Creactive protein concentration, erythrocyte sedimentation rate,or plasma viscosity.

Large vessel vasculitisGiant cell arteritis (temporal arteritis)Clinical features include unilateral throbbing headache, facialpain, and claudication of the jaw when eating. Visual loss is afeared symptom and may be sudden and painless, affecting partor all of the visual field. Diplopia may also occur. Giant cellarteritis is the most common type of primary systemic vasculitiswith an incidence of 200/million population/year.

Treatment is with high dose corticosteroids (4060 mg/day),which should be started as soon as the diagnosis is suspected toavoid visual loss. The diagnosis is confirmed by biopsy of theaffected artery, done within 24 hours of starting corticosteroids.The corticosteroid dose may be reduced to 10 mg/day over sixmonths and then more slowly to a maintenance of510 mg/day. Maintenance treatment may be required for twoyears. The disease is monitored by measuring C reactive proteinconcentrations, erythrocyte sedimentation rate, or plasmaviscosity.

Takayasu’s arteritisTakayasu’s arteritis is most common in Asia and the Far Eastand affects women more than men. Disease of the arteriessupplying the arms, head, neck, and heart leads to the aorticarch syndrome with claudication of the arm, loss of arm pulses,variation in blood pressure of more than 10 mm Hg betweenthe arms, arterial bruits, angina, aortic regurgitation, syncope,stroke, and visual disturbance. The descending aortic syndromemay cause bowel ischaemia or infarction, renovascularhypertension, and renal impairment.

Diagnosis is by angiography or magnetic resonanceangiography. Treatment of acute disease in patients with high Creactive protein concentration or erythrocyte sedimentationrate is with corticosteroids. Cytotoxic drugs such ascyclophosphamide can be added if steroids alone do notcontrol the disease. Surgery or angioplasty may be required forstenoses once active inflammation has been controlled.

Definitions of large vessel vasculitis

Giant cell arteritis (temporal arteritis)x Granulomatous arteritis of aorta and its major branches, especially

extracranial branches of carotid arteryx Often affects temporal arteryx Usually occurs in patients older than 50 yearsx Often associated with polymyalgia rheumatica

Takayasu’s arteritisx Granulomatous inflammation of aorta and its major branchesx Usually occurs in patients younger than 50 years

Temporal artery biopsy specimen with giant cell inflammation

Aorta (large artery)

Renal artery (medium sized artery)

Giant cell (temporal) arteritis

and Takayasu's arteritis

Polyarteritis nodosa andKawasaki disease

Microscopic polyangiitis, Wegener's granulomatosis and

Churg-Strauss syndrome

Henoch Schönlein purpura, essentialcryoglobulinaemic vasculitis and antiglomerularbasement membrane antibody mediated disease

Lobar artery (medium sized artery)

Arcuate artery (small artery)

Interlobular artery(small artery)

Arteriole

Glomerulus

Spectrum of systemic vasculitides organised according to predominant size ofvessels affected (adapted from Jennette et al, Arthritis Rheum 1994;37:18792)

0

9 da

ys b

efor

e

treat

men

t

Diagno

sis and

treat

men

t12

day

s

21 d

ays

27 d

ays

40 d

ays

100

150

200

250

300

C reactive protein (mg/l)Treatment with

immunosuppression

50

Erythrocyte sedimentation rate (mm/h)

C reactive protein concentration (>10 mg/l) and erythrocyte sedimentationrate (>18 mm/h) are raised at time of diagnosis of giant cell arteritis but fallto normal levels after starting immunosuppressant therapy

Clinical review



Medium vessel vasculitisPolyarteritis nodosaPolyarteritis nodosa is uncommon in the United Kingdom. It isassociated with hepatitis B virus in some patients. Arterial diseaseleads to ischaemia or infarction within affected organs. Thecondition can affect the gut causing bleeding or perforation, theheart causing angina or myocardial infarction, the kidneyscausing cortical infarcts leading to hypertension and renal failure,and the peripheral nerves causing mononeuritis multiplex.Hepatitis may reflect the presence of hepatitis B virus.

Diagnosis is based on the presence of arterial aneurysms onangiography of the renal, hepatic, splanchnic, or spleniccirculations. Biopsy of affected muscle or nerve may confirm thepresence of vasculitis. Treatment of polyarteritis associated withhepatitis B virus requires an antiviral drug such as interferonalfa combined with short course, high dose corticosteroids andplasma exchange. Nonhepatitis B virus polyarteritis usuallyresponds to corticosteroids alone, although cyclophosphamidemay be required for patients with more severe disease.

Kawasaki diseaseKawasaki disease affects children, usually under the age of 12years. In Japan the incidence exceeds 100/100 000 childrenyounger than 5 years but is less than 5/100 000 in this agegroup in the United Kingdom.

The most serious feature of Kawasaki disease is coronaryartery disease; aneurysms occur in a fifth of untreated patientsand may lead to myocardial infarction. They can be detected byechocardiography. High dose intravenous immunoglobulinsreduce the prevalence of coronary artery aneurysms, providedthat treatment is started within 10 days of onset of the disease.Low dose aspirin is recommended for thrombocythaemia.

Small vessel vasculitis associated withantineutrophil cytoplasmic antibodySmall vessel vasculitides are being recognised more frequently,mainly because of increased awareness. Estimates of incidencehave increased from fewer than 5 cases per million population inthe early 1980s to over 20 per million. The early symptoms ofthese disorders are nonspecific with fever, malaise, arthralgia,myalgia, and weight loss, and patients in whom such symptomsare persistent should be screened for antineutrophil cytoplasmicantibodies (ANCA); have their erythrocyte sedimentation rateand C reactive protein concentration measured; and have theirurine tested for blood with a dipstick. Early diagnosis is essentialto prevent potentially life threatening renal and pulmonaryinjury. Delays in diagnosis are unfortunately common, and thisoften leads to serious morbidity. Once respiratory or renal diseasedevelops, the course is usually rapidly progressive.

Wegener’s granulomatosisUpper respiratory tract disease occurs in more than 90% of casesand includes sinusitis; nasal crusting, bleeding, obstruction, andcollapse of the nasal bridge; serous otitis media with conductivedeafness; and tracheal stenosis. Limited Wegener’s refers todisease that affects only the respiratory tract at the time ofdiagnosis; many cases evolve to systemic disease. Lung disease iscommon with cough, haemoptysis, and dyspnoea and mayprogress to life threatening pulmonary haemorrhage. Thekidneys are affected in up to 80% of cases; blood, protein, andcasts are present in the urine and should be examined by dipsticktesting and microscopy. If untreated, there is loss of renalfunction, often within days. Other features include purpuricrashes, nail fold infarcts, and ocular manifestations including

Definitions of medium sized vessel vasculitis

Polyarteritis nodosax Necrotising inflammation of medium and small arteries without

glomerulonephritis, pulmonary capillaritis, or disease of otherarterioles, capillaries, or venules

Kawasaki diseasex Arteritis affecting large, medium, and small arteries and associated

with mucocutaneous lymph node syndromex Coronary arteries are usually affected and aorta and veins may be

affectedx Usually occurs in children

Features of mucocutaneous lymph node syndrome inKawasaki disease

x Fever for > 5 daysx Conjunctival congestionx Changes to lips and oral cavity: dry, red, fissured lips; strawberry

tongue; reddening of oral and pharyngeal mucosax Changes of peripheral extremities: red palms and soles; indurative

oedema; desquamation of finger tips during convalescencex Macular polymorphous rash on trunkx Swollen cervical lymph nodesAt least five features must be present

Definitions for diagnosis of vasculitides often associated withantineutrophil cytoplasm antibodies

Wegener’s granulomatosisx Granulomatous inflammation of the respiratory tractx Necrotising vasculitis affecting small to medium sized vessels

(capillaries, venules, arterioles, and arteries)x Necrotising glomerulonephritis is common

Microscopic polyangiitis (microscopic polyarteritis)x Necrotising vasculitis with few or no immune deposits affecting

small vessels (capillaries, venules, arterioles, and arteries)x Necrotising arteritis of small and medium sized arteries may be

presentx Necrotising glomerulonephritis very commonx Pulmonary capillaritis often occurs

ChurgStrauss syndromex Eosinophil rich and granulomatous inflammation of respiratory tractx Necrotising vasculitis affecting small to medium sized vesselsx Blood eosinophilia ( > 1.5 × 109/l )x Usually associated with asthma

Renal angiogram showing multiplearterial aneurysms

Clinical review



conjunctival haemorrhages, scleritis, uveitis, keratitis, proptosis, orocular muscle paralysis due to retroorbital inflammation. Thedisease can affect the gut causing haemorrhage, the heart causingcoronary artery ischaemia, and the neurological system causingsensory neuropathy or mononeuritis multiplex.

The two pathological hallmarks of Wegener’s disease arechronic granulomatous inflammation and vasculitis. Granulomas(localised microscopic collections of macrophages) are not alwayspresent. Granulomas in the lung may coalesce into large masseswhich cavitate. The vasculitis affects capillaries particularly in thelung, causing lung haemorrhage, and glomeruli, causingglomerulonephritis that may be segmental, global, focal, or diffusewith thrombosis, necrosis of capillary loops, and accumulation ofcells in Bowman’s space. Affected arteries or arterioles show aninflammatory infiltrate and fibrinoid necrosis. There is nodeposition of immunoglobulins within the kidney or vessel walls.

Microscopic polyangiitis (microscopic polyarteritis)Microscopic polyangiitis has many similarities to Wegener’sgranulomatosis, but disease of the upper respiratory tract isuncommon in microscopic polyangiitis, although pulmonaryhaemorrhage may occur. Patients with microscopic polyangiitisusually have glomerulonephritis, and, rarely, disease may belimited to the kidney. No granuloma formation is seen.

DiagnosisDiagnosis is based on typical clinical features, biopsy (usually ofkidney, occasionally of nasal mucosa or lung) and presence ofantineutrophil cytoplasmic antibodies. These antibodies usuallyhave specificity for the enzymes proteinase3 or myeloperoxidaseand can be detected by enzyme linked immunosorbent assay(ELISA). In indirect immunofluorescence tests, antineutrophilcytoplasmic antibodies against proteinase3 produce acytoplasmic staining pattern (cANCA) and antibodies againstmyeloperoxidase produce perinuclear staining pattern (pANCA).Combined testing by ELISA and indirect immunofluorescence isrecommended as this increases specificity at the cost of a 10%reduction of sensitivity. Sometimes antineutrophil cytoplasmicantibody tests are negative, particularly if disease is limited to theupper respiratory tract. Antibody titres usually fall and maydisappear completely when the disease is in remission.

TreatmentTreatment of Wegener’s granulomatosis and microscopicpolyangiitis comprises induction of remission and thenmaintenance of remission. Multicentre trials are in progress toassess the place of pulse cyclophosphamide, plasma exchange,and methylprednisolone in treatment and to assess theoptimum duration of maintenance therapy. Methotrexate issometimes used instead of cyclophosphamide for patients withno renal disease. Relapses occur in 4050% of patients duringthe first five years, so lifelong monitoring for recurring diseaseactivity is essential. The five year survival rate is over 80%.

ChurgStrauss syndromeChurgStrauss syndrome is associated with an atopic tendency,usually asthma. It may affect coronary, pulmonary, cerebral, andsplanchnic circulations. Rashes with purpura, urticaria, andsubcutaneous nodules are common. Glomerulonephritis maydevelop, but renal failure is uncommon.

Diagnosis depends on presence of typical clinical features,biopsy of skin, lung, and kidney, and blood eosinophilia. About25% of patients are positive for cANCA, 50% for pANCA, and25% have no antineutrophil cytoplasmic antibodies.

Many patients respond to high dose corticosteroids alone,although cyclophosphamide may be required for patients with

Specificity and sensitivity of ANCA serology testing forWegener’s granulomatosis and microscopic polyangiitis(adapted from Hagen et al, Kidney Int 1998;53:74353)

Specificity/

sensitivity (%)

Specificity of assays (related to disease controls)

Indirect immunofluorescence:

cANCA 95

pANCA 81

ELISAs:

PR3ANCA 87

MPOANCA 91

Combined indirect immunofluorescence and ELISA:

cANCA/PR3ANCA positive 99

pANCA/MPOANCA positive 99

Sensitivity of combined testing

Wegener’s granulomatosis 73

Microscopic polyangiitis 67

Treatment of small vessel vasculitis

Induction therapy (to 3 months after remission, usually 6 monthsfrom diagnosis)x Cyclophosphamide, 2.0 mg/kg/day (maximum 200 mg/day). Age

> 60 years, reduce dose by 25%, > 75 years by 50%x Prednisolone, 1 mg/kg/day (maximum 80 mg/day) reduced weekly

to 25mg/day by 8 weeks and then more slowly to 10 mg/day by 6months

In severe, life threatening disease (eg, pulmonary haemorrhage, severecrescentic glomerulonephritis with creatinine > 500 ìmol/l), considerplasma exchange, 710 treatments over 14 days, or three pulses ofmethylprednisolone, 15 mg/kg/day for 3 days

Maintenance therapy (to 1824 months, longer if clinically indicated)x Azathioprine, 2.0 mg/kg/day (maximum 200 mg/day). Age > 60

years, reduce dose by 25%, > 75 years by 50%x Prednisolone, 510 mg/day

Relapse therapyx Major relapse: return to induction therapyx Minor relapse: increase dose of corticosteroidsStop cyclophosphamide or azathioprine if white blood count 4x109/l;restart with a dose reduced by at least 25 mg when white bloodcount > 4x109/l on two consecutive testsConsider gastric and bone protection, and fungal and Pneumocystiscarinii prophylaxis

Cavitating granulomatous lesion in right lung of patient withWegener’s granulomatosis

Clinical review



more severe disease. Asthma requires conventional treatmentbut the recently introduced leukotriene receptor antagonistdrugs have been causally linked with the ChurgStrausssyndrome and should be avoided in these patients.

Small vessel vasculitis withoutantineutrophil cytoplasmic antibodiesHenochSchönlein purpuraHenochSchönlein purpura is most common in children butcan occur at any age. Typical clinical features are purpura overthe lower limbs and buttocks, haematuria, abdominal pain,bloody diarrhoea, and arthralgia.The pathological hallmarksare deposition of immunoglobulin A at the dermoepidermaljunction and within the glomerular mesangium, with amesangial hypercellular glomerulonephritis. Some patientsdevelop a glomerular lesion resembling that seen in small vesselvasculitis. Renal disease may occur without the rash or othertypical features.

The disease is usually self limiting and only supportivetreatment is required. Corticosteroids and immunosuppressionmay be needed for vasculitic glomerulonephritis or serious guthaemorrhage and ischaemia.

Cryoglobulinaemic vasculitis (“mixed, essential”)Cryoglobuins are immunoglobulins that precipitate in the cold.The mixed cryoglobulin consists of a monoclonalimmunoglobulin M rheumatoid factor complexed to polyclonalimmunoglobulin G. Vasculitis develops when cryoglobulinsdeposit in blood vessels. Mixed essential cryoglobulinaemia isdue to hepatitis C virus infection in over 80% of cases. Othercauses of cryoglobulinaemia include dysproteinaemias,autoimmune diseases, and chronic infections. Serumcomplement C4 and C3 concentrations are reduced. Clinicalfeatures include palpable purpura, arthralgia, distal necroses,peripheral neuropathy, abdominal pain, andglomerulonephritis. Renal biopsy specimens typically have theappearance of subendothelial membranoproliferativeglomerulonephritis with intraglomerular deposits.

In cryoglobulinaemia associated with hepatitis C, treatmentis directed at the viral infection. Interferon alfa over six monthsis beneficial, but many patients relapse when treatment isstopped. Prednisolone with or without immunosuppressantshas been used successfully in acute severe disease. The role ofplasma exchange remains unsubstantiated.

Isolated cutaneous leukocytoclastic vasculitisThis is often associated with a drug hypersensitivity responseand improves when the drug is stopped. Occasional patientsmay require corticosteroids for severe disease.

Antiglomerular basement membrane antibody mediateddisease (Goodpasture’s disease)No Chapel Hill definition exists for this rare disease, which hasconsiderable overlaps with antineutrophil cytoplasmic antibodyassociated vasculitis. The hallmarks are a rapidly progressiveglobal and diffuse glomerulonephritis, as seen in small vesselvasculitides, or presence of pulmonary haemorrhage, or both.Diagnosis depends on finding antibodies to glomerularbasement membrane in the serum and linear staining forimmunoglobulin G along the glomerular basement membrane.The antibodies have been implicated in disease pathogenesis.About 1530% of patients have detectable antineutrophilcytoplasmic antibodies. Treatment is as for small vessel vasculitiswith addition of daily plasma exchange until antiglomerularbasement membrane antibodies are no longer detectable.

Definitions of nonANCA associated small vessel vasculitis

HenochSchönlein purpurax Vasculitis with IgA dominant immune deposits affecting small

vessels (capillaries, venules, or arterioles)x Affects skin, gut, and glomerulix Associated with arthralgia or arthritis

Cryoglobulinaemic vasculitisx Vasculitis with cryoglobulin immune deposits affecting small vesselsx Associated with cryoglobulins in serumx Skin and glomeruli often affected

Isolated cutaneous leukocytoclastic vasculitisx Isolated cutaneous leukocytoclastic angiitis without systemic

vasculitis or glomerulonephritisx May evolve into systemic vasculitis

C O S Savage is professor of nephrology, University of Birmingham; LHarper is specialist registrar, P Cockwell is consultant physician, andD Adu is consultant physician, Queen Elizabeth Hospital,Birmingham; and A Howie is reader in renal pathology, University ofBirmingham.


BMJ 2000;320:13258

Purpuric rash on lower limb of patient with HenochSchönlein purpura

Renal biopsy specimen showing intraglomerular deposit of cryoglobulins

Clinical review



ABC of arterial and venous diseaseVaricose veinsNick J M London, Roddy Nash

Varicose veins are tortuous, twisted, or lengthened veins. Unlessthe enlargement is severe, size alone does not indicateabnormality because size can vary depending on ambienttemperature and, in women, hormonal factors. In addition,normal superficial veins in a thin person may appear large,whereas varicose veins in an obese person may be hidden.Varicose veins can be classified as trunk, reticular, ortelangiectasia. Telangiectasia are also referred to as spider veins,star bursts, thread veins, or matted veins. Most varicose veins areprimary; only the minority are secondary to conditions such asdeep vein thrombosis and occlusion, pelvic tumours, orarteriovenous fistulae.

Incidence and prevalenceA study of people aged 35 to 70 years in London in 1992concluded that the prevalence of varicose veins in men andwomen was 17% and 31% respectively. Although varicose veinshave traditionally been considered commoner in women, arecent study from Edinburgh of people aged 18 to 64 yearsfound that the prevalence of trunk varices was 40% in men and32% in women. Over 80% of the total population had reticularvaricosities or telangiectasia. There are few studies on theincidence of varicose veins; however, the Framingham studyfound that the two year incidence of varicose veins was39.4/1000 for men and 51.9/1000 for women.

Pathophysiology and risk factorsThe theory that varicose veins result from failure of valves inthe superficial veins leading to venous reflux and vein dilatationhas been superseded by the hypothesis that valve incompetencefollows rather than precedes a change in the vein wall. Thus, thevein wall is inherently weak in varicose veins, which leads todilatation and separation of valve cusps so that they becomeincompetent. This theory is strongly supported by theobservation that the dilatation of varicose veins is initially distalto the valve; if the primary abnormality was descending valveincompetence, the initial dilatation should be proximal to thevalve.

Risk factors for varicose veins include increasing age andparity and occupations that require a lot of standing. There isno evidence that social class, smoking, or genetic makeupinfluence the prevalence of varicose veins. Obesity is associatedwith the development of varicose veins in women but not inmen.

SymptomsThe Edinburgh vein study recently compared the prevalence ofsymptoms in men and women with and without varicose veins.In men, the only symptom that was significantly associated withtrunk varices was itching, whereas in women, heaviness ortension, aching, and itching were significantly associated withtrunk varices. No association was found between reticularvarices and lower limb symptoms in either men or women.

Symptoms associated with varicose veins

x Heavinessx Tensionx Achingx Itching

Trunk varices are varicosities in the line of the long (top, left) or short (top,right) saphenous vein or their major branches. Reticular veins (arrow,bottom) are dilated tortuous subcutaneous veins not belonging to the mainbranches of the long or short saphenous vein, and telangiectasia (bottom)are intradermal venules <1 mm

Clinical review



Complications of varicose veinsSome complications of varicose veins, such as haemorrhageand thrombophlebitis, result from the varicose veins themselves,whereas others, such as oedema, skin pigmentation, varicoseeczema, atrophie blanche, lipodermatosclerosis, and venousulceration result from venous hypertension. The size of varicoseveins does not seem related to the degree of venoushypertension. Indeed, 40% of limbs with ulceration due tosuperficial venous incompetence do not have visible varicoseveins. Venous ulceration is discussed in a subsequent article.

Recurrent varicose veinsIn the United Kingdom, about 20% of varicose vein surgery isfor recurrence, and the estimated annual cost of such surgery is£11m. Recurrent varicose veins can result from inadequate ordefective primary surgery or the development of new sites ofreflux. Improved patient assessment and more rigorous primarysurgery should reduce the socioeconomic impact of recurrentvaricose veins.

Clinical management

HistoryIt is important to determine precisely why the patient hassought treatment. One third of patients presenting with varicoseveins have symptoms unrelated to their varicose veins or areworried about deterioration or complications. Such patientssimply need reassurance. It is important to determine whetherthe patient has had deep vein thrombosis or thrombophlebitisand any family history of deep vein thrombosis. History of theseconditions increases the risk of deep vein thrombosis aftervaricose vein surgery and may lead to a decision not to operate.Patients with a history of deep vein thrombosis orthrombophlebitis who have surgery should receiveperioperative subcutaneous heparin prophylaxis. It is importantto note whether women are taking the contraceptive pill orhormone replacement therapy. Any history of skin changes isalso important because affected patients are at high risk ofdeveloping ulceration.

Examination and investigationExamination of the patient should include an abdominalexamination to exclude some of the secondary causes ofvaricose veins. With the patient standing, note the distributionof the varicose veins, in particular whether they are long orshort saphenous, or both. Secondary skin changes should benoted. Most vascular surgeons would then investigate thepatient in the clinic using handheld Doppler or colour duplexscanning. Although ideally all patients presenting with varicoseveins would have colour duplex scanning, the NHS does nothave the resources to allow this. Patients with recurrent varicoseveins should be scanned to determine the precise site ofrecurrence. Patients with varicose veins in limbs with a historyof deep vein thrombosis or thrombophlebitis should bescanned to make sure that the superficial veins are not acting ascollaterals in the presence of deep vein obstruction. Scanning isalso essential for patients with venohypertensive skin changes. Ifthe deep veins are competent in the presence of refluxingsuperficial veins, superficial venous surgery is potentiallycurative.

TreatmentAs discussed above, about a third of patients presenting withvaricose veins will require only reassurance or explanation that

Complications of varicose veins

x Haemorrhagex Thrombophlebitisx Oedemax Skin pigmentationx Atrophie blanchex Varicose eczemax Lipodermatosclerosisx Venous ulceration

Indications for colour duplex scanning of varicose veins

x Recurrent varicose veinsx History of superficial thrombophlebitisx History of deep venous thrombosisx Varicose eczemax Haemosiderin stainingx Lipodermatosclerosisx Venous ulceration

Saphenousvein

Deep outflowtract

Deep (pump)compartment

Superficialcompartment

Mechanisms of failure of calf muscle pump and venous hypertenion.Superficial veins do not normally allow reflux of blood (left). However, ifsuperficial veins are incompetent (right), some of the blood ejected by thecalf muscle pump during systole refluxes back down the superficial veinsinto the calf muscle pump during diastole. This retrograde circuit canoverload the calf muscle pump, leading to dilatation and failure. Thesubsequent rise in end diastolic volume leads to venous hypertension.Adapted from Browse et al

Thrombophlebitis presents as severe pain, erythema, pigmentation over, andhardening of the vein. Thrombophlebitis in varicose veins results from stasis,whereas thrombophlebitis occurring in normal veins should alert cliniciansto the possibility of an underlying malignancy or thrombophilia. Recurrentthrombophlebitis in varicose veins raises the possibility of underlyingthrombophilia

Clinical review



their symptoms are not related to their varicose veins. Patientswhose main symptoms are aching or oedema may benefit fromcompression hosiery. Indeed, if it is uncertain whether thepatient’s symptoms are caused by varicose veins, a trial ofcompression hosiery may help; a response to compressionindicates that surgery may be beneficial.

The treatment options for trunk varices are injectionsclerotherapy or surgery. The use of injection sclerotherapy fortrunk varices has fallen in recent years, partly because ofconcerns about complications such as skin staining andulceration and also because up to 65% of patients treated bysclerotherapy develop recurrent varicose veins within five years.Currently, sclerotherapy is most commonly used to treatresidual varicosities after surgery. Surgery is generally directedat the underlying abnormality, in the form of saphenofemoralor saphenopopliteal disconnection, and in the case of longsaphenous varices, stripping of the long saphenous vein withmultiple avulsions.

Many patients can be treated as day cases, most can returnto driving after one week, and the time off work varies betweenone and three weeks depending on the patient’s occupation.The risk of serious complication (deep venous thrombosis,pulmonary embolism, or arterial or nerve injury) is less than1%, but roughly 17% of patients will suffer minor complications,most commonly temporary saphenous or sural nerve neuralgia.All patients should be warned of this possibility. After surgery,2030% of patients develop recurrent varicose veins within 10years.

Reticular varices are not connected to major trunk varicesand are treated by sclerotherapy or avulsion through small stabincisions. Patients who present with capillary telangiectasiashould have colour duplex scanning because roughly 25% willhave clinically unapparent long or short saphenousincompetence. The telangiectasia are treated by microinjections,laser, or high intensity light. The last two methods are beingincreasingly used.

Management of complications

ThrombophlebitisThere is no indication for antibiotics in patients withthrombophlebitis. Patients should be referred to a vascularspecialist and surgery considered because thrombophlebitistends to recur if the underlying venous abnormality is notcorrected. Colour duplex studies have shown that up to aquarter of patients with superficial thrombophlebitis haveunderlying deep venous thrombosis, and it has therefore beensuggested that all patients with thombophlebitis should haveduplex scanning to exclude deep vein thrombosis. However, amore realistic suggestion is that patients with phlebitisextending up the long saphenous vein towards thesaphenofemoral junction should have urgent duplex scanning.If the thrombus extends into the femoral vein, urgentsaphenofemoral ligation should be considered.

Bleeding varicose veinsBleeding varicose veins can be stemmed by raising the footabove the level of the heart and applying compression. Thepatients should then be seen by a vascular surgeon with a viewto correcting the underlying abnormality. If the deep veins areincompetent, the patient should wear compression hosiery.

Varicose eczema, lipodermatosclerosis, and venous ulcerationPatients with varicose eczema or lipodermatosclerosis requirecolour duplex scanning to define the underlying venous

Management of thrombophlebitis

x Crepe bandaging to compress vein and minimise propogation ofthrombus

x Analgesia (preferably nonsteroidal antiinflammatory drug)x Low dose aspirin

One of the complications of injection sclerotherapy is brown skinpigmentation (arrows)

Skin pigmentation is due tohaemosiderin deposition. This patientalso has thrombophlebitis of the longsaphenous vein with overlyingpigmentation (arrow)

Varicose eczema occurs over prominent varicoseveins and in the lower third of the leg. It may bedry, scaly, and vesicular or weeping and ulcerated

Clinical review



abnormality. Generally, if the only abnormality is superficialvenous incompetence this should be surgically corrected. If,however, the deep veins are incompetent, then superficialsurgery will not help and the patient should be treated with atopical steroid and wear compression hosiery.

Areas of controversyWhose varicose veins should be treated?In the absence of clear national guidelines the decision aboutwho should receive varicose vein surgery under the NHS isbeing made at a local level. In general terms patients with onlycosmetic problems are not treated whereas patients with skinchanges (eczema, lipodermatosclerosis, and ulceration) aretreated. The most controversial group is patients withsymptomatic trunk varices and no skin changes. Unfortunately,there is no way of predicting which limbs with varicose veinswill subsequently develop venous ulceration, and it is clearly notsensible to operate on the 30% of the population with varicoseveins in order to prevent 1% developing an ulcer.

Varicose veins, deep vein thrombosis, contraceptive pill, andhormone replacement therapyAlthough varicose veins increase the risk of deep vein thrombosisafter major abdominal or orthopaedic surgery, there is noevidence that primary varicose veins are a risk factor forspontaneous deep vein thrombosis. Similarly, there is no evidencethat women with varicose veins who take the contraceptive pill orhormone replacement therapy are at increased risk of deep veinthrombosis compared with women without varicose veins.Evidence exists, however, that women with varicose veins whotake the pill are more likely to develop thrombophlebitis; ahistory of thrombophlebitis is therefore a contraindication to thepill and a reason for stopping the pill in current takers. Althoughnot evidence based, the same considerations should probablyapply to hormone replacement therapy.

Varicose vein surgery, contraceptive pill, and hormonereplacement therapyAlthough there is no evidence that varicose vein surgery is highrisk for deep vein thrombosis, women taking the combinedcontraceptive pill or hormone replacement therapy are atincreased risk of deep vein thrombosis after varicose vein surgery.Women taking the combined contraceptive pill should either stopthe pill four weeks before surgery and restart two weeks later orreceive subcutaneous heparin prophylaxis. If the pill is stoppedadvice must be given about alternative contraception. Womentaking hormone replacement therapy should continue taking itand receive heparin thromboprophylaxis.

Further reading

x Franks PJ, Wright DD, Moffatt CJ, Stirling J, Fletcher AE, Bulpitt CJ,et al. Prevalence of venous disease: a community study in WestLondon. Eur J Surg 1992:158:1437.x Brand FN, Dannenberg AL, Abbott RD, Kannell WB. Theepidemiology of varicose veins: the Framingham study. Am J Prev Med1988;4:96101.x Bradbury A, Evans C, Allan P, Lee A, Ruckley CV, Fowkes FGR.What are the symptoms of varicose veins? Edinburgh vein study crosssectional population survey. BMJ 1999;318:3536.x Campbell B. Thrombosis, phlebitis, and varicose vein surgery. BMJ1996;312:1989.x Royal College of General Practitioners’ oral contraception study:oral contraceptives, venous thrombosis, and varicose veins. J R CollGen Pract 1978;28:3939.x Drugs in the perioperative period: 3—Hormonal contraceptivesand hormone replacement therapy. Drug Ther Bull 1999;37:7880.x Tibbs DJ. Varicose veins and related disorders. Oxford:ButterworthHeinemann, 1992.x Tibbs DJ, Sabiston DC, Davies MG, Mortimer PS, Scurr JH. Varicoseveins, venous disorders, and lymphatic problems in the lower limbs. Oxford:Oxford University Press, 1997.x Ruckley CV, Fowkes FGR, Bradbury AW. Venous disease. London:SpringerVerlag, 1998.x Browse NI, Burnand KG, Irvine AT, Wilson NM. Diseases of the veins.London: Arnold, 1999.

Roddy Nash is consultant surgeon at Derbyshire Royal Infirmary,Derby. The ABC of arterial and venous disease is edited by RichardDonnelly, professor of vascular medicine, University of Nottinghamand Southern Derbyshire Acute Hospitals NHS Trust(richard.donnelly@ nottingham.ac.uk) and Nick J M London,professor of surgery, University of Leicester, Leicester([email protected]). It will be published as a book later this year.

BMJ 2000;320:13914

Varicose veins withcomplications

Uncomplicated trunk varicose veins

Reticular veins and telangiectasia

High priority

Medium priority

Low priority

Demand management. High priority cases should be refered for vascularassessment. Many regions are not offering NHS treatment for medium andlow priority cases on the basis that resources are needed more for otherconditions

One hundred years ago

Ophthalmology in Spain

Many travellers in Spain have been struck by the number of blindpersons everywhere met with. Dr. Camuset, writing in 1874, saidthat the streets of the large towns literally swarm with blind folk.They go about in bands of five or six, begging, and rolling abouttheir sightless orbs to excite compassion. For the most part theblindness is caused by purulent ophthalmia or affections of thecornea consecutive to granular ophthalmia. A few years later Dr.Vignes in a trip to San Sebastian saw a number of cases ofgranular ophthalmia and many of keratitis, which he attributed tothe bad food and filthy habits of life of the inhabitants of thewhole province of Guypuzcoa. Professor Hirschberg, of Berlin,

who was present at the International Congress of Hygiene held inMadrid in 1897, bore emphatic witness to the prevalence of eyediseases in Spain. Nowhere, not even in Egypt, had he met with somany blind persons as in Spain; among other instances hementioned that he had seen a band of musicians consisting ofnine blind men. He attributed this state of things to the neglect ofophthalmology in Spain, where he said there was not a singleprofessor of the subject in any of the medical schools. He addedthat there was no public institute for the treatment of diseases ofthe eye, and that such cases were treated either in the generalhospitals or in small private institutions. (BMJ 1900;ii:947)

Clinical review



ABC of arterial and venous diseaseSwollen lower limb—1: General assessment and deep vein thrombosisW Peter Gorman, Karl R Davis, Richard Donnelly

The most common cause of leg swelling is oedema, butexpansion of all or part of a limb may be due to an increase inany tissue component (muscle, fat, blood, etc). A correctdiagnosis requires consideration of whether the swelling is acuteor chronic, symmetrical or asymmetrical, localised orgeneralised, and congenital or acquired. Chronic swelling,particularly if asymmetrical, is usually a sign of chronic oedemaarising from venous or lymphatic disease, whereas symmetricallower limb swelling suggests a systemic or more central cause ofoedema, such as heart failure or nephrotic syndrome. Oedemadevelops when the rate of capillary filtration (lymph formation)exceeds lymphatic drainage, either because of increasedcapillary filtration, inadequate lymphatic flow, or both.Extracellular fluid volume is controlled prinicpally by thelymphatic system, which normally compensates for increases incapillary filtration. Most oedemas arise because filtrationoverwhelms the lymph drainage system. Increased capillaryfiltration may occur because of raised venous pressure,hypoalbuminaemia, or increased capillary permeability due tolocal inflammation. The two main causes of a swollen lowerlimb are deep vein thrombosis and lymphoedema (a failure ofthe lymph drainage system). This article concentrates on deepvein thrombosis and next week’s article on lymphoedema.

Deep vein thrombosisThrombosis usually develops as a result of venous stasis or slowflowing blood around venous valve sinuses; extension of theprimary thrombus occurs within or between the deep andsuperficial veins of the leg and the propagating clot causes venousobstruction, damage to valves, and possible thromboembolism.Deep vein thrombosis is often asymptomatic.

Assessment and investigationVarious clinical features suggest deep vein thrombosis, but thefindings of physical examination alone are notoriouslyunreliable. Deep vein thrombosis is confirmed in only one outof every three cases suspected clinically. Confirmation of asuspected deep vein thrombosis requires use of one or moreinvestigations, and the confirmation rate rises with the numberof clinical risk factors. Identification of an underlying cause, ifany, will guide both the treatment and the approach tosecondary prevention.

The standard investigation is contrast venography, but thisinvasive procedure is painful, often technically difficult and timeconsuming, and occasionally complicated by thrombosis and

Causes of swelling of lower limb

Acutex Deep vein thrombosisx Cellulitisx Superficial thrombophlebitisx Joint effusion or

haemarthrosisx Haematomax Baker’s cystx Torn gastrocnemius musclex Arthritisx Fracturex Acute arterial ischaemiax Dermatitis

Chronic

Congenital vascular abnormalitiesx Haemangiomax KlippelTrenaunay syndrome

Venous diseasex Postthrombotic syndromex Lipodermatosclerosisx Chronic venous insufficiencyx Venous obstruction

Lymphoedemax Cancer treatmentx Infectionx Tumourx Traumax Pretibial myxoedema

Otherx Heart failurex Reflex sympathetic dystrophyx Idiopathic oedema of womenx Hypoproteinaemia, such as

cirrhosis, nephrotic syndromex Armchair legsx Lipoedema

Risk factors for deep vein thrombosis

x Age > 40 yearsx Underlying malignancyx Obesityx Presence of varicose veinsx Personal or family history of deep vein thrombosis or pulmonary

embolismx Any surgical procedure lasting more than 30 minutes—especially

orthopaedic, neurosurgical, urological, and gynaecological surgeryx Paralysis or immobility—for example, recent strokex Combined contraceptive pillx Hormone replacement therapyx Pregnancy and puerperiumx Serious illness—for example, heart failure, myocardial infarction,

sepsis, inflammatory bowel diseasex Presence of hypercoagulable disorders

Colour duplex scan of deep vein thrombosis in common femoral veinadjacent to artery

Clinical features of acute deep vein thrombosis

x Calf pain or tenderness, or bothx Swelling with pitting oedemax Swelling below knee in distal deep vein thrombosis and up to groin

in proximal deep vein thrombosisx Increased skin temperaturex Superficial venous dilatationx Cyanosis can occur with severe obstruction

Clinical review


extravasation of contrast. Recent developments in noninvasivetesting mean that venography is now unnecessary in most cases,particularly in suspected first proximal vein thrombosis.

The accuracy of noninvasive techniques varies with theclinical circumstances. For example, compressionultrasonography and impedance plethysmography are accuratefor detecting symptomatic proximal (ileofemoral) deep veinthrombosis, but both techniques are less satisfactory inasymptomatic patients and for detecting distal (calf vein)thrombosis. Compression ultrasonography has become thepreferred first line investigation (see BMJ 2000;320:698701).

Imaging techniques are generally much less satisfactory inpatients with suspected recurrent deep vein thrombosis, whenconfirmation of the diagnosis requires evidence of newthrombus formation—for example, the appearance of a newnoncompressible venous segment on ultrasonography or anew intraluminal filling defect on venography.

Measurement of circulating ddimer concentrations (abyproduct of fibrin production) is a useful adjunct toultrasonography, with 98% sensitivity for deep vein thrombosisand a high negative predictive value. The sensitivity of the test islower for smaller calf vein thrombi. However ddimerconcentrations rise as a nonspecific response to concomitantillness, not just thrombosis, so ddimer testing can bemisleading in patients admitted to hospital for other reasons.

A combination of diagnostic approaches—for example,compression ultrasonography coupled with clinical pretestprobability scoring or ddimer measurements, or both, givesbetter diagnostic accuracy than any single investigation. Lensinget al have recently shown that the combination of compressionultrasonography and ddimer measurement is an efficientdiagnostic approach, with a rate of subsequentthromboembolism less than 1% in patients with false negativeresults who were not treated with heparin. A robustinvestigational algorithm has been devised that does not includeroutine use of venography.

ComplicationsThe main complications of deep vein thrombosis arepulmonary embolism, postthrombotic syndrome, andrecurrence of thrombosis. Proximal thrombi are a major sourceof morbidity and mortality. Distal thrombi are generally smallerand more difficult to detect noninvasively, and their prognosisand clinical importance are less clear. However, a fifth ofuntreated newly developing calf vein thrombi extendproximally, and a quarter are associated with long termsymptoms of postthrombotic syndrome; it is thereforeappropriate to treat proved significant calf vein thrombosis.

Postthrombotic syndrome develops as a result of highvenous pressure due to thrombotic damage to valves. Itcomplicates 5075% of deep vein thromboses, and there is astrong association with ipsilateral recurrence. Clinical featuresinclude pain, swelling, dermatitis, and ulceration. Proximal deepvein thrombosis is associated with a higher frequency andgreater severity of postthrombotic syndrome, but the risk ishalved by use of graded compression stockings after deep veinthrombosis.

PreventionPatients at significantly increased risk of deep veinthrombosis—for example, those having major pelvic orabdominal surgery for cancer or those with a history ofpulmonary embolism or deep vein thrombosis who have

Clinical model to determine pretest probability of deep veinthombosis (3 points=high risk, 1 or 2=moderate, 0=low)

Score

Active cancer (treatment ongoing, or within 6 months, orpalliative)

1

Paralysis, paresis or recent plaster immobilisation of the legs 1

Recent immobilisation > 3days or major surgery within 12weeks requiring general or regional anaesthesia

1

Localised tenderness along the distribution of the deepvenous system

1

Entire leg swollen 1

Calf swelling > 3 cm than asymptomatic side (measured10 cm below tibial tuberosity)

1

Pitting oedema confined to the symptomatic leg 1

Collateral superficial veins (nonvaricose) 1

Alternative diagnosis equally or more likely than deep veinthrombosis

− 2

Venogram showingthrombus in lower leg

Right ileofemoral deep veinthrombosis

Patient with suspected deep vein thrombosis

Compression ultrasonography

Positive

Positive

Positive

Low Moderate High

Negative

Negative

Negative

Repeat ultrasonography at one week

Treat for deep vein thrombosis

Treat for deep vein thrombosisDeep vein thrombosis excluded

Deep vein thrombosis excluded

Consider clinical probability D-dimer

Management options

Algorithm for investigation of deep vein thrombosis

Clinical review


serious trauma or illness or are having major surgery—shouldbe given prophylaxis. Early mobilisation and graduatedcompression stockings are effective, and antiplatelet drugs suchas aspirin provide additional protection.

Pneumatic compression devices have been proved effectivewhen used perioperatively and in some groups of medicalpatients. Low dose unfractionated heparin (5000 units twohours before surgery and 812 hourly postoperatively) given bysubcutaneous injection reduces the rate of postoperativethromboembolism in general surgical patients by 65%, withlittle increase in the risk of serious bleeding. Low molecularweight heparins are effective and have some advantages overunfractionated heparin, particularly in high risk patients such asthose having hip replacement.

TreatmentTreatment is aimed at reducing symptoms and preventingcomplications. Elevation of the leg with some flexion at the kneehelps reduce swelling, early mobilisation is beneficial, and use ofgraded compression stockings achieves a 60% reduction inpostthrombotic syndrome.

It is important to establish effective anticoagulation rapidly.Patients are usually given an intial intravenous heparin bolus of5000 units followed by unfractionated or low molecular weightheparin for at least five days. With unfractionated heparin anintravenous constant infusion and subcutaneaous injection twicedaily are equally effective. A heparin algorithm should be used toadjust the dose. The activated partial thromboplastin time shouldbe checked six hourly until the target is reached and then daily tomaintain the international normalised ratio at 1.52.5. Theplatelet count should be checked at the start of treatment and onday 5 to exclude thrombocytopenia. Warfarin should be startedon day 1, with the dose determined by a warfarin algorithm. Thetarget ratio is 23, and heparin can be stopped when the targetratio is maintained for more than 24 hours.

Patients with deep vein thrombosis who do not need to bein hospital (around 35%) can be treated with subcutaneous lowmolecular weight heparin in the community. This can beadministered subcutaneously once or twice daily. Lowmolecular weight heparin has the advantages of a slightly lowerrate of haemorrhage and thrombocytopenia and more reliableabsorption after injection, and anticoagulation monitoring isnot required routinely. Warfarin should be started on day 1, andthe duration of treatment guided by the risk profile.

Other approachesInferior vena cava filters reduce the rate of pulmonaryembolism but have no effect on the other complications of deep

Absolute risks of venous thrombotic complications in procedures or conditions of low, moderate, and high risk

Risk level Risk (%) Examples

Deep veinthrombosis

Proximal deep veinthrombosis

Fatal pulmonaryembolism

Low < 10 < 1 0.01 Minor surgery, trauma, or medical illnessMajor surgery at age < 40 with no other risk factors

Moderate 1040 110 0.11 Major surgery with another risk factorMajor trauma, medical illness, or burnsEmergency caesarean section in labourMinor surgery with previous deep vein thrombosis,pulmonary embolism, or thrombophiliaLower limb paralysis

High 4080 1030 110 Major pelvic or abdominal surgery for cancerMajor surgery, trauma, or illness with previous pulmonaryembolish, deep vein thrombosis, or thrombophilia

Duration of anticoagulation in patients with deep veinthrombosis

x Transient cause and no other risk factors: 3 monthsx Idiopathic: 36 monthsx Ongoing risk—for example, malignancy: 6 12 monthsx Recurrent pulmonary embolism or deep vein thrombosis: 612

monthsx Patients with high risk of recurrent thrombosis exceeding risk of

anticoagulation: indefinite duration (subject to review)

Indications for insertion of an inferior vena cava filter

x Pulmonary embolism with contraindication to anticoagulationx Recurrent pulmonary embolism despite adequate anticoagulation

Controversial indications:x Deep vein thrombosis with contraindication to anticoagulationx Deep vein thrombosis in patients with preexisting pulmonary

hypertensionx Free floating thrombus in proximal veinx Failure of existing filter devicex Post pulmonary embolectomy

Pneumatic compression devices

Vena cavagram showing umbrelladelivery device inserted into the inferiorvena cava through the jugular vein. Thefilter has been released just below therenal veins. Inferior vena cava filters helpprevent pulmonary embolism but notother complications of deep veinthrombosis, including recurrentthrombosis

Clinical review


vein thrombosis. Thrombolysis should be considered in patientswith major proximal vein thrombosis and threatened venousinfarction. Surgical embolectomy is restricted to life threateningproximal thrombosis where all else has failed.

PregnancyAnticoagulating doses of heparin are given for deep veinthrombosis in pregnancy. It is essential to confirm the presenceof a thrombus objectively. This is usually done by compressionultrasonography (serially if necessary).

Unfractionated heparin or low molecular weight heparin(which has a better risk profile but is not licensed in UnitedKingdom for this indication) should then be continuedthroughout the pregnancy and stopped temporarily beforedelivery. Anticoagulation should be restarted in the puerperiumand continued for six weeks to three months. Warfarin is usuallycontraindicated during pregnancy because it is teratogenic andincreases risk of maternal and fetal haemorrhage perinatally. Itcan be restarted 48 hours after delivery.

Deep vein thrombosis in pregnancy and puerperium and inwomen taking contraceptive pill or hormone replacementtherapy

x Normal pregnancy is a hypercoagulable statex Deep vein thrombosis occurs antepartum in 0.6/1000 women aged< 35 years and 1.2/1000 women > 35 and postpartum in 0.3/1000and 0.7/1000 respectivelyx Age, operative delivery, personal or family history, andthrombophilia are particular risksx Heparin does not cross the placenta and is not secreted in breastmilkx Prolonged heparin therapy raises concerns about osteoporosis,heparininduced thrombocytopenia, and allergyx The combined contraceptive pill increases the relative risk of deepvein thrombosis by 34 timesx Hormone replacement therapy also increases the relative risk ofdeep vein thrombosis by 34 times but is associated with a 10 foldhigher absolute risk because of the older age group

Further reading and useful references

x Levick JR. An introduction to cardiovascular physiology. 2nd ed.Oxford: ButterworthHeinemann, 1995.

x Lensing WA, Prandoni P, Prins MH, Buller HR. Deep veinthrombosis. Lancet 1999;353:47985.

x Second Thromboembolic Risk Factors (THRiFT II) ConsensusGroup. Risk of and prophylaxis for venous thromboembolism inhospital patients. Phlebology 1998;13:8797.

x Kearon C, Julian JA, Math M, Newman TE, Ginsberg JS.Noninvasive diagnosis of deep venous thrombosis. Ann Intern Med1998;128:66377.

x Anderson DR, Wells PS. Improvements in the diagnostic approachfor patients with suspected deep vein thrombosis or pulmonaryembolism. Thromb Haemost 1999;82:87886.

x Prins MH, Hutten BA, Koopman MMW, Buller HR. Longtermtreatment of venous thromboembolic disease. Thromb Haemost1999;82:8928.

W Peter Gorman is consultant physician and Karl R Davis is clinicalresearch fellow, Southern Derbyshire Acute Hospitals NHS Trust,Derby.


BMJ 2000;320:14536

A book that changed me

Understanding today’s Joads

Like all great books The Grapes of Wrath by John Steinbeck absorbsand entertains but also alters your perspective on life. Its principaltheme is intolerance; its uncomfortable lesson is that prejudice liesbeneath the surface of us all; its optimistic conclusion is the courageof the human spirit and the kernel of good that remains when allelse is stripped away. The poetic style and vernacular dialogue taketime at first, but once it hooks you it won’t let go.

It is the story of the Joad family. They are Oklahoma farmerswhose lives are ruined by the Dust Bowl of the 1930s; forced fromtheir land and fuelled by the American Dream of opportunitythey travel west to California. They endure dreadful hardship onthe way, and when they arrive their optimistic hopes and dreamsare shattered by the hostility they encounter.

Steinbeck’s greatest skill is showing us how the Joads engenderthis hostility, prickling our own innate prejudices. They are crude,crassly naive, violent, and hypocritical—they seem unable to makethe link that they are being driven from the land as theirforefathers drove the native Indians from it. Yet once you get toknow them, feel the pathos of their humanity, and share theirexperience you become so deeply attached that you are appallednot only at the treatment they receive but also at your own initialprejudicial reaction.

I have just reread the book after 20 years, and its relevancepersists. The homeless, the travellers in their caravans next to ourbusy dual carriageways, the asylum seekers and refugees in Dover

bedsits or imprisoned in detention centres—these are all today’sJoads.

Throughout the novel Steinbeck parodies faith that has nomoral depth; he uses many biblical themes and images, and somepassages of the book are written in a quasiscriptural tone. TheBible developed out of a collective human need to give lifecontext, meaning, and a moral structure, but Steinbeck suggeststhat this message has been lost along with its contemporaryrelevance. In a secular, multicultural age The Grapes of Wrathshows us that storytelling remains (second only to life itself) thepreeminent form in teaching us about ourselves and our world.It is a book that teaches empathy, compassion, and tolerance, butperhaps its greatest lesson is that these things need to be taught,and constantly retaught, to us all.

Simon Curtis general practitioner, Oxford


Clinical review


ABC of arterial and venous diseaseSwollen lower limb—2: LymphoedemaPeter S Mortimer

Lymph conducting pathways may become reduced in number,obliterated, obstructed, or dysfunctional (because of failure ofcontractility or valve incompetence). A lack of sensitive methodsfor investigation makes it difficult to distinguish between thesemechanisms. A defect in the lymph conducting pathways leadsto primary lymphoedema; in practice this means no identifiableoutside cause can be found. Secondary lymphoedema is due tofactors originating outside the lymphatic system.

Primary lymphoedemaCongenital lymphoedema presenting at or soon after birth israre. A family history suggests Milroy’s disease. Swellinginvariably affects both lower limbs, but the upper limbs and facemay also swell.

Limb swelling may be the presenting and majormanifestation of congenital lymphatic malformations either in apure form—for example, diffuse lymphangioma—or incombination with a congenital vascular syndrome—for example,KlippelTrenaunay syndrome (varicose veins, excessive longbone growth, and vascular birthmark).

Most forms of primary lymphoedema present after pubertywith foot and ankle swelling. Women are more often affected,and the condition may be familial—for example, Meige’sdisease. Lymph reflux due to lymphatic vessel hypertrophy ormegalymphatics is clinically distinguishable.

Secondary lymphoedemaLymphoedema manifesting with sudden onset of swelling ofone whole leg suggests proximal obstruction. Pelvic causes ofvenous or lymphatic obstruction such as tumour or thrombosismust be excluded. In the Western world cancer treatment—forexample, surgery or radiotherapy) is the commonest cause.Cancer itself rarely presents with lymphoedema except inadvanced cases presenting late, such as prostate cancer, wherevenous obstruction may coexist. Relapsed tumour should alwaysbe considered in someone with limb swelling after apparentcurative cancer treatment.

Filariasis is probably the most common cause of secondarylymphoedema worldwide and should be considered in anypatient with lymphoedema who has travelled or lived in anendemic area.

Clinical diagnosis of lymphoedemaThe clinical diagnosis of lymphoedema depends on the historyand characteristic skin changes. Although most swelling occursin the subcutaneous layer, the skin becomes thicker (asdemonstrated by the inablity to pinch a fold of skin at the baseof the second toe), skin creases become enhanced, and a wartytexture (hyperkeratosis) and papillomatosis develop. Such skinchanges are termed “elephantiasis.”

The differential diagnosis includes venous oedema,“armchair legs,” and lipodystrophy or lipoedema, which is oftenmisdiagnosed as lymphoedema.

Primary lymphoedema

FamilialCongenital (onset at or

soon after birth)

1. Congenital vascular

malformations with

lymphangioma

2. Chylous lymphoedema

1. Distal hypoplasia type

(bilateral below knee

swelling)

2. Proximal obstructive

type (unilateral whole

leg swelling)

3. Lymph reflux

(bilateral whole

leg swelling)

1. Meige's disease

2. Distichiasis-

lymphoedema

syndrome

Milroy's

disease

Postpubertal onset

Classification of primary lymphoedema

Primary lymphoedema with bilateral below knee swelling due to hypoplasiaof peripheral lymphatic vessels

KaposiStemmer sign: inability to pinch a fold of skin at base of second toebecause of thickened skin indicates lymphoedema

Clinical review

1527BMJ VOLUME 320 3 JUNE 2000 bmj.com

Investigation of lymphoedema

Lymphoscintigraphy (isotope lymphography)Lymphoscintigraphy is the best investigation for identifyingoedema of lymphatic origin. Radiolabelled colloid or protein isinjected into the first web space of each foot and monitoredusing a gamma camera as it moves to the draining lymphnodes. Measurement of tracer uptake within the lymph nodesafter a defined interval will distinguish lymphoedema fromoedema of nonlymphatic origin. The appearance of traceroutside the main lymph routes, particularly in the skin (dermalbackflow), indicates lymph reflux and suggests proximalobstruction. Poor transit of isotope from the injection sitesuggests hypoplasia of the peripheral lymphatic system.

Direct contrast x ray lymphography (lymphangiography)After the lymph vessels have been identified with a vital dye, acontrast medium such as Lipiodol is administered directly intoa peripheral lymphatic vessel, usually in the dorsum of the foot.In a normal limb the lymphangiogram will show opacificationof five to 15 main collecting vessels as they converge on thelowermost inguinal lymph nodes. In patients with lymphaticobstruction the contrast medium will often reflux into thedermal network, so called “dermal backflow.”

Computed tomography and magnetic resonance imagingBoth computed tomography and magnetic resonance imagingdetect a characteristic “honeycomb” pattern in thesubcutaneous compartment that is not seen with other causesof oedema. In postthrombotic syndrome the musclecompartment deep to the fascia is enlarged, whereas inlymphoedema it is unchanged. Thickening of the skin is alsocharacteristic of lymphoedema, although it is not diagnostic.Magnetic resonance imaging is more informative thancomputed tomography because it can detect water.

Management of lymphoedemaMost patients with lymphoedema are just told to live with it, butthis is neither necessary nor acceptable.

Dilatation of upper dermal lymphatics with consequent fibrosisgives rise to papillomatosis

Armchair legs (elephantiasis nostrasverrucosis) develop in patients who sit ina chair day and night with their legsdependent. Patients with with cardiac orrespiratory disease, stroke, spinal damage,or arthritis are predisoposed to thiscondition

Lipoedema only affects women and causesswelling between hip and ankle with sparingof the foot. The condition is symmetrical. Theskin and subcutaneous tissues are soft andoften tender with easy bruising

Lymphoscintigraphy. Radiolabelled colloid orprotein is injected into the first web space ofeach foot and followed with a gamma cameraas it moves to the draining lymph nodes. Tracercan be seen within the main lymphatic channelsand lymph nodes as well as within the infectionsite. Collateral drainage is seen within the leftthigh

Computed tomogram showing sections through normal thigh (left) andthigh with lymphoedema (right). Note thickened skin and honeycombpattern

Clinical review

1528 BMJ VOLUME 320 3 JUNE 2000 bmj.com

Physical treatment to reduce swellingTreatment is aimed at controlling lymph formation andimproving lymph drainage through existing lymphatic vesselsand collateral routes by applying normal physiologicalprocesses which stimulate lymph flow.

Prevention of infectionPrevention of acute inflammatory episodes (cellulitis orlymphangitis) is crucial because they can cause severeconstitutional upset and deterioration in swelling. Care of theskin, good hygiene, control of skin diseases such as tinea pedis,and careful antiseptic dressings after minor wounds are allimportant. Antibiotics must be given promptly when an acuteinflammatory episode occurs. In recurrent cellulitis the onlyeffective treatment is prophylactic antibiotics—for example,phenoxymethylpenicillin 500 mg daily, for an indefinite period.

Drug treatment for lymphoedemaDiuretics are of little benefit in lymphoedema because theirmain action is to limit capillary filtration. Improvement inpatients who are taking diuretics suggests that the predominantcause of the oedema is not lymphatic. The benefit ofbenzopyrones, such as coumarin or flavonoids, remainsunproved.

SurgerySurgery is of value in a few patients in whom the size andweight of a limb inhibit its use and interfere with mobility afterphysical treatment. Surgery is aimed at either removingexcessive tissue (reducing or debulking operations) or bypassinglocal lymphatic defects.

Peter S Mortimer is consultant skin physician, St George’s Hospitaland Royal Marsden Hospital, London.

The ABC of arterial and venous disease is edited by RichardDonnelly, professor of vascular medicine, University of Nottinghamand Southern Derbyshire Acute Hospitals NHS Trust(richard.donnelly@ nottingham.ac.uk) and Nick J M London,professor of surgery, University of Leicester, Leicester([email protected]). It will be published as a book later this year.

BMJ 2000;320:15279

Physical treatment for lymphoedema

Process Effect

Exercise Dynamic muscle contractions encourage bothpassive (movement of lymph along tissue planesand noncontractile lymph vessels) and active(increased contractility of collecting lymphvessels) drainage

Compression(hosiery)

Opposes capillary filtrationActs as a counterforce to muscle contractions(so generating greater interstitial pressurechanges)

Manual lymphaticdrainage

Form of massage that stimulates lymph flow inmore proximal, normally draining lymphatics to“siphon” lymph from congested areas(particularly trunk)

Multilayerbandaging

Used as an intensive treatment in combinationwith exercise to reduce large, misshapen lowerlimbs and permit subsequent maintenancetreatment with hosiery

Pneumaticcompression

Softens and reduces limb volume but canforcibly displace fluid into trunk and genitalia.Hosiery must always be worn afterwards

Elevation Does not stimulate lymph drainage but lowersvenous pressure and therefore filtration,allowing lymph drainage to catch up

Further reading

x Ko DS, Lerner R, Klose G, Cosimi AB. Effective treatment oflymphedema of the extremities. Arch Surg 1998;133:4528.

x Mortimer PS. The swollen limb and lymphatic problems. In: TibbsDJ, Sabiston DC, Davies MG, Mortimer PS, Scurr JH. Varicose veins,venous disorders and lymphatic problems in the lower limb. Oxford:Oxford University Press, 1997.

x Levick JR. An introduction to cardiovascular physiology. 2nd ed. Oxford:ButterworthHenemann, 1995.

An old friend

It was high time I chucked away my old stethoscope. Much waswrong with that battered, grubby Littman: the rubber ringmissing from the bell, the warped metal end tube, the left earpiece fallen off. All of which had little to do with the fact that Icould never hear anything through it.

Junior medical days had been a nightmare, the eminentphysician inviting us all to listen to his classic case of reversesplitting of the fifth heart sound, and me barely able to hearlupdup. Eventually I developed a perverse pride in this disability:I argued that such sounds were so highly subjective that theycould not support any diagnostic inference, and thus, in anepistemological sense, they were not there. I became entrenchedin this view after a visit to Sri Lanka, where the chest pathologycould be seen and heard from the end of the bed, just as themedical textbooks’ Edwardian authors would have encountered it;and with comparable social conditions at its root. With an attitudelike that, I was obviously destined for provincial obscurity andpublic health.

Midlife approached, and the millennium, and a spirit of chuckout the old, bring in the new. If I was going to carry a stethoscopeat all let it be a decent one. But I sensed that there were a coupleof last tasks in store for the old one.

The meningitis immunisation clinic was crowded just beforeChristmas, so I left my paperwork, pocketed the Littman and

walked up through town to lend a hand. And there it sat on thedesk, like a badge of office, through a busy but rewarding day.Luckily that was all it was required to do: imagine a public healthdoctor using a stethoscope? That’s like seeing a psychiatrist plyinga tendon hammer, or an orthopaedic surgeon with a pleasantbedside manner—nice in a curiously old fashioned way.

The “holidays” were spent sitting by my beloved, occasionallyfetching her juice or medicines, as machinery hissed and tubingsnaked around our little bedroom. Late afternoon on Boxing Daythe crisis came, her breathing faded, and her pupils widened withthat vision that is beyond life. I disconnected the assortedgadgetry and noted the time. And then I solemnly placed mystethoscope on her chest, and heard absolutely nothing at all.

Graham Sutton consultant in public health, Wakefield


Clinical review


ABC of arterial and venous diseaseUlcerated lower limbNick J M London, Richard Donnelly

Ulceration of the lower limb affects 1% of the adult populationand 3.6% of people older than 65 years. Leg ulcers aredebilitating and painful and greatly reduce patients’ quality of life.Ulcer healing has been shown to restore quality of life. Lowerlimb ulceration tends to be recurrent, and the total annual cost ofleg ulceration to the NHS has been estimated at £400m.

AetiologyVenous disease, arterial disease, and neuropathy cause over 90%of lower limb ulcers. It is useful to divide leg ulcers into thoseoccurring in the gaiter area and those occurring in the forefootbecause the aetiologies in these two sites are different. At leasttwo aetiological factors can be identified in one third of alllower limb ulcers.

Venous ulcers most commonly occur above the medial orlateral malleoli. Arterial ulcers often affect the toes or shin oroccur over pressure points. Neuropathic ulcers tend to occur onthe sole of the foot or over pressure points. Apart fromnecrobiosis lipoidica, diabetes is not a primary cause ofulceration but often leads to ulceration through neuropathy orischaemia, or both. The possibility of malignancy, particularly inulcers that fail to start healing after adequate treatment, shouldalways be borne in mind. The commonest malignancies arebasal cell carcinoma, squamous cell carcinoma, and melanoma.

Patients with reduced mobility or obesity may developulceration in the gaiter area because of venous hypertensionresulting from inadequate functioning of the calf muscle pump.The commonest causes of vasculitic ulcers are rheumatoidarthritis, systemic lupus, and polyarteritis nodosa. The blooddyscrasias that most commonly lead to leg ulceration are sicklecell disease, thalassaemia, thrombocythaemia, andpolycythaemia rubra vera.

Clinical assessment

HistoryIt is important to determine the duration of ulceration andwhether it is a first episode or recurrent. Pain is a majorproblem for patients with leg ulcers unless there is aneuropathic component. Lack of pain therefore suggests aneuropathic aetiology. Systemic diseases that may contribute tothe development of the leg ulceration (such as diabetes orrheumatoid arthritis) should be noted, as should a history oftrauma, deep vein thrombosis, or varicose vein treatment.Patients should also be asked about their mobility.

ExaminationExamination of the leg should include palpation of pulses and asearch for the signs of venous hypertension, including varicoseveins, haemosiderin pigmentation, varicose eczema, atrophieblanche, and lipodermatosclerosis. The range of hip, knee, andankle movement should be determined, and sensation shouldbe tested—for example, with a monofilament—to exclude aperipheral neuropathy.

In patients with ulcers on the sole of the foot, the soleshould be examined for signs of ascending infection, includingproximal tenderness and appearance of pus on proximal

Causes of lower limb ulceration

x Venous diseasex Arterial diseasex Mixed venousarterial diseasex Neuropathyx Traumax Obesity or immobilityx Vasculitisx Malignancy

x Underlying osteomyelitisx Blood dyscrasiasx Lymphoedemax Necrobiosis lipoidica

diabetecorumx Pyoderma gangrenosumx Self inflicted

Non-venous Venous

8% 5%

43% 87%

49%

Calf

Gaiter

Foot 8%

100% 100%

Distribution of nonvenous and venous ulcers of lower limb. The majority ofvenous ulcers are in the gaiter area and the majortiy of nonvenous ulcers infoot

Venous

Arterial Neuropathic

Above medial malleoli

Anterior shin

Over malleoli

Over toe joints

Under heel

Above lateral malleoli

Over malleoli

Inner side offirst metatarsalhead

Undermetatarsal

head

Over toe joints

Under heel

Common sites of venous, arterial, and neuropathic ulceration. Adapted fromTibbs et al

Neuropathic ulcers on sole of foot and dorsum of toe joints

Clinical review



compression of the sole. Note any surrounding callus typical ofneuropathic ulceration and look for tracking to affect the bonesof the foot.

InvestigationPatients with foot ulceration should be referred to hospital forinvestigation because many will have underlying arterialischaemia that requires prompt intervention. Diabetic patientswith signs of infection should have plain radiography of thefoot to look for osteomyelitis. Patients with venous ulcerationshould have their ankle brachial pressure index measured andcan be managed either primarily in the community by trainednurses or referred to hospital for further investigation into theunderlying venous abnormality.

ManagementThe management of the more unusual causes of lower legulceration is based on treating the underlying disease. However,because venous disease affects up to 30% of the population, it isnot uncommon for patients with, for example, rheumatoidarthritis to have lower limb ulceration caused by venous disease.Indeed, in up to half of patients with rheumatoid arthritis andleg ulcers the ulceration is due to venous disease rather than tothe rheumatoid arthritis.

Venous ulcerationDebate continues not only about how venous ulcers should betreated but also where they should be treated. It has recentlybeen suggested that patients with leg ulcers should have aninitial assessment in a hospital vascular clinic, with patients whoare unlikely to benefit from surgery then being cared for in thecommunity. Although this approach has the potential for largecost savings, clinical trials are required to establish costeffectiveness. There is no evidence that any form of drugtreatment improves venous ulcer healing, and antibiotics shouldbe used only if the patient has cellulitis.

Community managementCurrent evidence suggests that the mainstay of the communitymanagement of venous ulceration should be graduatedcompression bandaging. The compression bandaging should beelastic and have multiple layers with a simple, nonadherentdressing underneath. For compression bandaging to be safelyapplied the ankle brachial pressure index must be at least 0.8.Nurses caring for patients with venous ulcer need to be trained tomeasure the ankle brachial pressure index and applycompression bandages safely. The bandages should be changedonce or twice a week. The healing rate depends on the initial sizeof the ulcer, but 6570% of venous ulcers heal within six months.

The skin on the lower leg should be kept moist with anemollient such as simple aqueous cream or 50:50 liquid:whiteparaffin, and surrounding eczema should be treated with atopical steroid. It is important to keep both the primary wounddressing and any medicaments used as “bland” as possiblebecause many patients with venous ulcers develop a contactdermatitis to wound care products.

Hospital treatmentPatients referred to a hospital clinic will have colour duplexscanning to define the underlying venous abnormality. Recentstudies have shown that about 60% of patients with venousulcers have isolated superficial venous incompetence withnormal deep veins. Evidence is mounting that patients with longsaphenous or short saphenous incompetence in the presence of

Arterial ulcer affecting the heel and shin

Venous ulcers usually occur above the malleoli (left) but may affect thedorsum of the foot (right)

Components of Charing Cross four layer bandaging regimen. The primarywound dressing (left) is a nonadherent dressing, over which are placed(middle; top to bottom in order of use) wool, crêpe, Elset, and Cobanbandages. The bandages (right) need replacing once or twice a week

Clinical review

1590 BMJ VOLUME 320 10 JUNE 2000 bmj.com


normal deep veins should have surgery to correct the venousabnormality in the leg and allow ulcer healing. Patients withrefluxing deep veins do not benefit from superficial venoussurgery and are best managed by compression bandaging in thecommunity.

Prevention of recurrenceThe five year recurrence rate of healed venous ulcers can be ashigh as 40%, and preventing recurrence is therefore veryimportant. The rate of recurrence in patients who have hadsurgery to correct superficial venous incompetence has not yetbeen established, but it is expected to be low. In patients withhealed ulcers who have not had surgery, the mainstay ofpreventing recurrence is graduated elastic compression hosiery.One study found that ulcers recurred in 19% of patientswearing class 2 compression hosiery and in 69% ofnoncompliant patients. However, elderly patients with arthritisof the knee or hip may struggle to apply class 2 compressionhosiery, and class 1 hosiery is a sensible compromise. Suchpatients may find a hosiery applicator useful.

Arterial ulcerationFor arterial ulcers to heal, the underlying arterial abnormalitymust be corrected. Patients therefore require colour duplexscanning of their arterial system or diagnostic arteriography todefine the underlying arterial abnormality. Angioplasty is thetreatment of choice because bypass grafting in patients withulcers carries an increased risk of wound or graft infection. Forpatients in whom angioplasty is not possible, some form ofbypass operation, preferably using the saphenous vein, shouldbe attempted.

Neuropathic ulcerationThe commonest cause of neuropathic ulceration is diabetes,and many diabetic patients with neuropathic ulceration will alsohave an arterial problem that requires correction. In manyhospitals diabetic patients with foot ulcers are managed inspecialist foot clinics run by a combination of diabetesphysicians, vascular surgeons, specialist nurses, and podiatrists.The principles behind treatment are to optimise blood supply,debride callus and dead tissue, treat active infection, and protectthe ulcerated area so that healing can occur. This often requiresthe use of a protective plaster boot with a window cut out at thesite of the ulcer. Once healing has occurred, the patient is fittedwith footwear designed to minimise trauma and protect bonyprominences.

Classes of compression stocking: most patients can bemanaged with below knee class 2 stockings

Class

Pressure atankle

(mm Hg) Uses

1 1417 Mild varicose veins

2 1824 Treatment and prevention of venous ulcerrecurrence

3 2535 Treatment of severe venous hypertensionand ulcer prevention in large diametercalves


BMJ 2000;320:158991

Key references

x Ruckley CV. Caring for patients with chronic leg ulcer. BMJ1998;316:4078.

x Scottish Intercollegiate Guidelines Network. The care of patientswith chronic leg ulcer. SIGN 26 1998;July.

x Fletcher A, Cullum N, Sheldon TA. Systematic review ofcompression treatment for venous leg ulcers. BMJ 1997;315:57680.

x Scriven JM, Hartshorne T, Bell PRF, Naylor AR, London NJM.Singlevisit venous ulcer assessment clinic: the first year. Br J Surg1997;84:3346.

x Tibbs DJ, Sabiston DC, Davies MG, Mortimer PS, Scurr JH. Varicoseveins, venous disorders, and lymphatic problems in the lower limbs. Oxford:Oxford University Press, 1997.

x Ruckley CV, Fowkes FGR, Bradbury AW. Venous disease. London:SpringerVerlag, 1998.

x Browse NL, Burnand KG, Irvine AT, Wilson NM. Diseases of the veins.London: Arnold, 1999.

x Task Force on Chronic Venous Disorders of the Leg. Themanagement of chronic venous disorders of the leg. Phlebology1999;14(suppl 1).

Patients may find an applicator helps withputting on compression hosiery

Occlusion (arrows) of distal posteriortibial artery before (left) and afterangioplasty (right)

Protective plaster boot with windowcut out

Clinical review



abc of arterial and venous disease www[1].forumakademi.org

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