Chronic limb-threatening ischaemia

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

CLTI reflects advanced atherosclerotic PAD with inadequate perfusion to meet resting or wound-healing needs. Diagnosis is clinical plus objective evidence of arterial disease; symptom duration is usually more than 2 weeks, distinguishing it from ALI while retaining urgency.

Wound, ischaemia and foot infection jointly determine risk. A small infected ulcer in a neuropathic diabetic foot can deteriorate quickly, while ankle pressures may mislead because of medial arterial calcification.

The goal is survival with a functional limb. A vascular MDT balances endovascular and bypass options, conduit, anatomy, wound severity, operative risk and patient goals; palliative symptom control is appropriate only after an explicit, shared decision when revascularisation is not feasible or wanted.

Key points

CLTI is chronic PAD with ischaemic rest pain, non-healing ulceration or gangrene; it replaces the older term critical limb ischaemia.
Forefoot pain that is worse when supine and relieved by hanging the foot down is classic ischaemic rest pain.
Tissue loss is often distal and punched out, with a cool hairless foot, delayed refill and reduced pulses; neuropathy may blunt pain.
Refer urgently to a vascular multidisciplinary team—analgesia and dressings alone are not definitive care.
Measure ABPI, but do not exclude PAD from a normal or high value in diabetes or CKD because calcified arteries may be incompressible.
Toe pressure/toe-brachial index and Doppler waveforms help when ABPI is unreliable; anatomical imaging follows when revascularisation is being considered.
Offer angioplasty or bypass when revascularisation is required; major amputation should not occur until revascularisation options have been considered by a vascular team.
Treat smoking, lipids, antiplatelet indication, diabetes, blood pressure, infection and foot pressure as part of limb salvage, not as substitutes for restoring flow.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Advanced atherosclerotic peripheral disease

Smoking, diabetes, hypertension and dyslipidaemia accelerate multilevel arterial plaque. Progressive stenosis or occlusion eventually leaves insufficient perfusion for resting tissue and wound healing.

Diabetes and chronic kidney disease

Distal arterial disease, medial calcification, impaired immunity and poor healing increase risk. Neuropathy can mask rest pain while repetitive pressure creates an unnoticed portal for ulceration.

Recurrent or acute-on-chronic occlusion

Restenosis, graft failure or thrombosis superimposed on chronic disease can abruptly reduce an already marginal circulation. Sudden sensory or motor change suggests an acute emergency.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Progressive arterial narrowing
Atherosclerotic plaque reduces conduit flow through limb arteries. Collateral vessels initially maintain exercise or resting perfusion, but reserve declines as disease becomes more extensive.
2
Resting perfusion becomes inadequate
Distal pressure eventually cannot meet basal tissue demand, particularly when the foot is elevated. Dependency temporarily increases hydrostatic pressure and may ease forefoot rest pain.
3
Tissue repair fails
Poor microvascular oxygen and nutrient delivery prevents minor trauma or pressure injury from healing. Ischaemia also impairs immune-cell and antibiotic delivery to contaminated tissue.
4
Necrosis and infection interact
Persistent hypoxia causes ulceration and dry gangrene. Infection increases tissue demand and oedema, further compromising flow and potentially converting local tissue loss into wet gangrene or sepsis.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Ischaemic rest painRed flag

Persistent forefoot/toe pain, often nocturnal and worse with elevation, relieved transiently by dependency; requires urgent vascular assessment.

Arterial tissue loss

Non-healing distal ulcer, punched-out edge, pale base, dry gangrene, cool shiny skin, reduced hair and absent pulses.

Infected or wet gangreneRed flag

Spreading erythema, purulence, malodour, crepitus, systemic illness or wet tissue necrosis requires same-day surgical/vascular and antimicrobial care.

Diabetic/renal phenotype

Neuropathy can hide pain and calcification can produce a falsely normal/high ABPI; inspect every surface and obtain toe/waveform assessment.

Dependent rubor

A dusky red foot when dependent that pales on elevation supports severe arterial insufficiency; do not mistake it for cellulitis without examining temperature, distribution and pulses.

Acute-on-chronic deteriorationRed flag

A sudden increase in pain, coldness, sensory loss or weakness suggests superimposed ALI and moves the patient to an emergency pathway.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
ABPI with Doppler waveformsFirst step
Why
Objectify PAD and describe arterial signals.
Interpretation and limitations
ABPI <0.9 supports PAD; very low pressure indicates severe disease. Normal/high ABPI does not exclude PAD in diabetes/CKD or incompressible vessels—waveform quality matters.
02
Toe pressure or toe-brachial index
Why
Assess perfusion when ankle arteries are calcified and estimate healing potential.
Interpretation and limitations
Low toe pressure supports severe ischaemia; interpret with wound severity and local laboratory standards rather than as a stand-alone amputation threshold.
03
Duplex ultrasound
Why
Localise stenoses/occlusions without contrast and support revascularisation planning.
Interpretation and limitations
Shows flow and lesion distribution; more cross-sectional imaging may be needed for complex or multilevel disease.
04
CTA or contrast-enhanced MRA
Why
Map inflow, femoropopliteal and below-knee/pedal targets once revascularisation is being considered.
Interpretation and limitations
Choice depends on calcification, renal function, implants and expertise; image the arterial tree needed to plan treatment.
05
FBC, CRP, U&E/eGFR, glucose/HbA1c and wound/blood cultures when clinically infected
Why
Identify infection, anaemia, renal risk and glycaemic modifiers.
Interpretation and limitations
Culture after cleaning/debridement when possible; colonisation without clinical infection is not an antibiotic indication.
06
Foot radiograph or MRI for suspected deep infection
Why
Assess gas, foreign body and osteomyelitis.
Interpretation and limitations
Plain films may be initially normal; MRI is more sensitive for osteomyelitis when diagnosis remains uncertain and results will change management.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Acute limb ischaemia

A sudden painful, pale, cold limb with new sensory or motor deficit indicates abrupt arterial occlusion. The short onset and threatened viability distinguish it from stable chronic symptoms.

Neuropathic diabetic ulcer

Neuropathic ulcers favour plantar pressure points with callus, sensory loss and a relatively warm foot. Pulses may remain palpable, although mixed neuropathic and ischaemic disease is common.

Venous ulceration

Venous ulcers usually lie in the gaiter region with oedema, pigmentation or eczema and a shallow irregular bed. Distal punched-out lesions, coolness and absent pulses favour arterial disease.

Cellulitis

Diffuse warmth, tenderness, rapidly spreading erythema and systemic inflammatory features support infection. Dependent rubor instead fades with elevation and accompanies a cool, poorly perfused foot.

Neurological or musculoskeletal pain

Radiculopathy, peripheral neuropathy or arthritis may cause nocturnal limb pain without tissue perfusion signs. Normal skin temperature, pulses and vascular waveforms make isolated severe ischaemia less likely.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01urgentNew CLTIFirst stepRest pain, non-healing arterial ulcer or gangrene without acute motor/sensory loss.

1First: urgent vascular MDT referral; document wound, pulses/Doppler, sensation, infection and analgesic needs.
2Next: protect the foot, avoid trauma and inappropriate compression, and obtain ABPI plus toe/waveform testing where needed.
3Next: perform anatomical imaging when revascularisation is being planned and optimise antiplatelet, lipid, smoking, BP and diabetes care.
4EscalationEscalation: same-day acute referral for wet gangrene, spreading infection, sepsis or acute-on-chronic neurological change.

02revascularisationLimb-salvage decisionCLTI requiring restoration of perfusion for pain relief or wound healing.

1First: stage patient risk, limb/wound severity and anatomy in the vascular MDT.
2Next: offer angioplasty/endovascular treatment or bypass, considering comorbidity, lesion pattern, conduit and patient preference.
3Next: coordinate debridement, infection treatment, off-loading and wound care with restoration of perfusion.
4EscalationEscalation: do not perform major amputation until all revascularisation options have been considered, unless immediate source control/life-saving surgery is required.

03infected footCLTI with infectionPurulence, spreading erythema, systemic illness, deep collection, wet gangrene or suspected osteomyelitis.

1First: same-day acute surgical/vascular assessment, sepsis care and cultures when these do not delay antibiotics.
2Next: start severity-appropriate antibiotics under NICE diabetic-foot/antimicrobial guidance and obtain source control.
3Next: coordinate perfusion imaging/revascularisation with drainage or debridement; antibiotics cannot penetrate or heal an unperfused necrotic foot reliably.
4EscalationEscalation: urgent amputation may be life-saving in uncontrolled sepsis or non-salvageable tissue after senior MDT review.

04non-reconstructableWhen revascularisation is not feasibleNo suitable target, prohibitive risk, advanced frailty or informed preference against intervention.

1First: confirm the decision in a vascular MDT and explain prognosis and alternatives to the patient/family.
2Next: provide scheduled analgesia, wound/skin care, infection treatment where indicated and pressure protection.
3Next: involve pain and palliative-care services early; address function, place of care and anticipatory planning.
4EscalationEscalation: revisit amputation for uncontrolled pain, recurrent sepsis or a functional benefit consistent with the patient's goals.

Key medicines and prescribing safety4 treatments · regimens, roles and cautions

Single antiplatelet therapy for symptomatic PAD unless another antithrombotic strategy is indicated.

Clopidogrel

75 mg orally once daily.

Check bleeding, interacting anticoagulants/antiplatelets and planned surgery; do not add to full anticoagulation automatically.

High-intensity lipid lowering for established atherosclerotic CVD/PAD.

Atorvastatin

80 mg orally once daily for secondary prevention; use a lower dose if interactions, adverse-effect risk or patient preference require it.

Check baseline liver tests; review interactions and muscle symptoms. Avoid during pregnancy and breastfeeding under the product information.

Baseline analgesia while urgent vascular treatment is organised.

Paracetamol

1 g orally up to four times daily as needed (maximum 4 g/24 h; use a lower maximum in low body weight, frailty, liver disease or chronic alcohol excess).

Pain relief must not delay revascularisation; check combination products to avoid overdose.

Severe rest pain, including when awaiting intervention or for non-reconstructable disease.

Morphine immediate release

One licensed immediate-release tablet regimen is 10 mg orally every 4 hours; choose a lower starting dose in older/frail people or renal/hepatic impairment and titrate to analgesia and adverse effects with an explicit review/stop plan.

Dose from prior opioid exposure as well as frailty and organ function; prescribe a bowel regimen and monitor sedation and respiratory effects. Avoid or obtain specialist advice in severe renal failure because active metabolites accumulate.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Non-healing ulcer and gangrene

Persistent oxygen deficit prevents repair and causes progressive tissue necrosis. Even dry gangrene signifies severe ischaemia and can extend or become infected without restored perfusion.

Deep infection and sepsis

An ischaemic ulcer can progress to cellulitis, abscess or osteomyelitis because local immunity and antimicrobial delivery are impaired. Wet gangrene may produce rapidly life-threatening sepsis.

Acute limb loss

Thrombosis on severe chronic disease may suddenly threaten nerve and muscle viability. Failed or infeasible revascularisation can necessitate amputation to control necrosis, infection or intractable pain.

Functional decline after amputation

Major amputation can reduce mobility, independence and rehabilitation potential, particularly in frail people with cardiac or renal disease. It may nevertheless provide source control or functional benefit when carefully selected.

Systemic cardiovascular events

CLTI marks extensive atherosclerosis, so myocardial infarction, stroke and cardiovascular death remain major competing risks. Limb salvage should therefore accompany broader vascular risk reduction.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Track rest pain, sleep, analgesic use and any new sensory or motor change.
Measure wound dimensions, depth, exudate, tissue type and infection signs at each review using consistent documentation.
Reassess perfusion clinically and with Doppler/toe measures after revascularisation or if healing stalls.
Monitor renal function, haemoglobin, glucose control, BP, lipids, smoking status and medication tolerance.
After intervention, monitor access/graft patency and follow the vascular surveillance plan; urgent review for recurrent pain, coldness or tissue loss.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Dependency can relieve pain

Patients may sleep in a chair or hang the foot out of bed; ask directly because they may not use the term rest pain.

ABPI can lie in diabetes

Medial calcification makes arteries incompressible, so toe pressure and waveforms are essential when symptoms and ABPI disagree.

Dry is not the same as safe

Dry gangrene may be initially uninfected, but it still signifies severe ischaemia and needs urgent vascular planning.

Perfusion and infection are coupled

Debridement timing, antibiotics and revascularisation must be coordinated; treating only one component risks failure.

Amputation is a treatment, not a pathway default

It may restore comfort/function or control sepsis, but NICE requires consideration of revascularisation options before major amputation whenever circumstances allow.

11Common pitfallsFrequent interpretation and management errors.

01
Applying high compression to an ulcerated limb before excluding clinically important arterial disease.
02
Reassuring a diabetic patient because ABPI is normal or high despite monophasic signals and tissue loss.
03
Repeated antibiotics for a non-healing ischaemic ulcer without clinical infection or vascular assessment.
04
Managing rest pain with escalating opioids while delaying urgent revascularisation referral.
05
Planning major amputation before a vascular MDT has considered limb-salvage options, except when immediate source control is life-saving.