Overview

Critical limb ischaemia (CLI) represents grade III and IV chronic limb ischaemia (based on the Fontaine classification). It presents with rest pain, breakdown of skin and inability to heal an injury, which can lead to infection or gangrene. If left untreated it may be necessary to amputate the affected limb. CLI develops in 1% to 3% of patients with peripheral artery disease (PAD).

Chronic limb ischaemia can be classified using the Fontaine classification:

I – asymptomatic

II – intermittent claudication

III – rest pain

IV – ulcers/gangrene

Grades III and IV are classified as Critical Limb Ischaemia.

Aetiology

• Atherosclerosis (most common)
• Buerger’s disease (Thromboangiitis obliterans)
• Popliteal artery entrapment syndrome 
• Thoracic outlet syndrome

Risk Factors

• Age
• Smoking
• High Cholesterol
• Chronic kidney disease
• Hypertension
• Diabetes

Pathophysiology

Progressive narrowing and occlusion of arteries, mostly due to atherosclerosis, causes reduced blood flow to the extremities. Over time, there is impaired oxygen delivery, even at rest, which leads to tissue hypoxia. The tissue relies on anaerobic respiration, which leads to build up of lactic acid that activities pain receptors causing rest pain. Prolonged hypoxia results in cell death causing symptoms like non-healing ulcers and gangrene.

Clinical manifestation

• Rest pain unrelieved by analgesia
  • Typically worsens at night and during elevation of the limb
  • Relieved by hanging the limb dependent (eg. hanging limb over the side of the bed or standing up) as gravity increases blood flow to the limb
• Painful non-healing ulcers – mainly on toes and heels
• Gangrene that usually starts in distal part of limb

Examination

• Limb positioned dependent, muscle wasting, ulcers, gangrene, nail atrophy, skin changes (dryness and hair loss)
• Arterial pulses: weak or absent pulses distally to diseased artery
• Buerger’s test positive with angle <20°: pallor on elevation, rubor on dependency
• Neurological exam: sensory loss and motor weakness
• Prolonged capillary refill time

Differential diagnosis

• Diabetic neuropathy – causes sensory loss, pain worse at night and ulcers
• Nerve root entrapment (eg. entrapment of the sciatica can cause radiculopathy down to calve muscles)
• Ulcers associated with hematologic disease (eg. Sickle cell disease) – cause ulceration in feet
• Peripheral sensory neuropathy – due to vitamin B 12 deficiency or alcohol consumption 
• Venous ulcers – due to raised venous pressure over a long period, commonly over medial malleolus
• Inflammation (eg. rheumatoid arthritis, gout, plantar fasciitis) – causes pain at rest in distal limb

Investigations

Assess the severity of ischaemia:

• First line: Ankle-brachial Pressure Index (ABPI) – less than 0.4 indicates CLI
• In calcified vessels (eg. due to diabetic disease) ABPI is elevated and is therefore unreliable, so do:
  • Toe pressure – less than 30mmHg indicates CLI
  • Ankle pressure – less than 50mmHg indicates CLI
  • Transcutaneous oxygen pressure (TcPO2) – less than 20mmHg suggests CLI

Segmental blood pressure – measured at various points along the limb to help localise disease:

• A drop >20-30 mmHg between adjacent cuffs suggests significant arterial obstruction between those two levels.
• The site of greatest pressure drop indicates the location of significant stenosis or occlusion

Imaging – to precisely identify location and severity of all arterial stenoses involved:

• Duplex ultrasound – first choice for assessing infra-inguinal arterial disease 
• Computed Tomography Angiography (CTA) – usually superior for imaging the aortoiliac segment
• Digital Subtraction Angiography (DSA) – interventional, carries risk of injury and renal toxicity of contrast, good for popliteal and distal vessel assessment
• Magnetic Resonance Angiography (MRA)
• Abdominal ultrasound – to rule out aneurysm

ABPI (Ankle-brachial Pressure Index) is used to assess blood flow in legs. It is calculated by dividing the systolic blood pressure at the ankle by the systolic blood pressure at the arm (brachial artery). ABPI values:

• 1.0 – 1.4 – normal
• 0.9 to 0.5 – intermittent claudication
• <0.5 – critical limb ischaemia
• >1.4 – calcified vessels

Treatment

Risk factor modification:

• Stop smoking
• Oral statin
• Control BP and glucose
• Antiplatelet therapy (aspirin or clopidogrel)

Revascularise the limb via endovascular treatment or surgery:

• Endovascular treatment
  • Angioplasty + stent
    • Mostly done in aorto-iliac segment or superficial femoral
    • Not in popliteal and tibial due to high risk of occlusion
    • Useful in short stenoses/occlusions
• Surgery:
  • Bypass graft
    • Preferred for long segment, multilevel disease
    • If endovascular approach fails

Amputation (if limb is non-viable):

• Failed revascularisation
• Extensive gangrene or infection

Complications and Prognosis

Complications

• Infection (in ulcerated and gangrenous areas) – can lead to sepsis
• Psychosocial issues and depression (if limb is amputated)
• Higher risk of atherosclerotic morbidity – stroke and coronary artery disease
• Myalgia (side effect of statins)
• Bleeding (side effect of aspirin and clopidogrel)

Prognosis

Mortality rate:

• Up to 20% within 6 months
• Up to 50% within the first year
• Exceeding 50% at 5 years

Major amputation rate:

• Ranges between 10% to 40% in the first year

References

1. Peripheral vascular disease. In: McLatchie G, Borley N, Agarwal A, Jeyarajah S, Harries R, Weerakkody R, et al., editors. Oxford Handbook of Clinical Surgery: Oxford University Press; 2022. p. 0. https://doi.org/10.1093/med/9780198799481.003.0019 

2. Shishehbor MH, White CJ, Gray BH, Menard MT, Lookstein R, Rosenfield K, et al. Critical Limb Ischemia: An Expert Statement. Journal of the American College of Cardiology. 2016;68(18):2002-15. https://doi.org/10.1016/j.jacc.2016.04.071 

3. Armstrong EJ, Armstrong DG. Vascular Disease Patient Information Page: Critical limb ischemia. Vascular Medicine. 2021;26(2):228-31. https://journals.sagepub.com/doi/pdf/10.1177/1358863X20987611?utm 

4. Eun JC, Hiatt WR, Glebova NO. Nonatherosclerotic limb ischemia: Prompt evaluation and diagnosis. Cleveland Clinic Journal of Medicine. 2016;83(10):741-51. https://www.ccjm.org/content/ccjom/83/10/741.full.pdf 

5. D 2.3 – Differential diagnosis of critical limb ischemia. Journal of Vascular Surgery. 2000;31(1, Supplement 1):S184-S8. https://doi.org/10.1016/S0741-5214(00)81030-7 

6. Teraa M, Conte MS, Moll FL, Verhaar MC. Critical Limb Ischemia: Current Trends and Future Directions. Journal of the American Heart Association. 2016;5(2):e002938. https://doi.org/10.1161/JAHA.115.002938