Cold extremities

Cold extremities are hands, feet, fingers or toes that feel cold to the patient or to the examiner, sometimes with colour change (white, blue, red), numbness, pain or tissue loss.

Clinical relevance. Cold hands and feet are very common (up to 20% of women report cold sensitivity). Most cases are primary Raynaud phenomenon or constitutional. The danger is a missed acute arterial occlusion, shock, secondary Raynaud phenomenon from connective tissue disease (digital ulcers, gangrene), or cold injury. Classification.

• Vasospastic: primary Raynaud phenomenon (onset age 15 to 30, symmetrical, no tissue damage, normal capillaroscopy and antibodies), secondary Raynaud phenomenon, acrocyanosis, chilblains (pernio), vibration related vascular injury.
• Arterial occlusive: acute limb ischaemia (embolus, thrombosis, dissection), chronic limb ischaemia, atheroembolism (blue toe syndrome), thromboangiitis obliterans (Buerger disease), thoracic outlet syndrome, subclavian steal, large vessel vasculitis (Takayasu arteritis, giant cell arteritis).
• Low flow and systemic: shock and low cardiac output (cold peripheries with delayed capillary refill), hypovolaemia, sepsis, hypothermia, hypothyroidism, anaemia, anorexia nervosa and low body weight, adrenal insufficiency.
• Haematological and immune: cryoglobulinaemia, cold agglutinin disease, polycythaemia and hyperviscosity, antiphospholipid syndrome, paraproteinaemia.
• Drug and toxin related: beta blockers, ergot alkaloids, triptans, amphetamines and cocaine, clonidine, bleomycin and cisplatin, interferon, decongestants, nicotine, methysergide.
• Neuropathic and other: diabetic and other neuropathy with altered temperature sense, complex regional pain syndrome, spinal cord lesions, frostbite and cold injury.

Mechanism. Skin blood flow is controlled by sympathetic tone and local cold sensitivity. Digital vasospasm in Raynaud phenomenon shuts down flow (white), followed by deoxygenation (blue) and reactive hyperaemia on rewarming (red). Fixed arterial disease and low cardiac output cut flow regardless of temperature.

History.

• Pattern: which parts (fingers, toes, whole hand or foot, one side or both), triggers (cold, stress), colour sequence (white, blue, red), duration of attacks, age at onset, change over time, constant versus episodic coldness.
• Pain, numbness, tingling, ulcers, skin tightening, swelling, rash, joint pain, dry eyes and mouth, dysphagia, reflux, photosensitivity, mouth ulcers, muscle weakness.
• Acute symptoms: sudden cold, pale, painful, numb or weak limb (the six Ps: pain, pallor, pulselessness, paraesthesia, paralysis, perishing cold).
• Vascular risk: smoking (including cannabis and tobacco in Buerger disease), diabetes, hypertension, lipids, atrial fibrillation, previous embolism, claudication, family history.
• Occupation: vibrating tools, cold exposure, vinyl chloride, repetitive hand trauma, hand arm use (hypothenar hammer syndrome).
• Drugs: beta blockers, ergotamine, triptans, stimulants, chemotherapy, interferon, oral contraceptives.
• Weight loss, cold intolerance, fatigue, constipation (hypothyroidism), heavy menstrual loss (anaemia), eating disorder.
• Cold exposure, immersion, wet conditions (frostbite, trench foot).
• Family history of Raynaud phenomenon or connective tissue disease.

Examination.

• Vital signs: blood pressure in both arms (difference over 20 mmHg suggests subclavian or aortic disease), heart rate and rhythm, temperature, saturation, capillary refill centrally and peripherally.
• Hands and feet: temperature, colour, capillary refill, digital ulcers, pitting scars, gangrene, splinter haemorrhages, telangiectasia, calcinosis, sclerodactyly, puffy fingers, nail fold capillary changes (dilated loops, drop out), livedo reticularis, purpura, blue toes with palpable pulses.
• Pulses: radial, ulnar, brachial, subclavian, femoral, popliteal, dorsalis pedis, posterior tibial; Allen test; bruits; ankle brachial pressure index and Buerger test (elevation pallor, dependent rubor).
• Thoracic outlet manoeuvres (Adson, Roos); neck and supraclavicular fossa (cervical rib).
• Systemic: face (tight skin, beaking, microstomia), joints, muscles, thyroid, lung bases, heart (murmur, irregular rhythm).
• Neurological: sensation, power, reflexes.

Red flags.

• Acute onset cold, pale or mottled limb with pain, weakness or sensory loss.
• Digital ulcers, gangrene, rapidly progressive tissue loss, or ischaemic pain at rest.
• Asymmetric disease, onset after age 40, or onset in a single digit.
• Raynaud phenomenon with systemic features (skin thickening, dysphagia, dyspnoea, rash, joint swelling, weight loss, muscle weakness), positive antibodies or abnormal capillaroscopy.
• Cold peripheries with hypotension, tachycardia, confusion or oliguria (shock).
• Blue or purple toes with palpable pulses (atheroembolism) after angiography or surgery.
• Blood pressure difference between arms, absent pulses, bruits (large vessel disease).
• Cold exposure with numb, hard, white or blistered skin (frostbite).
• Heavy smoker under 45 with distal ischaemia (Buerger disease).

Primary Raynaud phenomenon. Young women, symmetrical, triggered by cold or stress, no tissue loss, normal nail fold capillaries, negative antinuclear antibody.

Secondary Raynaud phenomenon. Systemic sclerosis (limited and diffuse), systemic lupus erythematosus, Sjogren syndrome, dermatomyositis and polymyositis, mixed connective tissue disease, rheumatoid arthritis, vasculitis, cryoglobulinaemia, paraproteinaemia, antiphospholipid syndrome, hypothyroidism, carpal tunnel syndrome, thoracic outlet syndrome, vibration white finger, hypothenar hammer syndrome, drugs, occupational chemicals, malignancy (paraneoplastic).

Arterial occlusion. Acute embolus (atrial fibrillation, infarct, endocarditis, atrial myxoma, paradoxical), acute thrombosis on atherosclerosis or aneurysm (popliteal), aortic dissection, trauma, thromboangiitis obliterans, atheroembolism, giant cell and Takayasu arteritis, chronic atherosclerotic limb ischaemia, subclavian steal, coarctation, Leriche syndrome, compression syndromes, popliteal entrapment, fibromuscular dysplasia.

Low flow states. Shock of any type, heart failure with low output, hypovolaemia, hypothermia, hypothyroidism, adrenal insufficiency, anaemia, malnutrition and anorexia nervosa.

Blood and immune. Cryoglobulinaemia (hepatitis C related), cold agglutinin disease, polycythaemia vera and secondary polycythaemia, thrombocytosis, hyperviscosity (myeloma, Waldenstrom macroglobulinaemia), antiphospholipid syndrome, disseminated intravascular coagulation with purpura fulminans.

Cold injury. Frostbite, frostnip, trench (immersion) foot, chilblains.

Neuropathic and functional. Diabetic neuropathy, small fibre neuropathy, erythromelalgia (burning with warmth, opposite pattern), complex regional pain syndrome, acrocyanosis, constitutional cold hands.

1. Decide urgency from the history and pulses: acute limb ischaemia or shock needs immediate imaging and treatment; otherwise proceed stepwise.
2. Measure ankle brachial pressure index and toe pressures; segmental Doppler pressures and waveforms; finger pressures and digital photoplethysmography (digital systolic pressure under 70% of brachial, or a drop of 30 mmHg or more after cooling, supports vasospasm).
3. Nail fold capillaroscopy (dilated, giant or drop out capillaries point to secondary disease).
4. Blood tests: full blood count, film, ESR, C reactive protein, urea, creatinine, electrolytes, glucose or HbA1c, liver function, thyroid stimulating hormone, lipids, creatine kinase, urinalysis, urine protein to creatinine ratio.
5. Immunology when secondary Raynaud phenomenon is suspected: antinuclear antibody with extractable nuclear antigens (anti centromere, anti Scl-70, anti RNA polymerase III), rheumatoid factor, anti cyclic citrullinated peptide, complement C3 and C4, anti double stranded DNA. Also antiphospholipid antibodies, cryoglobulins (sample kept warm), cold agglutinins, serum protein electrophoresis, hepatitis B and C, HIV.
6. Arterial imaging when occlusion is suspected: duplex ultrasound, CT or MR angiography, catheter angiography, with echocardiography (embolic source), ECG and rhythm monitoring.
7. Large vessel imaging (CT or MR angiography, PET) when Takayasu or giant cell arteritis is suspected; blood pressure in all four limbs.
8. Thoracic outlet: chest and cervical spine radiographs for cervical rib, dynamic duplex or angiography.
9. Lactate and venous gas in shock; arterial blood gas when hypoxia is possible.
10. For frostbite: bone scan, technetium scintigraphy or angiography at 24 to 48 hours to define salvage.

Limits. Examiner and ambient temperature alter findings. Primary Raynaud phenomenon is a clinical diagnosis after exclusion of secondary causes. Antibodies may appear years before disease. Pulses can be normal with small vessel or embolic disease.

Emergencies. Acute limb ischaemia: unfractionated heparin 5,000 units intravenously bolus then infusion (18 units/kg/hour, adjust by activated partial thromboplastin time), analgesia, urgent vascular surgical assessment. Shock: resuscitation and treatment of the cause. Frostbite: rapid rewarming. Digital gangrene with infection: antibiotics and surgery.

Primary Raynaud phenomenon and mild secondary disease.

• Keep the whole body warm (gloves, mittens, hat, socks, heated gloves, hand warmers), avoid sudden cold, wear layers, warm hands in running warm water at the first sign of an attack.
• Stop smoking and nicotine; avoid caffeine excess, and vasoconstricting drugs (decongestants, ergots, amphetamines, beta blockers where possible).
• Reduce stress; vary hand movements (windmill arm swings) during attacks.
• Drug treatment when attacks are frequent or disabling: nifedipine modified release 30 mg daily increasing to 60 mg (maximum 90 mg), or amlodipine 5 to 10 mg daily; side effects headache, flushing, ankle swelling.
• Alternatives: losartan 50 mg daily, sildenafil 20 mg three times daily (or tadalafil 20 mg on alternate days), fluoxetine 20 mg daily, topical glyceryl trinitrate 0.2% ointment applied to the fingers, and low dose aspirin 75 mg where there is occlusive disease.

Severe or secondary Raynaud phenomenon with digital ulcers or critical ischaemia.

• Admit for severe attacks and ulcers; intravenous iloprost 0.5 to 2 nanograms/kg/minute for 6 hours daily for 3 to 5 days, repeated courses every 6 to 12 weeks; or alprostadil.
• Sildenafil 20 mg three times daily, increasing to 50 mg three times daily for digital ulcers; bosentan 62.5 mg twice daily for 4 weeks then 125 mg twice daily to prevent new ulcers in systemic sclerosis (monitor liver enzymes monthly; contraception essential).
• Local wound care, analgesia (paracetamol 1 g every 6 hours, maximum 4 g, 3 g if frail or under 50 kg; add opioid if needed).
• Prompt antibiotics for infected ulcers (flucloxacillin 500 mg to 1 g four times daily), debridement, chemical or surgical sympathectomy, botulinum toxin injection in selected cases.
• Treat the underlying disease: systemic sclerosis and lupus (immunosuppression by rheumatology), cryoglobulinaemia (antiviral therapy for hepatitis C, rituximab, plasma exchange), antiphospholipid syndrome (warfarin, target INR 2.0 to 3.0).
• Polycythaemia (venesection, hydroxycarbamide), vasculitis (prednisolone 40 to 60 mg daily), hypothyroidism (levothyroxine 1.6 micrograms/kg, starting at 25 micrograms in older adults or coronary disease), anaemia (iron).

Acute and chronic arterial occlusion.

• Antithrombotic therapy (aspirin 75 mg daily, clopidogrel 75 mg daily), statin (atorvastatin 40 to 80 mg).
• Anticoagulation for embolic sources (rivaroxaban 20 mg daily, or apixaban 5 mg twice daily in atrial fibrillation).
• Thrombolysis or embolectomy, revascularisation, smoking cessation.
• Buerger disease: absolute cessation of tobacco and cannabis, iloprost, sympathectomy.

Takayasu and giant cell arteritis. Prednisolone 40 to 60 mg daily (1 mg/kg) with taper, methotrexate 15 to 25 mg weekly with folic acid 5 mg weekly, tocilizumab, and revascularisation in the quiescent phase.

Frostbite.

• Remove wet clothing and jewellery.
• Rapid rewarming in 37 to 39 degrees Celsius water for 15 to 30 minutes once refreezing is impossible.
• Ibuprofen 400 mg every 8 hours.
• Iloprost 0.5 to 2 nanograms/kg/minute for 6 hours daily for 8 days in severe cases.
• Tetanus prophylaxis; clean dry dressings; delay amputation until demarcation (usually weeks).

Shock and low output. Fluid, vasopressors, treatment of cause; warm the patient and avoid vasoconstrictors that worsen digital flow once perfusion is restored.

Thoracic outlet syndrome. Physiotherapy; surgical decompression (first rib resection) for vascular compromise; anticoagulation for thrombosis.

Monitoring.

• Frequency and severity of attacks, new ulcers, nail fold capillaries.
• Antibody profile and organ screening every 6 to 12 months in secondary disease (lung function, echocardiography, creatinine, urinalysis in systemic sclerosis).
• Blood pressure and liver enzymes on bosentan.
• Blood pressure and heart rate on calcium channel blockers.

Referral and escalation. Rheumatology for secondary Raynaud phenomenon or ulcers; vascular surgery for ischaemia, thoracic outlet and aneurysm; haematology for hyperviscosity and cryoglobulinaemia; endocrinology for thyroid and adrenal disease; plastic and orthopaedic surgery for tissue loss; occupational health.

Admission. Acute limb ischaemia, shock, digital gangrene or severe ulceration with infection, intravenous prostanoid therapy, frostbite beyond mild, severe hypothermia, or unexplained systemic illness.

Safety netting. Return at once for a cold, pale or blue limb that does not recover within 30 minutes of warming, a new ulcer or black skin, severe pain, spreading redness, fever, chest pain, breathlessness, or numbness and weakness.

Special groups.

• Pregnancy: avoid bosentan, ACE inhibitors and angiotensin receptor blockers; nifedipine and warmth are safe; attacks often improve.
• Children: acrocyanosis and primary Raynaud phenomenon are common; secondary causes need antibody screening.
• Older adults: atherosclerotic disease predominates; reduce beta blocker use.
• Smokers: cessation is the most effective single treatment.
• Endemic regions: frostbite at altitude, HIV related and hepatitis related vasculopathy, Buerger disease in heavy smokers, tuberculous and syphilitic arteritis, and Takayasu arteritis.