Exercise intolerance

Exercise intolerance is a reduced ability to perform physical activity at the expected level, because of symptoms (breathlessness, fatigue, chest pain, leg pain, palpitations, dizziness, cramps) or a measured reduction in exercise capacity. It is a final common symptom of cardiac, pulmonary, vascular, haematological, muscular, endocrine and psychological disease. Exertional syncope or chest pain with exertion signals potentially lethal disease and needs urgent evaluation.

Clinical relevance. Reduced peak oxygen uptake predicts mortality in healthy and diseased populations. The commonest causes in practice are deconditioning, obesity, asthma, anaemia, heart failure and depression, but in some patients the cause is hypertrophic cardiomyopathy, aortic stenosis, pulmonary hypertension, pulmonary embolism, coronary disease, metabolic myopathy or arrhythmia.

Physiological framework. Oxygen uptake equals cardiac output multiplied by arteriovenous oxygen difference. Limitation can arise from the pump (stroke volume, heart rate), ventilation and gas exchange, oxygen carrying capacity (haemoglobin), vascular delivery, or muscle oxygen extraction and metabolism. Exercise tests identify which step is limiting.

Classification by mechanism.

• Cardiac: reduced stroke volume or chronotropic response.
• Pulmonary: ventilatory limitation, gas exchange impairment, pulmonary vascular disease.
• Haematological: anaemia, abnormal haemoglobin.
• Peripheral vascular: arterial insufficiency.
• Neuromuscular and metabolic: myopathy, neuromuscular junction, mitochondrial or glycogen disorders, endocrine disease.
• Deconditioning, obesity, psychological and functional causes.

Severity scales. The MRC dyspnoea scale (grades 1 to 5), New York Heart Association class (I to IV), Canadian Cardiovascular Society angina grade, and metabolic equivalents (1 MET equals 3.5 mL/kg/minute of oxygen uptake; inability to climb two flights of stairs corresponds to under about 4 METs).

History.

• What limits exercise: breathlessness, leg fatigue or pain, chest pain, palpitations, dizziness, cramps, sudden weakness, or a feeling of exhaustion. Level of activity at onset (walking distance, stairs, jogging), time course, and what stops activity.
• Cardiac: exertional chest pain, syncope or presyncope, palpitations, orthopnoea, paroxysmal nocturnal dyspnoea, ankle swelling, family history of sudden death under 50, cardiomyopathy or channelopathy, rheumatic fever.
• Respiratory: wheeze after exercise (exercise induced bronchoconstriction), inspiratory stridor and throat tightness at peak effort (exercise induced laryngeal obstruction), cough, sputum, smoking, occupational exposures, atopy, sleep apnoea.
• Vascular: calf, thigh or buttock pain on walking relieved by rest in a few minutes (intermittent claudication).
• Muscle and metabolic: cramps, stiffness early in exercise improving with rest (second wind phenomenon in McArdle disease), dark urine after exercise, fasting or illness provoked weakness, family history.
• Anaemia and blood loss: heavy menses, gastrointestinal bleeding, diet, sickle cell disease.
• Endocrine and systemic: weight change, cold or heat intolerance, thirst, symptoms of adrenal insufficiency, cancer, kidney disease.
• Psychological: anxiety, panic, depression, fear of exertion, hyperventilation, sleep, burnout, trauma.
• Infection: recent viral illness, COVID-19, post viral state, tuberculosis.
• Drugs: beta blockers, calcium channel blockers, statins, amiodarone, corticosteroids, fluoroquinolones, antipsychotics, opioids, chemotherapy, ACE inhibitor cough.
• Pregnancy, altitude, training load and history for athletes (overtraining, insufficient energy intake, iron deficiency).

Examination.

• Weight, body mass index, pulse, blood pressure in both arms, respiratory rate, oxygen saturation at rest and after walking or stair climbing (a fall of 4% or more, or under 90%, is abnormal).
• Pallor, cyanosis, clubbing, jaundice, goitre, lymph nodes.
• Cardiac: jugular venous pressure, apex beat, murmurs (aortic stenosis, hypertrophic cardiomyopathy, mitral regurgitation or stenosis), added sounds, signs of right ventricular strain, peripheral oedema.
• Chest: wheeze, crackles, hyperinflation, effusion, stridor.
• Peripheral pulses, bruits, ankle-brachial index (under 0.9 indicates peripheral arterial disease).
• Neuromuscular: power, fatigability, reflexes, muscle bulk, myotonia.
• Orthostatic pulse and blood pressure.
• Musculoskeletal and joint limitations.
• Mental state and signs of anxiety or hyperventilation.

Red flags.

• Syncope or presyncope on exertion.
• Chest pain with exertion, palpitations with dizziness, family history of sudden death under 50.
• Murmur with symptoms (aortic stenosis, hypertrophic cardiomyopathy).
• Progressive breathlessness, orthopnoea, hypoxaemia on exertion, haemoptysis.
• Rapidly progressive exercise limitation, weight loss, fever.
• Dark urine, severe muscle pain or weakness after exercise (rhabdomyolysis).
• Unilateral leg swelling or pleuritic pain (venous thromboembolism).
• Cyanosis, clubbing, signs of pulmonary hypertension.

Cardiac.

• Heart failure (reduced and preserved ejection fraction)
• coronary artery disease
• aortic stenosis
• hypertrophic cardiomyopathy
• dilated cardiomyopathy
• mitral valve disease
• rheumatic heart disease
• congenital heart disease
• arrhythmias (atrial fibrillation, supraventricular tachycardia, ventricular tachycardia)
• chronotropic incompetence and sinus node disease
• atrioventricular block
• pericardial constriction
• pulmonary hypertension
• myocarditis
• peripartum cardiomyopathy
• Chagas cardiomyopathy
• endomyocardial fibrosis
• anomalous coronary artery
• long QT syndrome and other channelopathies

Pulmonary and airway. Asthma and exercise induced bronchoconstriction, chronic obstructive pulmonary disease, interstitial lung disease, bronchiectasis, pulmonary embolism and chronic thromboembolic disease, pulmonary hypertension, sarcoidosis, pneumothorax, pleural effusion, kyphoscoliosis, obesity hypoventilation, exercise induced laryngeal obstruction (vocal cord dysfunction), dysfunctional breathing and hyperventilation.

Haematological and oxygen carrying. Iron deficiency and other anaemias, haemolytic anaemia, sickle cell disease, thalassaemia, carbon monoxide poisoning, methaemoglobinaemia, polycythaemia.

Vascular. Peripheral arterial disease with claudication, popliteal artery entrapment, vasculitis, spinal stenosis (neurogenic claudication), venous insufficiency.

Neuromuscular and metabolic.

• Myopathies: inflammatory, drug induced, endocrine, mitochondrial, glycogen storage disorders (McArdle disease, Pompe disease), carnitine palmitoyltransferase II deficiency, muscular dystrophy, periodic paralysis.
• Neuromuscular junction: myasthenia gravis, Lambert-Eaton syndrome.
• Neuropathy and motor neurone disease.

Endocrine and systemic. Hypothyroidism, hyperthyroidism, adrenal insufficiency, diabetes mellitus, Cushing syndrome, hypopituitarism, chronic kidney disease, chronic liver disease, malignancy, malnutrition, infection (HIV, tuberculosis), post viral and post COVID-19 states.

Psychological and functional. Deconditioning, obesity, anxiety, panic disorder, depression, burnout, chronic fatigue syndrome, postural orthostatic tachycardia syndrome, sleep disorders, relative energy deficiency in sport, overtraining syndrome.

Drugs. Beta blockers, calcium channel blockers, amiodarone, statins, corticosteroids, antipsychotics, opioids, chemotherapy.

1. History and examination identify the dominant limiting symptom. Exertional syncope, chest pain, or murmur with symptoms prompts urgent cardiac assessment before further exercise.
2. First line tests: full blood count, ferritin and transferrin saturation, urea, creatinine and electrolytes, glucose or HbA1c, thyroid stimulating hormone, creatine kinase, and liver function tests.
3. Also natriuretic peptide (NT-proBNP under 125 pg/mL makes chronic heart failure unlikely), ECG, chest radiograph, and spirometry with bronchodilator reversibility (increase of 12% and 200 mL in forced expiratory volume in 1 second).
4. Oxygen saturation at rest and after exercise (walking test or 6 minute walk). A fall of 4% or more, or under 90%, suggests lung or pulmonary vascular disease.
5. Cardiac imaging: transthoracic echocardiography for ventricular function, valves, pulmonary pressure and wall thickness; exercise ECG, stress echocardiography or perfusion imaging for ischaemia; cardiac MRI for cardiomyopathy and myocarditis; CT coronary angiography; ambulatory ECG monitoring or an event recorder; tilt table testing for orthostatic intolerance.
6. Cardiopulmonary exercise testing separates causes. Peak oxygen uptake under 80% predicted is reduced.
7. Early anaerobic threshold (under 40% of predicted peak) suggests cardiac or deconditioning limitation. Reduced breathing reserve (under 15%) suggests ventilatory limitation.
8. Elevated ventilatory equivalent for carbon dioxide (slope over 34) suggests heart failure or pulmonary vascular disease.
9. A low peak heart rate with normal oxygen pulse suggests chronotropic incompetence. A flat oxygen pulse suggests ischaemia or obstruction.
10. Respiratory: bronchial challenge (methacholine, mannitol or eucapnic voluntary hyperpnoea). A fall in forced expiratory volume in 1 second of 10% or more after exercise confirms exercise induced bronchoconstriction.
11. Other respiratory tests: continuous laryngoscopy during exercise for laryngeal obstruction, diffusing capacity, high resolution CT, CT pulmonary angiography or ventilation perfusion scan, right heart catheterisation for pulmonary hypertension, and sleep study.
12. Vascular: ankle-brachial index at rest and after exercise, arterial duplex ultrasound, CT or MR angiography.
13. Neuromuscular and metabolic: creatine kinase before and after exercise, and serum lactate and ammonia during a non ischaemic forearm exercise test (in McArdle disease lactate does not rise and ammonia rises excessively).
14. Also acylcarnitine profile, urine organic acids, electromyography, repetitive nerve stimulation, muscle MRI, muscle biopsy, and genetic testing.
15. Carboxyhaemoglobin and methaemoglobin levels when poisoning is suspected. Haemoglobin electrophoresis if sickle cell disease or thalassaemia is possible.
16. Screening for anxiety and depression (GAD-7, PHQ-9), the Nijmegen questionnaire for hyperventilation, and review of training load and energy intake in athletes.

Limits. Resting tests are often normal. Cardiopulmonary exercise testing needs specialist equipment and patient effort. Exercise ECG has limited sensitivity for coronary disease. Normal tests do not exclude a metabolic myopathy; a targeted exercise test is needed.

Safety first. Advise no strenuous exercise and no competitive sport until evaluation is complete in anyone with exertional syncope, chest pain, palpitations with dizziness, suspected hypertrophic cardiomyopathy or severe aortic stenosis. Seek immediate care for fainting or chest pain.

Cause directed treatment.

• Heart failure: diuretics (for example furosemide 40 mg orally once daily), and disease modifying drugs directed by cardiology, plus cardiac rehabilitation.
• Valve disease, hypertrophic cardiomyopathy, arrhythmia and pulmonary hypertension: cardiology and surgical care. Beta blockers such as metoprolol succinate 50 mg orally once daily (maximum 200 mg) reduce outflow obstruction in hypertrophic cardiomyopathy.
• Coronary disease: aspirin 75 mg daily, atorvastatin 40 to 80 mg daily, anti-anginal therapy (bisoprolol 2.5 mg daily increased to 10 mg), and revascularisation as directed.
• Exercise induced bronchoconstriction: salbutamol 200 to 400 micrograms inhaled 15 to 30 minutes before exercise, regular inhaled corticosteroid (for example budesonide 200 to 400 micrograms twice daily) when frequent, montelukast 10 mg orally daily as an alternative (monitor mood and sleep), and a warm up.
• Asthma and chronic obstructive pulmonary disease: inhaled therapy, pulmonary rehabilitation (6 to 8 weeks, 2 to 3 sessions weekly), smoking cessation, vaccination.
• Exercise induced laryngeal obstruction: breathing retraining by a speech and language therapist or physiotherapist.
• Iron deficiency anaemia: ferrous sulphate 200 mg (65 mg elemental iron) orally once daily or on alternate days for 3 months after haemoglobin normalises; find and treat the cause of the deficiency. Vitamin B12 deficiency: hydroxocobalamin 1 mg intramuscularly three times weekly for 2 weeks, then every 3 months.
• Peripheral arterial disease: supervised exercise (at least 30 to 60 minutes, 3 times weekly for 3 months), smoking cessation, atorvastatin 40 to 80 mg daily, and antiplatelet therapy (clopidogrel 75 mg daily or aspirin 75 mg daily).
• For persistent claudication, cilostazol 100 mg twice daily (30 minutes before or 2 hours after meals; contraindicated in heart failure). Revascularisation for limiting symptoms.
• Hypothyroidism: levothyroxine 1.6 micrograms/kg orally once daily on an empty stomach. Adrenal insufficiency: hydrocortisone 15 to 25 mg daily in divided doses.
• Metabolic myopathies: McArdle disease, sucrose 30 to 40 g in a drink 5 to 10 minutes before exertion, regular low intensity aerobic training, and avoidance of sudden high intensity or static exertion. Carnitine palmitoyltransferase II deficiency: avoid fasting and prolonged exercise, frequent carbohydrate intake, and medium chain triglyceride supplementation. Mitochondrial and other myopathies: specialist care.
• Neuromuscular junction disease: pyridostigmine 30 to 60 mg orally every 4 to 6 hours while awake (maximum 360 mg daily) with immunotherapy by neurologists.
• Postural orthostatic tachycardia syndrome: fluids 2 to 3 litres daily, salt 6 to 10 g daily, compression garments, recumbent or seated exercise first, and specialist drug therapy.
• Deconditioning and obesity: graded programme starting at 10 to 15 minutes of walking 3 to 5 times weekly, increasing duration by 10% each week toward 150 minutes of moderate activity weekly with resistance training twice weekly. Weight management.
• Post viral and post COVID-19 exertional intolerance: assess for orthostatic intolerance, cardiac and lung disease; use pacing, avoid forcing graded exercise when postexertional malaise is present, and increase activity only within symptom limits.
• Anxiety, depression and dysfunctional breathing: psychological therapy (cognitive behavioural therapy), breathing retraining, and an antidepressant such as sertraline 50 mg orally daily when indicated.
• Stop or substitute drugs that limit exercise (beta blocker, statin myopathy).
• Athletes: energy availability, iron status, training load, rest and psychological stress.

Monitoring. Review at 4 to 6 weeks with repeat walking distance, symptom scale and relevant tests (haemoglobin after iron, thyroid stimulating hormone after levothyroxine, spirometry after inhaled therapy). Repeat cardiopulmonary exercise testing after treatment where used.

Referral and escalation. Immediate: exertional syncope, ischaemic pain, severe hypoxaemia, suspected pulmonary embolism. Urgent cardiology for murmurs, abnormal ECG or echocardiogram, family history of sudden death, and athletes with symptoms. Respiratory, vascular, neuromuscular, metabolic or sports medicine clinics as indicated. Exercise physiologist or rehabilitation for deconditioning.

Admission. Syncope with arrhythmia or severe structural disease, acute coronary syndrome, pulmonary embolism, decompensated heart failure, rhabdomyolysis, severe anaemia, hypoxaemia, or haemodynamic instability.

Safety netting. Return for fainting, chest pain, palpitations, breathlessness at rest, leg swelling, dark urine, or cough with blood.

Special groups. Athletes: screen for hypertrophic cardiomyopathy, channelopathy and anomalous coronary arteries; consider exercise induced bronchoconstriction, iron deficiency, overtraining and relative energy deficiency; cardiac clearance before return to play. Children: congenital heart disease, asthma, anaemia, obesity and psychological factors.

Pregnancy: exertional breathlessness is common due to physiological change; exclude anaemia, peripartum cardiomyopathy and pulmonary embolism. Older adults: frailty, sarcopenia, heart failure with preserved ejection fraction, anaemia and drug effects.

Endemic regions: rheumatic heart disease, Chagas disease, endomyocardial fibrosis, peripartum cardiomyopathy, schistosomiasis, tuberculosis, hookworm anaemia and sickle cell disease are frequent causes.