Respiratory alkalosis

Respiratory alkalosis is a primary fall in arterial carbon dioxide (PaCO2 under 35 mmHg or 4.7 kPa) from alveolar hyperventilation, with an arterial pH over 7.45 unless compensation is complete. It is the commonest acid base disturbance in acutely ill patients, and often signals a serious cause (hypoxia, pulmonary embolism, sepsis, salicylate poisoning, brain injury) rather than anxiety.

Clinical relevance. Hyperventilation occurs in up to 50% of patients with sepsis, pulmonary embolism, asthma and pneumonia at presentation. Severe hypocapnia lowers cerebral blood flow, shifts the oxyhaemoglobin curve to the left, reduces ionised calcium (tetany), and causes hypokalaemia and hypophosphataemia.

Physiology. Ventilation is driven by CO2 (via central chemoreceptors), hypoxia (peripheral chemoreceptors), pH and non-chemical inputs (pain, anxiety, fever, drugs, hormones, lung receptors). Acute hypocapnia lowers pH by 0.08 for each 10 mmHg fall in PaCO2 with bicarbonate falling 2 mmol/L for each 10 mmHg. In chronic hypocapnia (after 2 to 3 days), renal compensation lowers bicarbonate by 4 to 5 mmol/L for each 10 mmHg, so pH falls only about 0.03 for each 10 mmHg.

Classification by duration.

• Acute: PaCO2 under 35 mmHg, pH over 7.45, bicarbonate near 20 to 24 mmol/L.
• Chronic: PaCO2 under 35 mmHg with near normal pH and bicarbonate under 20 mmol/L (high altitude, pregnancy, chronic liver disease, chronic lung disease).

Classification by severity.

• Mild: PaCO2 30 to 34 mmHg.
• Moderate: PaCO2 25 to 29 mmHg.
• Severe: PaCO2 under 25 mmHg or pH over 7.55.

Classification by cause.

• Hypoxic drive: pneumonia, pulmonary embolism, asthma, pulmonary oedema, interstitial lung disease, high altitude, anaemia, carbon monoxide poisoning, and shunt.
• Pulmonary receptor stimulation: pulmonary embolism, pneumothorax, pulmonary fibrosis, congestion, and pleural disease.
• Central stimulation: anxiety, panic, pain, fever, sepsis, stroke, subarachnoid haemorrhage, meningoencephalitis, tumour, and head injury.
• Metabolic and hormonal: salicylate toxicity, pregnancy (progesterone), hyperthyroidism, liver failure (hepatic encephalopathy), and hormonal therapy.
• Drugs: salicylates, theophylline, catecholamines, nicotine, progesterone, doxapram, methylxanthines, and caffeine.
• Mechanical ventilation with excessive minute volume.

Key distinctions. Respiratory alkalosis in a sick patient is a marker of severity. Primary hyperventilation syndrome (a functional disorder) is a diagnosis of exclusion, and a normal alveolar to arterial oxygen gradient with normal examination and investigations supports it.

History.

• Breathlessness, sighing, chest tightness, dizziness, light headedness, perioral and finger numbness and tingling, carpopedal spasm, palpitations, chest pain, visual blurring, anxiety, and fainting.
• Triggers: stress, panic, pain, exertion, fever, infection, medication, and pregnancy.
• Features of dangerous causes:

• Pleuritic pain, haemoptysis, leg swelling, recent surgery or immobility (pulmonary embolism).
• Fever, cough, sputum (pneumonia, sepsis).
• Tinnitus, vomiting, sweating, overdose history (salicylates).
• Headache, neck stiffness, neurological deficit (CNS cause).
• Abdominal symptoms, and thyroid symptoms.

• Drugs: aspirin and salicylates, theophylline, progesterone, caffeine, nicotine, stimulants, and catecholamines.
• Past history: asthma, lung disease, heart disease, liver disease, anxiety disorder, and previous episodes.

Examination.

• Respiratory rate (rapid, deep, sighing), pattern, oxygen saturation (normal in primary hyperventilation), pulse, blood pressure, temperature, and sweating.
• Chest examination: wheeze, crackles, reduced air entry, pleural rub, pneumothorax signs.
• Leg swelling and calf tenderness (venous thrombosis), tachycardia, raised jugular venous pressure, and loud pulmonary second sound.
• Neuromuscular: Chvostek and Trousseau signs, tetany, hyperreflexia, and paraesthesia.
• Neurological: focal signs, neck stiffness, confusion, and papilloedema. Thyroid, liver stigmata, and signs of pregnancy.

Red flags.

• Hypoxia (saturation under 94% on room air), tachycardia over 120 beats/min, or hypotension.
• Pleuritic chest pain, haemoptysis, unilateral leg swelling, recent surgery or cancer (pulmonary embolism).
• Fever, rigors, productive cough, or raised lactate (sepsis, pneumonia).
• Tinnitus, vomiting, sweating, drowsiness, or known overdose (salicylate poisoning).
• Neurological deficit, severe headache, neck stiffness, or reduced consciousness.
• pH over 7.55, PaCO2 under 20 mmHg, or tetany, seizures or arrhythmia.
• Metabolic acidosis coexisting with hyperventilation (mixed disorder).
• Age over 40 years with a first episode of hyperventilation, chest pain or cardiac risk factors.
• Pregnancy with severe hyperventilation or hypoxia.

Special groups. Pregnancy has a physiological mild respiratory alkalosis (PaCO2 about 4.0 kPa or 30 mmHg). High altitude residents have chronic compensated alkalosis. Children with anxiety and breath holding can show alkalosis. Older adults rarely have primary hyperventilation syndrome, and an organic cause is likely.

Hypoxic and pulmonary causes. Pulmonary embolism, pneumonia, asthma (early), pulmonary oedema, pneumothorax, interstitial lung disease, pulmonary hypertension, acute respiratory distress syndrome, high altitude, severe anaemia, and carbon monoxide poisoning.

Sepsis and systemic causes. Sepsis (often an early sign), fever, liver failure and hepatic encephalopathy, thyrotoxicosis, pregnancy, and hormone therapy.

Central nervous system causes. Subarachnoid haemorrhage, stroke, brainstem lesions, meningitis, encephalitis, trauma, tumour, and seizures.

Toxic and drug causes. Salicylate poisoning (often with metabolic acidosis), theophylline, caffeine, nicotine, catecholamines, progesterone, doxapram, and methylxanthines.

Functional causes. Anxiety, panic attack, hyperventilation syndrome, pain, and conversion disorder.

Iatrogenic. Mechanical ventilation with excessive minute ventilation, and non-invasive ventilation.

Conditions that cause similar symptoms. Hypocalcaemia, hypoglycaemia, cardiac arrhythmia, acute coronary syndrome, vestibular disorders, and carpal tunnel or other neuropathies.

Step 1. Take an arterial blood gas (pH, PaCO2, PaO2, bicarbonate, lactate) and compare the degree of compensation. Bicarbonate falls 2 mmol/L for each 10 mmHg fall in PaCO2 in acute disease and 4 to 5 mmol/L in chronic. Calculate the alveolar to arterial oxygen gradient. It is raised in lung disease, pulmonary embolism and shunt, and normal in primary hyperventilation and central causes.

Step 2. Laboratory tests:

• Electrolytes (potassium, phosphate, magnesium), ionised and total calcium, glucose, lactate.
• Urea, creatinine, liver tests, full blood count, CRP, thyroid function.
• Salicylate and paracetamol levels, troponin, D-dimer (low pretest probability only).
• Blood cultures and pregnancy test.

Step 3. Imaging and cardiac tests: chest radiograph, ECG, CT pulmonary angiography for suspected embolism, echocardiography, and CT head (and lumbar puncture) for suspected CNS disease.

Step 4. For suspected functional hyperventilation, confirm normal oxygen saturation, normal examination and investigations, and a typical history. Use a hyperventilation provocation test (voluntary hyperventilation reproducing symptoms) or the Nijmegen questionnaire where available.

Interpretation. A PaCO2 under 4.0 kPa (30 mmHg) with hypoxia and a raised alveolar to arterial gradient suggests pulmonary embolism or pneumonia. A respiratory alkalosis with a high anion gap metabolic acidosis suggests salicylate poisoning or sepsis. Isolated hypocapnia with a normal gradient and normal investigations suggests hyperventilation syndrome.

Limitations. Pulse oximetry can be normal in pulmonary embolism. D-dimer is non-specific. Severe hypocapnia can reduce ionised calcium without altering total calcium. Venous gas PCO2 is higher than arterial.

Principles. Treat the underlying cause, correct hypoxia, relieve symptoms, and avoid assuming anxiety until organic causes are excluded. Most respiratory alkalosis resolves when the cause is treated.

Immediate priorities. Assess airway, breathing and circulation. Give oxygen to keep saturation 94 to 98% if hypoxic. Do not give oxygen to a patient with normal saturation purely to treat hyperventilation. Obtain access and a gas, and examine for pulmonary embolism, sepsis, salicylate poisoning and central nervous system causes.

Hyperventilation syndrome (only after organic causes are excluded).

• Reassure, explain the mechanism, and coach slow diaphragmatic breathing: 6 to 8 breaths/min, inhalation through the nose for 4 seconds and slow exhalation for 6 seconds, for 5 to 10 minutes. Do not use paper bag rebreathing, which can cause dangerous hypoxia.
• If symptoms are severe or the patient is very distressed: lorazepam 0.5 to 1 mg orally once (maximum 2 mg daily; short term only) or diazepam 2 mg orally once (maximum 10 mg daily short term).
• With a benzodiazepine, monitor sedation and respiratory rate. Avoid with respiratory depression, sleep apnoea and in older adults. A benzodiazepine must not be used when a cause of hypoxia is possible.
• Longer term: breathing retraining with a physiotherapist, cognitive behavioural therapy, and treatment of anxiety or panic disorder.
• Sertraline 25 mg orally once daily for 1 week, then 50 mg once daily, increased by 25 to 50 mg every 1 to 2 weeks to a maximum of 200 mg daily. Monitor for activation, sleep change, and sodium.

Pulmonary embolism. Haemodynamically stable:

• Apixaban 10 mg orally twice daily for 7 days, then 5 mg twice daily for at least 3 months. Reduce or avoid with CrCl under 30 mL/min, weight under 50 kg, or interacting drugs. Monitor haemoglobin, creatinine and bleeding.
• Or low molecular weight heparin enoxaparin 1.5 mg/kg subcutaneously once daily (or 1 mg/kg every 12 hours; 1 mg/kg once daily if CrCl is under 30 mL/min), bridging to a direct oral anticoagulant. Monitor platelets from day 4 and anti-Xa in obesity, pregnancy and kidney impairment.

Unstable: thrombolysis with alteplase 100 mg IV over 2 hours (or 10 mg bolus then 90 mg over 2 hours) with unfractionated heparin. It is contraindicated by recent bleeding, surgery or stroke. The alternatives are catheter directed therapy and surgical embolectomy, depending on team assessment.

Sepsis. Blood cultures and antibiotics within 1 hour, for example ceftriaxone 2 g IV once every 24 hours (maximum 4 g daily). Give fluid resuscitation with 30 mL/kg isotonic crystalloid for hypotension or lactate of 4 mmol/L or more. Control the source. Use vasopressors (noradrenaline 0.05 to 0.5 micrograms/kg/minute IV titrated to mean arterial pressure over 65 mmHg).

Pneumonia, asthma and pulmonary oedema. Treat the cause.

• Severe asthma: salbutamol 5 mg nebulised every 20 minutes, ipratropium 500 micrograms nebulised, and hydrocortisone 100 mg IV. A normal or rising PaCO2 in a patient with severe asthma signals fatigue.
• Pulmonary oedema: furosemide 40 to 80 mg IV and glyceryl trinitrate.
• Pneumonia: amoxicillin 1 g IV or orally every 8 hours with clarithromycin 500 mg every 12 hours. Adjust for kidney function and monitor QTc.

Salicylate poisoning.

• Sodium bicarbonate 8.4% 1 to 2 mmol/kg IV bolus (50 to 100 mmol) over 15 to 30 minutes.
• Then an infusion of 150 mmol in 1 litre of 5% glucose at 1.5 to 2 times maintenance rate to keep urine pH 7.5 to 8.0, with potassium repletion (target potassium over 4.0 mmol/L).
• Salicylate levels every 2 hours. Activated charcoal 50 g orally within 1 hour of ingestion.
• Haemodialysis for level over 7.2 mmol/L (about 1000 mg/L), altered mental state, pulmonary oedema, kidney impairment, or pH under 7.2.

Avoid intubation where possible because loss of hyperventilation can cause rapid fatal acidosis. If intubation is unavoidable, use high minute ventilation and give bicarbonate beforehand.

Neurological causes. Treat the cause (subarachnoid haemorrhage, meningitis, stroke). Avoid excessive hyperventilation in head injury except for short term control of herniation (PaCO2 4.0 to 4.5 kPa).

Ventilator settings. Reduce tidal volume, respiratory rate or minute ventilation, add dead space where appropriate, adjust sedation and treat pain or agitation. Aim for a PaCO2 of 4.5 to 5.5 kPa (35 to 42 mmHg) unless another target is set by the cause.

Complications of hypocapnia.

• Tetany and low ionised calcium: calcium gluconate 10% 10 to 20 mL IV over 10 minutes with ECG monitoring if symptoms are severe or ionised calcium is low. Repeat after 10 minutes if needed. Avoid with digoxin without monitoring.
• Hypokalaemia: potassium chloride 40 mmol in 1 litre isotonic saline over 4 hours (maximum 10 mmol/hour peripherally; monitor potassium every 4 to 6 hours), once the cause is under treatment.
• Hypophosphataemia (severe alkalosis): sodium phosphate 10 to 20 mmol IV over 6 to 12 hours. Reduce in kidney impairment. Monitor phosphate, calcium and potassium.
• Arrhythmia and ischaemia: oxygen, correct electrolytes, and cardiac monitoring.

Chronic respiratory alkalosis. Treat the cause (liver disease, lung disease; pregnancy needs no treatment). For acclimatisation at altitude, give acetazolamide 125 to 250 mg orally twice daily starting 1 day before ascent and continuing for 2 days at altitude (maximum 750 mg daily). Monitor paraesthesia, potassium and renal stones. Avoid in sulphonamide allergy and severe liver or kidney disease.

Monitoring. Arterial or venous gas, lactate, potassium, calcium, magnesium and phosphate every 2 to 4 hours initially in severe cases. Continuous saturation, ECG, and respiratory rate. Neurological observations, and review of the cause.

Referral and escalation. Critical care for sepsis, pulmonary embolism with instability, severe salicylate poisoning, pH over 7.55 or ventilator adjustment. Respiratory medicine for hyperventilation syndrome and lung disease. Toxicology for overdose. Neurology and neurosurgery for CNS disease. Psychiatry or clinical psychology for panic disorder. Obstetrics for pregnancy.

Admission criteria. Hypoxia, abnormal vital signs, suspected pulmonary embolism, sepsis, salicylate poisoning, CNS disease, pH over 7.55, tetany or arrhythmia, new alkalosis with an unexplained cause, or age over 40 with a first episode. Young patients with a typical history, normal vital signs and normal tests can be managed in the community.

Discharge and safety netting. Discharge when the diagnosis is secure (functional hyperventilation only after organic causes are excluded), symptoms are controlled, saturation is normal, and a plan is made, with review in 1 to 2 weeks and referral to breathing retraining. Patients return for chest pain, breathlessness that does not settle, leg swelling, haemoptysis, fever, fainting, confusion or persistent tingling or spasm.