Dexamethasone

Dexamethasone is a long-acting, potent glucocorticoid with almost no mineralocorticoid activity. It is used for croup, cerebral oedema, bacterial meningitis, severe COVID-19 with hypoxia, antenatal lung maturation, chemotherapy-related nausea, and as an anti-inflammatory and immunosuppressant. Its long action suits single-dose regimens and its potency makes it a poor choice for adrenal replacement.

Classification. Glucocorticoid. Tablets 0.5 mg, 0.75 mg, 2 mg, 4 mg, and 8 mg; soluble tablets; oral solution; injection 4 mg/mL (phosphate); eye drops and intravitreal implants.

Mechanism. Binds the intracellular glucocorticoid receptor, altering gene transcription: reduced cytokines and capillary permeability, suppressed leukocyte migration and lymphocyte function, increased gluconeogenesis, and induced surfactant production in foetal lung. Reduces oedema around brain tumours.

Pharmacodynamics. Anti-inflammatory potency about 25 to 30 times hydrocortisone (0.75 mg equals hydrocortisone 20 mg, prednisolone 5 mg). Biological effect lasts 36 to 72 hours.

Pharmacokinetics. Oral bioavailability about 80 to 90%; peak 1 to 2 hours; 70% protein bound; plasma half-life 3 to 4 hours. Metabolised by CYP3A4 and an inducer of CYP3A4 at high doses; crosses the blood-brain barrier and the placenta (not inactivated by placental enzymes); excreted in urine.

Croup. Single dose 0.15 to 0.6 mg/kg (usually 0.15 mg/kg) orally, intramuscularly or intravenously, maximum 16 mg; a second dose after 12 to 24 hours is rarely needed.

Bacterial meningitis (adjunct).

• Adults 10 mg intravenously every 6 hours for 4 days, given 10 to 20 minutes before or with the first antibiotic dose. Children 0.15 mg/kg every 6 hours for 2 to 4 days. Stop if the cause is not pneumococcal or Haemophilus influenzae type b disease. In settings with high HIV prevalence and poor outcomes, benefit is less certain.

Tuberculous meningitis (adjunct). Adults 0.4 mg/kg/day intravenously, tapered over 6 to 8 weeks (higher doses for severe disease); children as directed by the specialist team.

Cerebral oedema (tumour) and raised intracranial pressure. 10 mg intravenously as a loading dose, then 4 mg every 6 hours, tapered over 5 to 7 days once symptoms improve (lower doses of 2 to 4 mg daily suffice for long-term control).

Severe COVID-19 with hypoxia needing oxygen or ventilation. 6 mg orally or intravenously once daily for up to 10 days.

Antenatal corticosteroids for lung maturation. Dexamethasone 6 mg intramuscularly every 12 hours for 4 doses (a total of 24 mg) in women at risk of preterm birth between 24 and 34 weeks, started when birth is expected within 7 days. A betamethasone course (12 mg every 24 hours for 2 doses) is an equally effective alternative; do not give both.

Chemotherapy-induced nausea and vomiting. 8 to 12 mg orally or intravenously before chemotherapy, then 4 to 8 mg daily on days 2 to 4 (reduced with aprepitant, which raises dexamethasone levels).

Haematological malignancy (multiple myeloma and other regimens). 20 to 40 mg orally or intravenously on set days, directed by an oncologist.

Postoperative nausea and vomiting prophylaxis. 4 to 8 mg intravenously at induction.

Anaphylaxis, severe allergy and acute asthma (adjunct). 8 to 16 mg intravenously or orally once; children 0.15 to 0.6 mg/kg (maximum 16 mg). In children with asthma 1 or 2 doses of 0.6 mg/kg on consecutive days is an alternative to prednisolone.

Adrenal suppression test. 1 mg orally at 11 pm, with morning cortisol the next day; failure of cortisol to suppress under 50 nmol/L suggests Cushing's syndrome.

Hypercalcaemia of malignancy, spinal cord compression. 8 to 16 mg intravenously, then 4 mg to 8 mg every 6 to 8 hours.

Adjustments.

• Kidney: no change.
• Liver: reduce dose in cirrhosis.
• Older adults: use the lowest dose; monitor glucose and mood.
• Weight: dose by weight in children.

Contraindications. Systemic fungal infection; untreated tuberculosis or sepsis (treat the infection alongside); hypersensitivity. Live vaccines at immunosuppressive doses.

Serious adverse effects.

• Hyperglycaemia and new diabetes; hypertension; fluid retention; hypokalaemia less than with other steroids.
• Psychiatric: insomnia, agitation, mania, psychosis, depression.
• Infection: reactivation of tuberculosis and hepatitis B, strongyloides hyperinfection, oral candidiasis.
• Gastrointestinal bleeding, especially with NSAIDs.
• Long courses: osteoporosis, myopathy, cataract, adrenal suppression, growth suppression, Cushingoid features.
• Rapid intravenous bolus: perineal burning and itching; give slowly.
• Neonatal: high doses given repeatedly after birth are linked to cerebral palsy; antenatal courses should be given once.

Major interactions.

• Reduced effect: rifampicin, phenytoin, carbamazepine, phenobarbital (inducers of CYP3A4).
• Increased effect: ketoconazole, itraconazole, clarithromycin, ritonavir, aprepitant.
• Dexamethasone lowers levels of CYP3A4 substrates: efavirenz, artemether lumefantrine, praziquantel, warfarin, oral contraceptives, some antiretrovirals.
• NSAIDs and aspirin: gastrointestinal bleeding.
• Diuretics: hypokalaemia; antidiabetic drugs: glucose rises.
• Vaccines: live vaccines are avoided.

Special groups.

• Pregnancy: used for lung maturation; the placenta passes dexamethasone to the foetus. Avoid repeat courses beyond one rescue course. Monitor glucose in diabetic women for 3 to 5 days after the course.
• Breastfeeding: compatible for short courses; avoid feeding for 4 hours after high doses.
• Children: growth suppression with long courses; single dose for croup.
• Older adults: delirium, hyperglycaemia and myopathy.
• Kidney impairment: no change; liver impairment: reduce dose.
• East Africa: widely available and cheap, so often the steroid of choice in hospital for meningitis, antenatal use and cerebral oedema. Use antenatal steroids only where gestational age is reliable and basic newborn care is available, to avoid harm to late preterm babies. Dexamethasone is often substituted for prednisolone for asthma in children, with the dose adjusted by potency.

Formulation and administration. Oral doses with food; soluble tablets dissolve in water. Intravenous doses of 4 to 8 mg are given by slow injection over 3 to 5 minutes (to limit perineal burning); larger doses are diluted and infused. Intramuscular injection for antenatal courses goes into the thigh or buttock. Store protected from light; use diluted solutions within 24 hours.

Baseline. Blood pressure, glucose, potassium, infection screen for prolonged courses, pregnancy status in women, and for adrenal testing the time and dose of the previous steroid.

Monitoring.

• Blood glucose daily during courses over 3 days, and in people with diabetes after antenatal courses.
• Blood pressure, mood, sleep and signs of infection.
• Potassium with diuretics.
• Cerebral oedema: neurological observations and imaging.
• Adrenal axis if courses exceed 3 weeks.

Dose reduction and stopping. Courses under 7 to 10 days stop without a taper. For longer courses taper over 1 to 2 weeks or longer (cerebral oedema over 5 to 7 days, tuberculous meningitis over 6 to 8 weeks).

Referral and escalation. Admit suspected adrenal crisis, psychosis, severe infection, uncontrolled hyperglycaemia or gastrointestinal bleeding. Refer cerebral oedema, spinal cord compression and haematological regimens to the relevant specialist.