What are the side effects of dexamethasone?

Dexamethasone Side Effects

Dexamethasone causes dose-dependent side effects, with high doses (≥0.5 mg/kg/day or 96 mg/day) associated with serious complications including gastrointestinal perforation, bleeding, neurodevelopmental impairment in neonates, and psychiatric disturbances, while moderate doses (8-16 mg/day) have a more manageable profile but still cause insomnia, hyperglycemia, and gastrointestinal symptoms. 1, 2

Dose-Dependent Toxicity Profile

High-Dose Dexamethasone (≥96 mg/day or ≥0.5 mg/kg/day)

Serious gastrointestinal complications occur at unacceptably high rates:

• 14.3% serious adverse events including fatal ulcer hemorrhage, rectal bleeding, gastrointestinal perforation, and sigmoid perforation in patients receiving 96 mg IV loading dose tapered over 14 days 3
• This high-dose regimen was abandoned due to the severity of complications 3

Neurodevelopmental harm in neonates:

• High-dose dexamethasone (0.5 mg/kg/day) causes neurodevelopmental impairment, decreased hippocampal volume, altered hippocampal synaptic plasticity, and impaired memory formation 1
• Neonates treated with high-dose dexamethasone show shorter stature, smaller head circumference, lower IQ scores, and more significant disabilities (cerebral palsy, IQ <5th percentile, vision/hearing impairment): 39% vs 22% in controls 1
• Major neurodevelopmental impairment rates: 36% vs 14% in placebo 1

Moderate-Dose Dexamethasone (8-16 mg/day)

Standard doses have a more manageable but still significant side effect profile:

• 65% of patients with greatest exposure (mean 243 mg over 27 days) experienced Grade 3+ adverse events vs 15% with no exposure (OR 15.1,95% CI 1.4-160.8) 4
• 23% hospitalization rate in patients receiving dexamethasone 4

Common moderate-severity side effects include:

• Insomnia (45% report moderate-severe problems) 5
• Indigestion/epigastric discomfort (27%) 5
• Agitation (27%) 5
• Increased appetite (19%) 5
• Weight gain (16%) 5
• Acne (15%) 5

Low-Dose Dexamethasone (<0.2 mg/kg/day or single perioperative doses)

Single intraoperative doses (0.15-1.0 mg/kg) have minimal side effects:

• Probably little or no difference in postoperative infection risk (Peto OR 1.01,95% CI 0.80-1.27) 6
• Mild glucose elevation in non-diabetic patients during first 12 hours (mean difference 13 mg/dL, 95% CI 6-21) 6
• More pronounced glucose increase in diabetic patients (mean difference 32 mg/dL, 95% CI 15-49) 6
• Uncertain effect on delayed wound healing due to imprecision in trial results 6

Specific Organ System Effects

Neuropsychiatric

Mood disturbances are dose-dependent and timing-dependent:

• Hypomania and mania most common during acute therapy 7
• Depression more common during long-term treatment 7
• Symptoms are dose-dependent and typically occur within first few weeks 7
• Reversible with dose reduction or discontinuation 7

Cognitive impairment:

• Decline in declarative and working memory during therapy 7
• Changes in temporal lobe structure and function detected on imaging 7
• Effects are reversible with dose reduction 7

Gastrointestinal

Risk increases dramatically with high doses:

• Peptic ulceration may occur with high-dose, short-term therapy 8
• Serious bleeding and perforation events at 14.3% with 96 mg/day regimen 3
• Indigestion/epigastric discomfort in 27% with moderate doses 5

Metabolic/Endocrine

Hyperglycemia occurs predictably:

• Mild elevation (13 mg/dL) in non-diabetic patients within 12 hours 6
• More pronounced elevation (32 mg/dL) in diabetic patients within 24 hours 6
• Increased appetite (19%) and weight gain (16%) with moderate doses 5

Infectious Complications

Single-dose dexamethasone probably does not increase infection risk:

• No significant difference in postoperative wound or systemic infection (Peto OR 1.01,95% CI 0.80-1.27) 6
• However, 17% infection rate reported in patients receiving prolonged moderate-dose therapy 4

Thromboembolic

Risk increases when combined with immunomodulatory drugs:

• Deep vein thrombosis risk rises when dexamethasone combined with lenalidomide or thalidomide 1
• Prophylactic anticoagulation recommended with these combinations 1

Special Population Considerations

Neonates

Dexamethasone has unique neurotoxicity in this population:

• Binds only to glucocorticoid receptors (not mineralocorticoid), causing hippocampal neuronal degeneration and necrosis in animal models 1
• Low-dose dexamethasone (<0.2 mg/kg/day) may decrease adverse effects but requires further study 1
• Hydrocortisone preferred over dexamethasone in neonates due to better neurodevelopmental outcomes 1

Diabetic Patients

Greater glycemic excursions occur:

• Very limited evidence suggests more pronounced glucose increase (32 mg/dL vs 13 mg/dL in non-diabetics) 6
• Clinical relevance for wound healing remains uncertain 6

Cancer Patients

Cumulative exposure matters:

• Greater total dexamethasone exposure associated with exponentially higher serious adverse event rates 4
• Prescribers must cautiously weigh risks versus benefits, especially for symptom palliation 4

Clinical Pitfalls and Risk Mitigation

Avoid high-dose regimens unless absolutely necessary:

• No evidence that high doses (≥0.5 mg/kg/day) confer additional therapeutic benefit over lower doses 1
• Standard doses (10-16 mg/day) maintain efficacy with better safety profile 2

Monitor glucose closely in all patients:

• Even single doses cause measurable hyperglycemia 6
• Diabetic patients require more intensive monitoring 6

Limit duration of therapy:

• Side effects are dose- and duration-dependent 4, 7
• Taper gradually after more than a few days of treatment 8

Consider prophylactic measures:

• Anticoagulation when combining with lenalidomide or thalidomide 1
• Lithium or phenytoin can prevent mood symptoms in controlled trials 7
• Lamotrigine and memantine may reverse memory effects 7

Recognize reversibility:

• Most psychiatric and cognitive effects reverse with dose reduction or discontinuation 7
• Early recognition and intervention prevent serious complications 3, 4