What are the side effects of an ibuprofen (nonsteroidal anti-inflammatory drug (NSAID)) overdose in patients with varying ages and pre-existing medical conditions, such as gastrointestinal issues or impaired renal function?

Ibuprofen Overdose: Side Effects and Clinical Manifestations

Ibuprofen overdose can cause life-threatening complications including cardiovascular collapse, severe metabolic acidosis, acute renal failure, gastrointestinal bleeding, and central nervous system depression, with fatalities reported at massive ingestions despite intensive supportive care. 1, 2

Gastrointestinal Toxicity

• Upper gastrointestinal bleeding, ulceration, and perforation can occur at any time during NSAID use, even with short-term therapy, affecting approximately 1% of patients within 3-6 months and 2-4% within one year. 1
• Nausea, vomiting, abdominal cramps, and hematemesis are common presenting symptoms in overdose cases. 3, 4
• Only one in five patients who develop serious upper GI adverse events will have warning symptoms beforehand. 1
• Patients with prior peptic ulcer disease have a greater than 10-fold increased risk for developing GI bleeding compared to those without these risk factors. 1

Renal Toxicity

• Acute renal insufficiency and oliguric renal failure can develop within 11-27 hours after massive ibuprofen ingestion, even in previously healthy children without prior renal problems. 5, 3
• Renal papillary necrosis and other renal injury can occur with long-term NSAID administration. 1
• NSAIDs cause dose-dependent reduction in prostaglandin formation, leading to decreased renal blood flow and precipitating overt renal decompensation. 1
• Patients at greatest risk include those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. 1
• Microscopic hematuria without casts or proteinuria may be present, with normalization of renal function typically occurring by 72 hours in survivors. 5

Cardiovascular Complications

• Massive ibuprofen overdose can cause refractory cardiovascular collapse, hypotension requiring vasopressors, and tachycardia, leading to death despite intensive supportive care. 2, 3
• NSAIDs increase the risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. 1
• Fluid retention and edema have been observed in patients treated with NSAIDs, with approximately two-fold increase in hospitalizations for heart failure. 1
• NSAIDs can lead to new-onset hypertension or worsening of preexisting hypertension. 1

Central Nervous System Effects

• Depressed level of consciousness, unresponsiveness, coma, and mild to severe CNS depression are characteristic features of ibuprofen overdose. 6, 2, 3
• Dizziness and mild sedation are common in typical overdose presentations. 6, 4
• In rare cases, naloxone administration has reversed CNS manifestations of ibuprofen overdose, suggesting potential opioid receptor interaction. 6

Metabolic Derangements

• Severe metabolic acidosis with or without respiratory alkalosis is a hallmark of massive ibuprofen overdose and contributes significantly to mortality. 2, 3, 4
• Hypothermia can develop in severe cases and is associated with poor prognosis. 2

Hepatic Toxicity

• Acute liver-cell injury and acute cholestasis can occur following massive ibuprofen ingestion. 3
• Hepatic damage from NSAIDs is rare but should not be used in patients with cirrhotic liver diseases due to increased risk of bleeding and renal failure. 7

Hematologic Effects

• Thrombocytopenia can develop as part of multisystem organ failure in severe overdose. 3
• NSAIDs have antiplatelet effects that can contribute to bleeding complications. 7

Respiratory Complications

• Respiratory failure and apnea can occur in severe ibuprofen overdose, requiring mechanical ventilation. 2, 3, 4

Dose-Toxicity Relationship

• Significant toxicity is typically associated with ingestions exceeding 400 mg/kg in children, with no toxic reactions observed in patients ingesting less than 104 mg/kg. 4
• Therapeutic serum ibuprofen concentration is 10-50 μg/mL (50-250 μmol), while toxic cases have reported levels of 260-352 μg/mL (897 μmol/L). 5, 2, 3
• Accumulation of metabolites (2-carboxyibuprofen and 2-hydroxyibuprofen) occurs in plasma following overdose. 3

Time Course of Toxicity

• All patients who developed toxic reactions did so within four hours of ingestion when the time was known. 4
• Peak creatinine elevation typically occurs by 27 hours post-ingestion in cases of acute renal insufficiency. 5
• Complete resolution of multiple organ failure can occur with supportive care, though fatalities have been reported despite intensive intervention including renal replacement therapy. 2, 3

High-Risk Populations

• Elderly or debilitated patients are at highest risk for fatal GI events and should receive special care. 1
• Patients with prior history of peptic ulcer disease, gastrointestinal bleeding, impaired renal function, heart failure, or liver dysfunction face substantially elevated risk. 1
• Concomitant use of oral corticosteroids, anticoagulants, longer duration of NSAID therapy, smoking, alcohol use, older age, and poor general health status increase GI bleeding risk. 1

Serious Dermatologic Reactions

• NSAIDs can cause serious skin adverse reactions including exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE), which can be fatal. 1
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported and may present with fever, rash, lymphadenopathy, facial swelling, hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. 1

Anaphylactoid Reactions

• Anaphylactoid reactions may occur in patients without known prior exposure to ibuprofen. 1
• Ibuprofen should not be given to patients with aspirin triad (asthma, rhinitis with or without nasal polyps, and severe bronchospasm after aspirin or NSAID use). 1

Critical Management Considerations

• Despite the use of continuous veno-venous hemofiltration, hemodialysis, vasopressors, and intensive supportive care, massive ibuprofen overdose may result in refractory multisystem organ failure and death. 2
• Renal function should be monitored in severe overdose cases, as acute renal insufficiency is reversible in survivors. 5
• Treatment requires supportive therapy until symptoms resolve over 24-48 hours in typical cases. 6