Continuing Education Activity

Ibuprofen, 2-(4-isobutylphenyl)propionic acid, belongs to the class of drugs called nonsteroidal anti-inflammatory drugs (NSAIDs) and was discovered by Dr. Stewart Adams in 1961. It was first marketed in 1969 in the United Kingdom and 1974 in the United States. Ibuprofen is prescribed commonly as an analgesic, antipyretic and anti-inflammatory agent in conditions like osteoarthritis, rheumatoid arthritis, juvenile idiopathic arthritis, and acutely painful musculoskeletal conditions. Off-label uses include for conditions like cystic fibrosis to slow progression. This activity serves to review the basic pharmacological characteristics of ibuprofen, clinical presentations during an overdose, and management of ibuprofen toxicity.

Objectives:

• Describe the epidemiology of ibuprofen toxicity.
• Identify common history and physical exam findings in patients with ibuprofen.
• Summarize the treatment options for ibuprofen toxicity.
• Explain modalities to improve care coordination among interprofessional team members in order to improve outcomes for patients affected by ibuprofen toxicity.

Introduction

Ibuprofen, 2-(4-isobutylphenyl)propionic acid, belongs to the class of nonsteroidal anti-inflammatory drugs (NSAIDs) and was discovered by Dr. Stewart Adams in 1961. It was first marketed in 1969 in the United Kingdom and 1974 in the United States.[1] Ibuprofen is commonly prescribed as an analgesic, antipyretic and anti-inflammatory agent in conditions like osteoarthritis, rheumatoid arthritis, juvenile idiopathic arthritis, and acutely painful musculoskeletal conditions. Off-label uses include for conditions like cystic fibrosis to slow progression.[2] This discussion serves to review ibuprofen's essential pharmacological characteristics, clinical presentations during an overdose, and management of ibuprofen toxicity.

Etiology

An overdose of ibuprofen may be self-injurious, suicidal, or accidental. Young children may develop ibuprofen toxicity following exploratory ingestions.

Epidemiology

Ibuprofen is one of the most commonly used and prescribed medications in the world. In the United States, 9% of overdoses in adolescents reported to poison control centers were from ibuprofen ingestion.[3] In the United Kingdom, after the legalization of ibuprofen as an over-the-counter drug in 1984, there was a marked increase in ibuprofen overdose.[4] According to the 2016 Annual Report of the American Association of Poison Control Centers’ National Poison Data System, analgesics constituted the most common drug class associated with adult exposures at 11.2% and the third most common amongst children at 9.2%. Among all analgesic overdoses, 29% had used ibuprofen exclusively or combined with other analgesics, making ibuprofen the most common NSAID involved in the overdose.[5] In the United Kingdom, ibuprofen is the second most common substance (after acetaminophen) in telephone and TOXBASE inquiries to the National Poison Information Service from 2016 to 2017.

Pathophysiology

The therapeutic effects of ibuprofen are mediated by reversible binding to COX receptors (both COX-1 and COX-2) on prostaglandin synthase (also called cyclooxygenase, COX), thereby preventing arachidonic acid from binding to these sites. This prevents the conversion of arachidonic acid to the various prostaglandins that are instrumental in causing the 4 defining features of inflammation, namely redness (rubor), heat (calor), swelling (tumor), and pain (dolor). Prostaglandins also play a role in sensitizing pain-sensing nerve fibers, which explains the analgesic effect of ibuprofen and other NSAIDs. Ibuprofen also works on the thermoregulatory center of the hypothalamus to control fever.

Adverse effects associated with chronic ibuprofen use stem from prostaglandins' important roles, and thromboxanes play in various organ systems, including maintaining gastric mucosal integrity and renal blood flow. Ibuprofen can, therefore, cause dyspeptic symptoms and gastrointestinal (GI) ulcers even at therapeutic doses. In the kidneys, this can lead to decreased renal perfusion in the afferent renal vessels, especially in individuals with preexisting dehydration or renal impairment, thereby leading to reduced glomerular filtration rate (GFR).

Thromboxane A2, another substance produced by the COX enzyme, is vital for platelet aggregation and hence, coagulation. The depletion of thromboxane A2 could, therefore, in theory, inhibit platelet aggregation and cause bleeding, especially in patients on anticoagulants or antiplatelets.

There have been reports of metabolic acidosis after an acute overdose of ibuprofen and other NSAIDs, which may be explained by the accumulation of acidic metabolites in the blood.

Toxicokinetics

Ibuprofen is available as tablets with strengths ranging from 200 to 800 mg. It is well absorbed orally, with peak plasma concentrations reached in 1 to 2 hours. The onset of action after oral ingestion is 30 to 60 minutes for analgesia.[6] The onset of antipyretic action varies with age ranging from less than an hour in adults to up to 3 hours in children.[7][8] It is rapidly metabolized with a half-life of 1.8 to 2 hours. Ibuprofen is completely metabolized and eliminated in 24 hours.[9] It is almost completely protein bound at 99%.[10]

Symptoms from ibuprofen toxicity are unlikely at doses of less than 100 mg/kg in children.[11] Ingestion of more than 400 mg/kg in a child is associated with serious or life-threatening toxicity.[11] No specific cutoff distinguishes asymptomatic from symptomatic overdose in adults.[11]

History and Physical

Important points to be noted in history include the amount of ibuprofen ingested, the time of ingestion, and any co-ingestants. In children, caregivers should be asked explicitly about acetaminophen ingestion, as it is commonly mistaken for ibuprofen. Most patients report no or mild symptoms following ibuprofen overdose.[12] When symptoms do occur, onset typically occurs within 4 hours.[11]

Ibuprofen toxicity can be discussed based on the organ system involved:

Gastrointestinal (GI) Toxicity

The COX-1 enzyme is found in the gastric mucosa and is instrumental in producing prostaglandins that regulate blood flow and bicarbonate production in the stomach. Ibuprofen, being a nonselective inhibitor of COX, can disrupt the mucosal integrity of the gastric mucosa. Intramucosal hemorrhages occur within a few hours of ingestion in all NSAIDs [13], especially with acidic ones like ibuprofen. These may progress to erosions with continued use but are typically reversible. In susceptible individuals, they may progress to peptic ulcer. The severity of GI adverse effects can range from dyspepsia to life-threatening upper GI hemorrhage or viscus organ rupture. Symptoms include nausea, vomiting, dyspeptic symptoms, and abdominal pain.[11] 

GI hemorrhage has been described in multiple case reports, particularly after large ingestions.[14][15] Perforation of the duodenum has been described in a patient after a single ingestion.[16]

Renal Toxicity

Renal impairment has been described in individuals who had consumed therapeutic as well as supratherapeutic doses of ibuprofen.[17][18] In children, there has been a report of a 2-year-old who had consumed 640 mg/kg of ibuprofen and developed acute renal failure with significant elevation of creatinine and microscopic hematuria with no proteins or casts in urine. Normalization of creatinine occurred after 72 hours.[19] A prospective study of ibuprofen poisoning at Rocky Mountain Poison Control Center showed that 2 out of 63 cases had an elevation of creatinine after ingesting 4 and 4.5 g of ibuprofen, respectively, suggesting that it is not a common occurrence.[20] In most cases, renal impairment is reversible after supportive care and intravenous fluids.[21] There has been a report of a patient requiring hemodialysis for months after developing renal failure following ingestion of massive amounts of ibuprofen, with the eventual recovery of renal function.[22]

Neurological

Acute ibuprofen overdose causing central nervous system (CNS) toxicity is not uncommon, particularly when the ingestion is massive at more than 400 mg/kg. In a prospective population-based ibuprofen overdose study, CNS depression was the second most clinical finding after gastrointestinal disturbances at 30%, but symptoms were mild.[23] In another study, CNS depression was reported in 10% of subjects.[11] 

One case report describes a 50-year-old woman who presented comatose after ingesting 40 to 60 ibuprofen 600 mg tablets. The patient was unresponsive to verbal stimuli but responded to noxious stimuli. She was endotracheally intubated for airway protection. She developed renal failure and GI hemorrhage in the form of a guaiac positive stool test. After a day in the intensive care unit (ICU), she clinically improved and was extubated with no further complications.[24] A similar case report of a male who reportedly ingested almost 20 grams of ibuprofen developed CNS depression, metabolic acidosis, thrombocytopenia, acute renal failure, and GI hemorrhage. His level of consciousness and other parameters improved with supportive management.[15]

Generalized seizures, depressed level of consciousness, and apnea have been reported in children by various authors after large ingestions.[11][25][26]

Biochemical

High anion gap metabolic acidosis is the most common abnormality reported, which usually occurs after massive ingestions.[26][27][28] This is believed to be due to the accumulation of acidic metabolites of ibuprofen, acute renal failure, and/or lactic acidosis from seizure activity. Apnea from respiratory depression can result in a concomitant respiratory acidosis.

Life-threatening hypokalemia has been reported secondary to renal tubular acidosis after ibuprofen overdose.[29] Metabolic acidosis, along with polyuria, has also been described.[30]

Hematological

Thrombocytopenia is common following ibuprofen overdose.[31][32] Thrombocytopenia secondary to immune-mediated thrombocytopenia, thrombotic thrombocytopenic purpura, and hemolytic-uremic syndrome from ibuprofen ingestion have all been described.[33][34][35][36][37] Prolonged prothrombin time may also occur. Pulmonary infiltrates with eosinophilia syndrome has been reported following ibuprofen overdose.[38] Severe pancytopenia has also been reported.[39]

Evaluation

Routine laboratory testing is unnecessary following an accidental overdose in asymptomatic patients, provided that a history of acetaminophen overdose be excluded by history. When acetaminophen overdose cannot be excluded, a serum acetaminophen level should be obtained. Following large or self-injurious/suicidal overdose and in symptomatic patients, laboratory testing may include a complete blood count, blood gas analysis, and metabolic panel. Assessment for co-ingestants like ethanol, toxic alcohols, and aspirin may be appropriate depending on patent presentation. Serum ibuprofen concentrations are typically not readily available in the acute care setting but may be obtained from reference laboratories if confirmation of ibuprofen exposure is necessary.

Treatment / Management

Management of an ibuprofen toxicity patient is primarily supportive. Most patients have no symptoms or mild GI symptoms that respond to symptomatic management. Asymptomatic patients with normal vital signs and no acetaminophen poisoning may be observed for 4 to 6 hours to develop symptoms.[20] Children who have consumed more than 400 mg/kg are at higher risk of ibuprofen toxicity and generally should be admitted to an acute care facility for further evaluation. In comparison, those who have ingested less than 100 mg/kg can be safely observed at home by their caretaker.

Gastrointestinal decontamination with activated charcoal may be used if there is a history of recent (within 2 hours) clinically significant ibuprofen overdose in adults and children with ingestion of more than 400 mg/kg.[40][28] Patients with life-threatening manifestations like respiratory depression, hypotension, seizures, and metabolic acidosis should be aggressively treated. Therapeutic interventions may include airway stabilization, mechanical ventilation, benzodiazepines for seizure control, intravenous fluids, and vasopressors to correct hypotension—monitor life-threatening arrhythmias, which can occur secondary to electrolyte imbalances like hypokalemia, with serial ECGs. As ibuprofen is heavily protein-bound, hemodialysis cannot remove the drug, although the latter can be used for associated conditions like hyperkalemia or refractory metabolic acidosis.

Differential Diagnosis

• Abdominal pain in elderly persons

• Acute lactic acidosis

• Anxiety disorder

• Chronic anemia

• Dyspnea

• Delirium, dementia, and amnesia in emergency medicine

• Encephalitis

• Peptic ulcer disease

• Stevens-Johnson syndrome

• Toxic epidermal necrolysis

Prognosis

Ibuprofen overdose is rarely fatal although there have been cases of death from ibuprofen toxicity. 

Complications

Complications can include both gastrointestinal problems as well as hepatic and renal damage.

Gastrointestinal blood loss following ibuprofen intake is dose-related. The more serious gastrointestinal effects are not common and include occult blood loss, GI hemorrhage, ulcer, and pancreatitis. While some patients experience increases in liver enzymes, hepatic side effects, including cholestasis, jaundice, hepatitis, and hepatic failure, are rare. Renal complications include urinary retention/insufficiency, acute renal failure, nephrotic syndrome, and acute tubular necrosis. These are more likely in patients with impaired renal function.

Other very rare complications include cardiovascular effects (e.g., elevated blood pressure), nervous system complications (dizziness, drowsiness), and hematological issues such as platelet dysfunction.[41]

Deterrence and Patient Education

Patients should call a poison center if they suspect ibuprofen overdose/toxicity and report to an emergency department.

Enhancing Healthcare Team Outcomes

Managing ibuprofen overdose requires teamwork from healthcare professionals, including the emergency physician, intensivist, medical toxicologist or poison control center, pharmacist, and nursing staff. The emergency physician is responsible for the following:

1. A complete history of the substance ingested, any co-ingestion, time of ingestion, any suicidal intent behind the ingestion, and any previous similar history in the past.
2. Initiating management of airway, breathing, circulation, decontamination.
3. Ordering initial labs, including acetaminophen levels, aspirin levels, blood gas, complete blood count (CBC), renal and liver function tests, electrolytes, and blood sugar.
4. Initiating correction of any electrolyte or blood gas abnormalities
5. If the patient is stable enough, obtaining a psychiatric history to assess the risk of self-harm.
6. Consulting with toxicology about further management of the patient.
7. Consulting with a pharmacist about the use of activated charcoal.
8. Consulting with nephrology if there is resistant metabolic acidosis, hyperkalemia, or renal failure to consider hemodialysis.

The management of ibuprofen toxicity should continue after the patient is admitted to an appropriate level of care. Patients should be admitted to an ICU level of care for respiratory depression, hypotension or shock, depressed mental status, severe metabolic acidosis, severe GI hemorrhage, life-threatening electrolyte imbalances or arrhythmias, or if the presumed clinical course of the patient is predicted to worsen based on the dose of ibuprofen consumed. Symptomatic but otherwise stable patients may be admitted to a general medical floor. Asymptomatic patients may be observed for 4 to 6 hours in the emergency department.[20] [Level 3]

The admitting team shall continue therapeutic interventions initiated in the emergency department in conjunction with consultants such as medical toxicologists or the poison control center, nephrologists, and/or pharmacists. Consult with a mental health counselor or psychiatrist to assess self-harm risk and the potential need for psychiatric admission in intentional or self-injurious exposures. These interprofessional interventions can drive better outcomes irrespective of the underlying cause of toxicity. [Level 5]