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Nonsteroidal Anti-inflammatory Drug (NSAID) Toxicity Workup

  • Author: Timothy J Wiegand, MD; Chief Editor: Asim Tarabar, MD  more...
 
Updated: Jun 29, 2016
 

Laboratory Studies

Routine determination of the specific plasma nonsteroidal anti-inflammatory drug (NSAID) concentration is not clinically useful in patients with NSAID toxicity; however, serum levels may be of use to establish diagnosis or for academic purposes. Although a nomogram has been developed for ibuprofen, it is not clinically useful since serum levels do not correlate with clinical symptoms. A typical therapeutic ibuprofen level is 3 mg/dL.

Obtain a serum acetaminophen (APAP) level, in view of the possibility of co-ingestion. In acute overdose, asymptomatic patients with no co-ingestions may not require specific serum or urine studies other than a serum acetaminophen level. A 4-hour acetaminophen level should be ordered in every patient with suspected ingestion due to the notorious lack of signs and symptoms in the initial 24 hours after acetaminophen ingestion. Consider obtaining baseline renal and hepatic function tests in patients with asymptomatic ingestions of phenylbutazone, mefenamic acid, and meclofenamate.

In symptomatic patients, obtain the following:

  • Serum electrolytes
  • Renal function studies
  • Liver function tests
  • Coagulation studies including a prothrombin time with International Normalize Ratio (INR)
  • Complete blood count (CBC)

In any patient with low bicarbonate on the chemistry panel, or an anion gap (see the Anion Gap calculator), and in patients with progressive decline in mental status or seizures, an arterial blood gas (ABG) and plasma lactate should be obtained. Additional electrolytes, including magnesium and phosphorus, should be considered in symptomatic patients because hypomagnesemia and hypophosphatemia may develop within a day or two after significant NSAID ingestion.

Obtain a serum salicylate level in any patient with drug overdose and an anion gap acidosis (see Toxicity, Salicylates).

Many of the NSAIDs are acidic compounds (carboxylic acids such as diclofenac, ibuprofen, and indomethacin) or are metabolized to acidic compounds (ibuprofen). An anion gap acidosis may be discovered in the setting of NSAID overdose simply due to parent and metabolite compound accumulation. Additionally, in severe overdoses, coma, multisystem organ failure, and refractory lactic acidosis have been reported. The etiology of this acidosis is likely due to both accumulation of parent compound and metabolites as well as inhibition of mitochondrial respiration and distributive shock in the setting of progressive acidosis.

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Imaging Studies

A computed tomography (CT) scan of the head may be warranted for workup of patients with any of the following:

  • Seizure
  • Altered mental status
  • Coma

Chest radiography or abdominal plain films are rarely indicated. Although NSAIDs may cause GI irritation, no imaging tests are necessary unless there is consideration for a perforated viscus (as in a patient with nausea and vomiting after acute ingestion).

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Other Tests

An electrocardiogram (ECG) is required in hyperkalemic patients and should be obtained in any patient who presents with an acute overdose to help exclude cyclic antidepressant toxicity or exposure to cardioactive drugs.

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Procedures

Lumbar puncture should be performed in patients with altered mental state and symptoms suggestive of CNS infection.

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Contributor Information and Disclosures
Author

Timothy J Wiegand, MD Director, Ruth A Lawrence Poison and Drug Information Center, Associate Clinical Professor of Medicine and Emergency Medicine, University of Rochester Medical Center and Strong Memorial Hospital

Timothy J Wiegand, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Medical Toxicology, American College of Physicians

Disclosure: Nothing to disclose.

Coauthor(s)

Constance M Vernetti, MD Resident Physician, Department of Emergency Medicine, University of Rochester Medical Center

Constance M Vernetti, MD is a member of the following medical societies: Society for Academic Emergency Medicine, Emergency Medicine Residents' Association

Disclosure: Nothing to disclose.

Specialty Editor Board

John T VanDeVoort, PharmD Regional Director of Pharmacy, Sacred Heart and St Joseph's Hospitals

John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists

Disclosure: Nothing to disclose.

Fred Harchelroad, MD, FACMT, FAAEM, FACEP Attending Physician in Emergency Medicine, Excela Health System

Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital

Disclosure: Nothing to disclose.

Additional Contributors

Lance W Kreplick, MD, FAAEM, MMM Medical Director of Hyperbaric Medicine, Fawcett Wound Management and Hyperbaric Medicine; Consulting Staff in Occupational Health and Rehabilitation, Company Care Occupational Health Services; President and Chief Executive Officer, QED Medical Solutions, LLC

Lance W Kreplick, MD, FAAEM, MMM is a member of the following medical societies: American Academy of Emergency Medicine, American Association for Physician Leadership

Disclosure: Nothing to disclose.

Acknowledgements

Michele B Delenick, MD Hospitalist, Maine Hospitalist Service, Department of Internal Medicine, Maine Medical Center, Portland

Michele B Delenick, MD is a member of the following medical societies: American College of Physicians

Disclosure: Nothing to disclose.

Neesha Suresh Desai, MD, MPH Staff Physician, Department of Emergency Medicine, New York University Hospital, Bellevue Hospital Center

Disclosure: Nothing to disclose.

Jingjing Hu, MD Attending Physician, Department of Internal Medicine, Maine Medical Center, Portland

Disclosure: Nothing to disclose.

Gregory S Johnston, MD Attending Physician, Beth Israel Medical Center

Disclosure: Nothing to disclose.

Carlyn Ko, MD Consulting Staff, Department of Emergency Medicine, Premier Healthcare

Disclosure: Nothing to disclose.

Fred Tilden, MD Consulting Staff, Department of Emergency Services, MidState Medical Center

Disclosure: Nothing to disclose.

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Table 1. Chemical Classifications of NSAIDs
NSAID Drug Class Maximum Daily Dose Half-Life Comments Clinical Symptoms
Salicylates



Examples: Aspirin and other salicylates, eg, sodium or magnesium salicylate (not covered in this article), diflunisal (Dolobid) – not metabolized to salicylic acid



1500 mg 8-12 h Salicylates: See Toxicity, Salicylate for discussion of acetylsalicylic acid toxicity Salicylates: See Toxicity, Salicylate



Diflunisal: This NSAID commonly causes drowsiness, vomiting, and diarrhea.



Hyperventilation, tachycardia, diaphoresis, tinnitus, disorientation, stupor, coma, cardiopulmonary arrest, and fatality are rarely observed and occur only with doses exceeding 15 g.



The lowest reported dose resulting in fatality is 15 g.



Pyrazolones



Examples: Phenylbutazone



600 mg 50-100 h Pyrazolones: Phenylbutazone (Butazolidin), one of the most toxic NSAIDs



Symptoms of mild poisoning include nausea, abdominal pain, and drowsiness; no longer approved for human use in the US.



Severe poisoning has multisystem effects that, early on, include the GI system (eg, nausea, vomiting, diarrhea), CNS (eg, dizziness, seizures, coma), the cardiovascular system (eg, pulmonary edema, arrest), metabolic and respiratory acidosis, and electrolyte abnormalities.



Delayed severe toxicity (2-7 d) includes renal, hepatic, and hematologic dysfunction.



Although the pyrazolones have been withdrawn from the market, phenylbutazone is available from veterinary sources and from other countries (eg, it has presented in southwestern United States)



Fenamates (anthranilic acids)



Examples: Meclofenamate (Meclomen), mefenamic acid (Ponstel)



1000 mg 2 h These drugs have not been studied thoroughly, but they have caused vomiting, diarrhea, muscle twitching, and seizures. Most patients recover completely within 24 h. Myoclonus, muscle twitching, or seizures are characteristic of symptomatic overdose. Seizures may be focal or general. In one series, 20% of 54 patients who developed abnormal neuromuscular activity described as, "twitching" developed seizures (generalized, grand mal, tonic-clonic).
         
Acetic acids



Examples:



Diclofenac (Voltaren),



etodolac(Lodine),



indomethacin (Indocin),



ketorolac (Toradol, Sprix),



sulindac (Clinoril)



PO ketorolac daily dosage limit is 40 mg. Not to exceed daily dose of 126 mg for intranasal ketorolac (63 mg/24 h if older than 65 y). Total cumulative ketorolac (any administration route) should not exceed 5 days in a row. Typically 8-30 h Sulindac is a prodrug. Peak concentrations may be delayed 2-5 h. Sulindac overdoses are very rare, but case reports have shown effects on renal function. Indomethacin poisoning can cause headache, lethargy, disorientation, seizure, nausea, vomiting, and GI bleeding. Seizures were reported in the case of a 6-year-old who ingested, "a bottle" of indomethacin.



Diclofenac can cause nausea, vomiting, tinnitus, hallucinations, and acute renal failure (3 cases).



COX-2 inhibitors



Examples: Celecoxib



400 mg -celecoxib 3-11 h Considered to be relatively safe Only available Cox-2 inhibitor in the US
Propionic acids Examples:



Ibuprofen (Motrin, Advil), naproxen (Naprosyn, Anaprox), carprofen (Rimadyl), ketoprofen (Orudis)



For ibuprofen- 3200 mg and T1/2 3 h



For naproxen-



1500 mg and T1/2 12-17 h



  Severe toxicity reported mainly in children and can occur in ingestions of 400 mg/kg or more; symptoms include seizures, apnea, hypertension, and renal and hepatic dysfunction Headache, tinnitus, drowsiness, nausea, vomiting, and abdominal pain are the most common symptoms, and commonly appear within 4 h of ingestion.



In a retrospective case series of 126 patients with ibuprofen overdose, 19% of patients developed symptoms, predominantly CNS depression and GI upset, typically within 4 h. In a prospective study of 45 adults and 39 pediatric patients, all patients who became ill did so within 4 h. In this study, coma, apnea, and/or metabolic acidosis occurred in 9% of adults and 5% of children. Ingestions of more than 400 mg/kg of ibuprofen are associated with seizures, apnea, hypotension, bradycardia, metabolic acidosis, and renal and hepatic dysfunction.



Oxicams Examples:



Piroxicam (Feldene)



20 mg 45-50 h   Occasionally, these NSAIDs can cause dizziness, blurred vision, seizures, and coma.
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