PEDIATRICS Vol. 107 No. 1 January 2001, pp. 176-177

EXPERIENCE AND REASON:
Carbamazepine Overdose Recognized by a Tricyclic Antidepressant Assay

	ABSTRACT

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Altered mental status in an adolescent presents a diagnostic challenge, and the clinician depends on clinical evaluation and laboratory studies to determine therapy and prognosis. We report the case of an adolescent with altered consciousness caused by carbamazepine overdose with a positive tricyclic antidepressant level to alert clinicians to the cross-reactivity of carbamazepine with a toxicology screen for tricyclic antidepressants.

The differential diagnosis of altered mental status in an adolescent is broad. It can be difficult to eliminate trauma, ingestion, or infection as the cause in any presentation of alteration of consciousness. The initial assessment and resuscitation are directed at the management of the patient's airway, breathing, and circulation.

Decreased level of consciousness is the most common serious complication of drug overdose. Toxicology screens for central nervous system depressants and for potentially lethal but treatable substances such as acetaminophen, aspirin, and tricyclic antidepressants (TCA) should be considered in diagnostic testing. However, the treatment of poisoning often must proceed without the results of extensive screening. Fortunately, in most cases, the correct diagnosis can be made after a careful history, clinical assessment, and limited laboratory testing.

We report a case of carbamazepine (CBZ) overdose in which knowledge of the cross-reactivity between CBZ and tricyclic antidepressants was the key to the diagnosis of the cause of altered mental status.

	CASE REPORT

A 16-year-old girl with a remote history of childhood seizures and a tic disorder presented in a coma.

She was last seen awake at approximately 11 pm the previous evening. At that time, she had been complaining of abdominal discomfort for which she reportedly took Pepto-Bismol, ibuprofen, and St John's Wort. In addition, she took her regular dose of clonidine (0.1 mg) which was used to control the tic disorder. There was no history of fever or other systemic symptoms. Her family reported recent social stressors but no change in behavior or suicidal threats. Her family denied knowledge of alcohol, illicit drug use, or any other medication exposure.

The next morning, the patient was found unresponsive, slumped over the side of her bed. She was transported to Children's Hospital, Boston for additional evaluation.

On presentation she was minimally responsive to pain, having a Glasgow Coma Scale of 7. Temperature was 37.2°C, pulse 100 beats/minute, respiratory rate 16 breaths/minute, and blood pressure of 90/58 mm Hg. Respirations were spontaneous and adequate. There were no obvious signs of trauma. Pupils were dilated at 9 mm bilaterally and were reactive to light. Her cardiac and pulmonary examinations were normal. Her neurologic examination was nonfocal except for her depressed mental status.

The patient was intubated for airway protection. Activated charcoal was given via a nasogastric tube. A head computed tomography scan revealed no evidence of intracranial pathology. An electrocardiogram (ECG) was normal for age. Her complete blood count, electrolytes, liver function tests, and urinalysis were unremarkable. Serum osmolality, acetaminophen, aspirin levels, a qualitative tricyclic antidepressant screen, and a comprehensive toxicology screen were obtained.

In discussion with the patient's parents, they were confident that she did not have access to any medications in the home other than her prescribed clonidine. They assured the treatment team that the clonidine vial had the appropriate number of remaining tablets.

The patient was admitted to the intensive care unit where she initially remained responsive only to painful stimulus. An electroencephalograph revealed abnormalities consistent with drug toxicity or metabolic defect. A lumbar puncture was performed which had a normal opening pressure and examination of the cerebral spinal fluid did not reveal any abnormality. Acyclovir was initiated pending herpes polymerase chain reaction results.

Shortly after transfer to the intensive care unit, the patient's serum screen for TCA was reported as positive. A repeat ECG showed no evidence of QRS or axis deviation. Over the subsequent days she was extubated and her mental status normalized. On recommendation from the clinical toxicology service, a serum CBZ level was obtained because of the possibility of a cross-reactivity of CBZ with the TCA screen. The CBZ level was elevated at 17 µg/mL (therapeutic range: 4-12 µg/mL).

Psychiatry and toxicology consults were involved, and supportive care continued. By hospital day 3, the patient was transferred to the medical floor with a CBZ level of 9 µg/mL. She was subsequently discharged from the hospital with outpatient psychiatry follow-up.

	DISCUSSION

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Antidepressant medications are among the most common used in self-poisonings and suicide attempts. TCAs are the most toxic and represent a major cause of poisoning, hospitalizations, and deaths. TCA toxicity may cause 3 major syndromes: anticholinergic, cardiovascular, and neurologic. Anticholinergic effects include sedation, delirium, coma, dilated pupils, dry skin and mucous membranes, absent bowel sounds, and urinary retention. Cardiovascular toxicity manifests as abnormal cardiac conduction and arrhythmia. Seizures are common with TCA overdose. Studies have shown that specific ECG changes are correlated with TCA overdoses. A prolonged QRS interval, 100 milliseconds, and a terminal 40 millisecond right axis deviation, 120 degrees are reliable predictors of serious cardiovascular and neurologic toxicity.¹ In this case, the ECG showed no evidence of QRS widening or deviation of the axis in the terminal segment. Although TCA ingestion was a possible cause of the depressed mental state, the ECG results were inconsistent with this cause. Therefore, it was unlikely that the positive TCA assay explained the altered consciousness in this patient. In contrast, although CBZ is structurally similar to TCAs it does not cause rhythm disturbances, alterations in heart rate, changes in QRS duration, or terminal segment axis deviation.²

Toxicology screens are increasingly becoming part of an evaluation of the pediatric patient with altered mental status. The most commonly used screen is a urine immunoassay for drugs of abuse. In addition, a serum immunoassay for TCA, aspirin, acetaminophen and other specific therapeutic medications may be part of an initial screen. A complete understanding of the basic principles of the screen allows for a proper interpretation of a positive or negative result. There are multiple types of immunoassays distinguishable by the marker of free drug in the sample. For example, in the enzyme-linked immunoassay performed at our institution, a drug-specific antibody binds to free drug. Therefore, the presence of the drug limits the antibody available to bind to the enzyme in the assay. The free enzyme produces a detectable product.³ This is an effective and inexpensive screen for drugs in serum or urine. However, there is the possibility of false-positive results from structural similarity of substances.

Examples of drugs with structural similarity include amphetamines with phenylephrine and ranitidine, opiates with poppy seeds, phencyclidine with diphenhydramine, dextromethorphan and ketamine, and TCAs with CBZ and diphenhydramine. Each of these drugs may cause false-positives on the immunoassay screen for the cross-reacting substance. If the patient's clinical presentation is inconsistent with the assay result, it may be necessary to obtain confirmatory testing for the positive result of an immunoassay screen. This can be done using gas chromatography coupled with mass spectrometry. However, it is a more expensive and labor-intensive study and therefore is used as a confirmatory test of a positive immunoassay result.

CBZ is a neutral lipophilic iminostilbene derivative with structural similarity to the tricyclic antidepressant imipramine. Schindler and Hafinger synthesized the compound in 1952.⁴ This structural similarity allows for cross-reactivity of the TCA immunoassay with CBZ. The reported cross-reactivity of the TCA immunoassay for CBZ is 0.3% with the Abbott assay.^5,6 The TCA assay can be positive in therapeutic as well as toxic ingestions of CBZ.

CBZ is most commonly used for prevention of seizures, analgesia for trigeminal neuralgia and affective disorders, particularly bipolar disorder. There is a relatively elevated risk of super-therapeutic ingestion of this substance because of the underlying conditions being treated. In a review of >400 patients diagnosed with CBZ overdose, Schmidt and Schmitz-Buhl⁷ revealed that the level of lethality is low particularly in patients under the age of 15 years. Coma, somnolence and cerebellar syndrome were the most common symptoms in overdose, with an increased incidence of seizures and respiratory depression in the lethal overdose group.

Management of CBZ overdose is mainly supportive. There should be a low threshold for intubation in patients with borderline mental status because of frequent emesis and neurologic compromise. Cardiovascular and respiratory monitoring is essential.⁸ Repeat doses of activated charcoal may increase the clearance because of enterohepatic circulation. The half-life of serum CBZ can be signficantly shortened by multiple doses of activated charcoal.⁹ Charcoal hemoperfusion is effective and may be considered for severe intoxication refractory to standard therapies.

This case illustrates that an understanding of the method and interpretation of drug screens, including the possibility of false-positive results attributable to cross-reactivity, is important when using toxicology screens as part of a patient evaluation. The knowledge of cross-reactivity between the TCA assay and CBZ resulted in the diagnosis in this case of toxic ingestion.

Amy Fleischman, MD^*
Vincent W. Chiang, MD^*,
* Department of Pediatrics
 Division of Emergency Medicine
Children's Hospital
Harvard Medical School
Boston, MA 02115

	FOOTNOTES

As previously cited in Matos ME, Burns MM, Shannon MW. False-positive tricyclic antidepressant drug screen results leading to diagnosis of carbamazepine intoxication. Pediatrics. 2000;105(5). URL: http://www.pediatrics.org/cgi/content/full/105/5/e66.

Received for publication Jan 7, 2000; accepted Apr 17, 2000.

Reprint requests to (V.W.C.) Children's Hospital, 300 Longwood Ave, Boston, MA 02115. E-mail: chiang{at}a1.tch.harvard.edu

	ABBREVIATIONS

TCA, tricyclic antidepressants; CBZ, carbamazepine; ECG, electrocardiogram; QRS, electrocardiographic wave.

	REFERENCES

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