Clinical Toxicology (2011), 49, 434–435

Copyright © 2011 Informa Healthcare USA, Inc.

ISSN: 1556-3650 print / 1556-9519 online

DOI: 10.3109/15563650.2011.586639

BRIEF REPORT

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Serum concentrations in three children with unintentional

tetrahydrozoline overdose

JENNIFER A. LOWRY 1 and UTTAM GARG 2

1 Department of Pediatrics, Children ’ s Mercy Hospitals and Clinics, University of Missouri School of Medicine, Kansas City, MO, USA 2 Department of Pathology and Laboratory Medicine, Children ’ s Mercy Hospitals and Clinics, University of Missouri School of Medicine, Kansas City, MO, USA

Background . Major symptoms can occur from tetrahydrozoline (THZ) overdoses in young children, requiring intensive care management. We report three cases that presented with CNS depression and cardiovascular effects where serum concentrations were performed. Case report . Case 1 ingested an unknown amount of eye drops containing THZ, resulting in altered mental status, bradycardia, hypothermia, and hypotension. Cases 2 and 3 ingested 7.5 mL of eye drops containing THZ. Case 2 presented to the emergency department (ED) without symptoms but became lethargic and bradycardic 90 min after ingestion. By contrast, Case 3 became lethargic 15 min after ingestion and required intubation on arrival to the ED. All children were admitted to ICU for observation and improved within 24 h of ingestion. Urine obtained for drug screening was positive for THZ. Blood was obtained to assess level using gas-chromatography mass-spectrometry (GC-MS). Case discussion . Case 1 had plasma levels of 51.4 and 23.6 ng/mL at 7 and 12 h, respectively, after ingestion, revealing a half-life of 4.4 h. Numerous case reports have been published documenting the dangers of ingesting these topical over-the-counter (OTC) products. However, human PK data are not available to help in our understanding of THZ toxicokinetics and disposition in humans after ingestion. Conclusion . We report three pediatric cases after ingestion of THZ where plasma concentrations were obtained with a calculated half-life of 4.4 h in one case.

Keywords Pharmacokinetics; CNS; Pediatrics; Cardiovascular

Introduction

Topical imidazolines are found in many over-the-counter (OTC) eye and nose decongestants. Products with imi-dazoline components are numerous and include: Visine ® (tetrahydrozoline), Naphcon ® (naphazoline), Afrin Nasal Spray/Pump ® (oxymetazoline), and Otrivin Pediatric Nasal ® (xylometazoline). Imidazolines have central and periph-eral alpha-2 agonist activity. However, unlike other alpha-2 agonists, they are designed to stimulate peripheral alpha-2 receptors on local vessels to achieve the intended clinical effect of vasoconstriction. Topically and orally, imidazolines have a rapid onset of action, which is often prolonged. 1 – 5 Signifi cant clinical consequences (hypotension and brady-cardia) can occur from tetrahydrozoline (THZ) ingestions in young children, requiring intensive care management.

In addition, imidazolines have been used in drug-facilitat-ed sexual assault to induce comatose victims that are unable to fend off the perpetrator. 6 Previously, no pharmacokinetic data were available to aid in the assessment of children

434

Received 10 March 2011 ; accepted 4 May 2011

Address correspondence to Jennifer A. Lowry, Department of Pediatrics, Division of Clinical Pharmacology and Medical Toxicology, Children ’ s Mercy Hospitals and Clinics, Kansas City, MO 64108, USA. Tel � 816-234-3059. Fax � 816-855-1958. E-mail: jlowry@cmh.edu

with these exposures to guide treatment and estimate time of exposure. We report three cases that presented with CNS depression and cardiovascular effects where serum THZ concentrations were evaluated.

Case Report

A previously well (13.2 kg) 2-year-old male (Case 1) pre-sented to an emergency department (ED) after his parents could not wake him from his afternoon nap. In the ED, he was found to be bradycardic (HR of 55 bpm), hypothermic (T 94.3 ° F, rectally), and had a Cheyne – Stokes respiratory pattern. Evaluation included an ECG (bradycardia), chest X-ray (normal), head CT (normal), and initial laboratory analyses (normal). Initial drug of abuse screen was negative. Concern for sepsis and encephalopathy were in the differ-ential, and the patient was admitted to the PICU on oxygen. Urine obtained for a drug screen analysis was positive by gas chromatography-mass spectrometry (GC-MS) for THZ. Blood was subsequently obtained to assess THZ levels. Fur-ther history revealed that a visiting aunt, who had been using eye drops, may have left the medication in the home. An empty bottle was subsequently found. Fluids were started, and he improved quickly without other interventions.

A 2-year-old previously well (11.4 kg) female (Case 2) was found by her mother chewing on a bottle of Visine ®

Pediatric tetrahydrozoline concentrations 435

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(THZ 0.05%). An estimated 7.5 mL (0.33 mg/kg THZ) was missing from the 15 mL bottle. She presented to the ED without symptoms but became lethargic (GCS 10 – 11 with stimulation), bradycardic (HR 65 bpm), and with gasp-ing breathing (RR 10 – 15/min), 90 min after ingestion. Her blood pressure remained stable (90/60). She was admitted to the PICU on oxygen for close observation. No other phar-macologic treatment was needed. Urine obtained for a drug screen analysis was positive by GC-MS for THZ. Blood was subsequently obtained to assess THZ levels. After a short observation stay, she quickly improved and was discharged within 24 h of her admission.

A previously well (12.4 kg) 20-month-old male (Case 3) was found by his father with an empty 15 mL bottle of Visine ® (THZ 0.05%). The bottle had been half full. Esti-mated THZ dose ingested was 0.30 mg/kg. Within 15 min of the incident, the child became tired and laid down for a nap. When the child was not arousable an hour later, he was taken to the ED. He was found to have a GCS of 10 with stimulation. Bradycardia was noted (70 bpm) with hyperten-sion (163/103) and gasping respirations (RR 20). His pupils were constricted to 1 – 2 mm. Due to CNS depression, he was intubated and required mechanical ventilation for 10 h. Urine obtained for a drug screen analysis was positive by GC-MS for THZ. Blood was subsequently obtained to assess THZ levels. After extubation, he recovered quickly and was symptom free within 24 h of ingestion.

Methods

After the addition of naphazoline as an internal standard, drugs from urine and plasma were extracted using methyl-ene chloride:cyclohexanes:isopropanol (9:9:2). The extract was concentrated under a stream of nitrogen and analyzed using GC-MS. The method was linear within the range of 10 ng/mL to 25 mcg/mL (r 2 � 0.99). 7

Results

Case 1 had plasma THZ concentrations of 51.4 and 23.6 ng/mL approximately 7 and 12 h after ingestion. PK calculations show a t 1/2 of 4.4 h. Urine concentration was 49.5 mcg/mL approximately 7 h after ingestion.

Case 2 had one plasma THZ concentration of 39.3 ng/mL at 2 h post-ingestion and a urine concentration of 9.2 mcg/mL within 45 min of ingestion.

Case 3 had one plasma THZ concentration of 24 ng/mL at 3 h post-ingestion. No urine concentrations were obtained.

Discussion

Numerous case reports have been published documenting the dangers of ingesting topical OTC products. 1 – 5 THZ is capable of depressing the CNS due to preferential effects of the drug on alpha-2 receptors, with an effect similar to that of clonidine. The CNS-depressant effect appears to be common among imi-dazolines. Although adverse effects are minimal with recom-mended doses and routes of THZ, profound CNS depression

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may be seen following overdoses in children. Signs and symp-toms include drowsiness, coma, hyperactivity, hypertension, hypotension, bradycardia, respiratory depression, and apnea. The onset of symptoms ranges from within minutes to hours of ingestion and can occur with small doses.

Limitations to this study include the lack of PK data of the medications. Prior to this report, no pharmacokinetic evalua-tion has been performed to assess the half-life and expected clinical course of children who have ingested THZ. Toxicol-ogy studies assessing oral ingestion in animals and humans have not been done as part of the pharmaceutical process in the USA. A minimum toxic dose for children has not been established as these medications are meant for ophthalmic and otic applications. Thus, pharmacokinetic data after an oral exposure do not exist for children or adults. One study in Germany 8 assessed absorption of other imidazolines in ani-mals and adult humans and found the elimination (65% urine and 22% feces) was “ fi nished ” at 96 h post-ingestion of a 390-mcg dose. As the pharmacokinetics in children differ greatly from adults for many medications, this information may not be able to be extrapolated to children. In addition, only one patient had more than one level obtained to allow calculation of the pharmacokinetic data, resulting in the elimination half-life of THZ in a pediatric patient. However, this is the fi rst report of a calculated half-life and of plasma concentrations in symptomatic children after ingestion of THZ.

In conclusion, we report three pediatric cases after inges-tion of THZ where plasma concentrations obtained a calcu-lated half-life of 4.4 h in one case. Due to lack of human or animal PK data, other parameters cannot be calculated. Further studies are needed to document the systemic concen-trations with ophthalmologic use as this drug is commonly used in drug-assisted sexual assault cases. Lastly, there is a need for animal or human pharmacokinetic data on topical formulations as these are common exposures in children (in-gestion and routes other than originally intended), but little information on the disposition of these chemicals is known.

References

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