Contact Us    Contact Us     |     Feedback
MOBILE VIEW  | 

IMIDAZOLINE DECONGESTANTS

Export To Excel

Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Naphazoline, tetrahydrozoline, oxymetazoline, and xylometazoline are members of this group and are vasoconstrictors.

Specific Substances

    A) OXYMETAZOLINE
    1) 6-tert-Butyl-3-(2-imidazolin-2-yl methyl)2,4-xylenol
    2) CAS 1491-59-4
    3) CAS 2315-02-8 (hydrochloride salt)
    NAPHAZOLINE
    1) 2-(1-Naphthylmethyl)-2-imidazoline
    2) CAS 835-31-4
    3) CAS 550-99-2 (hydrochloride)
    4) CAS 5144-52-5 (nitrate)
    TETRAHYDROZOLINE
    1) 2-(1,2,3,4-tetrahydro-1-naphthyl)-2-imidazoline
    2) Tetrizolina
    3) Tetryzoline
    4) CAS 84-22-0
    5) CAS 522-48-5 (hydrochloride)
    XYLOMETAZOLINE
    1) 2-(4-tert-Butyl-2,6-dimethylbenzyl)-2-imidazoline
    2) CAS 526-36-3
    3) CAS 1218-35-5 (hydrochloride)

Available Forms Sources

    A) FORMS
    1) Tetrahydrozoline, USP, 0.1% and 0.05% nasal solutions, and 0.05% ophthalmic solution
    2) Naphazoline Hydrochloride, USP, 0.05% nasal solution, and 0.012%, 0.02%, 0.025%, 0.03%, and 0.1% ophthalmic solutions
    3) Oxymetazoline Hydrochloride, USP, 0.025 and 0.05% nasal solutions, and 0.025% ophthalmic solution
    4) Xylometazoline Hydrochloride, USP, 0.05 and 0.1% nasal solutions.
    B) USES
    1) These agents are vasoconstrictors used for the symptomatic relief of rhinitis, sinusitis, or conjunctival inflammation.

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Used primarily as topical agents to cause vasoconstriction in the nasal mucosa and the eye. Common medications include oxymetazoline, tetrahydrozoline, and naphazoline. Surreptitious oral administration of these agents has been reported to facilitate sexual abuse in both adults and children.
    B) PHARMACOLOGY: These agents bind to peripheral alpha adrenergic receptors at the site of action (the eye or nose) causing vasoconstriction.
    C) TOXICOLOGY: They stimulate the central alpha-2 adrenergic receptors resulting in a net sympatholytic effect.
    D) EPIDEMIOLOGY: Uncommon poisoning which can theoretically result in significant morbidity, especially in children although it is very rare to see more than minimal effects.
    E) WITH THERAPEUTIC USE
    1) Headache, nervousness, nausea, dizziness. Rebound nasal congestion (rhinitis medicamentosa) has been described with prolonged use (greater than 5 days).
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Tachycardia, agitation, pallor, diaphoresis, somnolence, ataxia.
    2) SEVERE TOXICITY: Coma, hypotension, hypertension, bradycardia, respiratory depression, apnea, hypothermia, hyporeflexia.
    0.2.20) REPRODUCTIVE
    A) Oxymetazoline and tetrahydrozoline have been classified as US FDA pregnancy category C.

Laboratory Monitoring

    A) No specific lab work (CBC, electrolytes, urinalysis) is required.
    B) Consider arterial or venous blood gas measurements in serious cases.
    C) Obtain an ECG in symptomatic patients.
    D) Obtain a CT scan in patients with profound CNS depression to evaluate for other causes.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Management is primarily supportive. Initially, toxicity may manifest more as peripheral alpha effects causing generalized peripheral vasoconstriction. Agitation has also been described. These effects generally do not require therapy.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Management is primarily supportive. Manifestations are primarily due to central alpha effects. The main concerns in a serious overdose are CNS depression with loss of airway reflexes and respiratory depression. Supplemental oxygen should be administered as necessary. Intubation may be required for children who are severely depressed. Hypotension generally responds to intravenous fluid support only, but uncommonly may require a vasopressor such as dopamine. Hypertension is generally transient and does not require treatment. However, if there are signs of end organ compromise from hypertension, a short-acting antihypertensive (ie, nitroprusside or phentolamine) can be used with close monitoring since hypotension often follows the hypertension. Although there are reports suggesting that naloxone can reverse toxicity from clonidine (a drug with a mechanism of action similar to imidazolines), the use of naloxone for imidazoline poisoning is even less well characterized and cannot be routinely recommended.
    C) DECONTAMINATION
    1) PREHOSPITAL: Decontamination is unlikely to be of benefit in these cases since these are primarily liquid ingestions which will be absorbed quickly. In addition, these agents may cause CNS depression, so the risk of decontamination generally exceeds any potential benefit.
    2) HOSPITAL: Gastrointestinal decontamination is unlikely to be of benefit in these cases since these are primarily liquid ingestions which will be absorbed quickly. In addition, patients (children in particular) may become lethargic quickly.
    D) AIRWAY MANAGEMENT
    1) Patients who are comatose or with altered mental status may need mechanical respiratory support and orotracheal intubation.
    E) ANTIDOTE
    1) There are no specific antidotes. Although there are reports suggesting that naloxone can reverse toxicity from clonidine (a drug with a mechanism of action similar to imidazolines), the use of naloxone for imidazoline poisoning is even less well characterized and cannot be routinely recommended.
    F) HYPOTENSIVE EPISODE
    1) IV 0.9% NaCl 10 to 20 mL/kg, dopamine, norepinephrine.
    G) HYPERTENSIVE EPISODE
    1) Generally hypertension is transient and does not warrant treatment. If severe, short acting agents (ie, nitroprusside or phentolamine) should be used.
    H) BRADYCARDIA
    1) Treatment is only indicated in symptomatic patients with evidence of hemodynamic compromise. Atropine is the first line therapy. Atropine - Adult - 0.5 mg to 1 mg IV, repeat every 5 minutes if bradycardia persists. Pediatric - 0.02 mg/kg IV or intraosseously.
    I) ENHANCED ELIMINATION
    1) Enhanced elimination has no role in these ingestions.
    J) PATIENT DISPOSITION
    1) HOME CRITERIA: Any adult with an intentional ingestion or a symptomatic child should be referred to a healthcare facility. Young children have developed serious adverse effects after ingesting as little as 1 to 2 mL of formulations of eye drops or nasal spray (concentrations not specified) containing imidazoline decongestants (eg, tetrahydrozoline, oxymetazoline, or naphazoline).
    2) OBSERVATION CRITERIA: Patients should be observed for a minimum of 6 hours after a suspected ingestion and can be discharged if asymptomatic after that time.
    3) ADMISSION CRITERIA: Symptomatic patients should be admitted to a monitored setting.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing severe poisonings.
    K) PITFALLS
    1) Presentation may be very similar to the opiate toxidrome; consider this diagnosis especially in a situation where naloxone is ineffective.
    L) PHARMACOKINETICS
    1) Topically, these agents work rapidly generally within 20 minutes. Topical effects will persist between 4 to 8 hours, depending on the particular agent.
    M) TOXICOKINETICS
    1) After oral ingestion, symptoms generally develop rapidly within 20 to 60 minutes. Symptoms usually resolve by 24 hours.
    N) DIFFERENTIAL DIAGNOSIS
    1) The differential includes other ingestions which produce CNS and respiratory depression, primarily opiates, but may also include muscle relaxants, benzodiazepines, antipsychotics, clonidine, digoxin, and antidepressants, particularly when ingested concurrently. Trauma and intracranial hypertension may cause bradycardia and altered mental status.

Range Of Toxicity

    A) TOXICITY: The toxic dose after oral ingestions is not clear, but young children have developed serious adverse effects after ingesting as little as 1 to 2 mL of formulations of eye drops or nasal spray containing imidazoline decongestants (eg, tetrahydrozoline, oxymetazoline, or naphazoline). Systemic symptoms have also been described in young infants after therapeutic use of topical agents. Fatalities have not been reported after ingestion, but intravenous injection of xylometazoline was fatal in an adult. THERAPEUTIC DOSE: Generally, 1 to 2 drops are used in the eye and 1 to 3 sprays in each nostril for adults and children more than 6-years-old.

Clinical Effects

Summary Of Exposure

    A) USES: Used primarily as topical agents to cause vasoconstriction in the nasal mucosa and the eye. Common medications include oxymetazoline, tetrahydrozoline, and naphazoline. Surreptitious oral administration of these agents has been reported to facilitate sexual abuse in both adults and children.
    B) PHARMACOLOGY: These agents bind to peripheral alpha adrenergic receptors at the site of action (the eye or nose) causing vasoconstriction.
    C) TOXICOLOGY: They stimulate the central alpha-2 adrenergic receptors resulting in a net sympatholytic effect.
    D) EPIDEMIOLOGY: Uncommon poisoning which can theoretically result in significant morbidity, especially in children although it is very rare to see more than minimal effects.
    E) WITH THERAPEUTIC USE
    1) Headache, nervousness, nausea, dizziness. Rebound nasal congestion (rhinitis medicamentosa) has been described with prolonged use (greater than 5 days).
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Tachycardia, agitation, pallor, diaphoresis, somnolence, ataxia.
    2) SEVERE TOXICITY: Coma, hypotension, hypertension, bradycardia, respiratory depression, apnea, hypothermia, hyporeflexia.

Vital Signs

    3.3.3) TEMPERATURE
    A) HYPOTHERMIA: Mild hypothermia may develop (Alvarez-Pitti et al, 2006; Greenblatt, 1947; Hainsworth, 1948) and was reported in 5 of 19 (26%) children in one series of naphazoline toxicity (Mahieu et al, 1993).
    B) CASE SERIES: In a series of 72 children with acute exposure to imidazoline decongestants, 57 (79%) developed signs or symptoms of toxicity. Of these, 16 (28%) developed hypothermia (Bucaretchi et al, 2003).
    C) CASE REPORT: A 5-year-old boy was given a 10 mL solution containing 0.1 g of naphazoline-chlorhydrate, 9.7 g of sodium-tetraborate and 0.2 g methylparaben (twice the manufacturer's recommended dose), and developed somnolence, sweating, bradycardia and hypothermia within 2 hours of ingestion. Somnolence and hypothermia persisted for approximately 7 hours. The patient was discharged to home 20 hours later with no sequelae (Alvarez-Pitti et al, 2006).
    3.3.4) BLOOD PRESSURE
    A) WITH POISONING/EXPOSURE
    1) CASE REPORTS: Hypertension (range: 160/100 mmHg to 210/138 mmHg) was reported in 3 adults following intentional ingestion of an antiseptic first aid liquid containing 0.1% naphazoline (Fukushima et al, 2008).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) MACULAR ARTERIAL OCCLUSION developed in a 40-year-old man who used oxymetazoline nasal spray chronically for several years (Magargal et al, 1985).
    B) WITH POISONING/EXPOSURE
    1) PUPILLARY SIZE: Both miosis and mydriasis have been reported(Bucaretchi et al, 2003; Brainerd & Olmsted, 1956; Higgins et al, 1991; Mahieu et al, 1993; Lev & Clark, 1995; Holmes & Berman, 1999).
    2) ACUTE GLAUCOMA: Mydriasis with subsequent acute angle-closure glaucoma, resulting in blindness, was reported in 3 patients following chronic overuse of vasoconstricting eye drops (Rumelt, 1988).
    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) NASAL CONGESTION: Prolonged use of topical nasal decongestants (greater than 7 consecutive days) can result in persistent nasal obstruction (Capel & Swanston, 1986).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Imidazolines may also be used in combination with other sympathomimetics (e.g., phenylephrine or ephedrine) to produce hypertension (Heyman et al, 1991).
    2) WITH POISONING/EXPOSURE
    a) Hypertension may develop (Stamer et al, 2001; Higgins et al, 1991).
    1) ADULT: Hypertension (range: 160/100 mmHg to 210/138 mmHg) was reported in three adults following intentional ingestion of an antiseptic first aid liquid containing 0.1% naphazoline (Fukushima et al, 2008).
    2) PEDIATRIC: Hypertension was reported in 7 of 19 (37%) children with naphazoline toxicity in one case series (Mahieu et al, 1993).
    b) CHRONIC EXPOSURE: A 34-year-old man who chronically abused large doses of oxymetazoline (15 to 20 milligrams/day) phenylephrine hydrochloride (75 to 100 milligrams/day), trimeprazine tartrate (75 milligrams/day) and ephedrine hydrochloride (300 milligrams/day) developed hypertensive crisis with a blood pressure 180/140 complicated by congestive heart failure (Heyman et al, 1991).
    B) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Hypotension has been reported in both adults (Glazener et al, 1983; Lev & Clark, 1995) and children and may persist for hours in some patients (Osterhoudt & Henretig, 2004; Daggy et al, 2003; Mindlin, 1966; Jensen et al, 1989; Mahieu et al, 1993; Holmes & Berman, 1999; Stamer et al, 2001).
    b) CASE REPORT: A 17-year-old girl (74 kg) developed bradycardia and orthostatic hypotension after ingesting approximately 10 to 15 mL (approximately 67 to 102 mcg/kg) of tetrahydrozoline 0.05% ocular formulation. Following supportive care, she recovered completely 38 hours post-ingestion (Spiller & Griffith, 2008).
    C) BRADYCARDIA
    1) WITH POISONING/EXPOSURE
    a) Heart rate may be slightly elevated at first (Bucaretchi et al, 2003; Brainerd & Olmsted, 1956), but bradycardia is common, especially in children and may persist for several hours (Alvarez-Pitti et al, 2006; Daggy et al, 2003; Holmes & Berman, 1999; Lev & Clark, 1995; Higgins et al, 1991; Jensen et al, 1989; Glazener et al, 1983; House & Carey, 1948). Bradycardia developed in 12 of 19 (63%) children in one series of naphazoline toxicity (Mahieu et al, 1993).
    b) CASE REPORT: A 17-year-old girl (74 kg) developed bradycardia (39 beats/min) and orthostatic hypotension after ingesting approximately 10 to 15 mL (approximately 67 to 102 mcg/kg) of tetrahydrozoline 0.05% ocular formulation. Following supportive care, she recovered completely 38 hours post-ingestion (Spiller & Griffith, 2008).
    c) In a series of 72 children with acute exposure to imidazoline decongestants, 57 (79%) developed signs or symptoms of toxicity. Of these, 13 (23%) developed bradycardia (Bucaretchi et al, 2003).
    d) CASE REPORT: A 25-day-old infant who was prescribed nasal drops containing 0.05% tetrahydrozoline hydrochloride, presented with apnea and hypotonia after he was mistakenly administered the tetrahydrozoline orally (3 doses of 0.5 mL/day). On admission, he had a heart rate of 86 beats/min and respiratory rate of 4 breaths/min. Despite supportive care, he continued to have apnea and bradycardia. Within 3 minutes of receiving naloxone 0.1 mg/kg IV (total dose, 0.4 mg), apnea and bradycardia resolved. He was discharged on day 2 (Katar et al, 2010).
    D) VENTRICULAR ARRHYTHMIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: PVCs were reported in one case of IV use of naphazoline (van Montfrans et al, 1981).
    E) VASCULAR CONSTRICTION
    1) WITH POISONING/EXPOSURE
    a) Peripheral vasoconstriction was noted by Soderman et al (1984). Pale, cold extremities were reported in 68% of one series of naphazoline toxicity in infants (Mahieu et al, 1993).
    b) In a series of 72 children with acute exposure to imidazoline decongestants, 57 (79%) developed signs or symptoms of toxicity. Of these, 9 (16%) developed cold extremities (Bucaretchi et al, 2003).
    c) A 36-year-old man developed acute ischemia of the hand after intra-arterial injection of oxymetazoline (Shukla, 1995). He ultimately developed gangrene requiring disarticulation at the wrist despite therapy with nifedipine, heparin, stellate ganglion block, prednisone, oxygen and intra-arterial papaverine infusion.
    F) CEREBROVASCULAR ACCIDENT
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Cerebral infarction was associated with the use of 15 mg of oxymethazoline every 3 days for 20 years (as a nasal decongestant). Another patient developed cerebral infarction after 10 mg of phenoxazoline every 5 days for 15 years (Montalban et al, 1989).
    G) MYOCARDIAL ISCHEMIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 41-year-old man developed bradycardia, hypotension, substernal chest pain and ST elevations on ECG after ingesting 30 milliliters of 0.05% tetrahydrozoline (Lev & Clark, 1995). He improved with atropine treatment and ruled out for a myocardial infarction.
    H) SINUS ARREST
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 16-year-old boy developed sinoatrial node arrest after ingesting less than 15 mL of Visine(R) (containing 0.05% tetrahydrozoline) added to his milk by a classmate. Approximately 7 hours post-ingestion, ECG revealed a wide complex bradycardia (rate 44 beats/min) without discernible sinoatrial node activity. He also experienced a brief period of mild hypotension. Following supportive care, he recovered within 24 hours without further sequelae (Osterhoudt & Henretig, 2004).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) APNEA
    1) WITH POISONING/EXPOSURE
    a) Apnea, gasping respirations or respiratory depression may occur (Thompson, 1970; Greenblatt, 1947; Higgins et al, 1991; Dunn et al, 1993; Holmes & Berman, 1999; Stamer et al, 2001). Respiratory depression was reported in 10 of 19 (52%) children with naphazoline toxicity in one series (Mahieu et al, 1993).
    b) In a series of 72 children with acute exposure to imidazoline decongestants, 57 (79%) developed signs or symptoms of toxicity. Of these, 2 (3.5%) developed apnea and 3 (5%) developed bradypnea. One patient required mechanical ventilation (Bucaretchi et al, 2003).
    c) CASE REPORT: A 25-day-old infant who was prescribed nasal drops containing 0.05% tetrahydrozoline hydrochloride, presented with apnea and hypotonia after he was mistakenly administered the tetrahydrozoline orally (3 doses of 0.5 mL/day). On admission, he had a heart rate of 86 beats/min and respiratory rate of 4 breaths/min. Despite supportive care, he continued to have apnea and bradycardia. Within 3 minutes of receiving naloxone 0.1 mg/kg IV (total dose, 0.4 mg), apnea and bradycardia resolved. He was discharged on day 2 (Katar et al, 2010).
    B) PULMONARY EDEMA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: An 18-month-old boy developed non-cardiogenic pulmonary edema after receiving nebulized nephazoline (3 to 4 milligrams) during bronchoscopy to remove an aspirated foreign body. It was postulated that localized pulmonary vasoconstriction caused increased hydrostatic pressure on the pulmonary capillaries and fluid extravasation into the alveoli. Pulmonary edema resolved within 11 hours (Stamer et al, 2001).
    2) WITH POISONING/EXPOSURE
    a) CASE SERIES: Acute pulmonary edema developed in three adults after intentionally ingesting an antiseptic first aid liquid containing 0.1% naphazoline. The antiseptic also contains 0.1% dibucaine hydrochloride and 0.2% chlorpheniramine maleate and is available over-the-counter in Japan. Although the exact amount ingested was unknown in two patients, one patient ingested 225 mg of naphazoline. Chest x-ray revealed pulmonary edema in each patient with mild cardiac enlargement in two patients. Each patient recovered following intensive supportive care with no permanent sequelae. The authors suggested that naphazoline produced acute pulmonary edema similar to a sympathomimetic overdose (i.e., stimulation of the peripheral alpha-2 adrenergic receptor can produce intense vasoconstriction elevating cardiac afterload and left atrial-ventricular blood volume causing acute pulmonary edema) (Fukushima et al, 2008).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH POISONING/EXPOSURE
    a) Headache may occur (Spiller & Griffith, 2008; Fukushima et al, 2008; Glazener et al, 1983; van Montfrans et al, 1981).
    B) DIZZINESS
    1) WITH POISONING/EXPOSURE
    a) Dizziness, fatigue, and light-headedness may occur (Spiller & Griffith, 2008; Osterhoudt & Henretig, 2004; Glazener et al, 1983; van Montfrans et al, 1981).
    C) FEELING NERVOUS
    1) WITH POISONING/EXPOSURE
    a) Nervousness and insomnia have been reported (Glazener et al, 1983; van Montfrans et al, 1981).
    D) PSYCHOMOTOR AGITATION
    1) WITH POISONING/EXPOSURE
    a) In a series of 72 children with acute exposure to imidazoline decongestants, 57 (79%) developed signs or symptoms of toxicity. Of these, 7 (12%) developed restlessness (Bucaretchi et al, 2003).
    b) Periods of thrashing behavior (Greenblatt, 1947; Higgins et al, 1991) and tremor of the extremities has been reported (Kliment, 1966).
    E) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH POISONING/EXPOSURE
    a) CNS depression ranging from sleepiness, hypotonia and hyporeflexia to coma is common in children, (Alvarez-Pitti et al, 2006; Daggy et al, 2003; Stamer et al, 2001; Holmes & Berman, 1999; Dunn et al, 1993; Higgins et al, 1991; Jensen et al, 1989; Thompson, 1970; Greenstein & Friedman, 1955) and has been observed in two adults following intentional ingestion of an antiseptic first aid liquid containing 0.1% naphazoline (Fukushima et al, 2008).
    b) INCIDENCE: In a series of 19 children with naphazoline toxicity 14 (74%) developed sleepiness and 1 (5%) developed coma (Mahieu et al, 1993).
    1) In a series of 72 children with acute exposure to imidazoline decongestants, 57 (79%) developed signs or symptoms of toxicity. Of these, 34 (58%) developed somnolence (Bucaretchi et al, 2003).
    c) CASE REPORT: A 25-day-old infant who was prescribed nasal drops containing 0.05% tetrahydrozoline hydrochloride, presented with apnea and hypotonia after he was mistakenly administered the tetrahydrozoline orally (3 doses of 0.5 mL/day). On admission, he had a heart rate of 86 beats/min and respiratory rate of 4 breaths/min. Despite supportive care, he continued to have apnea and bradycardia. Within 3 minutes of receiving naloxone 0.1 mg/kg IV (total dose, 0.4 mg), apnea and bradycardia resolved. He was discharged on day 2 (Katar et al, 2010).
    d) CASE REPORT: A 17-year-old girl (74 kg) presented with lethargy, slowed speech, ataxia, dizziness, and headache 25 minutes after ingesting approximately 10 to 15 mL (approximately 67 to 102 mcg/kg) of tetrahydrozoline 0.05% ocular formulation. She recovered completely 38 hours post-ingestion (Spiller & Griffith, 2008).
    e) Lucidity upon arousal from a depressed mental state by vigorous verbal or tactile stimuli following imidazoline overdose is an important differential diagnostic finding(Daggy et al, 2003).
    F) SEIZURE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 5-year-old boy experienced epileptiform seizures following a therapeutic dose of oxymetazoline (Soderman et al, 1984).
    G) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) Insomnia and excitation may occur with therapeutic doses of oxymetazoline (Soderman et al, 1984).
    H) SUBARACHNOID HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Subarachnoid hemorrhage and irregularities of the intracranial vessels were associated with 5-year use of a xylometazoline nasal spray by a 26-year-old female. She reported using 10 mg every 5 to 6 days (Garcia-Albea, 1983).
    I) CEREBROVASCULAR DISEASE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 35-year-old man had used oxymetazoline 15 mg every 3 days for 20 years and developed an ischemic infarction of the left cerebral artery.
    b) CASE REPORT: A 40-year-old man, who had taken phenoxazoline 10 mg every 5 days for 15 years, was found to have an occluded left internal carotid artery and ischemic middle cerebral artery infarction.
    1) These patients had no other risk factors other than chronic excessive use of nasal decongestants (Montalban et al, 1989).
    c) CASE REPORT: A 13-year-old boy using xylometazolin aerosol after a middle ear infection died of a subarachnoid hemorrhage from a saccular aneurysm of the right posterior cerebral artery. There was no relationship to HLA antigen and the vessel wall appeared normal, leading the authors to speculate that transient hypertension caused by the xylometazolin and exercise may have caused rupture of the aneurysm (Meldgaard et al, 1997).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) VOMITING
    1) WITH POISONING/EXPOSURE
    a) Nausea and vomiting may occur following exposure (Fukushima et al, 2008; van Montfrans et al, 1981; Greenblatt, 1947).
    b) In a series of 72 children with acute exposure to imidazoline decongestants, 57 (79%) developed signs or symptoms of toxicity. Of these, 5 (9%) developed nausea/vomiting (Bucaretchi et al, 2003).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) EXCESSIVE SWEATING
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 5-year-old boy was given a 10 mL solution containing 0.1 g of naphazoline-chlorhydrate, 9.7 g of sodium-tetraborate and 0.2 g methylparaben (twice the manufacturer's recommended dose), and developed sweating, somnolence, bradycardia and hypothermia within 2 hours of ingestion. Hypothermia persisted for approximately 7 hours and sweating continued for 12 hours. The patient was discharged to home 20 hours later with no sequelae (Alvarez-Pitti et al, 2006).

Reproductive

    3.20.1) SUMMARY
    A) Oxymetazoline and tetrahydrozoline have been classified as US FDA pregnancy category C.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) OXYMETAZOLINE HYDROCHLORIDE/TETRACAINE HYDROCHLORIDE
    a) There are no adequate or well-controlled trials for the use of the combination oxymetazoline hydrochloride/tetracaine hydrochloride or the single agent tetracaine in pregnant women. However, limited data from epidemiologic studies of oxymetazoline used intranasally as a decongestant during pregnancy in humans did not show any associated teratogenicity (Prod Info KOVANAZE(TM) nasal spray, 2016).
    B) ANIMAL STUDIES
    1) OXYMETAZOLINE HYDROCHLORIDE/TETRACAINE HYDROCHLORIDE
    a) In animal studies, structural abnormalities, including short forelimb digits, fused and irregular shaped arches in thoracic vertebrae, fused ribs, irregular number of ribs, and unossified forelimb phalanx, and reduced fetal weights were observed following the subQ administration of oxymetazoline to rats during organogenesis at a maternally toxic dose approximately 7.6 times the exposure from oxymetazoline at the maximum recommended human dose (MRHD) of the combination (Prod Info KOVANAZE(TM) nasal spray, 2016).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) OXYMETAZOLINE HYDROCHLORIDE/TETRACAINE HYDROCHLORIDE
    a) There are no adequate or well-controlled trials for the use of the combination oxymetazoline hydrochloride/tetracaine hydrochloride in pregnant women (Prod Info KOVANAZE(TM) nasal spray, 2016).
    B) OXYMETAZOLINE
    1) Fetal heart rate changes, including late decelerations, were observed in a patient of 41 weeks' gestation. Delivery was performed because of the late decelerations and term pregnancy. The mother was subsequently found to have used a nasal spray containing oxymetazoline shortly before examination. These changes were thought to be suggestive of decreased uterine perfusion, or possibly due to an effect on the fetal central nervous system. The authors stressed that extreme caution must be exercised when using oxymetazoline in the pregnant patient, especially when uteroplacental competency or perfusion is already compromised (Baxi et al, 1985).
    C) PREGNANCY
    1) Oxymetazoline has been classified as US FDA pregnancy category C (Briggs et al, 1998).
    2) OXYMETAZOLINE HYDROCHLORIDE/TETRACAINE HYDROCHLORIDE: Use caution when administering the oxymetazoline hydrochloride/tetracaine hydrochloride combination to a pregnant woman, as there are no adequate or well-controlled studies of the combination's use in pregnant women (Prod Info KOVANAZE(TM) nasal spray, 2016).
    3) Tetrahydrozoline has been classified as US FDA pregnancy category C (Prod Info TYZINE(R) nasal solution, 1999).
    D) LACK OF EFFECT
    1) NAPHAZOLINE
    a) No increase in congenital defects was observed in children whose mothers used naphazoline during pregnancy (Heinonen et al, 1977).
    2) OXYMETAZOLINE
    a) The frequency of congenital anomalies was not greater than expected among infants exposed to oxymetazoline during the first trimester (Aselton et al, 1985; Jick et al, 1981).
    E) ANIMAL STUDIES
    1) OXYMETAZOLINE HYDROCHLORIDE/TETRACAINE HYDROCHLORIDE
    a) In animal studies, reduced implantation sites and live litter sizes were noted following subQ administration of oxymetazoline to rats at approximately 1.5 times the MRHD and increased pup mortality at 6 times the MRHD in a prenatal and postnatal development study. SubQ administration of tetracaine hydrochloride to rats and rabbits during organogenesis at 32 and 6 times, respectively, the exposure from tetracaine hydrochloride at the MRHD of the combination did not result in adverse developmental effects (Prod Info KOVANAZE(TM) nasal spray, 2016)
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) OXYMETAZOLINE HYDROCHLORIDE/TETRACAINE HYDROCHLORIDE
    a) It is unknown whether oxymetazoline, tetracaine, or their metabolites are excreted into human breast milk (Prod Info KOVANAZE(TM) nasal spray, 2016).
    B) OXYMETAZOLINE HYDROCHLORIDE/TETRACAINE HYDROCHLORIDE
    1) Consider the developmental and health benefits of breastfeeding, along with the mother's clinical need for the drug, and potential adverse effects on the nursing infant from the combination agent or from the mother's underlying condition when administering the oxymetazoline hydrochloride/tetracaine hydrochloride combination to a lactating woman (Prod Info KOVANAZE(TM) nasal spray, 2016).
    C) ANIMAL STUDIES
    1) OXYMETAZOLINE HYDROCHLORIDE/TETRACAINE HYDROCHLORIDE
    a) Following subQ administration of the oxymetazoline hydrochloride/tetracaine hydrochloride combination during the period of organogenesis through parturition and subsequent pup weaning, detectable levels of oxymetazoline, tetracaine, and the major tetracaine metabolite, p-butylaminobenzoic acid (PBBA), were present in the milk of lactating rats. The concentrations of oxymetazoline were dose dependent, with 2.5, 7, and 33.8 ng/mL of oxymetazoline corresponding to doses of 0.6, 1.5, and 7.6 times, respectively, the oxymetazoline exposure at the maximum recommended human dose (MRHD) of the combination. The concentrations of tetracaine and PBBA were generally consistent across all tetracaine dosing groups receiving 12 times the exposure as measured by PBBA at the MRHD, regardless of the oxymetazoline dose, with tetracaine concentrations ranging from 54.2 to 72.9 ng/mL and PBBA concentrations 100.5 to 131.2 ng/mL. However, animal data does not accurately predict human results (Prod Info KOVANAZE(TM) nasal spray, 2016).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) OXYMETAZOLINE HYDROCHLORIDE/TETRACAINE HYDROCHLORIDE
    a) In animal fertility studies, reduced percentage of mobile sperm and sperm counts were observed in rats administered subQ oxymetazoline hydrochloride at doses 2 times the oxymetazoline exposure at the maximum recommended human dose (MRHD) of the combination. No effect on male mating behavior were noted at any dose tested in this study. A reduction in the number of viable embryos occurred when female rats were administered oxymetazoline hydrochloride, alone or in combination with tetracycline hydrochloride, at doses equivalent to or greater than 0.7 times the MRHD. With oxymetazoline hydrochloride administration as monotherapy or in combination with tetracaine hydrochloride at doses 7.5 times the MRHD, the numbers of corpora lutea and implantation sites were reduced; however, when tetracaine hydrochloride was given alone, these effects were not observed. In fact, no effects on male or female fertility were observed following tetracaine hydrochloride administration to rats at doses 28 and 33 times the exposure for males and females, respectively, as measured by the major tetracaine metabolite, p-butylaminobenzoic acid, at the MRHD of the combination (Prod Info KOVANAZE(TM) nasal spray, 2016).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) No specific lab work (CBC, electrolytes, urinalysis) is required.
    B) Consider arterial or venous blood gas measurements in serious cases.
    C) Obtain an ECG in symptomatic patients.
    D) Obtain a CT scan in patients with profound CNS depression to evaluate for other causes.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Symptomatic patients should be admitted to a monitored setting.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Any adult with an intentional ingestion or a symptomatic child should be referred to a healthcare facility.
    B) Young children have developed serious adverse effects after ingesting as little as 1 to 2 mL of formulations of eye drops or nasal spray (concentrations not specified) containing imidazoline decongestants (eg, tetrahydrozoline, oxymetazoline, or naphazoline). The Food and Drug Administration (FDA) reported 96 cases of accidental ingestion of products containing tetrahydrozoline, oxymetazoline, or naphazoline by children (age range, 1 month to 5 years). Hospitalization was required in 53 cases because of symptoms such as nausea, vomiting, lethargy, tachycardia, decreased respiration, bradycardia, hypotension, hypertension, sedation, somnolence, mydriasis, stupor, hypothermia, drooling, and coma (U.S. Food and Drug Administration, 2012).
    C) In a retrospective series of 193 children who ingested 0.05% tetrahydrozoline, none of the 54 patients who ingested less than 7.5 mL developed symptoms (no follow-up was available in 4 of these children) (Kuffner et al, 1996).
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing severe poisonings.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients should be observed for a minimum of 6 hours after a suspected ingestion and can be discharged if asymptomatic after that time.
    B) In the published cases of accidental ingestion of imidazoline decongestants, patients who became symptomatic had an onset of symptoms ranging from "almost immediately" (Soderman et al, 1984; van Montfrans et al, 1981) and 30 minutes (Hainsworth, 1948; van Montfrans et al, 1981) to up to four hours (Klein-Schwartz et al, 1984).
    1) In all cases, symptoms resolved within approximately 24 hours.
    2) In one study, 92% of all imidazoline exposure patients remained asymptomatic (Lewis & Giffin, 1992).

Monitoring

    A) No specific lab work (CBC, electrolytes, urinalysis) is required.
    B) Consider arterial or venous blood gas measurements in serious cases.
    C) Obtain an ECG in symptomatic patients.
    D) Obtain a CT scan in patients with profound CNS depression to evaluate for other causes.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Decontamination is unlikely to be of benefit in these cases since these are primarily liquid ingestions which will be absorbed quickly. In addition, these agents may cause CNS depression, so the risk of decontamination generally exceeds any potential benefit.
    6.5.2) PREVENTION OF ABSORPTION
    A) Gastrointestinal decontamination is unlikely to be of benefit in these cases since these are primarily liquid ingestions which will be absorbed quickly. In addition, patients (children in particular) may become lethargic quickly.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Most patients do well on supportive respiratory and cardiac care and monitoring.
    2) Patient should be kept warm.
    3) Supportive care may be required for up to 24 hours in the seriously intoxicated patient (Bucaretchi et al, 2003).
    B) MONITORING OF PATIENT
    1) No specific lab work (CBC, electrolytes, urinalysis) is required.
    2) Consider arterial or venous blood gas measurements in serious cases.
    3) Obtain an ECG in symptomatic patients.
    4) Obtain a CT scan in patients with profound CNS depression to evaluate for other causes.
    C) FLUID/ELECTROLYTE BALANCE REGULATION
    1) Fluids and electrolytes should be monitored closely.
    D) BRADYCARDIA
    1) Evaluate for hypoxia; administer oxygen and manage airway as clinically indicated.
    2) ATROPINE/DOSE
    a) ADULT BRADYCARDIA: BOLUS: Give 0.5 milligram IV, repeat every 3 to 5 minutes, if bradycardia persists. Maximum: 3 milligrams (0.04 milligram/kilogram) intravenously is a fully vagolytic dose in most adults. Doses less than 0.5 milligram may cause paradoxical bradycardia in adults (Neumar et al, 2010).
    b) PEDIATRIC DOSE: As premedication for emergency intubation in specific situations (eg, giving succinylchoine to facilitate intubation), give 0.02 milligram/kilogram intravenously or intraosseously (0.04 to 0.06 mg/kg via endotracheal tube followed by several positive pressure breaths) repeat once, if needed (de Caen et al, 2015; Kleinman et al, 2010). MAXIMUM SINGLE DOSE: Children: 0.5 milligram; adolescent: 1 mg.
    1) There is no minimum dose (de Caen et al, 2015).
    2) MAXIMUM TOTAL DOSE: Children: 1 milligram; adolescents: 2 milligrams (Kleinman et al, 2010).
    3) Atropine was given to one patient to treat the bradycardia with negative results. Subsequently he developed an elevated blood pressure (150/120).
    4) Animal studies indicate that while atropine will increase the heart rate, it will also cause significant increases in the mean arterial pressure (van Montfrans et al, 1981).
    E) HYPERTENSIVE EPISODE
    1) Generally hypertension is transient and does not warrant treatment. In rare instances where hypertension is severe, short acting agents should be used.
    2) May be treated with intravenous nitroprusside (initiate 1 microgram/kilogram/minute intravenous infusion and adjust to control blood pressure) or phentolamine:
    a) Adult Dose: 2 to 5 milligrams intravenously, repeated every five minutes until hypertension is controlled, then every two to four hours as needed.
    b) Pediatric Dose: 0.05 to 0.1 milligram/kilogram dose, repeated every five minutes until hypertension is controlled, then every one to four hours as needed.
    F) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    G) NALOXONE
    1) Because the imidazoline decongestants produce sedation, hypotension, and bradycardia via a central alpha-adrenoreceptor stimulation, similar to clonidine, the naloxone has been administered for these exposures. However, based on mechanism, naloxone would not be expected to reverse imidazoline toxicity.
    2) CASE REPORT: A 36-month-old infant ingested approximately 30 milliliters of an eye drop solution containing tetrahydrozoline (0.05%) and presented to the ED approximately 1.5 hours later with increasing lethargy, decreased muscle tone, and progressive hypotension and bradycardia. Naloxone 1.5 milligrams (0.1 milligram/kilogram) was administered intravenously. Within 30 seconds of administration, the infant became alert and responsive, with an increasing heart rate and an elevation of blood pressure. Approximately 10 minutes after naloxone administration, the infant again became increasingly somnolent with another decrease in heart rate and blood pressure. Following supportive care, the child gradually recovered over the next 7.5 hours; no further naloxone was given (Holmes & Berman, 1999).
    3) CASE REPORT: A 25-day-old infant who was prescribed nasal drops containing 0.05% tetrahydrozoline hydrochloride, presented with apnea and hypotonia after he was mistakenly administered the tetrahydrozoline orally (3 doses of 0.5 mL/day). On admission, he had a heart rate of 86 beats/min and respiratory rate of 4 breaths/min. Despite supportive care, he continued to have apnea and bradycardia. Within 3 minutes of receiving naloxone 0.1 mg/kg IV (total dose, 0.4 mg), apnea and bradycardia resolved. He was discharged on day 2 (Katar et al, 2010).

Abstracts

Case Reports

    A) PEDIATRIC
    1) NAPHAZOLINE
    a) CASE REPORT: A 5-year-old boy was given a 10 mL solution containing 0.1 g of naphazoline-chlorhydrate, 9.7 g of sodium-tetraborate and 0.2 g methylparaben (twice the manufacturer's recommended dose), and developed diaphoresis, somnolence, bradycardia and hypothermia within 2 hours of ingestion. Signs and symptoms included bradycardia (pulse rate 45 to 50 BPM), hypothermia (35.5 degrees Celsius) and a blood pressure of 100/70 mm Hg. Treatment included supportive care. Somnolence, hypotension, and hypothermia persisted for about 7 hours and diaphoresis resolved in about 12 hours. The patient was discharged to home 20 hours later with no sequelae (Alvarez-Pitti et al, 2006).
    b) CASE REPORT: A 15-month-old girl was treated for approximately 1 week with a commercial preparation of OXYMETAZOLINE nose drops. This was exchanged for an extemporaneously prepared mixture containing NAPHAZOLINE 1 mg/mL, plus flunisolide, ipratropium bromide, neomycin, and bacitracin in saline, glycerine, and propylene glycol. Two doses of 5 drops each (0.02 mg/kg naphazoline) were administered at noon and evening.
    1) The next morning, the infant was found stuporous, pale, and with cold extremities. On admission findings included pulse 60 and regular; blood pressure 95/50 mmHg; bilateral pinpoint pupils; no rigidity or other neurologic deficits. Labs and CAT were within normal limits.
    2) Treatment included naloxone and flumazenil without effect. Spontaneous recovery without sequelae occurred over 24 hours(Mahieu et al, 1993).
    2) TETRAHYDROZOLINE
    a) Mindlin (1966) described accidental poisoning from ingestion of tetrahydrozoline eye drops (0.05%) in a 1-year-old girl.
    1) Two hours following ingestion of 0.5 to one teaspoonful the child became sluggish and was hospitalized. Three hours following ingestion, the child was drowsy and pale, respirations were slow, extremities were cool, and bradycardia was present.
    2) Pupils were constricted and did not react to light. The child was kept warm and in shock position and improved over the next 24 hours without specific treatment (Mindlin, 1966).
    b) Wick (1966) described severe intoxication in a 9-month-old boy following administration of 0.1% Tyzine(R) nasal spray for persistent rhinitis.
    1) The child became cyanotic and comatose with profuse perspiration. Visual reflexes were absent, and bradycardia (60 to 80/min) and hypotension (75/55) were observed. Respiratory depression was also evident. The child recovered within 9 hours following infusion of norepinephrine and plasma (Wick, 1966).
    c) A 17-month-old girl ingested 4 to 5 mL of tetrahydrozoline 0.1%. She became lethargic, but arousable. The heart rate and blood pressure were labile, with a tendency toward hypotension and bradycardia.
    1) The lowest pulse rate was approximately 70 beats/minute and lowest blood pressure about 100/35 mmHg. Hypotension and bradycardia responded rapidly to fluid challenge. She was discharged within 24 hours (Jensen et al, 1989).
    3) XYLOMETAZOLINE
    a) Coma followed a single intranasal administration of "1 drop" of 0.1% xylometazoline in each nostril in a 15-day-old female. Two hours after administration, the infant was noted to be grayish in color, hypotonic, and breathing irregularly.
    1) During hospitalization, she became progressively comatose with cluster-type breathing, remaining hypotonic and poorly responsive. Spontaneous recovery began 4 to 6 hours after admission and she was transferred from intensive care at 12 hours. She was without sequelae at 1 year follow up (Dunn et al, 1993).

Range Of Toxicity

Summary

    A) TOXICITY: The toxic dose after oral ingestions is not clear, but young children have developed serious adverse effects after ingesting as little as 1 to 2 mL of formulations of eye drops or nasal spray containing imidazoline decongestants (eg, tetrahydrozoline, oxymetazoline, or naphazoline). Systemic symptoms have also been described in young infants after therapeutic use of topical agents. Fatalities have not been reported after ingestion, but intravenous injection of xylometazoline was fatal in an adult. THERAPEUTIC DOSE: Generally, 1 to 2 drops are used in the eye and 1 to 3 sprays in each nostril for adults and children more than 6-years-old.

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) NAPHAZOLINE
    a) INTRANASAL: 1 to 2 sprays or drops of 0.05% solution into each nostril; no more often than every 6 hours or for more than 3 days (Prod Info PRIVINE(R) nasal spray, 2005).
    b) OPHTHALMIC: 1 to 2 drops of 0.1% solution into each eye every 3 to 4 hours (Prod Info AK-CON(TM) ophthalmic solution, 2008).
    2) OXYMETAZOLINE
    a) INTRANASAL: 2 to 3 sprays of 0.05% solution into each nostril every 10 to 12 hours for no more than 3 days. MAXIMUM: 2 doses over 24 hours (Prod Info VICKS(R) SINEX(R) nasal spray, 2005).
    b) OPHTHALMIC: 1 to 2 drops of 0.025% solution into each eye every 6 hours (Johnson & Johnson Healthcare Products, 2012).
    3) TETRACAINE HYDROCHLORIDE/OXYMETAZOLINE HYDROCHLORIDE
    a) INTRANASAL: 2 sprays ipsilateral (on the same side) to the maxillary tooth where the dental procedure will be performed 4 to 5 minutes apart; initiate dental procedure 10 minutes following second spray; if a test drill 10 minutes after administration of a second initial spray does not provide adequate anesthesia, may give 1 additional spray (Prod Info KOVANAZE(TM) nasal spray, 2016)
    4) TETRAHYDROZOLINE
    a) INTRANASAL: 3 to 4 sprays or 2 to 4 drops of 0.1% solution into each nostril as needed; no more than every 3 hours (Prod Info TYZINE(R) nasal solution, 1999).
    b) OPHTHALMIC: 1 to 2 drops of 0.05% solution into each eye up to 4 times daily for no more than 72 hours (Prod Info Visine(R) eye drops, 2004).
    7.2.2) PEDIATRIC
    A) SPECIFIC SUBSTANCE
    1) NAPHAZOLINE
    a) INTRANASAL (12 TO 18 YEARS OF AGE): 1 to 2 sprays or drops of 0.05% solution into each nostril; no more often than every 6 hours or for more than 3 days (Prod Info PRIVINE(R) nasal spray, 2005).
    b) OPHTHALMIC: Safety and effectiveness have not been established (Prod Info AK-CON(TM) ophthalmic solution, 2008).
    2) OXYMETAZOLINE
    a) INTRANASAL (6 TO 18 YEARS OF AGE): 2 to 3 sprays of 0.05% solution into each nostril every 10 to 12 hours for no more than 3 days. MAXIMUM: 2 doses over 24 hours (Prod Info VICKS(R) SINEX(R) nasal spray, 2005).
    3) TETRACAINE HYDROCHLORIDE/OXYMETAZOLINE HYDROCHLORIDE
    a) INTRANASAL (WEIGHING 40 KG OR MORE): 2 sprays ipsilateral (on the same side) to the maxillary tooth where the dental procedure will be performed 4 to 5 minutes apart; initiate dental procedure 10 minutes following second spray (Prod Info KOVANAZE(TM) nasal spray, 2016)
    4) TETRAHYDROZOLINE
    a) INTRANASAL (6 TO 18 YEARS OF AGE): 2 to 4 drops or 3 to 4 sprays of 0.1% solution into each nostril as needed; no more than every 3 hours (Prod Info TYZINE(R) nasal solution, 1999).
    b) INTRANASAL (2 TO 6 YEARS OF AGE): 2 to 3 drops of 0.05% pediatric solution into each nostril as needed; no more than every 3 hours (Prod Info TYZINE(R) nasal solution, 1999).
    c) OPHTHALMIC (6 TO 18 YEARS OF AGE): 1 to 2 drops of 0.05% solution into each eye up to 4 times daily for no more than 72 hours (Prod Info Visine(R) eye drops, 2004).

Minimum Lethal Exposure

    A) ROUTE OF EXPOSURE
    1) INTRAVENOUS: Death has been reported after intravenous injection of xylometazoline (Vanezis & Toseland, 1980).
    2) ORAL: No deaths could be documented in the literature after ingestion.

Maximum Tolerated Exposure

    A) Young children have developed serious adverse effects after ingesting as little as 1 to 2 mL of formulations of eye drops or nasal spray containing imidazoline decongestants (eg, tetrahydrozoline, oxymetazoline, or naphazoline). The Food and Drug Administration (FDA) reported 96 cases of accidental ingestion of products containing tetrahydrozoline, oxymetazoline, or naphazoline by children (age range, 1 month to 5 years). Hospitalization was required in 53 cases because of symptoms such as nausea, vomiting, lethargy, tachycardia, decreased respiration, bradycardia, hypotension, hypertension, sedation, somnolence, mydriasis, stupor, hypothermia, drooling, and coma (U.S. Food and Drug Administration, 2012).
    B) An in vitro study used 3 different over-the-counter products containing oxymetazoline 0.05% (20 mL to 30 mL bottles) from 3 local stores, to determine the volume released after a single depression of the container that is inverted following an intranasal administration to a supine child. The container was also held at a 45 degrees angle which reproduced an unintentional ingestion of a small child standing or sitting with an elevated container in the mouth. The following measurements were obtained: A 30 mL bottle from Kroger: 0.66 mL +/- 0.07 mL (660 mcL +/- 70 mcL); range: 0.59 to 0.73 mL (590 to 730 mcL). A 30 mL bottle from Target: 0.9 mL +/- 0.09 mL (900 mcL +/- 90 mcL); range: 0.8 to 0.96 mL (800 to 960 mcL). A 20 mL bottle from Merck: 0.72 mL +/- 0.04 mL (720 mcL +/- 40 mcL); range: 0.68 to 0.75 mL (680 to 750 mcL) (Nordt et al, 2016).
    C) When an oxymetazoline bottle is held upright in "normal" position, about 30 mcL of oxymetazoline is released with each actuation. In an in vitro study of 3 over-the-counter products containing oxymetazoline 0.05% (20 mL to 30 mL bottles), the volume of oxymetazoline was 20 to 30-fold higher (590 to 960 mcL) when the bottle was held inverted at 45 degrees. If each nostril is administered these volumes, the total volume would be doubled (1180 to 1920 mcL) (Nordt et al, 2015).
    D) SPECIFIC SUBSTANCE
    1) NAPHAZOLINE
    a) PEDIATRIC
    1) A 3-month-old child who has given 7 mL of 0.1% naphazoline developed bradycardia, hypothermia, and irregular breathing (Krajci, 1966).
    2) A child who ingested 5 mg of naphazoline nitrate developed bradypnea, somnolence, and tachycardia (Kliment, 1966).
    3) A 7-year-old boy received a dose of unknown quantity of naphazoline nose drops inadvertently mixed by the pharmacy to a 4% concentration (40 mg/mL); equivalent to approximately 80 times the normal concentration. Various assays of urine and gastric contents revealed drug levels as follows (Musshoff et al, 2003):
    1) Urine: 1.32 mg/L
    2) Gastric content: 0.64 mg/L
    3) Nose drop solution: 40 mg/L
    a) The patient was discharged after a 2 day hospitalization for somnolence, bradycardia, hypotonus and rolling of the eyes (Musshoff et al, 2003).
    4) CASE REPORT: A 17-year-old girl (74 kg) developed lethargy, slowed speech, ataxia, dizziness, bradycardia, and orthostatic hypotension after ingesting approximately 10 to 15 mL (approximately 67 to 102 mcg/kg) of tetrahydrozoline 0.05% ocular formulation. She recovered completely 38 hours post-ingestion (Spiller & Griffith, 2008).
    b) ADULT
    1) An adult intentionally ingested three bottles (total: 225 mg naphazoline) of a topical first aid liquid containing 0.1% naphazoline and developed hypertension (210/138 mmHg), pulmonary edema, mild cardiac enlargement and CNS depression. Following supportive care, the patient recovered completely (Fukushima et al, 2008).
    2) OXYMETAZOLINE
    a) In one case report, seizures followed administration of one drop per nostril of oxymetazoline 0.25 milligram/milliliter in a 5-year-old male (Soderman et al, 1984). Based on currently available literature this is a relatively rare effect.
    3) TETRAHYDROZOLINE/PEDIATRIC
    a) In a retrospective study of 193 children who ingested 0.05% tetrahydrozoline, none of the 54 children who ingested less than 7.5 milliliters developed toxicity (follow-up was not done on 4 of these patients) (Kuffner et al, 1996). Of 43 patients who ingested more than 7.5 milliliters 6 developed symptoms and 1 was not followed up. Of 97 children in whom the amount ingested was not known 6 developed symptoms and 15 were not followed up.
    b) On rare occasions the sedative response to tetrahydrozoline may follow nasal administration of as little as 1 to 2 drops of the 0.1 percent solution to infants (Brainerd & Olmsted, 1956).
    c) Bradycardia, and respiratory depression were reported after ingestion of 0.5 to 1 teaspoonful of tetrahydrozoline 0.05 percent eye drops in a one year old child (Mindlin, 1966).
    d) Coma was reported in a 2-year-old boy who ingested 7.5 milliliters of 0.05 percent tetrahydrozoline, and lethargy in a 20-month-old boy who ingested 15 milliliters of 0.05 percent (Klein-Schwartz et al, 1984).
    e) Lethargy, bradycardia, and hypotension were reported in a 17-month-old child who ingested 4 to 5 milliliters of 0.1 percent tetrahydrozoline (Jensen et al, 1989).
    f) A 16-year-old boy developed sinoatrial node arrest after ingesting less than 15 mL of Visine(R) (containing 0.05% tetrahydrozoline) added to his milk by a classmate. Approximately 7 hours post-ingestion, ECG revealed a wide complex bradycardia (rate 44 beats/min) without discernible sinoatrial node activity. He also experienced a brief period of mild hypotension. Following supportive care, he recovered within 24 hours without further sequelae (Osterhoudt & Henretig, 2004).
    g) A 25-day-old boy who was prescribed nasal drops containing 0.05% tetrahydrozoline hydrochloride, presented with apnea and hypotonia after he was mistakenly administered the tetrahydrozoline orally (3 doses of 0.5 mL/day). On admission, he had a heart rate of 86 beats/min and respiratory rate of 4 breaths/min. Despite supportive care, he continued to have apnea and bradycardia. Within 3 minutes of receiving naloxone 0.1 mg/kg IV (total dose, 0.4 mg), apnea and bradycardia resolved. He was discharged on day 2 (Katar et al, 2010).
    4) XYLOMETAZOLINE
    a) Use of xylometazoline 10 milligrams over 5 to 6 days for 5 years was associated with subarachnoid hemorrhage in a 26-year-old woman (Garcia-Albea, 1983).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) SPECIFIC SUBSTANCE
    a) XYLOMETAZOLINE
    1) A fatal case of xylometazoline poisoning after injection was reported by Vanezis & Toseland (1980). Levels in the blood were: peripheral blood 0.14 microgram/milliliter, liver blood 0.37 microgram/milliliter. Death appeared to be due to CNS depression.

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) NAPHAZOLINE
    1) LD50- (SUBCUTANEOUS)RAT:
    a) 385 mg/kg
    B) OXYMETAZOLINE
    1) LD50- (ORAL)MOUSE:
    a) 10 mg/kg
    C) TETRAHYDROZLINE
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 116 mg/kg
    2) LD50- (ORAL)MOUSE:
    a) 335 mg/kg
    3) LD50- (SUBCUTANEOUS)MOUSE:
    a) 252 mg/kg
    D) XYLOMETAZOLINE
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 46 mg/kg
    2) LD50- (ORAL)MOUSE:
    a) 215 mg/kg
    3) LD50- (SUBCUTANEOUS)MOUSE:
    a) 63 mg/kg

Pharmacology Toxicology

Pharmacologic Mechanism

    A) These agents are used for decongestion of nasal and nasopharyngeal mucosa, and as ophthalmic decongestants. They are sympathomimetics with the chemical structure of an imidazoline derivative, which causes vasoconstriction when applied topically.
    1) The relative pressor effect (established in dogs) of naphazoline was from 1/5 to 1/3 that of epinephrine (Craver et al, 1944). Naphazoline acts more like ephedrine than epinephrine (Craver et al, 1944).
    B) The pharmacology of these imidazoles is complicated in that they react at various receptor sites.
    C) Oxymetazoline and naphazoline do not activate histamine 1 or 2 receptors or beta adrenoceptors. They are specific alpha stimulants.
    D) Tetrahydrozoline and tolazoline interact with H2 and alpha adrenoceptors but not H1 or beta adrenoceptors (Sanders et al, 1975).
    1) Animal studies seem to indicate that naphazoline induced sedation is due to EEG synchronization through stimulation of the central alpha-adrenergic receptors (Delbarre & Schmitt, 1971; Florio et al, 1975).
    E) Imidazole receptors have been discovered in the brain, and drugs like rilmenidene were developed as antihypertensives (Bousquet et al, 1992; Reis et al, 1992).

Physicochemical

Physical Characteristics

    A) OXYMETAZOLINE HYDROCHLORIDE: white hydroscopic crystalline powder
    B) NAPHAZOLINE HYDROCHLORIDE: white crystalline powder

Ph

    A) OXYMETAZOLINE HYDROCHLORIDE
    1) A 5% aqueous solution has a pH of 4 to 6.5 (JEF Reynolds , 2000).
    B) TETRAHYDROZOLINE HYDROCHLORIDE
    1) A 1% aqueous solution has a pH of 5 to 6.5 (Budavari, 1996).
    C) XYLOMETAZOLINE HYDROCHLORIDE
    1) A 5% aqueous solution has a pH of 5 to 6.6 (JEF Reynolds , 2000).

Molecular Weight

    A) OXYMETAZOLINE HYDROCHLORIDE: 296.8
    B) NAPHAZOLINE HYDROCHLORIDE: 246.7
    C) TETRAHYDROZOLINE HYDROCHLORIDE: 236.7
    D) XYLOMETAZOLINE HYDROCHLORIDE: 280.8

References

General Bibliography

    1) Alvarez-Pitti J, Rodriguez-Varela A, Morales-Carpi C, et al: Naphazoline intoxication in children. Eur J Pediatr 2006; 165(11):815-816.
    2) Aselton P, Jick H, & Milunsky A: First-trimester drug use and congenital disorders. Obstet Gynec 1985; 65:451-455.
    3) Baxi LV, Gindoff PR, Pregenzer GJ, et al: Fetal heart rate changes following maternal administration of a nasal decongestant. Am J Obstet Gynecol 1985; 153:799-800.
    4) Bousquet P, Feldman J, & Tibirica E: Imidazoline receptors: a new concept in central regulation of the arterial blood pressure. Am J Hypertens 1992; 5(4 Pt 2):47S-50S.
    5) Brainerd WK & Olmsted RW: Toxicity due to the use of tyzine hydrochloride. J Pediatr 1956; 48:157-164.
    6) Briggs GG, Freeman RK, & Yaffe SJBriggs GG, Freeman RK, & Yaffe SJ (Eds): Drugs in Pregnancy and Lactation, 5th. Williams & Wilkins, Baltimore, MD, 1998.
    7) Bucaretchi F, Dragosavac S, & Vieira RJ: Acute exposure to imidazoline derivatives in children. J Pediatr (Rio J) 2003; 79:519-524.
    8) Budavari S: The Merck Index, 12th ed, Merck & Co, Inc, Whitehouse Station, NJ, 1996.
    9) Capel LH & Swanston AR: Beware congesting nasal decongestants. Br Med J 1986; 293:1258-1259.
    10) Craver BN, Chase HF, & Yonkman FF: Pharmacologic studies of a new vasoconstrictor: 2-naphthyl-(1')-methyl- imidazoline hydrochloride-III. J Pharmacol Exp Ther 1944; 82:275-287.
    11) Daggy A, Kaplan R, Roberge R, et al: Pediatric Visine(R) (tetrahydrozoline) ingestion: Case report and review of imidazoline toxicity. Vet Hum Toxicol 2003; 45:210-212.
    12) Delbarre B & Schmitt H: Sedative effects of alpha-sympathomimetic drugs and their antagonism by adrenergic and cholinergic blocking drugs. Eur J Pharmacol 1971; 13:356-365.
    13) Dunn C, Gauthier M, & Gaudreault P: Coma in a neonate following single intranasal dose of xylometazoline. Eur J Pediatr 1993; 152:541.
    14) Escobar JI & Karno M: Chronic hallucinosis from nasal drops. JAMA 1982; 247:1859-1860.
    15) Florio V, Bianchi L, & Longo VG: A study of the central effects of sympathomimetic drugs: EEG and behavioural investigations on clonidine and naphazoline. Neuropharmacology 1975; 14:707-714.
    16) Fukushima H, Norimoto K, Seki T, et al: Acute pulmonary edema associated with naphazoline ingestion. Clin Toxicol (Phila) 2008; 46(3):254-256.
    17) Garcia-Albea I: Subarachnoid haemorrhage and nasal vasoconstrictor abuse (letter). J Neurol Neurosurg Psych 1983; 46:875-876.
    18) Glazener F, Blake K, & Gradman M: Bradycardia, hypotension, and near syncope associated with Afrin (oxymetazoline) nasal spray. N Engl J Med 1983; 309:731.
    19) Greenblatt J: Hypersensitivity to privine. J Pediatr 1947; 31:355-356.
    20) Greenstein NM & Friedman HT: Reactions following use of nasal decongestants. JAMA 1955; 157:1153.
    21) Hainsworth WC: Accidental poisoning with naphazoline (Privine) hydrochloride. Am J Dis Child 1948; 75:76-80.
    22) Heinonen OP, Slone D, & Shapiro SHeinonen OP, Slone D, & Shapiro S (Eds): Birth Defects and Drugs in Pregnancy, Publishing Sciences Group, Littleton, MA, 1977, pp 346-347.
    23) Heyman SN, Mevorach D, & Ghanem J: Hypertensive crisis from chronic intoxication with nasal decongestant and cough medications. DICP 1991; 25:1068-1070.
    24) Higgins GL, Campbell B, & Wallace K: Pediatric poisoning from over-the-counter imidazoline-containing products. Ann Emerg Med 1991; 20:655-658.
    25) Holmes JF & Berman DA: Use of naloxone to reverse symptomatic tetrahydrozoline overdose in a child. Ped Emerg Care 1999; 15:193-194.
    26) House LR & Carey WC: Constitutional effects from the use of sympathomimetic drugs as nasal medication in children. Report of case of privine toxicity. Laryngoscope 1948; 58:1294-1298.
    27) JEF Reynolds : Martindale: The Extra Pharmacopoeia (Electronic Version). The Pharmaceutical Press. London, UK (Internet Version). Edition expires 2000; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    28) Jensen P, Edgren B, & Hall L: Hemodynamic effects following ingestion of an imidazoline-containing product. Pediatr Emerg Care 1989; 5:110-112.
    29) Jick H, Holmes L, & Hunter J: First-trimester drug use and congenital disorders. JAMA 1981; 246:343-346.
    30) Johnson & Johnson Healthcare Products: VISINE(R) L.R.(R): long lasting relief. Johnson & Johnson Healthcare Products. New Brunswick, NJ. 2012. Available from URL: http://www.visine.com/product-visine-lr. As accessed 2012-01-18.
    31) Katar S, Taskesen M, & Okur N: Naloxone use in a newborn with apnea due to tetrahydrozoline intoxication. Pediatr Int 2010; 52(3):488-489.
    32) Klein-Schwartz W, Gorman R, & Odera GM: Central nervous system depression from ingestion of nonprescription eyedrops. Am J Emerg Med 1984; 2:217-218.
    33) Kleinman ME, Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 14: pediatric advanced life support. Circulation 2010; 122(18 Suppl.3):S876-S908.
    34) Kliment J: Intoxication by the naphazoline nasal drops (Sanorin Galena in emulsion 0.1%) in a three year old boy. Internat Pharm Abstracts 1966; 32:1152.
    35) Krajci L: Cslka Pediatr 1966; 21:277.
    36) Kuffner EK, Falbo SC, & Bogdan GM: Dose related effects of tetrahydrozoline (THZ) ingestion in children (abstract). J Toxicol Clin Toxicol 1996; 34:579.
    37) Lev R & Clark RF: Visine(R) overdose: case report of an adult with hemodynamic compromise. J Emerg Med 1995; 5:649-652.
    38) Lewis S & Giffin SL: Pediatric imidazoline exposures; incidence of serious effects. Vet Hum Toxicol 1992; 34:333.
    39) Magargal LE, Sanborn GE, & Donoso LA: Branch retinal artery occlusion after excessive use of nasal spray. Ann Ophthalmol 1985; 17:500-501.
    40) Mahieu LM, Rooman RP, & Goossens E: Imidazoline intoxication in children. Eur J Pediatr 1993; 152:944-946.
    41) Meldgaard K, Vesterby A, & Ostergaard JR: Sudden death due to rupture of a saccular intracranial aneurysm in a 13-year-old boy. Am J Forensic Med Path 1997; 18:342-344.
    42) Mindlin RL: Accidental poisoning from tetrahydrozoline eyedrops (letter). N Engl J Med 1966; 275:112.
    43) Montalban J, Ibanez L, & Rodriguez C: Cerebral infarction after excessive use of nasal decongestants (letter). J Neurol Neurosurg Psychiatry 1989; 52:541-542.
    44) Musshoff F, Gerschlauer A, & Madea B: Naphazoline intoxication in a child - a clinical and forensic toxicological case. Forensic Sci Int 2003; 134:234-237.
    45) Neumar RW , Otto CW , Link MS , et al: Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122(18 Suppl 3):S729-S767.
    46) Nordt SP, Vivero LE, & Cantrell FL: Comparison of various oyxmetalozine nasal decongestants in inverted position: 2015 Annual Meeting of the North American Congress of Clinical Toxicology (NACCT). Clin Toxicol 2015; 53(7):657-658.
    47) Nordt SP, Vivero LE, & Cantrell FL: Not Just a Drop in the Bucket-Inversion of Oxymetazoline Nasal Decongestant Container Increases Potential for Severe Pediatric Poisoning. J Pediatr 2016; 168:240-241.
    48) Osterhoudt KC & Henretig FM: Sinoatrial node arrest following tetrahydrozoline ingestion (letter). J Emerg Med 2004; 27(3):313-315.
    49) Peberdy MA , Callaway CW , Neumar RW , et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care science. Part 9: post–cardiac arrest care. Circulation 2010; 122(18 Suppl 3):S768-S786.
    50) Product Information: AK-CON(TM) ophthalmic solution, naphazoline HCl 0.1% ophthalmic solution. Akorn, Inc. (per Manufacturer), Lake Forest, IL, 2008.
    51) Product Information: KOVANAZE(TM) nasal spray, tetracaine HCl oxymetazoline HCl nasal spray. St. Renatus, LLC (per FDA), Fort Collins, CO, 2016.
    52) Product Information: PRIVINE(R) nasal spray, naphazoline hcl nasal spray. Insight Pharmaceuticals, Langhorne, PA, 2005.
    53) Product Information: TYZINE(R) nasal solution, tetrahydrozoline hcl nasal solution. Kenwood Therapeutics, Pawtucket, RI, 1999.
    54) Product Information: VICKS(R) SINEX(R) nasal spray, oxymetazoline hcl nasal spray. Proctor & Gamble, Cincinnati, OH, 2005.
    55) Product Information: Visine(R) eye drops, tetrahydrozoline. Pfizer, 2004.
    56) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    57) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
    58) Reis DJ, Regunathan S, & Meeley MP: Imidazole receptors and clonidine-displacing substance in relationship to control of blood pressure, neuroprotection, and adrenomedullary secretion. Am J Hypertens 1992; 5(4 Pt 2):51S-57S.
    59) Rogers GW: Safe use of eye drops. N Engl J Med 1966; 275:447.
    60) Rumelt MB: Blindness from misuse of over-the-counter eye medications. Ann Ophthalmol 1988; 20:26-30.
    61) Saadah HA: A case of panic disorder precipitated by oxymetazoline withdrawal. J Clin Psychiatry 1987; 48:293.
    62) Sanders J, Miller DD, & Patil PN: Alpha adrenergic and histaminergic effects of tolazoline-like imidazoles. J Pharmacol Exp Ther 1975; 195:362-371.
    63) Shukla PC: Acute iscehmia of the hand following intra-arterial oxymetazoline injection. J Emerg Med 1995; 13:65-70.
    64) Soderman P, Sahlberg D, & Wiholm BE: CNS reactions to nose drops in small children (letter). Lancet 1984; 1:573.
    65) Spiller H & Griffith J: Prolonged cardiovascular effects after unintentional ingestion of tetrahydrozoline. Clin Toxicol (Phila) 2008; 46(2):171-172.
    66) Stamer UM, Buderus S, & Wetegrove S: Prolonged awakening and pulmonary edema after general anesthesia and naphazoline application in an infant. Anesth Analg 2001; 93:1162-1164.
    67) Thompson RE: Nose drop intoxication in an infant. JAMA 1970; 211:123-124.
    68) Ticoll B & Shugar G: Paranoid psychosis induced by oxymetazoline nasal spray. Can Med Assoc J 1994; 150:375-376.
    69) U.S. Food and Drug Administration: FDA Drug Safety Communication: Serious adverse events from accidental ingestion by children of over-the-counter eye drops and nasal sprays. U.S. Food and Drug Administration. Silver Spring, MD. 2012. Available from URL: http://www.fda.gov/Drugs/DrugSafety/ucm325257.htm#healthcare. As accessed 2012-10-28.
    70) Vanezis P & Toseland PA: Xylometazoline poisoning - a report of a case. Med Sci Law 1980; 20:35-36.
    71) Wick H: Ueber tyzine-vergiftung. Praxis 1966; 55:791-792.
    72) de Caen AR, Berg MD, Chameides L, et al: Part 12: Pediatric Advanced Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2015; 132(18 Suppl 2):S526-S542.
    73) van Montfrans GA, van Steenwijk KRP, & Vyth A: Intravenous naphazoline intoxication. Acta Med Scand 1981; 209:429-430.