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PEDIATRIC ANESTHESIA

Prolonged Awakening and Pulmonary Edema After General Anesthesia and Naphazoline Application in an Infant

Ulrike M. Stamer, MD^*, Stephan Buderus, MD, Silke Wetegrove, MD^*, Michael J. Lentze, MD, and Frank Stüber, MD^*

*Department of Anesthesiology and Intensive Care Medicine, and Department of Pediatrics and Poison Control Centre Nordrhein-Westfalen, University of Bonn, Bonn, Germany

Address correspondence and reprint requests to Ulrike M. Stamer, MD, Department of Anesthesiology and Intensive Care Medicine, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany. Address e-mail to stamer{at}mailer.meb.uni-bonn.de

	Abstract

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IMPLICATIONS: Naphazoline intoxication by intrabronchial overdose caused prolonged unconsciousness of an 18-mo-old child after general anesthesia for tracheal rigid bronchoscopy. The leading symptoms were side effects involving the cardiovascular, pulmonary, and central nervous systems. Intensive care unit admission with the need for mechanical ventilation was necessary. Recovery was uneventful.

	Introduction

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The imidazoline derivate naphazoline (Norvartis Pharma GmbH, Nürnberg, Germany) belongs to the class of -adrenergic drugs. It is used as a local vasoconstrictor in nose drops and is widely available without a medical prescription. However, the use of naphazoline is discouraged in children under 12 yr of age. This restriction applies because intoxication causes central nervous system (CNS) depression and adverse cardiovascular effects. These symptoms are especially pronounced in young children and after application of large doses.

	Case Report

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An 18-mo-old boy was admitted to our hospital because of aspiration of several pieces of pistachio approximately 5 h before admission. The boy (body weight 11 kg) had no history of any previous diseases. The chest radiograph showed an overdistension of the left lung suspicious for a ball-valve obstruction caused by a foreign body. There were no signs of respiratory insufficiency. The patient was scheduled for emergency bronchoscopy.

General anesthesia was induced by inhaled sevoflurane 5 vol% in oxygen via a mask. When the child was anesthetized, a venous catheter was placed and an IV bolus of thiopental 25 mg was injected. Anesthesia was maintained by sevoflurane 1.5–3 vol%. During the first 15 min 3 additional boluses of thiopental (20 mg each) were injected IV. Further doses of IV hypnotics during the procedure were not necessary. No muscle relaxants or opioids were used.

Bronchoscopy of the trachea and the main bronchi was then performed by the surgeon using a rigid endoscope. Mucus was found within the trachea and the left main bronchus appeared inflamed and swollen. Several fragments of a pistachio were visible in the left lower lobe bronchus. Three distal bronchi were nearly occluded by the foreign bodies. To reduce the swelling of the mucosa, a vasoconstrictor was administered repeatedly via the endoscope using a nebulizer. Six fragments of pistachios were removed during the course of bronchoscopy.

At the end of the endoscopic procedure the child was breathing spontaneously with adequate tidal volumes (80–120 mL), and the endoscope was removed during emergence. Respiratory rate was approximately 30–35. The child was kept with a face mask delivering oxygen at a flow of 6 L per minute. Pulse oxygen saturation was 99%; however, discontinuing the oxygen delivery led to fast desaturation. The child did not regain consciousness and did not show any kind of reaction to different, even painful, stimuli. Subsequently, a high blood pressure (130/80 mm Hg) became evident and the boy was sweating all over his pale body. Body temperature remained stable at 37.9°C to 38.1°C.

Clinical signs of a pulmonary edema developed. Bilateral wet rales and rhonchi were audible. In parallel, the patient developed respiratory distress and decreasing oxygen saturation. Thirty-five minutes after the end of the operation the child’s trachea was intubated with a 4.0 mm (inner diameter) endotracheal tube. No additional drugs for hypnosis or muscle relaxation were required to facilitate intubation. The boy did not show any kind of reaction. Frothy secretions were observed in the tracheal tube and suctioned repeatedly.

Pulmonary symptoms and diaphoresis decreased during the next three hours. Capillary blood sampling revealed the following results: pH = 7.31, PCO₂ = 49 mm Hg, PO₂ = 228.5 mm Hg, and base deficit = -3.1. FIO₂ was decreased to 0.5 and an assisted mode of ventilation was applied.

A more detailed investigation revealed that naphazoline 0.1% was used as vasoconstrictor; the total dosage added up to 3–4 mL, corresponding to 3–4 mg of naphazoline. Naphazoline intoxication was suspected. Because of unconsciousness and the need for assisted mechanical ventilation, the boy was transferred to the pediatric intensive care unit (ICU).

On admission to the ICU the physical examination was unremarkable excepting a slightly increased blood pressure and a heart rate of up to 160 bpm. His blood pressure decreased to normal measures within 4 h, later to hypotensive measures (mean arterial pressure 40 mm Hg), which were corrected by fluid administration. Chest radiograph was performed 6 h after naphazoline administration and showed pulmonary congestion with an evenly distributed haziness of the lung fields predominating the proximal hilar regions. The boy remained unconscious for the first 8 h in the ICU. After 11 h all symptoms of CNS depression had disappeared and the patient’s trachea could be extubated. At this time he was awake, his spontaneous movements were symmetric, and the muscle tone was regular. His pupils were equal and showed normal reaction to light. His interaction with his parents was judged to be normal by the parents and the physician. The boy was discharged home in good condition and without any residual sequelae.

	Discussion

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Imidazoline intoxication causes severe CNS depression and adverse cardiovascular effects (1–7). Small children are especially susceptible to imidazoline toxicity.

A retrospective analysis of 108 cases of imidazoline intoxication revealed that 80% of the patients were children younger than four years (1). The majority of the exposures (70%) were from accidental oral ingestions of nose drops. Twenty-four percent occurred after nasal instillation of naphazoline containing nose drops, mainly in very young children (1). One additional case is described after application of collyrium, whereas one death resulting from CNS depression has been reported after IV injection of xylometazoline (1,2). Drugs containing these derivatives are widely available without medical prescription (3,5).

According to the manufacturer’s information, naphazoline may also be used for diagnostic procedures such as rhinoscopy or cystoscopy to reduce mucosa swelling. In our institution this topical vasoconstrictor is commonly used for endoscopic diagnostic, however, its use is generally restricted to adults. Neither toxic overdose by this route of administration nor simultaneous general anesthesia with subsequent prolonged awakening have been described.

Imidazoline derivates have a narrow therapeutic window and side effects are possible after normal therapeutic dosages, especially in children (4,5,7). Administration of as little as 1 to 2 drops of a 0.1% solution may induce deep sedation in infants (4,7). Drowsiness may occur in as many as 74% of the patients (1). Some of the imidazoline derivates are available as a diluted pediatric solution; some are discouraged in children younger than 12 years (naphazoline) or 2 years (tetrahydrozoline, oxymetazoline), respectively (personal communication, Poison Control Center). Intoxication occurs regularly at doses of naphazoline 0.05 mg/kg body weight after nasal administration, 0.1 mg/kg after oral ingestion in babies and 0.3 mg/kg after oral ingestion in children older than 2 years. Considering a body weight of 11 kg (as in our case), the applicated dosage amounted to a toxic dose of 0.27–0.36 mg/kg.

Because of rapid absorption, symptoms of intoxication develop within the first hour, peak after 8 hours, and disappear after approximately 12–36 hours (1,4). Symptoms may be complex because of the multiple actions of this adrenergic drug. Signs and symptoms depend on whether pre- or postsynaptic peripheral or central ₂-receptor stimulation predominates (8,9). Furthermore, some ₁-agonistic effects are proposed, especially with larger doses (10). The role of imidazoline receptors that have been identified in a variety of tissues has been discussed (8).

Although the therapeutic effect results from local vasoconstriction by interaction with peripheral ₁-receptors as well as postsynaptic ₂-receptors, toxicity results from interaction with central ₂-receptors (4). Central ₂-adrenergic stimulation produces decreased central sympathetic outflow. CNS depression is a leading symptom varying from sleepiness to coma. Respiratory depression, severe hypoventilation, apnea, and gasping respiration may occur. Respiratory depression was reported in 52% of the children with naphazoline intoxication by Mahieu et al. (1). Alternating periods of hyperactivity and thrashing behavior have been reported in children (5,8). Reduction in centrally mediated sympathetic tone and increased activity of the parasympathetic system can produce bradycardia and hypotension (8). Paleness, cold extremities, and sweating have been reported (1,4). Diaphoresis resulting from increased secretion of sweat glands of the skin was a striking symptom in our case.

In contrast to clonidine, naphozoline predominantly displays its peripheral activity on the postsynaptic ₂-receptors and ₁-receptor, producing opposite hemodynamic effects with hypertension (1,6). Hypertension was reported in 37% of the children with naphazoline toxicity by Mahieu et al. (1). Pronounced pulmonary vasoconstriction was probably the cause of the pulmonary edema seen in our patient. Massive vasoconstriction of vessels distal from the pulmonary capillaries by -agonistic stimulation results in an increase of hydrostatic pressure in pulmonary capillaries and fluid extravasation into the alveolar space. Probably, in our case this symptom was especially pronounced as a result of intrabronchial application of naphazoline. It persisted for approximately four hours, which is consistent with the half-life time of the drug.

Diagnosis of intoxication is ensured only by clinical symptoms after previous topical application or ingestion. Plasma levels of the drug or its metabolites are not clinically useful. No specific laboratory measures are available.

For a differential diagnosis one had to consider prolonged awakening because of anesthesia (sevoflurane, thiopental) or intake of other CNS-depressing drugs (opioids, sedatives). The first diagnosis became unlikely with proceeding time after discontinuation of anesthesia. The second diagnosis also did not seem to be likely, as the child obviously did not receive any other drugs.

There is no specific antidote to imidazoline derivates (5). Naloxone was administered up to doses of 0.1 mg/kg without effect by several authors supposing opioid overdose (1,5,6). Therapy has to be symptomatic, consisting of expansion of intravascular volume in case of hypotension and positive chronotropic drugs such as atropine in case of bradycardia. In some reports, hypertension was corrected with phentolamine (3). Close observation of the neurological and hemodynamic status for at least 24 hours is indicated in all cases of exposure to the drug.

In conclusion, CNS symptoms in this patient with naphazoline intoxication were masked by general anesthesia. However, diagnosis was made early and recovery was uneventful. We recommend that the use of large dosages of imidazoline derivates in children for diagnostic endoscopic procedures should be avoided. If these drugs are considered to be necessary, diluted solutions should be used and the body weight should be taken into consideration. Anesthesiologists should be familiar with the narrow therapeutic range and the potential toxicity of these drugs.

	References

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1. Mahieu LM, Rooman RP, Goosens E. Imidazolin intoxication in children. Eur J Pediatr 1993; 152: 944–6.[Web of Science][Medline]
2. Vanezis P, Toseland PA. Xylometazoline poisoning–report of a case. Med Sci Law 1980; 20: 35–6.[Web of Science][Medline]
3. Claudet I, Fries F. Danger of nasal vasoconstrictors in infants. Apropos of a case. Arch Pediatr 1997; 4: 538–41.[Web of Science][Medline]
4. Tobias JD. Central nervous system depression following accidental ingestion of Visine eye drops. Clin Pediatr 1996; 35: 539–40.[Free Full Text]
5. Higgins GL, Campbell B, Wallace K, Talbot S. Pediatric poisoning from over-the-counter imidazoline-containing products. Ann Emerg Med 1991; 20: 655–8.[Web of Science][Medline]
6. van Montfrans GA, van Steenwijk P, Vyth A, Borst C. Intravenous naphazoline intoxication. Acta Med Scand 1981; 209: 429–30.[Web of Science][Medline]
7. Söderman P, Sahlberg D, Wiholm BE. CNS reactions to nose drops in small children. Lancet 1984; 10: 573.
8. Wiley JF. Clonidine and related imidazoline derivates. In: Haddad LM, Shannon MW, Winchester JF, eds. Clinical poisoning and drug overdose, 3rd ed. Philadelphia: WB Saunders, 1997: 1050–4.
9. Jones MEP, Maze M. Can we characterize the central nervous system action of ₂-adrenergic agonists? Br J Anaesth 2001; 86: 1–3.[Free Full Text]
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