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Turk Arch Pediatr
Turk Arch Pediatr
Turkish Archives of Pediatrics
2757-6256
Turkish Pediatrics Association

10.5152/TurkArchPediatr.2024.24040
tap-59-5-510
Scientific Letter
An Alarming Sign of Nebulized Ipratropium Bromide in a Case Series: Anisocoria
Çavdar Zeynep 1http://orcid.org/0009-0000-0519-5781

İlbilge Ertoy Karagöl Hacer 1http://orcid.org/0000-0002-8190-062X

Köken Gizem 1http://orcid.org/0000-0001-7972-3436

Polat Terece Sinem 1http://orcid.org/0000-0001-7107-5489

Çetin Kenan 1http://orcid.org/0000-0001-9405-9828

Kübra Baskın Avniye 2http://orcid.org/0000-0002-4294-7492

Bakırtaş Arzu 1http://orcid.org/0000-0002-7694-8944

1 Department of Pediatric Allergy, Gazi University Faculty of Medicine, Ankara, Türkiye
2 Department of Pediatric Immunology and Allergy, Gazi University Faculty of Medicine, Ankara, Türkiye
Corresponding author:Hacer İlbilge Ertoy Karagöl ક theilbilge@yahoo.com.au
Cite this article as: Çavdar Z, Ertoy Karagöl Hİ, Köken G, et al. An alarming sign of nebulized ipratropium bromide in a case series: Anisocoria. Turk Arch Pediatr. 2024;59(5):510-512 .

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https://creativecommons.org/licenses/by-nc/4.0/ Content of this journal is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
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pmcWhen anisocoria is noticed, frightening intracranial pathologies like uncal herniation often come to mind, and there is a desire to rapidly determine its etiology. However, aside from these alarming conditions, anisocoria can also occur physiologically or pharmacologically. In this report, we highlight three pediatric cases with asthma who experienced pharmacological anisocoria due to nebulized ipratropium bromide (NIB). Our aim is to raise awareness of NIB-related anisocoria, which is commonly encountered in pediatric emergency departments (PED) and allergy practice, to prevent unnecessary imaging and wasted time, and to explore its potential mechanisms through these cases.

Case 1

An 8-year-old male was admitted to the PED with a severe asthma attack following an upper respiratory tract infection (URTI). The symptoms and physical examination findings are provided in Table 1. The patient received oxygen at a rate of 10 L/min via a reservoir mask, three doses of nebulized salbutamol (Ronkotol 2.5 mg/mL), and ipratropium bromide (İprabül 500 mcg/mL), along with systemic steroids at a dose of 60 mg/day. Anisocoria was observed 13 hours after the last NIB dose (Figure 1A), with a normal neurological examination. Ophthalmologic examination revealed a larger left pupil diameter, normal eye movements, without ptosis. The light reflex was only present in the right eye. Since cranial magnetic resonance imaging was performed and yielded normal results, the anisocoria was attributed to NIB. The patient was monitored, and the anisocoria resolved 11 hours after detection.

Case 2

A 4-year-old male was admitted to the PED with a moderate to severe asthma attack following an URTI (Table 1). The patient received oxygen at a rate of 10 L/min via a reservoir mask, three doses of nebulized salbutamol (Ronkotol 2.5 mg/mL), and ipratropium bromide (İprabül 500 mcg/mL), along with systemic steroids at a dose of 40 mg/day. Anisocoria was noticed immediately after the last NIB dose (Figure 1B), with a normal neurological examination. Similarly, ophthalmologic examination revealed a larger left pupil diameter, normal eye movements, without ptosis. The light reflex was present only in the right eye. The anisocoria was attributed to NIB and resolved after 18 hours.

Case 3

A 9-year-old male was admitted to the PED with a severe asthma attack following an URTI (Table 1). The patient received oxygen at a rate of 10 L/min via a reservoir mask, three doses of nebulized salbutamol (Ronkotol 2.5 mg/mL), and ipratropium bromide (İprabül 500 mcg/mL), along with systemic steroids at a dose of 60 mg/day. Anisocoria was noticed 9 hours after the last NIB dose (Figure 1C), with a normal neurological examination. Similar to previous cases, ophthalmologic examination revealed a larger left pupil diameter, normal eye movements, without ptosis. The light reflex was only present in the right eye. The anisocoria was attributed to NIB and resolved after 13 hours.

Anisocoria, defined as a pupil diameter difference of over 0.1 mm, is evaluated to determine whether the larger or smaller pupil is pathological, aiding in the identification of defects in the parasympathetic or sympathetic systems.1 Constriction of the pupil is controlled by the parasympathetic system, while dilation is controlled by the sympathetic system. If anisocoria is more pronounced in the dark, a sympathetic defect is considered; if more pronounced in bright light, a parasympathetic defect is considered. In anisocoria evaluation, the next step is to consider a defect in the pupil that responds weakly to light, as physiological anisocoria and sympathetic pathologies show a normal light response. When the light response is weak, the near response is assessed. Typically, a normal light response indicates a normal near response. Light-near dissociation, where there is a near response without a light response, occurs in conditions like tonic pupil or syphilis.2,3 Although not evaluated in our patients, light-near dissociation would not be expected in cases of suspected pharmacological anisocoria.

Ipratropium bromide, derived from atropine, is commonly used as a bronchodilator alongside salbutamol in managing moderate to severe asthma attacks.4 Additionally, ipratropium bromide is one of the medical treatments used in tracheomalacia and bronchomalacia according to the European Respiratory Society statement on children.5 The anisocoria induced by NIB is attributed to aerosols escaping into the affected eye through mucosal absorption, leading to mydriasis.6 However, pharmacological anisocoria related to salbutamol could be developed. Since salbutamol is a sympathomimetic drug, it can cause dilation by stimulating the dilator muscle of the iris. In other reported cases, we did not encounter anisocoria solely attributed to the use of salbutamol.7,8 Our patients, after consecutive treatment with three doses of NIB and salbutamol in the PED, continued to receive salbutamol, and their anisocoria resolved within 11-18 hours. Therefore, we are no longer convinced that salbutamol is to blame.

In the context of NIB-induced anisocoria, the malposition of the mask used for nebulization can lead to aerosol leakage due to poor fit or loose attachment, especially in young children who may resist wearing the mask.8 In our cases, we ensured that the masks were well-fitted to their faces, but they may not have been properly placed on their faces. Another hypothesis is related to the presence of valves/openings on top of the standard masks that allow for carbon dioxide exhalation.9 These openings can be forgotten to be closed during nebulization. We noticed that these openings were not closed during NIB administration to our patients. To avoid this side effect, treatments in patients older than 5 years can be given with a spacer with a mouthpiece.

It remains unclear whether NIB-induced anisocoria is dose-related, as most reported cases lack dosage and frequency details. We observed anisocoria after the third dose (cumulative dose: 1500 mcg). Additionally, there are reported cases of anisocoria with lower NIB doses. Considering the duration of anisocoria, reported cases varied between 6 and 48 hours. Given the half-life of NIB (6-8 hours), the duration of anisocoria exceeded expectations. Therefore, it may be appropriate to monitor NIB-induced anisocoria for at least 6-8 hours.10

After the first case, we did not perform imaging on the remainder since we knew about their NIB use, and their neurological exams, except for anisocoria, were normal. However, in other cases in the literature, cranial CT imaging was done even with suspected pharmacological anisocoria. Besides imaging, a pilocarpine test can help distinguish between pharmacological and pathological anisocoria, making it a cost-effective option that reduces radiation exposure due to imaging. Pilocarpine is a parasympathomimetic agent that directly stimulates cholinergic receptors in the eye. It induces miosis by contracting the iris sphincter muscle and ciliary muscle. If pharmacological anisocoria is suspected in a patient, the diagnosis can be confirmed with the pilocarpine test. When 1% pilocarpine is administered, it causes miosis in a normal pupil and in a pupil dilated due to third cranial nerve palsy. However, in pharmacological mydriasis, there is no change because atropine-like drugs block muscarinic receptors.2,3 Therefore, in our other consecutive cases, neither imaging nor the pilocarpine test was conducted due to the experiences gained from the first case.

In conclusion, it should be kept in mind that pharmacological anisocoria may develop due to the use of NIB, commonly in asthma treatment. To mitigate this, physicians should ensure appropriate mask selection and usage to prevent aerosol leakage into the eyes. When anisocoria is observed during NIB administration, a pilocarpine test should be considered before resorting to unnecessary imaging for the differential diagnosis.

Figure 1. (A, B, C) Images of anisocoria resulting from left-eye mydriasis in 3 consecutive cases associated with nebulized ipratropium leakage to the left eye.

Table 1. Symptoms and Physical Examination Findings of Cases Presenting to the Pediatric Emergency Department

	Symptoms	Fever (°C)	Pulse (Per Minute)	SpO2 (%)	Respiratory Rate (Per Minute)	Respiratory System Examination	
Case-1	Cough, shortness of breath, wheezing	36.7	112	91	32	Diffuse rhonchi during expiration, subcostal retraction	
Case-2	Increased respiratory rate, cough	36.5	116	94	48	Sibilant rhonchi on expiration, subcostal retraction	
Case-3	Cough, shortness of breath	36.8	104	86	44	Rhonchi on both inspiration and expiration, subcostal retraction	

Informed Consent: The written informed consent was obtained from the parents of the patients for publication.

Peer-review: Externally peer-reviewed.

Author Contributions: Concept – H.I.E.K., Design – H.I.E.K., Z.C.; Resources – H.I.E.K., Z.C.; Materials – Z.C., G.K., S.P.T., K.C., A.K.B., A.B.; Processing – H.I.E.K., Z.C.; Interpretation – Z.C., A.K.B.; Literature Search – H.I.E.K., Z.C., A.B.; Writing – H.I.E.K., Z.C.; Critical review – H.I.E.K., A.K.B.

Declaration of Interests: The authors have no conflicts of interest to declare.
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