Official Case Reports Journal of the Asian Pacific Society of Respirology

Respirology Case Reports

Paradoxical bronchospasm: a rare adverse effect
of fenoterol use
Ching-Han Lai & Xin-Min Liao
Division of Pulmonary Medicine, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.

Keywords Abstract
Asthma, beta-agonist inhalers, paradoxical
bronchospasm. Paradoxical bronchospasm refers to the constriction of the airways after
treatment with a sympathomimetic bronchodilator. Theoretically, broncho-
Correspondence dilators, such as beta-agonist inhalers, act to ease asthma symptoms by
Xin-Min Liao, Division of Pulmonary Medicine, relaxing the muscles surrounding the walls of the bronchial tubes, which
Department of Internal Medicine, National Cheng relieve bronchial constriction. However, in rare instances, some patients
Kung University Hospital, No. 138, Sheng-Li Rd., Tainan
develop respiratory distress or even respiratory failure after inhaled bron-
704, Taiwan. E-mail: atmosphere0411@gmail.com
chodilator use, although the exact mechanism for this adverse effect is
Received: 15 July 2020; Revised: 19 October 2020; unknown. We report a male, with a known asthma history diagnosed for
Accepted: 22 November 2020; Associate Editor: more than one decade, receiving fenoterol (Berotec®) for wheezing control
Tow Keang Lim. and the worsening of his clinical condition immediately after bronchodila-
tor administration.
Respirology Case Reports, 9 (4), 2021, e00698

doi: 10.1002/rcr2.698

Introduction which had been diagnosed for over one decade. Drug allergy
to penicillin was also documented in his previous medical
Paradoxical bronchospasm means a constriction of the air-
records. In mid-June of 2013, he had one common cold
ways after treatment with a sympathomimetic bronchodila-
event took one puff of fenoterol (Berotec) due to dyspnoea.
tor. Selective beta 2-agonist inhalers are the most potent
However, his dyspnoea worsened, and his wheezing sound
bronchodilators currently approved for clinical use in
became more prominent after fenoterol (Berotec) inhala-
asthma and obstructive lung disease. Theoretically, bron-
tion. He was sent to the emergency department of a
chodilators act to ease symptoms by relaxing the muscles
regional hospital in Kaohsiung for treatment. The symp-
surrounding the walls of the bronchial tubes, which relieve toms were relieved after ipratropium and terbutaline inhala-
bronchial constriction [1–3]. However, in rare cases, some tion, and he was discharged via the emergency room on the
patients develop aggravating ordinary respiratory discom- same day. One week later in late June, he suffered another
forts, even respiratory distress or acute respiratory failure wheezing attack and had one puff of fenoterol (Berotec)
events, after bronchodilator use. Be that as it may, the exact inhalation for symptoms relief at home; however, his dys-
mechanism for this adverse effect remains unclear. Here, we pnoea worsened. He was sent to the hospital again, and
report a man, with a known asthma history diagnosed for this time, received intubation due to acute respiratory
over one decade, receiving fenoterol (Berotec®, Boehringer- failure. The patient was extubated and discharged in early
ingelheim, Taiwan) for wheezing control and the worsening July after a good recovery. A similar event also happened
of his clinical condition, including being intubated twice due once in early August, but he did not receive invasive
to acute respiratory failure, which occurred less than 5 min mechanical ventilation therapy because it presented as a
immediately after one puff of fenoterol (Berotec) inhalation. milder clinical condition. The patient reported that he
had had one puff of fenoterol (Berotec) inhalation before
wheezing worsened.
Case Report
He was admitted to one regional hospital in Kaohsiung
The 50-year-old gentlemen had a previous history of type in early September 2013 due to acute respiratory failure.
2 diabetes mellitus (DM) and bronchial asthma, both of Common cold-associated symptoms, such as productive

© 2021 The Authors. Respirology Case Reports published by John Wiley & Sons Australia, Ltd 2021 | Vol. 9 | Iss. 4 | e00698
on behalf of The Asian Pacific Society of Respirology Page 1
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the
original work is properly cited.
Paradoxical bronchospasm in fenoterol C.-H. Lai & X.-M. Liao

Figure 1. Spirometry of bronchodilator

(fenoterol) test is demonstrated. The
blue circuit is the pre-bronchodilator spi-
rometry and the red circuit is the post-
bronchodilator spirometry. Chg, change;
FEF, forced expiratory flow; FEV1, forced
expiratory volume in 1 sec; FVC, forced
vital capacity; MVV, maximal voluntary
ventilation; PEF, peak expiratory flow;
PRE-RX, pre-prescription; PRED, predic-
tion; POST-RX, post-prescription.

cough and dyspnoea, were noted for one week before he at a regional hospital in Kaohsiung. However, there is no
was sent to the hospital. On the same day, he was admitted known asthma history for any of his family members.
to the hospital, and dyspnoea with a wheezing breathing Fluticasone/salmeterol has been prescribed as the control-
sound developed in the morning. He received one puff ler since the asthma was diagnosed and it was well toler-
inhalation of fenoterol (Berotec) at home, yet dyspnoea ated. The asthma was under good control since hardly did
was aggravated instead of being relieved. He was sent to he have acute exacerbation, as he reported. Although
the hospital by ambulance, and intubation was performed fenoterol (Berotec) had been prescribed for wheezing con-
immediately after his arrival at the emergency room due to trol in the prior decade, not until the June 2013 event did
his poor respiratory pattern. After 30 min of intubation, he he receive inhaled fenoterol (Berotec) therapy for a wheez-
was extubated as his clinical condition improved. Upon ing attack.
going to our pulmonology outpatient department for fur- Considering his clinical presentations, paradoxical bron-
ther evaluation, the chest X-ray showed no obvious lung chospasm was suspected. We reported this case and made
lesion. The blood eosinophil count was 354/μL and the IgE bronchodilator adjustments at our pulmonology clinic
level was 564 IU/mL. We noticed he had a prior intubation later. After discussing with the patient, bronchodilator
episode mentioned above due to acute respiratory failure (fenoterol) test was performed in mid-September of 2013
in late June 2013. Coincidentally, one puff of fenoterol under close monitoring and informed consent, which
(Berotec) was inhaled by the gentleman before each intu- reported negative impact on both forced expiratory volume
bation episode, according to his statements. in 1 sec (FEV1) and forced vital capacity (FVC) (Fig. 1).
Tracing back his medical records, his occupation was an He previously had fluticasone/salmeterol (Seretide®
office worker in a factory (screw manufacturer) and was Accuhaler, GSK, Taiwan) as the controller for asthma treat-
rarely exposed to the raw materials. He had been diag- ment. The controller was switched to fluticasone/vilanterol
nosed as having DM for more than two decades and was (Relvar 92/22®, GSK, Taiwan), and umeclidinium (Incruse®,
under regular follow-ups at the outpatient department of GSK, Taiwan) was added consecutively. Symbicort®,
family medicine at National Cheng Kung University Hos- Astrazeneca, Taiwan, as the reliever, was administered once
pital (NCKUH). He took metformin, vildagliptin, and and no paradoxical bronchospasm event developed. He is
glimepiride for DM control. As for his asthma history, he now under regular outpatient department follow-up at
was diagnosed as having asthma when he was 40 years old NCKUH.

2 © 2021 The Authors. Respirology Case Reports published by John Wiley & Sons Australia, Ltd
on behalf of The Asian Pacific Society of Respirology
C.-H. Lai & X.-M. Liao Paradoxical bronchospasm in fenoterol

Discussion studies have revealed that the statistical incidence of para-

doxical bronchospasm was <1%.
Paradoxical bronchospasm is defined as the sudden onset
We reviewed the literature concerning paradoxical bron-
of an unanticipated contraction of smooth muscle in the
chospasm, the published case reports of which are shown
walls of the bronchi occurring soon after the administra-
in Table 1 and the prevalence of paradoxical broncho-
tion of an aerosolized bronchodilator. Rare, but not iso-
spasm for SABA, LABA, and long-acting muscarinic
lated, transient reductions of FEV1 have been observed in
antagonist (LAMA) are listed in Table 2. We reviewed the
previously healthy subjects after inhalation in two phase I
literature on the PubMed®, using “paradoxical broncho-
trials [4].
spasm/bronchoconstriction” as the key word and 63 results
Several mechanisms have been proposed to account for
were searched. The results narrowed down to 18 if we add
the paradoxical bronchoconstriction observed with beta
“case report” as the key word. The literature was limited
2-agonist metered-dose inhaler (MDI), including an IgE-
to studies that have open access to the full text and in
mediated reaction to excipients in the MDI (e.g. soya bean
English (or English translations), which resulted in
lecithin) [5], as well as secondary irritation to propellants,
preservatives, or turbulence of airflow due to inappropriate
inhaler technique [6]. Hypotheses have been proposed to Table 2. Prevalence of paradoxical bronchospasm for SABA,
account for the paradoxical bronchospasm that has LABA, and LAMA.
occurred with nebulized beta 2-agonists, including bron-
chial irritation caused by the hyper-/hypo-osmolality and Prevalence
acidity [7] of the solution as well as preservatives Medication (%) Reference
(e.g. sodium metabisulphite, benzalkonium chloride, and Albuterol/salbutamol 1–8 14, 15
ethylenediaminetetraacetic acid (EDTA)) [8,9] (Table 1). Salmeterol (Seretide <0.01 16
Zhong et al. demonstrated a case that did not induce para- Evohaler)
doxical bronchospasm from the same inhaler by removing Tiotropium <1 17
the preservatives [11]. Moreover, the same major content
with different excipients or preservatives led to a different LABA, long-acting beta2 agonist; LAMA, long-acting muscarinic
impact on FEV1 [10,13]. Several previous retrospective antagonist; SABA, short-acting beta2 agonist.

Table 1. Cases of paradoxical bronchospasm from 1986 to 2018.

Number of cases/
Age and Sex
Reference or details Diagnosis Medication Possible aetiology Final medication
Magee and Pittman, 1/25 M Asthma Albuterol Excipient Ipratropium
2018 [10]
George et al., 1/17 F Asthma Albuterol BAC Levabuterol/
2017 [8] BAC free
Zhong et al., 2014 [11] 1/68 F Asthma Salbutamol Enantiomer Not mentioned
Broski and Amundson, 1/36 M Asthma Levalbuterol At least not HFA Salmeterol and
2008 [12] fluticasone
Spooner and Olin, 1/92 M COPD Albuterol Not mentioned Not mentioned
2005 [13]
Mutlu et al., 2000 [9] 1/22 F Asthma Albuterol/ EDTA ICS, theophylline
metaproterenol
Facchini et al., 1/age not Asthma Not mentioned Soya-derived Not mentioned
1996 [18] reported F excipients
Jorup et al., 2014 [4] 5/3 COPD and COPD/healthy LAMA AZD9164 Not mentioned Not mentioned
2 healthy FEV1#
O’Callaghan et al., 17/Infants Wheezing/ Salbutamol High osmolality Not mentioned
1986 [7] asthma and acidity

BAC, benzalkonium chloride; COPD, chronic obstructive pulmonary disease; EDTA, ethylenediaminetetraacetic acid; FEV1, forced expiratory vol-
ume in 1 sec; HFA, hydrofluoroalkane; ICS, inhaled corticosteroid; LAMA, long-acting muscarinic antagonist.

© 2021 The Authors. Respirology Case Reports published by John Wiley & Sons Australia, Ltd 3
on behalf of The Asian Pacific Society of Respirology
Paradoxical bronchospasm in fenoterol C.-H. Lai & X.-M. Liao

exclusion of 4 studies. The time of publication is not lim- 5. Facchini G, Antonicelli L, Cinti B, et al. 1996. Paradoxical
ited. Eight studies were excluded because the broncho- bronchospasm and cutaneous rash after metered-dose
spasm is not bronchodilator-induced. The phenomenon inhaled bronchodilators. Monaldi Arch. Chest Dis. 51:
was more prevalent in asthma subjects than in those with 201–203.
chronic obstructive pulmonary disease (COPD), indicating 6. Nicklas RA. 1990. Paradoxical bronchospasm associated
that asthma sufferers might be more susceptible to the with the use of inhaled beta agonists. J. Allergy Clin.
development of paradoxical bronchospasm. Within the six Immunol. 85:959–964.
reported paradoxical bronchospasm cases, four patients 7. O’Callaghan C, Milner AD, and Swarbrick A. 1986. Para-
doxical deterioration in lung function after nebulized sal-
were using albuterol, while the other two cases were using
butamol in wheezy infants. Lancet 2(8521-22):1424–1425.
salbutamol. The speculated aetiology of paradoxical bron-
8. George M, Joshi SV, and Concepcion E. 2017. Paradoxical
chospasm varied, including excipient, preservatives (benz-
bronchospasm from benzalkonium chloride (BAC) preser-
alkonium chloride), and enantiomer.
vative in albuterol nebulizer solution in a patient with acute
In this brief study, we presented a case with a rarely
severe asthma. A case report and literature review of airway
seen adverse effect after fenoterol inhalation. Paradoxical effects of BAC. Respir. Med. Case Rep. 6(21):39–41.
bronchospasm is one of the adverse effect listed on the 9. Mutlu GM, Moonjelly E, Chan L, et al. 2000. Laryngospasm
package insert of fenoterol (Berotec®) but it is rarely and paradoxical bronchoconstriction after repeated doses of
reported. Bronchodilator test using fenoterol as the bron- beta 2-agonists containing edetate disodium. Mayo Clin.
chodilator was performed on this patient and showed Proc. 75:285–287.
reductions of FEV1 and FVC, compatible with the 10. Magee JS, and Pittman LM. 2018. Paradoxical
fenoterol-induced paradoxical bronchospasm. It is crucial bronchoconstriction with short-acting beta agonist. Am.
that clinicians are aware of this unexpected adverse event J. Case Rep. 19:1204–1207.
to provide prompt monitoring of patients to improve 11. Zhong G, Shen NY, and Sammut J. 2014. Nebulised sal-
outcomes. butamol challenge confirming life-threatening paradoxical
bronchospasm. Emerg. Med. Australas. 26(2):202–203.
12. Broski SE, and Amundson DE. 2008. Paradoxical response
Disclosure Statement to levalbuterol. J. Am. Osteopath. Assoc. 108(4):211–213.
Appropriate written informed consent was obtained for 13. Spooner LM, and Olin JL. 2005. Paradoxical broncho-
publication of this case report and accompanying images. constriction with albuterol administered by metered-dose
inhaler and nebulizer solution. Ann. Pharmacother. 39(11):
1924–1927.
Acknowledgment 14. DailyMed. 2009. Albuterol sulfate inhalation solution,
We appreciate Han-Yu Chang, Professor at the Division of 0.083% 2.5 mg*/3 ml. Nephron Pharmaceuticals Corpora-
Pulmonary Medicine, Department of Internal Medicine, tion, Orlando, FL, USA. Available at: https://dailymed.nlm.
National Cheng Kung University Hospital, Tainan, Tai- nih.gov/dailymed/drugInfo.cfm?setid=574824f3-51cc-4b94-
wan, for offering this case at his outpatient clinic. 9c10-e3204d8b19f8. Accessed on March 01, 2019.
15. Shaheen MZ, Ayres JG, and Benincasa C. 1994. Incidence of
acute decreases in peak expiratory flow following the use of
References metered-dose inhalers in asthmatic patients. Eur. Respir. J. 7:
1. Sorkness CA. 2009. Beta-adrenergic agonists. Pp. 1485– 2160–2164.
1503 in N. F. Adkinson, B. S. Bochner, W. W. Busse, et al., 16. Perrio MJ, Wilton LV, and Shakir SA. 2007. A modified
eds. Middleton’s allergy: principles and practice, 7th ed. prescription-event monitoring study to assess the introduc-
Mosby, Philadelphia, PA, USA. tion of Seretide Evohaler in England: an example of study-
2. Johnson M. 2001. Beta 2-adrenoceptors: mechanisms of ing risk monitoring in pharmacovigilance. Drug Saf. 30(8):
action of beta2-agonists. Paediatr. Respir. Rev. 2:57. 681–695.
3. Johnson M. 2006. Molecular mechanisms of beta 2- 17. Hodder R, Pavia D, Lee A, et al. 2011. Lack of paradoxical
adrenergic receptor function, response, and regulation. bronchoconstriction after administration of tiotropium via
J. Allergy Clin. Immunol. 117:18. Respimat® Soft Mist™ Inhaler in COPD. Int. J. Chron.
4. Jorup C, Bengtsson T, and Strandgården K. 2014. Transient Obstruct. Pulmon. Dis. 6:245–251.
paradoxical bronchospasm associated with inhalation of the 18. Facchini G, Antonicelli L, and Cinti B. Paradoxical broncho-
LAMA AZD9164: analysis of two phase I, randomised, double- spasm and cutaneous rash after metered-dose inhaled bron-
blind, placebo-controlled studies. BMC Pulm. Med. 14:52. chodilators. Monaldi. Arch. Chest. Dis. 1996;51(3):201–203.

4 © 2021 The Authors. Respirology Case Reports published by John Wiley & Sons Australia, Ltd
on behalf of The Asian Pacific Society of Respirology