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A Controlled Trial of Inhaled Bronchodilators in Familial Dysautonomia

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Abstract

Background

Chronic lung disease is a leading cause of premature death in patients with familial dysautonomia (FD). A significant number of patients have obstructive airway disease, yet it is not known whether this is pharmacologically reversible.

Methods

We conducted a double-blind, placebo-controlled, randomized clinical trial comparing the beta 2 agonist albuterol with the muscarinic blocker ipratropium bromide in patients homozygous for the IKBKAP founder mutation. Albuterol, ipratropium bromide, and placebo were administered on 3 separate days via nebulizer in the seated position. Airway responsiveness was evaluated using spirometry and impulse oscillometry 30 min post dose. Cardiovascular effects were evaluated by continuous monitoring of blood pressure, RR intervals, cardiac output, and systemic vascular resistance.

Results

A total of 14 patients completed the trial. Neither active agent had significant detrimental effects on heart rate or rhythm or blood pressure. Albuterol and ipratropium were similar in their bronchodilator effectiveness causing significant improvement in forced expiratory volume in 1-s (FEV1, p = 0.002 and p = 0.030). Impulse oscillometry measures were consistent with a reduction in total airway resistance post nebulization (resistance at 5 Hz p < 0.006).

Conclusion

Airway obstruction is pharmacologically reversible in a number of patients with FD. In the short term, both albuterol and ipratropium were well tolerated and not associated with major cardiovascular adverse events.

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References

  1. Slaugenhaupt SA et al (2001) Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. Am J Hum Genet 68(3):598–605

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Norcliffe-Kaufmann L, Axelrod F, Kaufmann H (2010) Afferent baroreflex failure in familial dysautonomia. Neurology 75(21):1904–1911

    Article  PubMed  PubMed Central  Google Scholar 

  3. Lefcort F et al (2017) Animal and cellular models of familial dysautonomia. Clin Auton Res 27(4):235–243

    Article  PubMed  Google Scholar 

  4. Norcliffe-Kaufmann L, Slaugenhaupt SA, Kaufmann H (2017) Familial dysautonomia: history, genotype, phenotype and translational research. Prog Neurobiol 152:131–148

    Article  PubMed  Google Scholar 

  5. Palma JA et al (2014) Current treatments in familial dysautonomia. Expert Opin Pharmacother 15(18):2653–2671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Giarraffa P et al (2005) Assessing efficacy of high-frequency chest wall oscillation in patients with familial dysautonomia. Chest 128(5):3377–3381

    Article  PubMed  Google Scholar 

  7. Finney PA et al (2000) Albuterol-induced downregulation of Gsalpha accounts for pulmonary beta(2)-adrenoceptor desensitization in vivo. J Clin Invest 106(1):125–135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Quirce S, Dominguez-Ortega J, Barranco P (2015) Anticholinergics for treatment of asthma. J Investig Allergol Clin Immunol 25(2):84–93

    CAS  PubMed  Google Scholar 

  9. O’Callaghan C, Barry PW (1997) The science of nebulised drug delivery. Thorax 52(Suppl 2): S31–S44

  10. Taylor RG, Maclagan J, Cook DG (1989) Bronchodilator action of inhaled fenoterol and ipratropium in normal subjects: a teaching exercise for medical students. Br J Clin Pharmacol 28(6):709–713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cekici L et al (2009) Short-term effects of inhaled salbutamol on autonomic cardiovascular control in healthy subjects: a placebo-controlled study. Br J Clin Pharmacol 67(4):394–402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Palma JA et al (2017) Sudden unexpected death during sleep in familial dysautonomia: a case-control study. Sleep. https://doi.org/10.1093/sleep/zsx083

    PubMed  Google Scholar 

  13. Nussinovitch U et al (2009) Echocardiographic abnormalities in familial dysautonomia. Pediatr Cardiol 30(8):1068–1074

    Article  PubMed  Google Scholar 

  14. Norcliffe-Kaufmann L et al (2013) Hyperdopaminergic crises in familial dysautonomia: a randomized trial of carbidopa. Neurology 80(17): 1611–1617

    Article  PubMed  PubMed Central  Google Scholar 

  15. Norcliffe-Kaufmann L, Axelrod FB, Kaufmann H (2011) Developmental abnormalities, blood pressure variability and renal disease in Riley Day syndrome. J Hum Hypertens 27(1):51–55

    Article  PubMed  PubMed Central  Google Scholar 

  16. Norcliffe-Kaufmann L, Palma JA, Kaufmann H (2016) Mother-induced hypertension in familial dysautonomia. Clin Auton Res 26(1):79–81

    Article  PubMed  Google Scholar 

  17. Spalink CL et al (2017) Intranasal dexmedetomidine for adrenergic crisis in familial dysautonomia. Clin Auton Res 27(4):279–282

    Article  PubMed  Google Scholar 

  18. Smith AA, Dancis J (1964) Exaggerated response to infused norepinephrine in familial dysautonomia. N Engl J Med 270:704–707

    Article  CAS  PubMed  Google Scholar 

  19. Mendoza-Santiesteban CE et al (2017) Familial dysautonomia: a disease with hidden tears. J Neurol 264(6):1290–1291

    Article  PubMed  Google Scholar 

  20. Miller MR et al (2005) Standardisation of spirometry. Eur Respir J 26(2):319–338

    Article  CAS  PubMed  Google Scholar 

  21. Bickel S et al (2014) Impulse oscillometry: interpretation and practical applications. Chest 146(3):841–847

    Article  PubMed  Google Scholar 

  22. Tang WH, Tong W (2009) Measuring impedance in congestive heart failure: current options and clinical applications. Am Heart J 157(3):402–411

    Article  PubMed  Google Scholar 

  23. Ebert TJ et al (1984) Impedance cardiograms reliably estimate beat-by-beat changes of left ventricular stroke volume in humans. Cardiovasc Res 18(6):354–360

    Article  CAS  PubMed  Google Scholar 

  24. Bogaard HJ et al (1997) Assessment of the haemodynamic response to exercise by means of electrical impedance cardiography: method, validation and clinical applications. Physiol Meas 18(2):95–105

    Article  CAS  PubMed  Google Scholar 

  25. Komarow HD et al (2011) Impulse oscillometry in the evaluation of diseases of the airways in children. Ann Allergy Asthma Immunol 106(3):191–199

    Article  PubMed  PubMed Central  Google Scholar 

  26. Snyder EM et al (2011) Effects of an inhaled beta2-agonist on cardiovascular function and sympathetic activity in healthy subjects. Pharmacotherapy 31(8):748–756

    Article  PubMed  Google Scholar 

  27. Fuente Mora C et al (2017) Cerebral autoregulation and symptoms of orthostatic hypotension in familial dysautonomia. J Cereb Blood Flow Metab 37(7):2414–2422

    Article  PubMed  Google Scholar 

  28. Filler J et al (1965) Respiratory control in familial dysautonomia. J Pediatr 66:509–516

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We wish to thank staff at the Centers for their assistance including Cristina Fuente Mora, Ginny Devi Chou, Yehonatan Sharabi, Moran Lavie, Ifat Sarouk, Adi Dagan, Moshe Ashkenazi, and Daphna Vilozni. We acknowledge Kenneth Berger for his helpful discussions in developing the trial design.

Funding

LN-K, J-AP, and HK receive salary support from the National Institutes of Health (U54-NS065736) and the Food and Drug Administration. All authors receive salary support from the Dysautonomia Foundation, Inc.

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Correspondence to Bat-el Bar-Aluma.

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The authors declare that they have no conflict of interests.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

Research Involving with Human and Animal Rights

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Bar-Aluma, Be., Efrati, O., Kaufmann, H. et al. A Controlled Trial of Inhaled Bronchodilators in Familial Dysautonomia. Lung 196, 93–101 (2018). https://doi.org/10.1007/s00408-017-0073-7

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  • DOI: https://doi.org/10.1007/s00408-017-0073-7

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