Intermittent Hypoxia in Treatment of Bronchial Asthma in Childhood

  • Tatiana V. SerebrovskayaEmail author
  • Alexander N. Bakunovsky
  • Klaudia V. Nesvitailova
  • Iryna N. Mankovska


According to the World Health Organization, bronchial asthma (BA) is a serious public health problem with over 300 million sufferers of all ages. In this chapter, we demonstrate the possibility to treat BA in childhood with intermittent hypoxia treatment/training (IHT) programs and provide clinical evidence, adverse effects, and latest experience in IHT implementation. Particularly, it was shown that 2-week IHT resulted in a significant decline in breath shortness and feelings of chest congestion in BA children (aged 9–13 years). The cough was diminished or disappeared, and the amount of sputum was reduced and passed more easily. The attacks of asphyxia disappeared or became more occasional. Considerable augmentation of ventilatory response to hypoxic stimuli was observed as well as a diminution of heart rate (HR) reactions to increased hypoxia and an attenuated fall of SaO2 under hypoxic conditions. Mitochondrial enzymes activity of immune cells such as succinate dehydrogenase (SDG) and alpha-glycerophosphate dehydrogenase (GPDG) increased significantly under IHT. Strong correlation between individual hypoxic sensitivity and enzymes activities was found. In conclusion, IHT represents a promising approach in prevention and treatment of bronchial asthma in childhood. The proper choice of the hypoxic dosage depending on individual’s reactivity must be titrated for each patient in order to avoid negative effects of hypoxia and to augment the favorable ones.


Bronchial Asthma Chronic Obstructive Pulmonary Disease Obstructive Sleep Apnea Syndrome Intermittent Hypoxia Hypoxic Ventilatory Response 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Bronchial asthma




Chronic obstructive pulmonary disease




Alpha-glycerophosphate dehydrogenase




Hypoxia-inducible factor


Heart rate


Hypoxic ventilatory response


Intermittent hypoxia


Intermittent hypoxia training/treatment


Method of expert assessing scales


Nitric oxide


Nitric oxide synthase


Obstructive sleep apnea syndrome


Reactive oxygen species


Arterial oxygen saturation


Succinate dehydrogenase

Cu,Zn – SOD

Cu,Zn-superoxide dismutase


Minute ventilation


  1. 1.
    Anokhin MI, Geppe NA, Dairova RA. Effects of hypoxic stimulation observed in the animal experiments and in children with bronchial asthma. Fiziol Zh. 1992;38:33–9 [In Russian].PubMedGoogle Scholar
  2. 2.
    Baker TL, Fuller DD, Zabka AGGS, et al. Respiratory plasticity: differential actions of continuous and episodic hypoxia and hypercapnia. Respir Physiol. 2001;129:25–35.PubMedCrossRefGoogle Scholar
  3. 3.
    Bass JL, Corwin M, Gozal D, et al. The effect of chronic or intermittent hypoxia on cognition in childhood: a review of the evidence. Pediatrics. 2004;114:805–16.PubMedCrossRefGoogle Scholar
  4. 4.
    Belikova VV. Correlation between clinical and cytochemical changes in bronchial asthma in children. Pediatriia. 1976;11:30–3 [In Russian].PubMedGoogle Scholar
  5. 5.
    Berezovskiĭ VA, Levashov MI. Physiological premises and mechanisms of normalizing effect of normobaric hypoxia and inhalation therapy. Fiziol Zh. 1992;38:3–12 [In Russian].PubMedGoogle Scholar
  6. 6.
    Berezovskii VA, Levashov MI. Introduction in orotherapy. Kiev: Academy of Hypoxia Problems of Russian Federation; 2000. p. 75 [In Russian].Google Scholar
  7. 7.
    Berezovskii VA, Levashov MI. The build-up of human reserve potential by exposure to intermittent normobaric hypoxia. Aviakosm Ekolog Med. 2000;34:39–43 [In Russian].PubMedGoogle Scholar
  8. 8.
    Berezovskii VA, Serebrovskaia TV, Lipskii PI. Respiratory function in twins under different gas mixtures. Fiziol Zh. 1981;27:20–5 [In Russian].PubMedGoogle Scholar
  9. 9.
    Bloom B, Cohen RA, Freeman G. Summary health statistics for U.S. children: National Health Interview Survey 2009. Vital Health Stat 10. 2010;1–82.Google Scholar
  10. 10.
    Borukaeva IK. Intermittent hypoxic training in the sanatorium and spa treatment for patients with chronic obstructive pulmonary disease. Vopr Kurortol Fizioter Lech Fiz Kult. 2007;5:21–4 [In Russian].PubMedGoogle Scholar
  11. 11.
    Bousquet J, Mantzouranis E, Cruz AA. Uniform definition of asthma severity, control, and exacerbations: document presented for the World Health Organization Consultation on Severe Asthma. J Allergy Clin Immunol. 2010;126:926–38.PubMedCrossRefGoogle Scholar
  12. 12.
    Brzecka A. Brain preconditioning and obstructive sleep apnea ­syndrome. Acta Neurobiol Exp (Wars). 2005;65:213–20.Google Scholar
  13. 13.
    Chizhov AI. Physiologic bases of the method to increase nonspecific resistance of the organism by adaptation to intermittent normobaric hypoxia. Fiziol Zh. 1992;38:13–7 [In Russian].PubMedGoogle Scholar
  14. 14.
    Chizhov AI, Bludov AA. Efficiency of intermittent and resonance intermittent normobaric hypoxia therapy in patients with infection-dependent bronchial asthma. Vestn Ross Akad Med Nauk. 2000;9:48–50 [In Russian].PubMedGoogle Scholar
  15. 15.
    Damon M, Cluzel M, Chanez P, et al. Phagocytosis induction of chemiluminescence and chemoattractant increased superoxide anion release from activated human alveolar macrophages in asthma. J Biolumin Chemilumin. 1989;4:279–86.PubMedCrossRefGoogle Scholar
  16. 16.
    Daniliak IG, Kogan AK, Bolevich S. The generation of active forms of oxygen by the blood leukocytes, lipid peroxidation and antiperoxide protection in bronchial asthma patients. Ter Arkh. 1992;64:54–7 [In Russian].PubMedGoogle Scholar
  17. 17.
    Dewhirst MW. Intermittent hypoxia furthers the rationale for hypoxia-inducible factor-1 targeting. Cancer Res. 2007;67:854–5.PubMedCrossRefGoogle Scholar
  18. 18.
    Donenko YI. Comparison of intermittent normobaric hypoxic therapy and hypobaric therapy in treatment of chronic nonspecific lung diseases. In: Intermittent hypoxic training – effectiveness and mechanisms of action. Kiev: Institute of Physical Culture; 1992. p. 65–8 [In Russian].Google Scholar
  19. 19.
    Eckes L. Altitude adaptation. Part III. Altitude acclimatization as a problem of human biology. Gegenbaurs Morphol Jahrb. 1976;122:535–69 [In German].PubMedGoogle Scholar
  20. 20.
    Ehrenburg IV, Kordykinskaya II. Effectiveness of the use of intermittent normobaric hypoxia in treatment of chronic obstructive lung diseases. In: Intemittent hypoxic training – effectiveness, mechanisms of action. Kiev: Institute of Physical Culture; 1992. p. 96–8 [In Russian].Google Scholar
  21. 21.
    Fesenko ME, Lisyana TO. Approach to employment of hypoxic stimulation for treatment of lingering and relapsing bronchitis in children of early age. Fiziol Zh. 1992;38:31–3 [In Russian].PubMedGoogle Scholar
  22. 22.
    Fursova ZK, Balika IuD, Abubakirova AM. Dynamics of the activity of redox enzymes in peripheral blood lymphocytes of the newborn with a history of chronic intrauterine hypoxia. Akush Ginekol (Mosk). 1995;4:29–31 [In Russian].Google Scholar
  23. 23.
    Gerasimov SV. Lipid peroxidation and antioxidant defense in patients with bronchial asthma. Ukr Med Chasopys. 2000;1:86–94 [In Ukrainian].Google Scholar
  24. 24.
    Gladwin MT, Kato GJ. Cardiopulmonary complications of sickle cell disease: role of nitric oxide and haemolytic anemia. Hematology Am Soc Hematol Educ Program. 2005;51–7.Google Scholar
  25. 25.
    Gonchar OO, Steshenko MM, Mankovska IM, et al. Correction of mitochondrial dysfunction in rat myocardium under hypoxia. Zagalna Patoligia ta Patologichna Phyziologia. 2010;3:44–8 [In Ukrainian].Google Scholar
  26. 26.
    Gordon E, Lazarus SC. Management of chronic obstructive pulmonary disease: moving beyond the asthma algorithm. J Allergy Clin Immunol. 2009;124:873–80.PubMedCrossRefGoogle Scholar
  27. 27.
    Gordan JD, Simon MC. Hypoxia-inducible factors: central regulators of the tumor phenotype. Curr Opin Genet Dev. 2007;17:71–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Hanta I, Kocabas A, Canacankatan N, et al. Oxidant–antioxidant balance in patients with COPD. Lung. 2006;184:51–5.PubMedCrossRefGoogle Scholar
  29. 29.
    Jones SL, Herbison P, Cowan JO, et al. Exhaled NO and assessment of anti-inflammatory effects of inhaled steroid: dose–response relationship. Eur Respir J. 2002;20:601–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Karash YM, Strelkov RB, Chizhov AY. Normobaric hypoxia in treatment, prophylaxis and rehabilitation. Moscow: Meditsina; 1988 [In Russian].Google Scholar
  31. 31.
    Katayama K. Effect of intermittent hypoxia on hypoxic ventilatory response. In: Xi L, Serebrovskaya TV, editors. Intermittent hypoxia: from molecular mechanisms to clinical applications. New York: Nova; 2009. p. 245–59.Google Scholar
  32. 32.
    Katayama K, Sato Y, Morotome Y, et al. Intermittent hypoxia increases ventilation and SaO2 during hypoxic exercise and hypoxic chemosensitivity. J Appl Physiol. 2001;90:1431–40.PubMedGoogle Scholar
  33. 33.
    Kiernan MC, Bullpitt P, Chan JH. Mitochondrial dysfunction and rod-like lesions associated with administration of beta2 adrenoceptor agonist formoterol. Neuromuscul Disord. 2004;14:375–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Kirkham FJ, Datta AK. Hypoxic adaptation during development: relation to pattern of neurological presentation and cognitive disability. Dev Sci. 2006;9:411–27.PubMedCrossRefGoogle Scholar
  35. 35.
    Kolchinskaya AZ, Hatsukov BH, Zakusilo MP. Oxygen insufficiency: destructive and constructive actions. Nalchik: Kabardino-Balkaria Scientific Center; 1999 [In Russian].Google Scholar
  36. 36.
    Konga DB, Kim Y, Hong SC, et al. Oxidative stress and antioxidant defenses in asthmatic murine model exposed to printer emissions and environmental tobacco smoke. J Environ Pathol Toxicol Oncol. 2009;28:325–40.PubMedCrossRefGoogle Scholar
  37. 37.
    Korkushko OV, Serebrovskaya TV, Shatilo VB, et al. Selection of the optimal modes for intermittent hypoxia training in medical practice and sports medicine. Methodical recommendations. Kiev Health Ministry; 2010 [In Ukrainian].Google Scholar
  38. 38.
    Kowalski J, Gutkowski P, Serebrovskaya T. Beneficial either detrimental consequences for respiration and hemodynamics. Vestn Hyg Epidemiol. 2007;11:9–13.Google Scholar
  39. 39.
    Kulberg AY. Regulation of the immune response. Moscow: Nauka; 1997. p. 148–57 [In Russian].Google Scholar
  40. 40.
    Kurhalyuk NM, Serebrovskaya TV. Intermittent hypoxic training influences on antioxidant enzymes activity, processes of lipid peroxidation under acute hypoxia and nitric oxide donor treatment. Med Chem. 2001;3:69–71.Google Scholar
  41. 41.
    Kurhalyuk NM, Serebrovskaya TV, Kolesnikova EE, et al. Exogenous L-arginine modulates the effects of acute and intermittent hypoxia on liver mitochondrial and microsomal oxidation. Fiziol Zh. 2002;48:67–73.Google Scholar
  42. 42.
    Louis M, Punjabi NM. Effects of acute intermittent hypoxia on glucose metabolism in awake healthy volunteers. J Appl Physiol. 2009;106:1538–44.PubMedCrossRefGoogle Scholar
  43. 43.
    Lukyanova LD. Molecular, metabolic and functional mechanisms of individual resistance to hypoxia. In: Sharma BK, Takeda N, Ganguly NK, et al., editors. Adaptation biology and medicine. New Delhi: Narosa Publishing House; 1997. p. 236–50.Google Scholar
  44. 44.
    Lukyanova LD, Dudchenko AM, Tsybina TA, et al. Effect of intermittent normobaric hypoxia on kinetic properties of mitochondrial enzymes. Bull Exp Biol Med. 2007;144:795–801.PubMedCrossRefGoogle Scholar
  45. 45.
    Lukyanova LD, Germanova EL, Kopaladze RA. Development of resistance of an organism under various conditions of hypoxic preconditioning: role of the hypoxic period and reoxygenation. Bull Exp Biol Med. 2009;147:400–4.PubMedCrossRefGoogle Scholar
  46. 46.
    Lysenko GI, Serebrovskaya TV, Karaban IN, et al. Use of gradually increasing normobaric hypoxia in medical practice. Methodical recommendations. Kiev: Ukrainian Ministry of Health Care; 1998 [In Russian].Google Scholar
  47. 47.
    Mahamed S, Mitchell G. Is there a link between intermittent hypoxia-induced respiratory plasticity and obstructive sleep apnoea? Exp Physiol. 2007;92:27–37.PubMedCrossRefGoogle Scholar
  48. 48.
    Mallet RT, Ryou M-G, Manukhina EB, et al. β-Adrenergic signaling and ROS: pivotal roles in intermittent, normobaric hypoxia-induced cardioprotection. In: Xi L, Serebrovskaya TV, editors. Intermittent hypoxia: from molecular mechanisms to clinical applications. New York: Nova; 2009. p. 151–74.Google Scholar
  49. 49.
    Man’kovskaia IN, Vavilova GL, Kharlamova ON, et al. Activity of the cell membrane marker enzymes in rats under adaptation to hypoxia. Ukr Biochem J. 1997;69:79–87 [In Russian].Google Scholar
  50. 50.
    Mankovskaya IN. Peculiarities of lipid peroxidation realization mechanisms in intermittent hypoxic hypoxia. Hypoxia Med J. 1993;4:8–11 [In Russian].Google Scholar
  51. 51.
    Manukhina EB, Downey HF, Mallet RT. Role of nitric oxide in ­cardiovascular adaptation to intermittent hypoxia. Exp Biol Med. 2006;231:343–65.Google Scholar
  52. 52.
    Manukhina EB, Mashina SY, Smirin BV, et al. Role of nitric oxide in adaptation to hypoxia and adaptive defense. Physiol Res. 2000;49:89–97.PubMedGoogle Scholar
  53. 53.
    Meerson FZ. Adaptation to intermittent hypoxia: mechanisms of protective effects. Hypoxia Med J. 1993;3:2–8 [In Russian].Google Scholar
  54. 54.
    Meerson FZ, Frolov BA, Volianik MN, et al. The effect of adaptation to the periodic action of hypoxia on the indices of the immunity system and on the course of allergic diseases. Patol Fiziol Eksp Ter. 1990;3:16–21 [In Russian].PubMedGoogle Scholar
  55. 55.
    Moroz LA, Sukhorukov VV, Kravchenko LF, et al. Significance of a complex of laboratory methods of study in the differential diagnosis of various forms of bronchial asthma. Med Tr Prom Ekol. 1994;2:32–4 [In Russian].PubMedGoogle Scholar
  56. 56.
    Nesvitalova KV, Gonchar OA, Drevitskaya TI, et al. Changes in mRNA and protein expression of antioxidant enzymes as markers of the interval hypoxic training effectiveness in children with bronchial asthma. Fiziol Zh. 2011;57(6):13–7 [In Ukrainian].Google Scholar
  57. 57.
    Prabhakar NR, Fields RD, Baker T, et al. Intermittent hypoxia: cell to system. Am J Physiol. 2001;281:L524–8.Google Scholar
  58. 58.
    Prasad K, Gupta JB. Relaxant effect of oxygen free radicals on rabbit tracheal smooth muscle. Pulm Pharmacol Ther. 2002;15:375–84.PubMedCrossRefGoogle Scholar
  59. 59.
    Ragozin ON. Effectiveness of intermittent normobaric hypoxia in patients with bronchial asthma in various modes of chronotherapy. Vopr Kurortol Fizioter Lech Fiz Kult. 2002;2:8–10 [In Russian].PubMedGoogle Scholar
  60. 60.
    Ragozin ON, Balykin MV, Charikova EI, et al. The analysis of rhythm spectrum of respiratory and cardiovascular parameters in bronchial asthma patients under normobaric hypoxitherapy. Fiziol Zh. 2001;47:36–9 [In Russian].Google Scholar
  61. 61.
    Razumovskiĭ AE, Komissarova IA, Shatalov NN, et al. Effect of atmospheric pressure on leukocyte enzyme activity in bronchial asthma. Sov Med. 1980;12:19–22 [In Russian].PubMedGoogle Scholar
  62. 62.
    Redzhebova OK, Chizhov AI. Results of utilization of intermittent normobaric hypoxia in patients with bronchial asthma and chronic obstructive bronchitis. Fiziol Zh. 1992;38:39–42 [In Russian].PubMedGoogle Scholar
  63. 63.
    Rice L, Alfrey CP. The negative regulation of red cell mass by neocytolysis: physiologic and pathophysiologic manifestations. Cell Physiol Biochem. 2005;15:245–50.PubMedCrossRefGoogle Scholar
  64. 64.
    Safronova OS, Serebrovskaya TV, Hordiĭ SK. Pro- and antioxidant system during the adaptation to intermittent hypoxia in healthy subjects and patients with bronchial asthma. Exper Clin Physiol Biochem. 1999;4:61–6 [In Russian].Google Scholar
  65. 65.
    Semenza GL. HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol. 2000;88:1474–80.PubMedGoogle Scholar
  66. 66.
    Serebrovs’ka TV, Safronova OS, Hordiĭ SK. Free-radical processes under different conditions of body oxygen allowance. Fiziol Zh. 1999;45:92–103 [In Ukrainian].PubMedGoogle Scholar
  67. 67.
    Serebrovska TV, Lopata VA, Roy VV, et al. Device for breathing with hypoxic mixtures “Hypoxytron”. 2009. Patent 44179, MПК A61M 16/00; Ukraine, 25 Sept 2009, bulletin № 18 [In Ukrainian].Google Scholar
  68. 68.
    Serebrovskaia TV. Hereditary defect of sensitivity to hypoxia in normal sensitivity to hypercapnia. Patol Fiziol Eksp Ter. 1982;4:80–3.PubMedGoogle Scholar
  69. 69.
    Serebrovskaia TV, Man’kovskaia IN, Lysenko GI, et al. A method for intermittent hypoxic exposures in the combined treatment of bronchial asthma patients. Lik Sprava. 1998;6:104–8 [In Ukrainian].PubMedGoogle Scholar
  70. 70.
    Serebrovskaia ZA, Serebrovskaia TV, Afonina GB. Chemilum­inescence, blood lipid peroxidation and neutrophil activity during the hypoxic training of persons subjected to ionizing radiation exposure. Radiats Biol Radioecol. 1996;36:394–9.PubMedGoogle Scholar
  71. 71.
    Serebrovskaya TV. Intermittent hypoxia research in the former Soviet Union and the Commonwealth of Independent States (CIS): history and review of the concept and selected applications. High Alt Med Biol. 2002;3:205–21.PubMedCrossRefGoogle Scholar
  72. 72.
    Serebrovskaya TV, Karaban IN, Kolesnikova EE, et al. Human hypoxic ventilatory response with blood dopamine content under intermittent hypoxic training. Can J Physiol Pharmacol. 1999;77:967–73.PubMedCrossRefGoogle Scholar
  73. 73.
    Serebrovskaya TV, Lopata VA. Apparatus for breathing with hypoxic gaseous mixtures. 2010. Patent International Application to all countries of PCT # PCT/UA 2010/000071, 7 Oct 2010.Google Scholar
  74. 74.
    Serebrovskaya TV, Nikolsky IS, Nikolska VV, et al. Intermittent hypoxia mobilizes hematopoietic progenitors and augments cellular and humoral elements of innate immunity in adult men. High Alt Med Biol. 2011;12:243–52.PubMedCrossRefGoogle Scholar
  75. 75.
    Serebrovskaya TV, Serebrovskaya ZA, Afonina G. Effect of intermittent hypoxic training on human respiration, free radical processes and immune system. In: Ueda G et al., editors. High altitude medicine. Matsumoto: Shinshu University Press; 1992. p. 77–82.Google Scholar
  76. 76.
    Serebrovskaya TV, Swanson RJ, Kolesnikova EE. Intermittent hypoxia: mechanisms of action and some applications to bronchial asthma treatment. J Physiol Pharmacol. 2003;54:35–41.PubMedGoogle Scholar
  77. 77.
    Serebrovsky A, Serebrovska T. Models and algorithms for the assessment of intermittent hypoxia application safety and efficacy in medical practice. In: Hypoxia and consequences: from molecule to malady. 2009. Book of abstracts, Session II, abstract #25, New York, 12–14 Mar 2009.Google Scholar
  78. 78.
    Tsvetkova AM, Tkatchouk EN. “Hypoxia user” – the opportunity of individual programming of interval hypoxic training. In: Hypoxia, mechanisms, adaptation, correction. BEBIM, Moscow; 1999. p. 83–4 [In Russian].Google Scholar
  79. 79.
    Vinnitskaya RS, Davidov EG, Ctruchkov PV. Hypoxic and hypercapnic gas mixtures in complex treatment and rehabilitation of patients with chronic obstructive diseases. In: Intermittent hypoxic training, effectiveness, and mechanisms of action. Kiev: Institute of Physical Culture; 1992. p. 62–4 [In Russian].Google Scholar
  80. 80.
    Vogtel M, Michels A. Role of intermittent hypoxia in the treatment of bronchial asthma and chronic obstructive pulmonary disease. Curr Opin Allergy Clin Immunol. 2010;10:206–13.PubMedCrossRefGoogle Scholar
  81. 81.
    Zhong H, Belardinelli L, Maa T, et al. Synergy between A2B adenosine receptors and hypoxia in activating human lung fibroblasts. Am J Respir Cell Mol Biol. 2005;32:2–8.PubMedCrossRefGoogle Scholar
  82. 82.
    Zietkowski Z, Bodzenta-Lukaszyk A. Nitric oxide in bronchial asthma. Pol Merkur Lekarski. 2002;12:519–21 [In Polish].PubMedGoogle Scholar

Copyright information

© Springer-Verlag London 2012

Authors and Affiliations

  • Tatiana V. Serebrovskaya
    • 1
    Email author
  • Alexander N. Bakunovsky
    • 1
  • Klaudia V. Nesvitailova
    • 1
  • Iryna N. Mankovska
    • 1
  1. 1.Department of HypoxiaBogomoletz Institute of Physiology, National Academy of Sciences of UkraineKievUkraine

Personalised recommendations