Advertisement

Effect of Intermittent Hypoxia on Breathing Stability in Individuals with Sleep Apnea

  • Jason H. MateikaEmail author
Chapter

Abstract

There is much speculation that respiratory motor long-term facilitation may have a significant impact on apnea severity in individuals with sleep apnea because this disorder is characterized by exposure to intermittent hypoxia, one stimulus known to initiate long-term facilitation. It has been suggested that activation of long-term facilitation may serve to mitigate apnea by facilitating minute ventilation and, perhaps more importantly, upper airway muscle activity. The less discussed but equally plausible situation is that exposure to intermittent hypoxia might ultimately lead to the promotion of apnea. There are at least two scenarios in which apnea might be promoted following exposure to intermittent hypoxia. In both scenarios, long-term facilitation of upper airway muscle activity is initiated but ultimately rendered ineffective because of muscle fatigue or the initiation of other forms of respiratory plasticity, more specifically progressive augmentation of the hypoxic ventilatory response. The primary goal of this chapter is to discuss whether the complex interactions of various forms of respiratory motor neuronal plasticity have a beneficial or a detrimental impact on breathing stability in individuals with sleep apnea. The overall conclusion is that exposure to intermittent hypoxia should not be considered exclusively beneficial or detrimental to breathing stability in individuals with sleep apnea. Rather, the beneficial or detrimental outcomes of exposure to intermittent hypoxia are likely dependent on a variety of circumstances and the complex interactions between various forms of respiratory motor plasticity.

Keywords

Obstructive Sleep Apnea Sleep Apnea Intermittent Hypoxia Central Apnea Chronic Intermittent Hypoxia 
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.

Notes

Acknowledgments

This work was supported by a grant from the National Heart, Lung, and Blood Institute and a VA Merit Award.

References

  1. 1.
    Aboubakr SE, Taylor A, Ford R, et al. Long-term facilitation in obstructive sleep apnea patients during NREM sleep. J Appl Physiol. 2001;91:2751–7.PubMedGoogle Scholar
  2. 2.
    Ahuja D, Mateika JH, Diamond MP, et al. Ventilatory sensitivity to carbon dioxide before and after episodic hypoxia in women treated with testosterone. J Appl Physiol. 2007;102:1832–8.PubMedCrossRefGoogle Scholar
  3. 3.
    Ancoli-Israel S, Kripke DF, Klauber MR, et al. Sleep-disordered breathing in community-dwelling elderly. Sleep. 1991;14:486–95.PubMedGoogle Scholar
  4. 4.
    Babcock MA, Badr MS. Long-term facilitation of ventilation in humans during NREM sleep. Sleep. 1998;21:709–16.PubMedGoogle Scholar
  5. 5.
    Bach KB, Mitchell GS. Hypoxia-induced long-term facilitation of respiratory activity is serotonin dependent. Respir Physiol. 1996;104:251–60.PubMedCrossRefGoogle Scholar
  6. 6.
    Badr MS. Effect of ventilatory drive on upper airway patency in humans during NREM sleep. Respir Physiol. 1996;103:1–10.PubMedCrossRefGoogle Scholar
  7. 7.
    Badr MS, Kawak A, Skatrud JB, et al. Effect of induced hypocapnic hypopnea on upper airway patency in humans during NREM sleep. Respir Physiol. 1997;110:33–45.PubMedCrossRefGoogle Scholar
  8. 8.
    Badr MS, Toiber F, Skatrud JB, et al. Pharyngeal narrowing/occlusion during central sleep apnea. J Appl Physiol. 1995;78:1806–15.PubMedGoogle Scholar
  9. 9.
    Baker-Herman TL, Bavis RW, Dahlberg JM, et al. Differential expression of respiratory long-term facilitation among inbred rat strains. Respir Physiol Neurobiol. 2010;170:260–7.PubMedCrossRefGoogle Scholar
  10. 10.
    Behan M, Zabka AG, Thomas CF, et al. Sex steroid hormones and the neural control of breathing. Respir Physiol Neurobiol. 2003;136:249–63.PubMedCrossRefGoogle Scholar
  11. 11.
    Bradford A, McGuire M, O’Halloran KD. Does episodic hypoxia affect upper airway dilator muscle function? Implications for the pathophysiology of obstructive sleep apnoea. Respir Physiol Neurobiol. 2005;147:223–34.PubMedCrossRefGoogle Scholar
  12. 12.
    Cala SJ, Sliwinski P, Cosio MG, et al. Effect of topical upper airway anesthesia on apnea duration through the night in obstructive sleep apnea. J Appl Physiol. 1996;81:2618–26.PubMedGoogle Scholar
  13. 13.
    Charbonneau M, Marin JM, Olha A, et al. Changes in obstructive sleep apnea characteristics through the night. Chest. 1994;106:1695–701.PubMedCrossRefGoogle Scholar
  14. 14.
    Chowdhuri S, Pierchala L, Aboubakr SE, et al. Long-term facilitation of genioglossus activity is present in normal humans during NREM sleep. Respir Physiol Neurobiol. 2008;160:65–75.PubMedCrossRefGoogle Scholar
  15. 15.
    Chowdhuri S, Shanidze I, Pierchala L, et al. Effect of episodic hypoxia on the susceptibility to hypocapnic central apnea during NREM sleep. J Appl Physiol. 2010;108:369–77.PubMedCrossRefGoogle Scholar
  16. 16.
    Dale-Nagle EA, Hoffman MS, Macfarlane PM, et al. Spinal plasticity following intermittent hypoxia: implications for spinal injury. Ann N Y Acad Sci. 2010;1198:252–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Dempsey JA. Crossing the apnoeic threshold: causes and consequences. Exp Physiol. 2005;90:13–24.PubMedCrossRefGoogle Scholar
  18. 18.
    Dempsey JA, Smith CA, Przybylowski T, et al. The ventilatory responsiveness to CO2 below eupnoea as a determinant of ventilatory stability in sleep. J Physiol. 2004;560:1–11.PubMedCrossRefGoogle Scholar
  19. 19.
    Dempsey JA, Veasey SC, Morgan BJ, et al. Pathophysiology of sleep apnea. Physiol Rev. 2010;90:47–112.PubMedCrossRefGoogle Scholar
  20. 20.
    Duffin J. The role of the central chemoreceptors: a modeling perspective. Respir Physiol Neurobiol. 2010;173:230–43.PubMedCrossRefGoogle Scholar
  21. 21.
    Duffin J. Measuring the ventilatory response to hypoxia. J Physiol. 2007;584:285–93.PubMedCrossRefGoogle Scholar
  22. 22.
    Duffin J, Mohan RM, Vasiliou P, et al. A model of the chemoreflex control of breathing in humans: model parameters measurement. Respir Physiol. 2000;120:13–26.PubMedCrossRefGoogle Scholar
  23. 23.
    Fanfulla F, Patruno V, Bruschi C, et al. Obstructive sleep apnoea syndrome: is the “half-night polysomnography” an adequate method for evaluating sleep profile and respiratory events? Eur Respir J. 1997;10:1725–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Foster GE, McKenzie DC, Milsom WK, et al. Effects of two protocols of intermittent hypoxia on human ventilatory, cardiovascular and cerebral responses to hypoxia. J Physiol. 2005;567:689–99.PubMedCrossRefGoogle Scholar
  25. 25.
    Fuller DD. Episodic hypoxia induces long-term facilitation of neural drive to tongue protrudor and retractor muscles. J Appl Physiol. 2005;98:1761–7.PubMedCrossRefGoogle Scholar
  26. 26.
    Fuller DD, Baker TL, Behan M, et al. Expression of hypoglossal long-term facilitation differs between substrains of Sprague–Dawley rat. Physiol Genomics. 2001;4:175–81.PubMedGoogle Scholar
  27. 27.
    Gerst III DG, Yokhana SS, Carney LM, et al. The hypoxic ventilatory response and ventilatory long-term facilitation are altered by time of day and repeated daily exposure to intermittent hypoxia. J Appl Physiol. 2011;110:15–28.PubMedCrossRefGoogle Scholar
  28. 28.
    Harris DP, Balasubramaniam A, Badr MS, et al. Long-term facilitation of ventilation and genioglossus muscle activity is evident in the presence of elevated levels of carbon dioxide in awake humans. Am J Physiol Regul Integr Comp Physiol. 2006;291:R1111–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Hudgel DW, Chapman KR, Faulks C, et al. Changes in inspiratory muscle electrical activity and upper airway resistance during periodic breathing induced by hypoxia during sleep. Am Rev Respir Dis. 1987;135:899–906.PubMedGoogle Scholar
  30. 30.
    Jordan AS, Catcheside PG, O’Donoghue FJ, et al. Long-term facilitation of ventilation is not present during wakefulness in healthy men or women. J Appl Physiol. 2002;93:2129–36.PubMedGoogle Scholar
  31. 31.
    Katayama K, Smith CA, Henderson KS, et al. Chronic intermittent hypoxia increases the CO2 reserve in sleeping dogs. J Appl Physiol. 2007;103:1942–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Khodadadeh B, Badr MS, Mateika JH. The ventilatory response to carbon dioxide and sustained hypoxia is enhanced after episodic hypoxia in OSA patients. Respir Physiol Neurobiol. 2006;150:122–34.PubMedCrossRefGoogle Scholar
  33. 33.
    Koehle MS, Sheel AW, Milsom WK, et al. Two patterns of daily hypoxic exposure and their effects on measures of chemosensitivity in humans. J Appl Physiol. 2007;103:1973–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Lavie P. Incidence of sleep apnea in a presumably healthy working population: a significant relationship with excessive daytime sleepiness. Sleep. 1983;6:312–8.PubMedGoogle Scholar
  35. 35.
    Lee DS, Badr MS, Mateika JH. Progressive augmentation and ventilatory long-term facilitation are enhanced in sleep apnoea patients and are mitigated by antioxidant administration. J Physiol. 2009;587:5451–67.PubMedCrossRefGoogle Scholar
  36. 36.
    Ling L, Fuller DD, Bach KB, et al. Chronic intermittent hypoxia elicits serotonin-dependent plasticity in the central neural control of breathing. J Neurosci. 2001;21:5381–8.PubMedGoogle Scholar
  37. 37.
    Lusina SJ, Kennedy PM, Inglis JT, et al. Long-term intermittent hypoxia increases sympathetic activity and chemosensitivity during acute hypoxia in humans. J Physiol. 2006;575:961–70.PubMedCrossRefGoogle Scholar
  38. 38.
    Mahamed S, Mitchell GS. Respiratory long-term facilitation: too much or too little of a good thing? Adv Exp Med Biol. 2008;605:224–7.PubMedCrossRefGoogle Scholar
  39. 39.
    Mahamed S, Mitchell GS. Is there a link between intermittent hypoxia-induced respiratory plasticity and obstructive sleep apnoea? Exp Physiol. 2007;92:27–37.PubMedCrossRefGoogle Scholar
  40. 40.
    Mateika JH, Fregosi RF. Long-term facilitation of upper airway muscle activities in vagotomized and vagally intact cats. J Appl Physiol. 1997;82:419–25.PubMedCrossRefGoogle Scholar
  41. 41.
    Mateika JH, Mendello C, Obeid D, et al. Peripheral chemoreflex responsiveness is increased at elevated levels of carbon dioxide after episodic hypoxia in awake humans. J Appl Physiol. 2004;96:1197–205.PubMedCrossRefGoogle Scholar
  42. 42.
    Mateika JH, Millrood DL, Kim J, et al. Response of human tongue protrudor and retractors to hypoxia and hypercapnia. Am J Respir Crit Care Med. 1999;160:1976–82.PubMedGoogle Scholar
  43. 43.
    Mateika JH, Narwani G. Intermittent hypoxia and respiratory plasticity in humans and other animals: does exposure to intermittent hypoxia promote or mitigate sleep apnoea? Exp Physiol. 2009;94:279–96.PubMedCrossRefGoogle Scholar
  44. 44.
    McEvoy RD, Popovic RM, Saunders NA, et al. Effects of sustained and repetitive isocapnic hypoxia on ventilation and genioglossal and diaphragmatic EMGs. J Appl Physiol. 1996;81:866–75.PubMedGoogle Scholar
  45. 45.
    McGuire M, Ling L. Ventilatory long-term facilitation is greater in 1- vs. 2-mo-old awake rats. J Appl Physiol. 2005;98:1195–201.PubMedCrossRefGoogle Scholar
  46. 46.
    McGuire M, MacDermott M, Bradford A. The effects of chronic episodic hypercapnic hypoxia on rat upper airway muscle contractile properties and fiber-type distribution. Chest. 2002;122:1400–6.PubMedCrossRefGoogle Scholar
  47. 47.
    McGuire M, Zhang Y, White DP, et al. Chronic intermittent hypoxia enhances ventilatory long-term facilitation in awake rats. J Appl Physiol. 2003;95:1499–508.PubMedGoogle Scholar
  48. 48.
    McKay LC, Janczewski WA, Feldman JL. Episodic hypoxia evokes long-term facilitation of genioglossus muscle activity in neonatal rats. J Physiol. 2004;557:13–8.PubMedCrossRefGoogle Scholar
  49. 49.
    Millhorn DE, Eldridge FL, Waldrop TG. Prolonged stimulation of respiration by a new central neural mechanism. Respir Physiol. 1980;41:87–103.PubMedCrossRefGoogle Scholar
  50. 50.
    Mitchell GS, Baker TL, Nanda SA, et al. Invited review: intermittent hypoxia and respiratory plasticity. J Appl Physiol. 2001;90:2466–75.PubMedGoogle Scholar
  51. 51.
    Mitchell GS, Johnson SM. Neuroplasticity in respiratory motor control. J Appl Physiol. 2003;94:358–74.PubMedGoogle Scholar
  52. 52.
    Morelli C, Badr MS, Mateika JH. Ventilatory responses to carbon dioxide at low and high levels of oxygen are elevated after episodic hypoxia in men compared with women. J Appl Physiol. 2004;97:1673–80.PubMedCrossRefGoogle Scholar
  53. 53.
    Morris KF, Baekey DM, Shannon R, et al. Respiratory neural activity during long-term facilitation. Respir Physiol. 2000;121:119–33.PubMedCrossRefGoogle Scholar
  54. 54.
    Morris KF, Gozal D. Persistent respiratory changes following intermittent hypoxic stimulation in cats and human beings. Respir Physiol Neurobiol. 2004;140:1–8.PubMedCrossRefGoogle Scholar
  55. 55.
    Nakamura A, Olson Jr EB, Terada J, et al. Sleep state dependence of ventilatory long-term facilitation following acute intermittent hypoxia in Lewis rats. J Appl Physiol. 2010;109:323–31.PubMedCrossRefGoogle Scholar
  56. 56.
    Olson Jr EB, Bohne CJ, Dwinell MR, et al. Ventilatory long-term facilitation in unanesthetized rats. J Appl Physiol. 2001;91:709–16.PubMedGoogle Scholar
  57. 57.
    Onal E, Burrows DL, Hart RH, et al. Induction of periodic breathing during sleep causes upper airway obstruction in humans. J Appl Physiol. 1986;61:1438–43.PubMedGoogle Scholar
  58. 58.
    Pavlova MK, Duffy JF, Shea SA. Polysomnographic respiratory abnormalities in asymptomatic individuals. Sleep. 2008;31:241–8.PubMedGoogle Scholar
  59. 59.
    Peng YJ, Overholt JL, Kline D, et al. Induction of sensory long-term facilitation in the carotid body by intermittent hypoxia: implications for recurrent apneas. Proc Natl Acad Sci USA. 2003;100:10073–8.PubMedCrossRefGoogle Scholar
  60. 60.
    Peng YJ, Prabhakar NR. Reactive oxygen species in the plasticity of respiratory behavior elicited by chronic intermittent hypoxia. J Appl Physiol. 2003;94:2342–9.PubMedGoogle Scholar
  61. 61.
    Peng YJ, Yuan G, Ramakrishnan D, et al. Heterozygous HIF-1alpha deficiency impairs carotid body-mediated systemic responses and reactive oxygen species generation in mice exposed to intermittent hypoxia. J Physiol. 2006;577:705–16.PubMedCrossRefGoogle Scholar
  62. 62.
    Pialoux V, Hanly PJ, Foster GE, et al. Effects of exposure to intermittent hypoxia on oxidative stress and acute hypoxic ventilatory response in humans. Am J Respir Crit Care Med. 2009;180:1002–9.PubMedCrossRefGoogle Scholar
  63. 63.
    Pierchala LA, Mohammed AS, Grullon K, et al. Ventilatory long-term facilitation in non-snoring subjects during NREM sleep. Respir Physiol Neurobiol. 2008;160:259–66.PubMedCrossRefGoogle Scholar
  64. 64.
    Powell FL, Milsom WK, Mitchell GS. Time domains of the hypoxic ventilatory response. Respir Physiol. 1998;112:123–34.PubMedCrossRefGoogle Scholar
  65. 65.
    Ray AD, Magalang UJ, Michlin CP, et al. Intermittent hypoxia reduces upper airway stability in lean but not obese Zucker rats. Am J Physiol Regul Integr Comp Physiol. 2007;293:R372–8.PubMedCrossRefGoogle Scholar
  66. 66.
    Reite M, Jackson D, Cahoon RL, et al. Sleep physiology at high altitude. Electroencephalogr Clin Neurophysiol. 1975;38:463–71.PubMedCrossRefGoogle Scholar
  67. 67.
    Salloum A, Rowley JA, Mateika JH, et al. Increased propensity for central apnea in patients with obstructive sleep apnea: effect of nasal continuous positive airway pressure. Am J Respir Crit Care Med. 2010;181:189–93.PubMedCrossRefGoogle Scholar
  68. 68.
    Serebrovskaya TV, Swanson RJ, Karaban IN, et al. Intermittent hypoxia alters hypoxic ventilatory responses. Fiziol Zh. 1999;45:9–18.PubMedGoogle Scholar
  69. 69.
    Sforza E, Krieger J, Petiau C. Nocturnal evolution of respiratory effort in obstructive sleep apnoea syndrome: influence on arousal threshold. Eur Respir J. 1998;12:1257–63.PubMedCrossRefGoogle Scholar
  70. 70.
    Shkoukani M, Babcock MA, Badr MS. Effect of episodic hypoxia on upper airway mechanics in humans during NREM sleep. J Appl Physiol. 2002;92:2565–70.PubMedGoogle Scholar
  71. 71.
    Tamisier R, Gilmartin GS, Launois SH, et al. A new model of chronic intermittent hypoxia in humans: effect on ventilation, sleep, and blood pressure. J Appl Physiol. 2009;107:17–24.PubMedCrossRefGoogle Scholar
  72. 72.
    Teppema LJ, Dahan A. The ventilatory response to hypoxia in mammals: mechanisms, measurement, and analysis. Physiol Rev. 2010;90:675–754.PubMedCrossRefGoogle Scholar
  73. 73.
    Terada J, Nakamura A, Zhang W, et al. Ventilatory long-term facilitation in mice can be observed during both sleep and wake periods and depends on orexin. J Appl Physiol. 2008;104:499–507.PubMedCrossRefGoogle Scholar
  74. 74.
    Veasey SC, Zhan G, Fenik P, et al. Long-term intermittent hypoxia: reduced excitatory hypoglossal nerve output. Am J Respir Crit Care Med. 2004;170:665–72.PubMedCrossRefGoogle Scholar
  75. 75.
    White DP. Pathogenesis of obstructive and central sleep apnea. Am J Respir Crit Care Med. 2005;172:1363–70.PubMedCrossRefGoogle Scholar
  76. 76.
    Young T, Palta M, Dempsey J, et al. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med. 1993;328:1230–5.PubMedCrossRefGoogle Scholar
  77. 77.
    Zabka AG, Behan M, Mitchell GS. Long term facilitation of respiratory motor output decreases with age in male rats. J Physiol. 2001;531:509–14.PubMedCrossRefGoogle Scholar
  78. 78.
    Zabka AG, Mitchell GS, Behan M. Ageing and gonadectomy have similar effects on hypoglossal long-term facilitation in male Fischer rats. J Physiol. 2005;563:557–68.PubMedCrossRefGoogle Scholar
  79. 79.
    Zabka AG, Mitchell GS, Olson Jr EB, et al. Selected contribution: chronic intermittent hypoxia enhances respiratory long-term facilitation in geriatric female rats. J Appl Physiol. 2003;95:2614–23.PubMedGoogle Scholar

Copyright information

© Springer-Verlag London 2012

Authors and Affiliations

  1. 1.Department of PhysiologyWayne State University School of MedicineDetroitUSA
  2. 2.Department of Internal MedicineWayne State University School of MedicineDetroitUSA
  3. 3.Division of Research and DevelopmentJohn D. Dingell Veterans Affairs Medical CenterDetroitUSA

Personalised recommendations