Semin Respir Crit Care Med 2005; 26(1): 5-12
DOI: 10.1055/s-2005-864197
Copyright © 2005 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Physiology of Breathing and Respiratory Control during Sleep

William R. Krimsky1 , James C. Leiter1 , 2
  • 1Departments of Medicine
  • 2Physiology, Dartmouth Medical School, Lebanon, New Hampshire
Further Information

Publication History

Publication Date:
22 February 2005 (online)


Studies of respiratory control during sleep have revealed that multiple sites of central CO2 chemosensitivity exist within the brainstem, and different chemosensory sites may function only during certain sleep states. In general, chemical control of respiratory function, related to both hypercapnia and hypoxia, appears to be blunted during sleep. The decline in respiratory activity during sleep is particularly marked in the muscles of the upper airway. A variety of neuromechanical factors originating in the lungs, chest wall, and upper airway also modify respiratory function during sleep. Cardiorespiratory function seems to be less stable during sleep, and arousal responses represent a final element in the control system that preserves cardiorespiratory function by terminating the sleep state and restoring more effective control mechanisms.


  • 1 Krueger J M, Obál F. Function of sleep. In: Lee-Chiong TL, Sateia MJ, Carskadon MA Sleep Medicine Philadelphia; Hanley & Belfus, Inc. 2002: 23-30
  • 2 Kryger M H, Roth T, Dement W C. Principles and Practice of Sleep Medicine. Philadelphia, PA; Saunders 1995
  • 3 Berthon-Jones M, Sullivan C E. Ventilation and arousal responses to hypercapnia in normal sleeping humans.  J Appl Physiol. 1984;  57 59-67
  • 4 Johnson M W, Remmers J E. Accessory muscle activity during sleep in chronic obstructive pulmonary disease.  J Appl Physiol. 1984;  57 1011-1017
  • 5 Rist K E, Daubenspeck J A, McGovern J F. Effects of non-REM sleep upon respiratory drive and the respiratory pump in humans.  Respir Physiol. 1986;  63 241-256
  • 6 Gervasoni D, Peyron C, Rampon C et al.. Role and origin of GABAergic innervation of dorsal raphe serotonergic neurons.  J Neurosci. 2000;  20 4217-4225
  • 7 Gallopian T, Fort P, Eggerman E et al.. Identification of sleep-promoting neurons in vitro.  Nature. 2000;  404 992-995
  • 8 Joseph V, Pequignot J M, Van Reeth O. Neurochemical perspectives on the control of breathing during sleep.  Respir Physiol Neurobiol. 2002;  130 253-263
  • 9 Nattie E E. Central chemosensitivity, sleep, and wakefulness.  Respir Physiol. 2001;  129 257-268
  • 10 Nattie E E. Multiple sites for central chemoreception: their roles in response sensitivity and in sleep and wakefulness.  Respir Physiol. 2000;  122 223-235
  • 11 Nattie E E, Li A. CO2 dialysis in nucleus tractus solitarius region of rat increases ventilation in sleep and wakefulness.  J Appl Physiol. 2002;  92 2119-2130
  • 12 Parisian K, Wages P, Hewitt A, Leiter J C, Erlichman J S. Ventilatory effects of gap junction blockade in the NTS in awake rats.  Respir Physiol Neurobiol. 2004;  142 127-143
  • 13 Manning H L, Leiter J C. Respiratory control and respiratory sensation in a patient with a ganglioma within the dorsocaudal brain stem.  Am J Respir Crit Care Med. 2000;  161 2100-2106
  • 14 Morrell M J, Heywood P, Moosavi S H, Guz A, Stevens J. Unilateral focal lesions in the rostro-lateral medulla influence chemosensitivity and breathing during wakefulness, sleep, and exercise.  J Neurol Neurosurg Psychiatry. 1998;  67 637-645
  • 15 Akilesh M R, Kamper M, Li A, Nattie E E. Effects of unilateral lesion of retrotrapezoid nucleus on breathing in awake rats.  J Appl Physiol. 1997;  82 469-479
  • 16 Nattie E E, Li A. CO2 dialysis in the medullary raphe of the rat increases ventilation in sleep.  J Appl Physiol. 2001;  90 1247-1257
  • 17 Curran A K, Darnall R A, Filiano J J, Li A, Nattie E E. Muscimol dialysis in the rostral ventral medulla reduces the ventilatory response to CO2 in awake and sleeping piglets.  J Appl Physiol. 2001;  90 971-980
  • 18 Messier M L, Li A, Nattie E E. Muscimol inhibition of medullary raphé neurons decreases the CO2 response and alters sleep in newborn piglets.  Respir Physiol Neurobiol. 2002;  133 197-214
  • 19 Dempsey J A, Smith C A, Harms C A, Chow C, Saupe K W. Sleep-induced breathing instability.  Sleep. 1996;  19 236-247
  • 20 Wang W, Bradley S R, Richerson G B. Quantification of the response of rat medullary raphe neurones to independent changes in pHo and PCO2 .  J Physiol (Lond). 2002;  540 951-970
  • 21 Filosa J A, Dean J B, Putnam R W. Role of intracellular and extracellular pH in the chemosensitive response of rat locus coeruleus neurones.  J Physiol (Lond). 2002;  541 493-509
  • 22 Erlichman J S, Cook A, Schwab M C, Budd T W, Leiter J C. Heterogeneous patterns of pH regulation in glial cells in the dorsal and ventral medulla.  Am J Physiol. 2004;  286 R289-302
  • 23 Nottingham S, Leiter J C, Wages P, Buhay S, Erlichman J S. Developmental changes in intracellular pH regulation in medullary neurons of the rat.  Am J Physiol. 2001;  281 R1940-1951
  • 24 Ritucci N A, Chambers-Kersh L, Dean J B, Putnam R W. Intracellular pH regulation in neurons from chemosensitive and nonchemosensitive areas of the medulla.  Am J Physiol. 1998;  275 R1152-R1163
  • 25 Prabhakar N R, Peng Y J. Peripheral chemoreceptors in health and disease.  J Appl Physiol. 2004;  96 359-366
  • 26 Pan L G, Forster H V, Martino P et al.. Important role of carotid afferents in control of breathing.  J Appl Physiol. 1998;  85 1299-1306
  • 27 Forster H V. Plasticity in the control of breathing following sensory denervation.  J Appl Physiol. 2003;  94 784-794
  • 28 Golanov E V, Ruggiero D A, Reis D J. A brainstem area mediating cerebrovascular and EEG responses to hypoxic excitation of rostral ventrolateral medulla in rat.  J Physiol (Lond). 2000;  529 413-429
  • 29 Solomon I C, Edelman N H, Neubauer J A. Pre-Bötzinger complex function as a central hypoxic chemosensor for respiration in vivo.  J Neurophysiol. 2000;  83 2854-2868
  • 30 Teppema L J, Veening J G, Kranenburg A, Dahan A, Berkenbosch A, Olievier C. Expression of c-fos in the rat brainstem after exposure to hypoxia and to normoxic and hyperoxic hypercapnia.  J Comp Neurol. 1997;  388 169-190
  • 31 Gozal D, Gaultier C. Evolving concepts of the maturation of central pathways underlying the hypoxic ventilatory response.  Am J Respir Crit Care Med. 2001;  164 325-329
  • 32 Gargaglioni L H, Coimbra N C, Branco L GS. The nucleus raphe magnus modulates hypoxia-induced hyperventilation but not anapyrexia in rats.  Neurosci Lett. 2003;  347 121-125
  • 33 Lovering A T, Dunin-Barkowski W L, Vidruk E H, Orem J M. Ventilatory response of the cat to hypoxia in sleep and wakefulness.  J Appl Physiol. 2003;  95 545-554
  • 34 Berthon-Jones M, Sullivan C E. Ventilatory and arousal responses to hypoxia in sleeping humans.  Am Rev Respir Dis. 1982;  125 632-639
  • 35 Douglas N J, White D P, Weil J V et al.. Hypoxic ventilatory response decreases during sleep in normal men.  Am Rev Respir Dis. 1982;  125 286-289
  • 36 Hedemark L L, Kronenberg R S. Ventilatory and heart responses to hypoxia and hypercapnia during sleep in adults.  J Appl Physiol. 1982;  53 307-312
  • 37 White D P, Douglas N J, Pickett C K, Weil J V, Zwillich C W. Hypoxic ventilatory response during sleep in normal premenopausal women.  Am Rev Respir Dis. 1982;  126 530-533
  • 38 Darnall R A, Curran A K, Filiano J J, Li A, Nattie E E. The effects of GABAA agonist in the rostral ventral medulla on sleep and breathing in newborn piglets.  Sleep. 2001;  24 514-527
  • 39 Berry R B, Gleeson K. Respiratory arousal from sleep: mechanisms and significance.  Sleep. 1997;  20 654-675
  • 40 Sanders M H, Costantino J P, Owens G R et al.. Breathing during wakefulness and sleep after human heart-lung transplantation.  Am Rev Respir Dis. 1989;  140 45-51
  • 41 Sciurba F C, Owens G R, Sanders M H et al.. Evidence of an altered pattern of breathing during exercise in recipients of heart-lung transplants.  N Engl J Med. 1988;  319 1186-1192
  • 42 Kagawa F T, Duncan S R, Theodore J. Inspiratory timing of heart-lung transplant recipients during progressive hypercapnia.  J Appl Physiol. 1991;  71 945-950
  • 43 Henke K G, Arias A, Skatrud J B, Dempsey J A. Inhibition of inspiratory muscle activity during sleep: chemical and nonchemical influences.  Am Rev Respir Dis. 1988;  138 8-15
  • 44 Simon P M, Dempsey J A, Landry D M, Skatrud J B. Effect of sleep on respiratory muscle activity during mechanical ventilation.  Am Rev Respir Dis. 1993;  147 32-37
  • 45 BuSha B F, Stella M H, Manning H L, Leiter J C. Termination of inspiration by phase-dependent respiratory vagal feedback in awake normal humans.  J Appl Physiol. 2002;  93 903-910
  • 46 BuSha B, Judd B, Manning H L et al.. Identification of respiratory vagal feedback in awake normal subjects using pseudo-random unloading.  J Appl Physiol. 2001;  90 2330-2340
  • 47 Iber C, Simon P, Skatrud J B, Mahowald M W, Dempsey J A. The Breuer-Hering reflex in humans.  Am J Respir Crit Care Med. 1995;  152 217-224
  • 48 Simon P M, Habel A M, Daubenspeck J A, Leiter J C. Vagal feedback in the entrainment of respiration to mechanical ventilation in sleeping humans.  J Appl Physiol. 2000;  89 760-769
  • 49 Bakers J HCM, Tenney S M. The perception of some sensations associated with breathing.  Respir Physiol. 1970;  10 85-92
  • 50 Bartlett Jr D, St. John W M. Influence of lung volume on phrenic, hypoglossal and mylohyoid nerve activities.  Respir Physiol. 1988;  73 97-110
  • 51 Kuna S T. Inhibition of inspiratory upper airway motoneuron activity by phasic volume feedback.  J Appl Physiol. 1986;  60 1373-1379
  • 52 Wilson C R, Satoh M, Skatrud J B, Dempsey J A. Non-chemical inhibition of respiratory motor output during mechanical ventilation in sleeping humans.  J Physiol. 1999;  518 605-618
  • 53 Pillar G, Malhotra A, Fogel R B et al.. Upper airway muscle responsiveness to rising PCO2 during NREM sleep.  J Appl Physiol. 2000;  89 1275-1282
  • 54 Horner R L, Liu X, Gill H, Nolan P, Liu H, Sood S. Effects of sleep-wake state on the genioglossus vs. diaphragm muscle responses in CO2 in rats.  J Appl Physiol. 2002;  92 878-887
  • 55 Parisi R A, Santiago T V, Edelman N H. Genioglossal and diaphragm EMG responses to hypoxia druing sleep.  Am Rev Respir Dis. 1988;  138 610-616
  • 56 Schneider H, Boudewyns A, Smith P L et al.. Modulation of upper airway collapsibility during sleep: influence of respiratory phase and flow regimen.  J Appl Physiol. 2002;  93 1365-1376
  • 57 Basner R C, Ringler J, Berkowitz S et al.. Effect of inspired air temperature on genioglossus activity during nose breathing in awake humans.  J Appl Physiol. 1990;  69 1098-1103
  • 58 Basner R C, Simon P M, Schwartzstein R M, Weinberger S E, Weiss J W. Breathing route influences upper airway muscle activity in awake normal adults.  J Appl Physiol. 1989;  66 1766-1771
  • 59 Kimoff R J, Sforza E, Champagne L, Ofiara L, Gendron D. Upper airway sensation in snoring and obstructive sleep apnea.  Am J Respir Crit Care Med. 2001;  164 250-255
  • 60 Larsson H, Carlsson-Nordlander B, Lindblad L E, Norbeck O, Svanberg E. Temperature thresholds in the oropharynx of patients with obstructive sleep apnea syndrome.  Am Rev Respir Dis. 1992;  146 1246-1249
  • 61 Akay M, Leiter J C, Daubenspeck J A. Reduced respiratory-related evoked activity in subjects with obstructive sleep apnea syndrome.  J Appl Physiol. 2003;  94 429-438
  • 62 Afifi L, Guilleminault C, Colrain I M. Sleep and respiratory specific dampening of cortical responsivenss in OSAS.  Respir Physiol Neurobiol. 2003;  136 221-234
  • 63 Henke K G, Badr M S, Skatrud J B, Dempsey J A. Load compensation and respiratory muscle function during sleep.  J Appl Physiol. 1992;  72 1221-1234
  • 64 Wiegand D A, Latz B, Zwillich C W, Wiegand L. Upper airway resistance and geniohyoid muscle activity in normal men during wakefulness and sleep.  J Appl Physiol. 1990;  69 1252-1261
  • 65 Henke K G, Dempsey J A, Kowitz J M, Skatrud J B. Effects of sleep-induced increases in upper airway resistance on ventilation.  J Appl Physiol. 1990;  69 617-624
  • 66 Wiegand L, Zwillich C, White D P. Collapsibility of the human upper airway during normal sleep.  J Appl Physiol. 1989;  66 1800-1808
  • 67 Milic-Emili J, Tyler J M. Relation between work output of respiratory muscles and end-tidal CO2 tension.  J Appl Physiol. 1963;  18 497-504
  • 68 Hendricks J C, Kline L R, Kovalski R J, O'Brien J A, Morrison A R, Pack A I. The English bulldog: a natural model of sleep-disordered breathing.  J Appl Physiol. 1987;  63 1344-1350
  • 69 Negus V E. The Comparative Anatomy and Physiology of the Larynx. London; W. Heinemann Medical Books 1949
  • 70 Tuck S A, Dort J C, Olson M E, Remmers J E. Monitoring respiratory function and sleep in the obses Vietnamese pot-bellied pig.  J Appl Physiol. 1999;  87 444-451

James C LeiterM.D. 

Department of Medicine, Dartmouth Medical School

One Medical Center Dr., Lebanon, NH 03756