Supplemental Oxygen Needs During Sleep. Who Benefits? Robert L Owens MD Introduction Control of Breathing During Wakefulness Changes in Respiration During Sleep Sleep and Lung Disease Nocturnal Oxygen Desaturation Physiological Consequences of Nocturnal Oxygen Desaturation Sleep Deprivation and Lung Disease Interactions Between Lung Disease and Sleep Apnea: The Overlap Syndromes COPD and OSA: “The” Overlap Syndrome Other Overlap Syndromes Diagnosis Treatment Oxygen Can Supplemental Oxygen Cause Harm? Treatment of the Underlying Pulmonary Disease Noninvasive Ventilation Summary The physiologic changes that occur in ventilation during sleep contribute to nocturnal oxygen desaturation in those with lung disease. Nocturnal supplemental oxygen is often used as therapy, although convincing data exist only for those who are hypoxemic both during sleep and wake. Ongoing trials may help address whether oxygen should be used in those with only desaturation during sleep. If used, oxygen should be dosed as needed, and patients should be monitored for hypercapnia. Because of its prevalence, obstructive sleep apnea may commonly overlap with lung disease in many patients and have important consequences. Patients with overlap syndromes may be good candidates for noninvasive ventilation during sleep. Key words: nocturnal oxygen desatura- tion; sleep deprivation; overlap syndrome. [Respir Care 2013;58(1):32–44. © 2013 Daedalus Enterprises] Introduction cretion, and maintenance of acid-base status. However, some mechanisms are altered by the sleep state. Although Breathing is tightly controlled by a number of mecha- oxygenation and ventilation remain adequate in those with nisms to ensure adequate oxygenation, carbon dioxide ex- Dr Owens is affiliated with the Division of Pulmonary and Critical Care The author has disclosed no conflicts of interest. Medicine, and the Division of Sleep Medicine, Brigham and Women’s Hospital, Boston Massachusetts. Correspondence: Robert L Owens MD, Division of Sleep Medicine, Brigham and Women’s Hospital, 75 Francis Street, Boston MA 02115. Dr Owens presented a version of this paper at the 50th RESPIRATORY E-mail: [email protected]. CARE Journal Conference, “Oxygen,” held April 13–14, 2012, in San Fran- cisco, California. DOI: 10.4187/respcare.01988 32 RESPIRATORY CARE • JANUARY 2013 VOL 58 NO 1 SUPPLEMENTAL OXYGEN NEEDS DURING SLEEP.WHO BENEFITS? normal respiratory function, in those with lung disease, hypoxemia becomes more pronounced. These receptors sleep can lead to hypoxemia and/or hypercapnia. Further- are actually more sensitive to decreases in arterial pH. more, sleep-disordered breathing (obstructive sleep apnea Traditionally, the central and peripheral chemical controls [OSA] or central sleep apnea) can independently lead to of ventilation were thought to behave independently, but blood gas abnormalities. Here, basic concepts of control of there is emerging evidence that they are interdependent.5 breathing during wake and sleep are reviewed, ultimately For example, the sensitivity of the medullary chemorecep- with an emphasis on clinical management in those with tors may be partially determined from the input from the lung disease (particularly COPD, which has been reason- carotid body chemoreceptors. Some data also suggest that ably well studied) and concomitant sleep-disordered breath- the degree of central stimulation can affect the sensitivity ing. Nocturnal oxygen is commonly used in those with of the peripheral chemoreceptors.6 Thus, the prevailing nocturnal hypoxemia, with little data to guide clinicians. evidence suggests a hyperadditive model, such that the responsiveness of central chemoreceptors can be increased Control of Breathing During Wakefulness by stimuli at the peripheral chemoreceptors. In addition to chemoreceptor inputs, breathing is also Breathing arises from the respiratory “pacemaker”: a affected by input from both the limbic system and cortex, collection of cells located in the medulla. The output of by efferent input from muscles of locomotion, and by this pacemaker is subsequently and continuously modified receptors within the lungs themselves. Cortical inputs al- by multiple sources to regulate breathing. These include low emotion (eg, anxiety) to affect respiration. During other central nervous system components, from the pons strenuous exercise, O2 consumption and CO2 production through the cortex; central and peripheral chemo-recep- can increase 20-fold. These marked changes are matched tors; and lung stretch receptors and muscles of respiration, by an increase in ventilation and cardiac output that keep all of which can influence breathing frequency, tidal vol- P ,P , and arterial pH relatively constant. Interest- aCO2 aO2 ume, and inspiratory time. These inputs allow the respira- ingly, the ventilation increases in parallel with muscle ac- tory system to maintain homeostasis across a wide range tivity and cannot be explained simply by changes in blood of activities, from sleep to maximal exercise, without con- gases, since ventilation increases precede any change in scious effort. The overall goal of the respiratory system is P or P . The stimulus underlying exercise-induced aO2 aCO2 to maintain stable levels of oxygen, carbon dioxide, and hyperpnea remains unclear, although emerging evidence hydrogen ions in the body. Thus, hypercapnia, acidemia, supports the hypothesis of feedback from exercising and hypoxemia are the stimuli that modify ventilation via limbs.7,8 In a recent trial, men were injected with lumbar chemoreceptors. So-called “central” chemo-receptors are intrathecal fentanyl, which impaired centrally projecting located in the medulla and are in direct contact with ce- muscle afferents, before being asked to exercise. The in- rebrospinal fluid, owing to their proximity to the medulla’s jected subjects had significant hypoventilation (4–7 mm Hg ventral surface. The central chemoreceptors are separated rise at peak exercise), compared to subjects injected with from blood flow by the semipermeable blood-brain bar- saline. The influences of systemic absorption of fentanyl ϩ – rier, which allows passage of CO2 but not H or HCO3 . and possible direct medullary effects were excluded. Thus, Lipid soluble CO2 enters the central nervous system, where these results illustrate the importance of muscle afferent it is rapidly hydrated, leading to an increase in the Hϩ feedback to the central nervous system and overall control concentration. Hϩ ions, in turn, stimulate the central chemo- of breathing. receptors to increase ventilation.1-3 Since there is minimal Finally, in certain disease states, receptors within the buffering of CO2 in the cerebrospinal fluid, alveolar ven- lung are important. J or “juxta-capillary” receptors are tilation is very sensitive to changes in P . For example, located in the alveolar walls, adjacent to capillaries. They aCO2 alveolar minute ventilation increases by 2–3 L/min for are stimulated by interstitial fluid volume and can lead to each millimeter of mercury rise in P . After 1–2 days of rapid, shallow breathing, associated with dyspnea.9-11 These aCO2 increased ventilation, the kidneys increase excretion of J receptors are thought to be important in the dyspnea – HCO3 in the urine, which helps to restore the CO2 level associated with congestive heart failure and may increase in the cerebrospinal fluid and decreases the stimulus for ventilatory drive in patients with Cheyne-Stokes breath- increased ventilation. ing. Pulmonary stretch receptors are located in the smooth Classically, “peripheral” chemoreceptors (located in the muscle of large and small airways. The Hering-Breuer carotid bodies at the bifurcation of the common carotid inflation reflex is triggered to prevent overinflation of the arteries and in the aortic bodies located above the aortic lungs. It is activated only at large tidal volumes arch) respond to drops in P by increasing ventilation.4 (Ͼ 1,000 mL).12 When the pulmonary stretch receptors are aO2 The effect of hypoxemia is nonlinear, with only mild ef- stretched, they send impulses via the vagus nerve to the fects of hypoxemia on nerve activity and ventilation until brainstem, which responds by increasing expiratory time the P decreases to Ͻ 60 mm Hg, when the effect of and decreasing breathing frequency.13,14 The opposite is aO2 RESPIRATORY CARE • JANUARY 2013 VOL 58 NO 133 SUPPLEMENTAL OXYGEN NEEDS DURING SLEEP.WHO BENEFITS? Fig. 1. Control of ventilation during sleep. The hypercapnic respi- ratory response, the major determinant of ventilation, decreases from wakefulness to sleep, and falls further during rapid-eye- movement (REM) sleep. (From Reference 17, with permission.) also true: the Hering-Breuer deflation reflex describes how sudden lung collapse initiates inspiratory activity. Changes in Respiration During Sleep The same basic mechanisms active during wakefulness are also relevant during sleep. Importantly, however, there is a lack of behavioral control, and the responses of spe- cific mechanisms are altered during sleep and during the Fig. 2. Example of nocturnal oxygen desaturation (NOD) and its different sleep stages. The major changes are blunted ven- physiological consequences. Sleep stage (rapid eye movement tilatory response to hypoxia and hypercapnia (Fig. 1).15-17 [REM] in bold) and transcutaneous oxygen measurements during sleep in a subject with COPD. Hypoxemia worsens during sleep, These changes lead to a higher CO2 set point: approxi- mately 45 mm Hg, as opposed to 40 mm Hg during wake-