SANTRAL UYKU APNE SENDROMU

SANTRAL UYKU APNE SENDROMU
Doç. Dr. Banu Eriş Gülbay A.Ü.T.F Göğüs Hastalıkları AD

Santral Uyku Apne Sendromu
Tanım Patofizyoloji Epidemiyoloji Sınıflama* Klinik özellikler ve sonuçları Tanısal değerlendirme Tedavi

Santral Uyku Apne Sendromları (CSAS)
CSAS’nın sınıflandırılmasında (nozolojisi) standardizasyon ile ilgili eksiklikler (+) AASM ICSD-2 (2005) ile Uyku hastalıklarını gruplamış. The nosology of the central sleep apnea (CSA) syndromes have lacked rigid standardization, probably owing to the relative infrequency with which some of the clinical disorders are encountered in clinical practice. The AASM published the Second Edition of the International Classification of Sleep Disorders (ICSD-2) in 2005

Santral Uyku Apne “Tanım”
Santral Uyku Apne (CSA); Uyku sırasında santral solunum merkezinden  solunum kaslarına giden uyarıların; epizodlar halinde tam ya da kısmi azalması sonucunda meydana gelen bir hastalık grubudur. CSA is characterized by episodes of apnea or hypopnea related to loss of ventilatory output from the central respiratory generator in the brainstem to the respiratory pump. CSA’nin farklı klinik manifestasyonları (+)

Santral apne; En az 10 sn süre ile solunum çabası olmaksızın hava akımında duraklama (+)

Santral apne; En az 10 sn süre ile solunum çabası olmaksızın hava akımında duraklama (+) It should be recognized from the beginning that a central pause in breathing may result from a variety of physiologic or pathophysiologic events. The term central sleep apnea reflects several breathing patterns, all of which include pauses in inspiratory effort; it does not represent a single entity or result from a single cause.

Obstrüktif apnenin aksine; santral apne sırasında respiratuar drive’ın kesilmesine bağlı olarak solunum eforu yoktur. Bu iki apnenin birbirnden ayırt edilebilmesi için RIP ya da NP yöntemleri kullanılmalıdır. (oro nazal termistörler ile piezo elektrik kristal bantlarının santral apneyi tespit etmedeki duyarlılığı düşüktür) While the esophageal balloon is considered the gold standard to confirm reductions or absence of respiratory effort, central apneas appear to be adequately scored by plethysmographic measurement of chest wall and abdominal motion, a technique with reasonable reliability that is unlikely to misclassify a patient’s sleep-related breathing disorder. Cardiogenic oscillations noted in the airflow signal seen with a patent upper airway may further confirm that an apneic event is not obstructive.

Santral Uyku Apne “Santral / Obstrüktif Hipopne Tanım”
In the case of obstructive hypopneas, airflow decreases mainly as a consequence of upper airway obstruction, and therefore evidence of upper airway obstruction should be present, such as out of-phase thoraco-abdominal motion on RIP, or flow limitation on the nasal pressure signal. In the case of central hypopneas, airflow decreases mainly as a consequence of reduced respiratory drive, so that there should be no evidence of upper airway obstruction; thoraco-abdominal motion should be inphase, and there should be no evidence of flow-limitation on the nasal pressure signal. Although the ability of RIP and nasal pressure to distinguish between central and obstructive hypopneas has not been specifically addressed, both techniques have been validated against esophageal pressure as means of detecting airflow limitation. Consequently, both techniques can be used under most circumstance to distinguish central from obstructive apneas and hypopneas. Nevertheless, it is not always possible to distinguish central and obstructive hypopneas with these techniques. In such cases, esophageal pressure and diaphragmatic electromyogram can be used, but are invasive and require specialized equipment not available in most sleep laboratories. These techniques are not suitable for routine monitoring, but are usually reserved for research purposes. Kullanılan hipopne tanımları PSG raporunda belirtilmeli Ösafagal manometre, kalibre RIP ya da diafragmatik EMG kullanılmadan hipopne obstrüktif/santral/mikst olarak gruplandırılmamalıdır.

Santral Uyku Apne “Santral / Obstrüktif Hipopne Tanım”
Hipopnelerin büyük kısmı  obstrüktif olarak skorlanır. Ancak, KY ya da stroke’lu hastalarda bu ayırımın yapılması önemlidir. However, when studying patients with cardiovascular diseases, especially those with HF and stroke, where CSA is much commoner than in the general population, distinguishing central from obstructive events assumes greater importance. Since, in the majority of patients with sleep apnea, most respiratory events are hypopneas, the determination of hypopnea type is also far more important in patients with cardiovascular diseases than in the general population. This is of practical importance, since in patients with HF, OSA is rapidly and completely reversed by continuous positive airway pressure (CPAP), whereas CSA responds more slowly and less completely to CPAP.

Santral Uyku Apne Sendromu “Tanısı”
Polisomnografide saptanan apne & hipopnelerin %50’den fazlasının* santral özellikte olması “Santral Uyku Apne Sendromu (CSAS)” tanısını koydurur. Polisomnografide saptanan apne & hipopnelerin %50’den fazlasının* santral özellikte olması “Santral Uyku Apne Sendromu (CSAS)” tanısını koydurur. Based on this evidence, we propose that in patients with HF, a diagnosis of CSA can be established on overnight polysomnography, using either RIP or nasal pressure cannula for respiratory monitoring, when there is an AHI of at least 5 to 15, and when at least 50% of apneas and hypopneas are central.

Santral Uyku Apne Sendromu “Tanısı”
Total AHİ, Obstrüktif/ santral olayların oranı, Solunumsal olayla ilişkili 02 desatürasyonun derecesi, Hastalarda eşlik eden semptomlar ile ilgili tutarlı kriterler Ø However, the diagnostic criteria for CSA and CSA syndrome are not well defined. For example, there are no consistent criteria for the total apnea–hypopnea index (AHI), the proportion of central versus obstructive events, nor for the degree of O2 desaturation in association with a respiratory event required for this diagnosis. There are also no consistent criteria for the diagnosis of CSA syndrome: most HF patients with CSA do not complain of excessive daytime sleepiness or snoring, and there are no data on the frequency of potential symptoms, such as nocturnal dyspnea, morning headaches, and restless sleep. Consequently, until more data emerge, the diagnosis of CSA in patients with HF rests on the demonstration of recurrent central apneas and hypopneas during overnight polysomnography. Although there is no consistent AHI criteria to define a clinically significant degree of CSA, the majority of evidence show that in patients with HF, those with CSA defined as an AHI of > 5 to > 30, in which at least 50% of events are central, have worse survival than patients with AHI below these threshold levels after controlling for confounding factors. In terms of O2 desaturation, there is generally less desaturation during central apnea and hypopnea than during obstructive ones in patients with HF. Studies on the relationship of Cheyne-Stokes respiration (CSR)-CSA to mortality risk have not identified whether the degree of desaturation related to apneas and hypopneas contributes to mortality. In addition, Series and colleagues (25) found that a 2% or greater SaO2 dip rate is more sensitive than a 4% or greater dip rate for identifying apneas and hypopneas defined by reductions in ventilation assessed by RIP. Accordingly, several studies of patients with HF have defined hypopneas by reductions in tidal volume or ventilation alone without any O2 desaturation criterion. Based on these observations, it may not be appropriate to use an O2 desaturation criterion to define hypopneas during CSR-CSA, because if one did, many episodes in which tidal volumes fell below 50% of baseline would not be considered a hypopnea, and the severity of sleep-disordered breathing would be underestimated. Consequently, the diagnosis of CSA and the rationale for exploring the efficacy of treatments for it rest almost entirely on the evidence that CSA increases the risk of death in patients with HF, but not on evidence that CSA causes distinct clinical symptoms. According to the 1999 Guidelines, more than 5 central events per hour of sleep are required to make a diagnosis of CSA. However, absence of outcomes research does not allow severity grading of CSA based upon the apnea/hypopnea index (AHI) as has been applied to patients with OSA. Central apneas usually result in oxyhemoglobin desaturation but, on account of enhanced ventilatory drive and less obesity-related chest wall restriction, are often modest in comparison to those encountered during obstructive apneas in OSA. In general, cardiovascular sequelae of CSA are thought to be relatively mild [37], although systematic studies to confirm this are lacking. As there are no high level clinical trials comparing treatment options and efficacy in CSA, the literature has been largely based upon clinical case reports or series. That said, there appears to be a number of viable treatment options for the CSA patient suffering from sleep disruption and/or resultant daytime functional sequelae.

Santral Uyku Apne Sendromu “Patofizyoloji; Solunum kontrolü”
1) Otomatik ya da Metabolik Kontrol; Kemoreseptörler Carotid arter & Aorta Medüller 2) Davranışsal Kontrol (yüksek kortikal merkezler); Konuşurken/yemek yerken ventilasyon kontrolü sağlanır Uyanıklık stimulusu 3) Mekanik Kontrol;  Gerim & J reseptörleri NREM’de solunum tek başına kemoreseptörler ve vagal intrapulmoner reseptörlerce kontrol edilir. Solunum kaslarına giden nöronal outputun idamesinde kemoreseptörlerden gelen stimulusların uykuda solunumun devamının sağlanmasında kritik önemi (+) Unlike the heart, the respiratory muscles do not have a built-in pacemaker. These muscles receive impulses from the medulla from a region that has been called the respiratory center, respiratory oscillator, respiratory signal generator, and respiratory pacemaker. For breathing to change as physiologic conditions change, the respiratory center receives and responds to three general types of information: chemical information (from chemoreceptors responding to pH and to the partial pressures of oxygen [PaO2] and carbon dioxide [PaCO2]), mechanical information (from receptors in the lung and chest wall), and behavioral information (from higher cortical centers). These aspects of awake control also have an impact on the control of breathing during sleep. The major goal of the respiratory control system is homeostatis-that is, keeping blood gases in a tight range so that the metabolic functions of the body remain normal. Sleep is a time when the respiratory tranquility of resting wakefulness is replaced by marked respiratory variability due to changes in both the drive to the ventilatory pump muscles and the upper airway opening muscles. Breathing during wakefulness is controlled by several factors, including voluntary and behavioral elements, chemical factors (e.g., low oxygen levels, high carbon dioxide levels, and acidosis), and mechanical signals from the lung and chest wall. During sleep, there is loss of voluntary control and a decrease in the usual ventilatory response to both low oxygen and high carbon dioxide levels. Both hypoxemic and hypercapnic responses are most depressed in rapid eye movement (REM) sleep. * Ventilation is broadly controlled by both chemical/ metabolic stimuli (PaO2 and PaCO2) as well as neurobehavioral factors. The latter are prominent during wakefulness, and include stimuli from higher cortical centers related to daily living behaviors, such as phonation and deglutition as well as visual and auditory cues thought to contribute to an overall increase in tonic output from the cerebral cortex to the respiratory centers in the brainstem. During sleep, with loss of this neurobehavioral input, ventilation is driven by an automatic system which integrates afferent signals from peripheral (primarily sensing PaO2) and central (sensing PaCO2) chemoreceptors as well as vagally mediated feedback from lung and chest wall mechanoreceptors [7].

Santral Uyku Apne Sendromu “Patofizyoloji”
Medullada; dorsal ve ventral nöronlardan çıkan afferent lifler; diafragma ve İK kaslara gider. Medullada ayrıca pnömotaksik merkez de var; apnestik merkezi ve inspirasyonu inhibe eder. Hava yollarında gerim reseptörleri var; gerim reseptörleri  akciğer inflasyonu ile stimüle olur ve inspirasyon sonlanır, ekspirasyon başlar solunum sayısı azalır. Slowly adapting pulmonary stretch receptors located in the airways with vagal afferents that are stimulated by increases in lung volume. For example, when functional residual capacity is raised or when lung volume is held at its end-inspiratory level, a reduction in respiratory frequency results primarily from prolongation of the expiratory period (inflation reflex of Hering–Breuer). A reduction in activity of these receptors with lung deflation stimulates inspiratory onset (deflation reflex) and may contribute to the tachypnea that accompanies atelectasis. • Rapidly adapting pulmonary stretch receptors concentrated near the carina and central bronchi, also with vagal afferents, are stimulated both mechanically and chemically to generate the cough reflex. • C-fiber endings attached to unmyelinated afferent fibers are found close to the pulmonary capillaries, where they have been called type J (juxtapulmonary capillary) receptors and are also present in the bronchi in proximity to the bronchial circulation. Both types of C-fiber endings are stimulated by endogenously produced substances, including histamine, some prostaglandins, bradykinin, and serotonin, and may have a role in conditions such as asthma, pulmonary venous congestion, and pulmonary embolism. C-fiber endings also are mechanically sensitive and can be activated by lung hyperinflation. • Musculoskeletal afferents stimulated by the stretching of skeletal muscle increase ventilation and may contribute to the initial hyperpnea of exercise.

Uykuda; İstemli (Davranışsal) kontrol ortadan kalkar Solunum merkezinin C02’a duyarlılığı azalır* Uyku sırasında normal C02 düzeyinde hafif artış olur (~ 2-4 mmHg) Solunum merkezinin apne eşiği yükselir (apneye neden olan en düşük PaC02 düzeyi) Uyku sırasında faringeal hava yolu kollapsı, solunumu inhibe eden refleksleri başlatarak santral apneye yol açabilir NREM’de solunum tek başına kemoreseptörler ve vagal intrapulmoner reseptörlerce kontrol edilir. Solunum kaslarına giden nöronal outputun idamesinde kemoreseptörlerden gelen stimulusların uykuda solunumun devamının sağlanmasında kritik önemi (+) The transition from wakefullness to sleep is an inherently unstable period in terms of cardiorespiratory control.With sleep onset, there is a loss of the wakefulness stimulus and behavioral influences.In addition, several respiratory control mechanisms are down regulated at sleep onset. Upper airway (UA) dilator and respiratory pump muscle tone is reduced, and there is an accompanying increase in UA resistance leading to a reduction in ventilation for a given level of drive. Uyanıklık sona erdiğinde ventilasyon tümüyle metabolik kontrol mekanizmalarına bağımlı olur. Ventilatuar kontrolü defektli olan kişilerde; uyanıklıkta solunum, davranışsal kontrol ve uyanıklık stimulusu ile devam ettirilebilir. Ancak uyku sırasında bu mekanizmalar daha fazla faal olamaz ve metabolik ontrol mekanizmaları da defektli olduğu için; ventilasyon devam ettiirilemez ve santral apne gelişir.

Uykuda; İstemli (Davranışsal) kontrol ortadan kalkar Solunum merkezinin C02’a duyarlılığı azalır* Uyku sırasında normal C02 düzeyinde hafif artış olur (~ 2-4 mmHg) Solunum merkezinin apne eşiği yükselir (apneye neden olan en düşük PaC02 düzeyi) Uyku sırasında faringeal hava yolu kollapsı, solunumu inhibe eden refleksleri başlatarak santral apneye yol açabilir

Uykuda; İstemli (Davranışsal) kontrol ortadan kalkar Solunum merkezinin C02’a duyarlılığı azalır* Uyku sırasında normal C02 düzeyinde hafif artış olur (~ 2-4 mmHg) Solunum merkezinin apne eşiği yükselir (apneye neden olan en düşük PaC02 düzeyi) Uyku sırasında faringeal hava yolu kollapsı, solunumu inhibe eden refleksleri başlatarak santral apneye yol açabilir In addition to the changes that occur at sleep onset, ventilatory responses to hypoxia and hypercapnia and respiratory load compensation are reduced across sleep stages, particularly during rapid eye movement (REM) sleep.23–25 The resultant reduction in ventilation with progressive sleep is coupled with a gradual rise in Paco2 on the order of approximately 3 to 8 mm Hg,26 depending on the prevailing metabolic conditions. Decreased Basal Metabolic Rate Basal metabolic rate falls during sleep, with no major differences between the levels in the different sleep stages.Both ventilation and ventilatory responses are reduced when metabolic rate falls,62 although the sensor for this is unclear. The decreased basal metabolic rate during sleep is probably a factor in the decreased chemosensitivity during sleep, but it cannot explain the further reduction in ventilatory response from NREM to REM sleep. Relationship between Cerebral Blood Flow and Metabolism Cerebral blood flow increases during sleep. The 4% to 25% increase in brain blood flow in slow wave sleep over that in wakefulness is explicable on the basis of the mild hypercapnia that results from hypoventilation.65 Brain blood flow increases markedly during REM sleep; this increase was as large as 80% in one study.64 In goats, Santiago et al.65 found a 26% increase in brain blood flow during REM sleep, and an increase that was greater than could be explained by the increase in CO2. They also found that brain metabolism in REM sleep was similar to that in wakefulness. This increase in the ratio of brain blood flow to brain metabolism would depress central chemoreceptor activity during REM sleep and might be a factor in reducing ventilatory responses during REM sleep. However, in humans, Madsen and colleagues67 reported that changes in cerebral blood flow paralleled changes in cerebral oxygen metabolism during both slow wave and REM sleep. Neurologic Changes during Sleep Cortical activity can influence breathing, with mental concentration increasing both ventilation68 and ventilatory responses.10 It seems probable that the hypoventilation and decreased responses to chemical and mechanical stimuli in NREM sleep partially reflect the loss of the wakefulness drive to ventilation. During REM sleep, sensory and motor functions are impaired. There is both presynaptic and postsynaptic inhibition of afferent neurons,70 which results in raised arousal thresholds to external stimuli71 and in postsynaptic inhibition of motoneurons,72 which produces the postural hypotonia typical of REM sleep.73 This combination of decreased sensory and motor function probably contributes to the marked impairment of ventilatory responses during REM sleep. It has been suggested that irregular breathing and impaired ventilatory responses during REM sleep result from alteration of the control of ventilation by behavioral factors.69 However, evidence suggests that chemical stimuli are the most important factor during REM sleep in people.74 Furthermore, at least in cats,52 there seems to be a positive correlation between the activity of some medullary respiratory neurons during REM sleep and pontine-generated discharges termed ponto-geniculo-occipital waves. Ponto-geniculo-occipital waves are one of the basic electrophysiologic phenomena of REM sleep, and thus the dysrhythmic nature of breathing in REM sleep may relate directly to the dysrhythmic nature of REM sleep itself. This is supported by the observation that tidal volume is closely related to the density of eye movements during REM sleep in humans. Neuromechanical Factors It has been suggested that a decreased ventilatory response in REM sleep results from hypotonia of the intercostal muscles. Although chest movement and levels seen on the intercostal electromyogram are decreased during REM sleep, as compared with NREM sleep, studies that included measurements during wakefulness show that chest movement contributes similar proportions to tidal volume in wakefulness and in REM sleep Further electromyogram studies are required, as are studies on the contribution of the chest to ventilation during the different components of REM sleep. Functional residual capacity is decreased during REM sleep.80 Although this might contribute to the hypoxia in REM sleep, it is unlikely to contribute to the decreased ventilatory responses, because volume reduction usually increases these responses. Airflow resistance increases during sleep. The increase is maximal in NREM sleep in humans.82,83 However, in cats, resistance seems to be highest during REM sleep.53 This increased resistance results from hypotonia of the muscles that open the upper airway during sleep. Some of the diminution in ventilatory responses between wakefulness and NREM sleep may be caused by changes in upper airway resistance, because the occlusion pressure response to hypercapnia is well maintained during NREM sleep.19 One study84 looked at the threshold CO2 level for respiratory muscle activation in intubated subjects, in whom upper airway resistance was thus kept constant. The authors suggested that there are sleep stage-related differences in the neuromuscular response to CO2. The CO2 level at which respiratory muscle augmentation occurred rose significantly from wakefulness to NREM sleep. The occlusion pressure response to hypercapnia is markedly reduced during REM sleep,19 which indicates diminution of neuromuscular function.

Uykuda; İstemli (Davranışsal) kontrol ortadan kalkar Solunum merkezinin C02’a duyarlılığı azalır* Uyku sırasında normal C02 düzeyinde hafif artış olur (~ 2-4 mmHg) Solunum merkezinin apne eşiği yükselir (apneye neden olan en düşük PaC02 düzeyi) Uyku sırasında faringeal hava yolu kollapsı, solunumu inhibe eden refleksleri başlatarak santral apneye yol açabilir While behavioral influences and neurocompensatory responses strongly appose apnea even in the presence of marked decreases in Paco2 during wakefulness,this is not the case during sleep.

Uykuda; İstemli (Davranışsal) kontrol ortadan kalkar Solunum merkezinin C02’a duyarlılığı azalır* Uyku sırasında normal C02 düzeyinde hafif artış olur (~ 2-4 mmHg) Solunum merkezinin apne eşiği yükselir (apneye neden olan en düşük PaC02 düzeyi) Uyku sırasında faringeal hava yolu kollapsı, solunumu inhibe eden refleksleri başlatarak santral apneye yol açabilir Uyanıklık Uyku PaC02 40 mmHg 45 mmHg Eşik PaC02 35 mmHg 41-42 mmHg

Uykuda; İstemli (Davranışsal) kontrol ortadan kalkar Solunum merkezinin C02’a duyarlılığı azalır* Uyku sırasında normal C02 düzeyinde hafif artış olur (~ 2-4 mmHg) Solunum merkezinin apne eşiği yükselir (apneye neden olan en düşük PaC02 düzeyi) Uyku sırasında faringeal hava yolu kollapsı, solunumu inhibe eden refleksleri başlatarak santral apneye yol açabilir Uyanıklık Uyku PaC02 40 mmHg 45 mmHg Eşik PaC02 35 mmHg 41-42 mmHg Apne eşiği – saptanan PaC02  SA gelişiminde önemli

Uykuda; İstemli (Davranışsal) kontrol ortadan kalkar Solunum merkezinin C02’a duyarlılığı azalır* Uyku sırasında normal C02 düzeyinde hafif artış olur (~ 2-4 mmHg) Solunum merkezinin apne eşiği yükselir (apneye neden olan en düşük PaC02 düzeyi) Uyku sırasında faringeal hava yolu kollapsı, solunumu inhibe eden refleksleri başlatarak santral apneye yol açabilir ÜSY’da non-nazal faringeal hava yolu refleksleri; apneyi başlatabilir. Aslında koruyucu bir reflekstir. Faringeal obstrüksyon yaparak, solunumu korumak amaçlanır ve apneye neden olur. Supin pozisyonda daha sıktır ve bu grup santral apneler CPAP’a daha iyi yanıt verir. ÜSY’da nazal obstrüksiyonlar (nezle/allerjik rinit gibi) uyku sırasında solunum paternini etkileyebilir. Hava akımı burundaki reseptörlerce tespit edilir ve bunlarda kalkan uyarılar solunum paternini değiştirebilir. (SA ve/veya OA) Bazı hastalarda CSA sırasında farengeal kollaps da gösterilmiştir. Bu kollaps, PaCO2 düştüğünde farengeal kas tonusunun da düşmesi ile ilişkilidir. Üst solunum yolu rezistansının horlama sırasında artması arousal oluşturarak hiperventilasyon neden olarak solunumu inhibe eder ya da ÜSY kollapsı ile hipoventilasyona yol açarak santral apneye neden olmaktadır

Sonuçta Uykuda; Multifaktöriyel olarak Ventilasyon azalır. The reduction in ventilation associated with sleep appears to be multifactorial in origin. NREM sleep is associated with a twofold increase in upper airway resistance [9] which appears to be due in part to reduced neuromuscular input as demonstrated by electromyographic recordings of upper airway muscles. This reduction in neuromuscular control originates primarily from the tonic background, although decrements may be seen on phasic stimulation during inspiration [10]. These regional effects coupled with reductions in both the hypoxic and hypercapnic ventilatory response [8], result in modest hypoventilation associated with 2–4% reductions in oxyhemoglobin saturation and a 3–6mm Hg increase in the partial pressure of carbon dioxide [11, 12]. Further decrements in the ventilatory response occur during REM sleep [13], despite the return of behavioral cortical activity which is characterized by an irregular breathing pattern thought to be associated with dreaming. During both wakefulness and sleep, the most sensitive determinant of ventilation is PaCO2, the level of which is linearly related to minute ventilation. Thus, small changes in arterial CO2 tension actuate a change in ventilation. Oxygen tension also appears to play a role in the drive to breathe, but relatively large decrements (PaO2 60mm Hg) are required before an appreciable increase in minute ventilation is encountered (a hyperbolic response) [16]. Skatrud and Dempsey [17] were among the first to describe an apneic threshold, a PaCO2 level below which was frequently associated with central apnea during NREM sleep in healthy individuals. Hypoxia appears to promote apnea indirectly by stimulating ventilation with resultant hypocapnia sufficient to cross the apneic threshold [17].

Santral apnede; Solunum çabası Ø’tur (intratorasik basınç değişimi Ø’tur) Solunumsal olay sırasında; solunum kaslarına giden nöronal output kesilir ve ventilatuar duraklamanın bitiminde tekrar başlar. Uyku sırasında; santral solunum merkezi; solunum kaslarına komut vermeyi durdurur. SA gelişiminde tek bir mekanizma yok, çeşitli mekanizmaların sonucunda; solunum merkezinin instabilitesi (+)

Santral apne; Tek bir klinik antite değildir Tek bir klinik sebepten kaynaklanmamaktadır. SA’ler farklı mekanizmalarla meydana gelmektedir. After tracheostomy for obstructive sleep apnea, many patients develop central apnea, which generally resolves over a period of months.4 This may also occur when continuous positive airway pressure (CPAP) is initiated to alleviate upper airway obstruction. In addition, it has been observed that the treatment of central apneas with either a respiratory stimulant (e.g., acetazolamide5) or diaphragmatic pacing6 can result in obstructive events. Finally, studies report objective evidence of pharyngeal airway narrowing during purely central apneas. These observations imply some commonality in the pathophysiology of the various types of apnea, so it is not surprising that central and obstructive apneas are frequently seen in the same individual. It should be recognized from the beginning that a central pause in breathing may result from a variety of physiologic or pathophysiologic events. The term central sleep apnea reflects several breathing patterns, all of which include pauses in inspiratory effort; it does not represent a single entity or result from a single cause. Examples include Cheyne-Stokes respiration, periodic breathing at altitude, and the idiopathic central sleep apnea observed at sea level. Each has a different pathogenesis but is manifested by central apneas during sleep. To understand central sleep apnea, the normal mechanisms controlling ventilation awake and asleep and pathologic influences on these mechanisms must be understood. All possible causes of central apnea must be considered in caring for patients with this disorder. Sonuç olarak; uyanıklık stimulusu olmadığı zaman ventilatuar ritm kritik olarak kemoreseptör stimülasyonuna bağlıdır. artmış TV hipokapni olmaksızın da solunumu inhibe eden bir mekanizma olabilir. Uyku başlangıcında disritmik bir solunum görülebilir. Uyanıklıktan evre 1-2’ye geçişte; uyanıklıkta ventilasyon için sorun oluşturmayan PaC02 düzeyi; uyku için apne eşiğinin altında kalır ve ventilasyonun devamı için yetersiz olur ve apne gelişir.

Santral Apne Mekanizmaları
CA’ler neden evre 1-2’de daha fazla ama REM’de daha az? Çünkü recp kemosensitivitesi daha az REM’de Artmış solunumsal Nöronal aktivitesi (+); solunum kontrolü metabolikten çok  davranışsal kontrol altında Solunum drive’ı ve solunum kas aktivitesi daha az ve PC02 NREM’e göre daha yüksek Eckert DJ, et al. Central sleep apnea. Chest 2007; 131:

Santral Uyku Apne Sendromu “Epidemiyoloji”
Santral apne; CSA Apneik hastaların %5-10’nunda görülür İnsidansı ~ %12 (araştırılan popülasyon belirleyici) Erkek hakimiyeti ?* Orta-ileri yaş KY, stroke, DM’lu hastalarda CSA sıklığı daha fazla If abnormal nocturnal breathing is to be understood and recognized, it is important to determine how commonly central apneas occur in normal individuals. The reported frequency of disordered breathing, and in particular the individual patterns, varies depending on the population studied, the methods used for apnea detection, and the threshold used to define abnormalities.50 Carskadon and Dement found that 37.5% of all subjects over the age of 62 had apneas or hypopneas, and that most of the time, "when determinations were possible, apneas were primarily of central type." Other studies report an incidence of central sleep apnea of between 12% and 66%,depending on the population investigated. Lugaresi et al. stated that "central apneas lasting 5-15 sec may appear during light and REM sleep" in normal subjects.With these limitations in mind, a frequency of more than five central apneas per hour of sleep is generally considered abnormal. Although most research-based studies require a greater frequency of events for inclusion, a recent report from the American Academy of Sleep Medicine defined idiopathic central sleep apnea syndrome as the presence of five or more central apneas per hour of sleep in patients with an arterial Pco2 of less than 45 mm Hg who are either excessively sleepy during the day or have frequent nocturnal arousals or awakenings.This same report defined the Cheyne-Stokes respiration syndrome as the presence of at least three consecutive respiratory cycles, with a crescendo-decrescendo pattern and a cycle length near 60 seconds, in a patient with either congestive heart failure or cerebrovascular disease. In addition, these patients must have either five or more central apneas or hypopneas per hour of sleep or 10 consecutive minutes of crescendo-decrescendo breathing.5Thus, a standard now exists for defining these syndromes. In the four studies that specifically considered patients with symptomatic idiopathic central sleep apnea, no consistent epidemiologic trends emerge. Guilleminault et al.,1 White et al.,58 and Bradley et al.27 reported a strong male predominance; Roehrs et al.7 observed central apneas more commonly in women. No explanation can be offered for this discrepancy. All studies, however, noted this disorder to occur most commonly in middle-aged to older adult individuals, although a few younger patients have been reported. In the case of Cheyne-Stokes respiration, a number of reports suggest that patients with congestive heart failure, without obvious breathing abnormalities during the day, may have periodic breathing during sleep.59,60 One study suggests that 45% of patients with congestive heart failure (left ventricular ejection fraction of less than 40%) have more than 20 central apneas plus hypopneas per hour of sleep.61 Thus, Cheyne-Stokes respiration during sleep in patients with congestive heart failure is likely to be quite common. Santral uyku apne sendromu [central sleep apnea syndrome (CSAS)] ise, uykuda solunum bozuklukları spektrumu içerisinde, apneik hastaların %5-10’unda görülen, tüm apne ve hipopnelerin %50’den fazlasının santral tipte olması ile karakterize ve obstrüktif uyku apne sendromu (OSAS)’ndan belirgin farklılıkları bulunan bir hastalık tablosudur. Ancak çoğu zaman obstrüktif veya mikst tip uyku apnesi ile birlikte görülür (3). CAI> 20/sa ciddi olarak kabul edildiğinde < 65 yaş görülmrmiş, > 65y prevelansı %5 Bradley TD, et al: Clinical and physiological heterogeneity of the central sleep apnea syndrome. Am Rev Respir Dis 1986;134: Roehrs T, et al: Sleep complaints in patients with sleep-related respiratory disturbances. Am Rev Respir Dis 1985;132:

Santral Uyku Apne Sendromu “Klinik”
Semptom CSAS OSAS GAUH Değişken Var Rahatsız uyku Horlama Noktürnal ND Sabah BA İnsomnia NOD PND, sık noktürnal arousal- awakenings (+) Horlama, GAUH, obezite nadir

Santral Uyku Apne Sendromu “Klinik Sınıflama*”
Hiperkanik CSAS: Hiperkapnik ventilatuar yanıt düşük Kronik Solunum kontrolü ya da solunum mekaniği bozuktur (uyku & uyanıklıkta) As will be discussed later, those disorders associated with daytime hypercapnia (some hypoventilation syndromes) appear to result from global derangements in ventilation and ventilatory drive during both wakefulness and sleep. *Bradley TD, et al: Clinical and physiologic heterogeneity of the central sleep apnea syndrome. Am Rev Respir Dis 1986;134:217–221.

Santral Uyku Apne Sendromu “*Klinik Sınıflama”
Hiperkanik CSAS: Hiperkapnik ventilatuar yanıt düşük Kronik Solunum kontrolü ya da solunum mekaniği bozuktur (uyku& uyanıklıkta) Normo-hipkapnik CSAS: Hiperkapnik ventilatuar yanıt yüksek Solunum kontrolü instabilitesi (+) Nonhiperkapnik formu daha sıktır. Horlama veya üst solunum yolu (ÜSY) obstrüksiyonu olmaksızın farklı mekanizmalarla oluşur. Disorders without hypercapnia, and importantly often associated with hypocapnia, include primary CSA syndrome, Cheyne-Stokes breathing pattern (also been referred to as periodic breathing) seen most commonly in the setting of heart failure (HF) or central neurologic disease, and high altitude periodic breathing (HAPB).

Santral Uyku Apne Sendromu “*Klinik sınıflama”
Hiperkapnik CSAS; Santral solunum uyarısının bozulması Primer: Konjenital santral hipoventilasyon (PHOX2B) Sekonder: Ensefalit, beyinde tümör, infarkt, kanama, narkotik ve opioid ilaçlar, obezite-hipoventilasyon Solunum kaslarının etkin çalışmaması Kas hastalıkları: Myopatiler, myotonik distrofi, ALS, postpolio sendromu, myastenia gravis, MS Kifoskloyoz Nonhiperkapnik CSAS; Cheyne-stokes solunumu Kalp yetmezliği Yüksek irtifa Cerebrovasküler hastalıklar İdiyopatik santral uyku apne sendromu Diğer: Obtrüktif uyku apne sendromu, hipotiroidi, akromegali, fizyolojik (uyku başlangıcı, arousal sonrası, fazik REM) Solunum sisteminin asıl amacı hücrelere metabolizmalarına yetecek kadar oksijeni ulaştırıp, ortaya çıkan karbondioksitin atmosfere geri dönmesini sağlamaktır. Bu gaz alışverişinin çeşitli mekanizma ve nedenler ile bozulması yaşamsal fonksiyonları tehlikeye sokar. Bunlardan biri, alveoler hipoventilasyon yani alveollere giden gaz volümünde azalmadır. Alveoler hipoventilasyon karbondioksit retansiyonuna ve hiperkapniye yol açar. Hiperkapnik CSAS yeni sınıflamalarda “hipoventilasyon sendromları” içerisinde ele alınmaktadır.

ICSD-2 sınıflaması Santral Uyku Apne Sendromları
II- Uykuda Solunum Bozuklukları Santral Uyku Apne Sendromları Obstrüktif Uyku Apne Sendromları Uyku ile ilişkili Hipventilasyon/Hipoksemi Sendromları Diğer Uykuda Solunum Bozuklukları, tanımlanmamış

Primer Santral Uyku Apnesi Medikal Sorunlara bağlı diğer Santral Uyku Apnesi  Cheyne-Stokes Solunumuna bağlı Santral Uyku Apnesi  Yüksek irtifada periyodik solunuma bağlı Santral Uyku Apnesi  Cheyne-Stokes ya da Yüksek İrtifa dışındaki hastalıklara bağlı Santral Uyku Apnesi  İlaçlara bağlı Santral Uyku Apnesi  Çocukluk çağı primer Santral Uyku Apnesi Central Sleep Apnea Syndromes Primary Central Sleep Apnea Other Central Sleep Apnea Due to Medical Condition Cheyne–Stokes Breathing Pattern High-Altitude Periodic Breathing Central Sleep Apnea Due to Medical Condition Not Cheyne–Stokes or High-Altitude Central Sleep Apnea Due to Drug or Substance Other Sleep-Related Breathing Disorder Due to Drug or Substance Primary Sleep Apnea of Infancy (formerly Primary Sleep Apnea of Newborn)

ICSD-2 sınıflaması Santral Uyku Apne Sendromu
Santral Uyku Apne Sendromları Primer Santral Uyku Apnesi Medikal Sorunlara bağlı diğer Santral Uyku Apnesi  Cheyne-Stokes Solunumuna bağlı santral uyku apnesi  Yüksek irtifada periyodik solunuma bağlı santral uyku apnesi  Cheyne-Stokes ya da Yüksek İrtifa dışındaki hastalıklara bağlı santral uyku apnesi  İlaçlara bağlı santral uyku apne  Çocukluk çağı primer santral uyku apnesi Also referred as idiopathic CSA, this remains a relatively uncommon disorder and, as a result, the pathophysiology and natural history are not well understood.

Santral Uyku Apne Sendromları Primer Santral Uyku Apnesi Medikal Sorunlara bağlı diğer Santral Uyku Apnesi  Cheyne-Stokes Solunumuna bağlı santral uyku apnesi  Yüksek irtifada periyodik solunuma bağlı santral uyku apnesi  Cheyne-Stokes ya da Yüksek İrtifa dışındaki hastalıklara bağlı santral uyku apnesi  İlaçlara bağlı santral uyku apne  Çocukluk çağı primer santral uyku apnesi What does appear to be a consistent finding among these patients is an exaggerated ventilatory response to PaCO2 during both wakefulness and sleep, representative of high loop gain predisposing to respiratory control system instability, as described in a series of papers by Bradley’s group [6, 31, 32]. This increased sensitivity to blood carbon dioxide tensions results in lower baseline PaCO2 (around 35mm Hg), close to the apneic threshold, thereby predisposing to apnea. Associated arousals manifest with abrupt hyperventilation [32] and further propagation of ventilatory instability. That arousals and ventilatory pattern in SA are not the cyclical waxing and waning as seen in Cheyne-Stokes respiration suggest additional or pathophysiologically distinct mechanisms at work. However, raising the PaCO2 by inhaled CO2 or increasing dead space was sufficient to nearly eradicate central apneas in a group of patients

Santral Uyku Apne Sendromları Primer Santral Uyku Apnesi Medikal Sorunlara bağlı diğer Santral Uyku Apnesi  Cheyne-Stokes Solunumuna bağlı santral uyku apnesi  Yüksek irtifada periyodik solunuma bağlı santral uyku apnesi  Cheyne-Stokes ya da Yüksek İrtifa dışındaki hastalıklara bağlı santral uyku apnesi  İlaçlara bağlı santral uyku apne  Çocukluk çağı primer santral uyku apnesi Polysomnographically, central apneic events are typically seen during NREM sleep, probably because the reduction in CO2 sensitivity during REM sleep [13] renders the ventilatory response less capable of crossing the apneic threshold. SA’ler ani olarak biter ve ventilasyonda kademeli artış olmaz. Given the uncommon occurrence of CSA, its epidemiology is not well described. Most, but not all [34] studies suggest a middle to older age male predominance. Evidence for heritability of chemosensitivity in other clinical settings, such as chronic obstructive pulmonary disease (COPD) and neuromuscular disease [36], suggests a possible familial role in CSA, although this has not been confirmed. Dominant clinical features of CSA include fragmented sleep with frequent awakenings which may lead to daytime hypersomnolence. Insomnia is often reported, and it is possible that each condition feeds the other, as the apneic threshold is frequently violated during wake-sleep transitions.

Santral Uyku Apne Sendromları Primer Santral Uyku Apnesi Medikal Sorunlara bağlı diğer Santral Uyku Apnesi  Cheyne-Stokes Solunumuna bağlı santral uyku apnesi  Yüksek irtifada periyodik solunuma bağlı santral uyku apnesi  Cheyne-Stokes ya da Yüksek İrtifa dışındaki hastalıklara bağlı santral uyku apnesi  İlaçlara bağlı santral uyku apne  Çocukluk çağı primer santral uyku apnesi İdiyopatik CSAS’de tedavi, gündüz aşırı uyku hali, huzursuz uyku, sabah baş ağrıları, horlama veya insomni yakınmaları söz konusu olduğunda gündeme gelir. Nadir bir hastalık olduğu için tedavisi ile ilgili yapılmış çalışma da azdır. İdiyopatik CSAS’de nadiren hipoksemi vardır. Hipoksemi varlığında yüksek irtifaya bağlı periyodik solunumda olduğu gibi oksijen tedavisi verilir ama her zaman iyi yanıt alınamaz. Santral apnelerin nedeni PaCO2 değerinin apne eşiğinin altında kalması olduğu için CO2 inhalasyonu ile PaCO2’yi yükseltmek teorik olarak anlamlıdır. CO2 ile zenginleştirilmiş hava vermek güvenli olmadığı için ölü boşluk hacmini arttıran maske kullanılması tercih edilir. Bu yöntemlerle PaCO2’nin 1-3 mmHg arttırılması santral uyku apnesi engellemeye yeter. Ancak PaCO2’yi arttırmak solunumu ve solunum çabasını arttırmak anlamına gelir ki zaten hiperventile olan hasta için oldukça yorucudur. Santral uyku apne sendromunda solunum stimülanları da kullanılabilir. Asetazolamid, bir karbonik anhidraz inhibitörüdür ve santral solunum merkezinde metabolik asidoz oluşturarak solunumu stimüle eder. Santral apneler üzerine etkisi konusunda çelişkili çalışmalar bulunmaktadır. Bir haftalık tedavi ile santral apnelerin %70 oranında azaldığı ve gün içi semptomların düzeldiği gösterilmiştir. Bir ayda santral apnelerin %70 azaldığını ama obstrüktif olayların değişmediğini gösteren çalışmalar da vardır. Ancak uzun dönem kullanımı sakıncalıdır. As there are no high level clinical trials comparing treatment options and efficacy in CSA, the literature has been largely based upon clinical case reports or series. That said, there appears to be a number of viable treatment options for the CSA patient suffering from sleep disruption and/or CPAP been shown to be effective in some patients with CSA [29,30]. Given the pathophysiologic similarities between CSA and OSA previously outlined and evidence for dysfunctional upper airway mechanics in CSA, this finding is not surprising, although the effects of CPAP may be independent of upper airway closure and more related to influences on ventilatory drive. Furthermore, since OSA and CSA often co-exist, a trial of CPAP seems warranted in many instances, particularly in the somnolent, obese, and/or snoring patient with central apneas on PSG. Very limited data suggest that supplemental oxygen may be effective in reducing central apneic events in CSA [38], although possibly at the risk of increasing the frequency of obstructive apneas in those with mixed disease [39]. Its mechanism of action is not completely clear but it probably acts to suppress ventilatory drive and hyperventilation, thus moving the PaCO2 away from the apneic threshold. The efficacy of acetazolamide in CSA has also been reported in two studies with treatment duration of 7–30 days [40, 41]. This carbonic anhydrase inhibitor is believed to act by inducing a mild metabolic acidosis, resulting in a widened gap between the prevailing PaCO2 and the PaCO2 associated with the apneic threshold [42]. A third study described emergence of obstructive apneas following acetazolamide therapy for mixed sleep apnea CSA [43], a finding possibly explained by heightened respiratory muscle force in response to metabolic acidosis, resulting in more negative upper airway intralumenal pressures. CPAP’ın daha çok farengeal kollapsa bağlı reflekslerin yol açtığı santral uyku apnelerini ortadan kaldırdığı bilinmektedir. Arousal ve hiperventilasyonu tetikleyen ÜSY kollapsını engeller.

Primer Santral Uyku Apnesi Medikal Sorunlara bağlı diğer Santral Uyku Apnesi  Cheyne-Stokes Solunumuna bağlı santral uyku apnesi  Yüksek irtifada periyodik solunuma bağlı santral uyku apnesi  Cheyne-Stokes ya da Yüksek İrtifa dışındaki hastalıklara bağlı santral uyku apnesi  İlaçlara bağlı santral uyku apne  Çocukluk çağı primer santral uyku apnesi

Cheyne- Stokes Solunumu (CSR); 1818’de John Cheyne, sonra 1854’de William Stokes tarafından kalp ve/veya nörolojik hastalığı olanlarda tanımlanmış Periyodik bir solunum paternidir. Tidal volümün kreşendo- dekreşendo tarzında artıp azalması ve arada oluşan santral apneler ile karakterizedir CSR is a form of periodic breathing in which, according to the original description by Cheyne, the ventilatory period is characterized by a prolonged waxing waning pattern of tidal volume followed by central apnea or hypopnea. It is noteworthy that the patient in whom Cheyne first described this breathing disorder suffered from HF, atrial fibrillation, and a stroke, and undoubtedly had a low cardiac output and prolonged circulation time. CSA-CSR, an increasingly common form of SDB most often encountered in the setting of HF, is a breathing pattern characterized by crescendo-decrescendo tidal volumes with intervening central apneas. This waxing and waning pattern has also been referred to as periodic breathing. In contrast to OSA, where arousals typically occur with apnea termination, arousals from sleep in CSA-CSR tend to occur at the height of the hyperpneic phase following apnea. Considering this propensity for sleep disruption, it is not clear why daytime symptoms in CSA-CSR may not be as prominent as in OSA .CSA-CSR in HF has been associated with increased mortality .The severity of CSA is thought to be, to some extent, a reflection of underlying cardiac dysfunction, which could partially explain the mortality association.

Cheyne- Stokes Solunumu (CSR); The characteristic waxing and waning pattern of alternating apneas and hyperpneas in CSA-CSR is readily recognized on PSG. The cycle length, found to approximate 60 s, is significantly longer than those encountered in primary CSA ,and appears to correlate with circulatory delay. The 1999 Guidelines require 5 or more central apneas or hypopneas per hour of sleep as well as at least 10 consecutive minutes of cyclic crescendo and decrescendo changes in breathing amplitude. There are scant outcome data upon which to base severity criteria in CSA-CSR. Reported variables include the central apnea index ,the central AHI, and the quantity or percentage of sleep time with periodic breathing. Lanfranchi et al. found prognostic significance in the central AHI but not in the percentage of sleep time spent with periodic breathing. Son yayınlarda periyodik solunum prevalansının iskemik kalp hastalıklarında maksimum ejeksiyon fraksiyonu %40 olan ve optimal medikal tedavi alan hastalarda %45-50 olduğu bildirilmektedir. Erkeklerde kadınlara göre ve ileri yaşta daha sık görülür. CSR can be observed both during sleep and wakefulness, although it appears to be far more common during sleep. When it occurs during sleep, it is simply a form of CSA with a prolonged hyperpnea. When specifying the occurrence of CSR during sleep, we have used the term ‘‘Cheyne-Stokes respiration with central sleep apnea (CSR-CSA).’’ This term also connotes CSA in the presence of a low cardiac output state. In general, the use of the term ‘‘CSA’’ in patients with HF is synonymous with CSR or CSR-CSA.

Cheyne- Stokes Solunum Skorlanma
Solunum amplitüdünde kreşendo ve dekreşendo gösteren en az 3 adet birbirini takip eden siklus bulunması ve aşağıdakilerden en az birinin olması 1) Uyku saati başına 5 ve üzerinde santral apne-hipopne olması 2) Kreşendo-dekreşendo siklusunun en az 10 dakikalık bir süre içinde izlenmesi

ICSD-2 sınıflaması CSR Cheyne- Stokes Solunumu (CSR);
KKY’li olguların (EF<%40) %45-50’sinde (+) Erkeklerde & ileri yaşta daha sık Cheyne- Stokes Solunumu (CSR); .

ICSD-2 sınıflaması CSR-CSA
KKY’li olguların (EF<%40) %45-50’sinde (+) Erkeklerde & ileri yaşta daha sık Cheyne- Stokes Solunumu (CSR); CSR uyanıklıkta ve egzersizde de görülebilir (kötü prognoz)

CSR-CSA (+) olanlarda; EF daha düşük Kardiyak aritmi prevalansı yüksek Prognoz kötü ve mortalite yüksektir Cheyne-Stokes solunumu ve CSAS olan KKY’lilerde sol ventrikül ejeksiyon fraksiyonu daha düşük ve kardiyak aritmi prevalansı daha yüksektir. Prognoz daha kötü, mortalite daha yüksektir. CSS-CSAS’li KKY’lilerde mortalitenin yüksek olmasının nedeni santral uyku apnelerine bağlı olarak artmış sempatik aktivite, düşük kalp atımı, düşük barorefleks sensitivitesidir. Apneye bağlı hipoksi ve arousal, sempatik aktivite artışına yol açar. Sempatik aktivite artınca, dolaşımda katekolaminler artar ve bunlar kardiyotoksik etki yapar. Sonuçta kalp yetmezliği ağırlaşır, noktürnal kan basıncı artar, kardiyak iskemi oluşur ve mortalite yükselir

Santral apnelere bağlı, Artmış sempatik aktivite Düşük kalp atımı Düşük barorefleks sensitivitesi CSR-CSA (+) olanlarda; EF daha düşük Kardiyak aritmi prevalansı yüksek Prognoz kötü ve mortalite yüksektir

Santral apnelere bağlı, Artmış sempatik aktivite Düşük kalp atımı Düşük barorefleks sensitivitesi CSR-CSA (+) olanlarda; EF daha düşük Kardiyak aritmi prevalansı yüksek Prognoz kötü ve mortalite yüksektir Sonuçta; KY ağırlaşır Noktürnal kan basıncı artar Kardiyak iskemi oluşur

Polysomnographic recordings demonstrating differences in periodic breathing patterns between a patient with and without heart failure (HF). The upper panel shows a recording from a patient with idiopathic central sleep apnea (ICSA) during stage 2 sleep. Apnea length (AB) is 18 seconds, hyperpnea length (BD) is 7 seconds, and cycle length (AD) is 25 seconds. C represents the nadir of SaO2 (arterial oxygen saturation), detected by an oximeter placed on the ear in close proximity to the carotid body chemoreceptors. From the end of apnea (B) to the nadir in SaO2 (C) is the lung-to-ear circulation time (BC), which is 8 seconds and approximates lung-to carotid body circulation time. The lower panel is a recording from a patient with HF and Cheyne-Stokes respiration with central sleep apnea (CSR-CSA) during stage 2 sleep. Compared with the patient with ICSA, lung-to-ear circulation time (BC 5 26 s), hyperpnea (BD 5 46 s), and cycle lengths (AD 65 s) are substantially longer. However, apnea length (AB 5 21 s) is similar. In patients with HF and CSR, the periodic cycle duration averaged approximately 60 seconds, similar to that described by Cheyne, compared with only 35 seconds in patients with idiopathic CSA or high-altitude periodic breathing without HF (18, 28). Thus it is the presence of a prolonged hyperpnea with a waxing-waning pattern of tidal volume, and prolonged cycle duration, that distinguishes CSR from other forms of periodic breathing. Therefore, if the term ‘‘Cheyne-Stokes respiration’’ is to have any distinctive meaning, its use should be confined to periodic breathing in which the hyperpnea and cycle durations are prolonged. Since this pattern is characteristic of prolonged lung to chemoreceptor circulation time, it appears to be a manifestation of a low cardiac output as one would observe in patients with HF or bradyarrhythmias. CSR İdiopatik CSA HABD Periyodik siklus süresi 60 sn ~ 35 sn

The characteristic waxing and waning pattern of alternating apneas and hyperpneas in CSA-CSR is readily recognized on PSG (fig. 2). The cycle length, found to approximate 60 s, is significantly longer than those encountered in primary CSA [50], and appears to correlate with circulatory delay. The 1999 Guidelines require 5 or more central apneas or hypopneas per hour of sleep as well as at least 10 consecutive minutes of cyclic crescendo and decrescendo changes in breathing amplitude [1]. There are scant outcome data upon which to base severity criteria in CSA-CSR. Reported variables include the central apnea index [51], the central AHI, and the quantity or percentage of sleep time with periodic breathing [47]. Lanfranchi et al. [47] found prognostic significance in the central AHI but not in the percentage of sleep time spent with periodic breathing

It has subsequently been shown that the number of breaths in, and duration of, hyperpnea are directly proportional to the lung to peripheral chemoreceptor circulation time, and inversely proportional to cardiac output (18, 28, 29). In contrast, apnea duration bears no relation to circulation time or cardiac output.

Klinik (Fragmente uyku) GAUH Yorgunluk

KY’de CSR-CSA Mekanizmaları
Solunum instabilitesi: Solunum merkezinin stimülasyonu ve inhibisyonu arasındaki dengenin bozulması solunumu instabilleştirmektedir.Yüksek ventilatuar kontrol, apne eşiği ile ökapnik PaCO2 arasında çok küçük fark olması, arteryel kan gazı ve solunum kontrolleri arasında uyumsuzluğa yol açan uzamış dolaşım zamanı ve CO2’ye verilen bozulmuş serebrovasküler yanıt, CSS olan hastalardaki stabil olmayan solunumun başlıca nedenleridir. CSR-CSA in patients with HF arises because of respiratory control system instability. Ventilation is dependent mainly on the metabolic rather than the behavioral respiratory control system during sleep, and the primary stimulation for ventilation while asleep is PaCO2. Central apnea during sleep occurs when PaCO2 falls below the apnea threshold. CSR-CSA is present when central apnea occurs cyclically. Several factors that destabilize the respiratory control system predispose to the development of CSR-CSA. This illustrates the proposed mechanisms leading to periodic oscillations in ventilation in HF. A key factor predisposing to respiratory control system instability and CSR-CSA is chronic hyperventilation with eupneic PaCO2 close to the apnea threshold. Patients with HF with CSRCSA have lower PaCO2 than those without CSR-CSA in both the waking and sleeping states. This chronic hyperventilation occurs because of pulmonary vagal irritant receptor stimulation by pulmonary congestion and increases in central and peripheral chemosensitivity. Pulmonary congestion activates pulmonary vagal afferent C fibers, which stimulate central respiratory drive. Compared with patients with HF without CSR-CSA, those with CSR-CSA have significantly higher pulmonary capillary wedge pressures, and presumably, more pulmonary congestion. Indeed, in patients with HF, PaCO2 is inversely proportional to pulmonary capillary wedge pressure. Lowering wedge pressure with drugs or CPAP is associated with a rise in PaCO2 and alleviation of CSRCSA. Compared with patients with HF without CSRCSA, those with CSR-CSA have increased peripheral and central chemoresponsiveness that promotes hyperventilation and hypocapnia. While the reason for this increased chemoresponsiveness is not well understood, there is evidence that induction of HF in experimental animals augments peripheral chemoresponsiveness, but the mechanism for the effect is poorly understood. CSR occurs more frequently during NREM sleep than either wakefulness or REMsleep. In NREM sleep, ventilation is predominantly under metabolic control, and therefore is very tightly linked to alterations in PaCO2, the apneic threshold for PaCO2, and CO2 sensitivity. Owing to a reduction in central respiratory drive and the loss of the nonchemical wakefulness drive to breath that maintains ventilation even when PaCO2 falls below the apnea threshold, breathing becomes critically dependent on the metabolic control system during NREM sleep. Ventilation therefore decreases, and PaCO2 and the apneic PaCO2 threshold increase during the transition from wakefulness to NREM sleep. As long as PaCO2 remains greater than the apneic threshold, rhythmic breathing continues. However, in patients with HF with CSR-CSA, PaCO2 tends not to increase from wakefulness to sleep, but the apneic threshold does. This predisposes to central apnea in two ways. First, if prevailing PaCO2 remains below the new, higher apnea threshold at the onset of sleep, central apnea will ensue. PaCO2 will rise during apnea, and once it reaches the ventilatory threshold for NREM sleep, ventilation will resume. Second, even if PaCO2 does not remain below the higher apnea threshold of NREM sleep, it will be closer to this apnea threshold than during wakefulness. During NREM sleep, episodes of central apnea are most frequently triggered by abrupt increases in ventilation and reduction in PaCO2, usually precipitated by spontaneous arousals from sleep (33). The closer the prevailing PaCO2 is to the apnea threshold, the more likely it is that central apnea will occur in response to a given increase in ventilation. The critical role of hypocapnia in triggering central apneas is demonstrated by the observation that raising PaCO2 by inhalation of a CO2-enriched gas abolishes CSR-CSA instantaneously. While in OSA arousals act as a defense mechanism to terminate apneas, and activate pharyngeal muscles that allow resumption of airflow, in CSA they appear to instigate central apneas by provoking ventilatory overshoot. The important role of arousal in sustaining ventilatory overshoot during periodic breathing is indicated by the strong correlation between the magnitude of arousal, and both ventilation during hyperpnea and subsequent apnea duration (31, 33, 44). Increases in ventilation in response to arousals occur due to both nonchemical and chemical factors. The abrupt change in state elicits reinstitution of the nonchemical, waking neurogenic drive to breathe. In addition, the change in state causes a sudden increase in chemical respiratory drive, and reversion to the lower PaCO2 setpoint of wakefulness. Since PaCO2 has risen during NREM, following arousal, it is higher than the wakefulness set-point. This, combined with the greater ventilatory responsiveness of wakefulness, causes the respiratory control system to quickly augment ventilation to lower PaCO2 to the wakefulness set-point. If there is an abnormally high sensitivity to PaCO2, which is characteristic of patients with HF with CSR-CSA, ventilatory overshoot occurs, which drives PaCO2 down below the set-point. If the patient then returns to NREM sleep, PaCO2 is now below the higher apnea threshold, and central apnea occurs. Recurrent arousals during the ventilatory phase of CSR-CSA propagate CSR-CSA. However, if recurrent arousals do not occur during the ventilatory phase, ventilatory overshoot is dampened, respiration stabilizes and CSR-CSA resolves. This latter observation indicates that arousals seem not to play a critical role in resumption of normal ventilation following central events. This sequence of events illustrates how shifts in state of consciousness, either due to transition from wakefulness to NREM sleep, or to spontaneous arousals from sleep, destabilize the respiratory control system and facilitate the development of central apneas and periodic breathing. Because CSR-CSA is a consequence of instability of the respiratory metabolic control system, it occurs mainly during NREM sleep when breathing is predominantly under metabolic control. In contrast, CSR occurs much less frequently in wakefulness where breathing is less dependent on the metabolic control system, and where the nonchemical wakefulness drive to breath stabilizes breathing . Similarly, CSR-CSA is much less common in REM sleep than in NREM sleep for several reasons. First, ventilation is under predominantly behavioral rather than metabolic control, such that it is insensitive to changes in PaCO2. Second, respiratory drive and muscle activity are reduced in REM sleep, such that PaCO2 rises above NREM levels and the difference between prevailing PaCO2 and the apnea threshold increases. Third, arousability to chemical respiratory stimuli is diminished compared with NREM sleep, and this, combined with weakness of the respiratory muscles, diminishes the likelihood of ventilatory overshoot and hypocapnia. Abnormalities of cerebrovascular reactivity to CO2 in patients with HF may also contribute to respiratory instability. Normal reflex changes in cerebrovascular blood flow provides an important counterregulatory mechanism that serves to minimize the change in hydrogen ion concentration ([H1]) at the central chemoreceptor, thereby stabilizing the breathing pattern in the face of perturbations in PaCO2. For example, arterial hypocapnia normally causes marked cerebral vasoconstriction and reduced cerebral blood flow, which attenuates the decrease in brain PaCO2 relative to that in the arterial blood. Accordingly, ventilatory inhibition in response to reduced arterial PaCO2 will be diminished due to the attenuated decrease in central chemoreceptor [H1]. Compared with patients with HF without CSRCSA, those with CSR-CSA have impaired cerebral blood flow responses to CO2, such that the fall in flow for a given decrease in arterial PaCO2 is reduced. This permits a greater reduction in brain PaCO2 and [H1]. The chemoreceptors will then be exposed to a greater degree of alkalosis than normal, with a consequent greater tendency to develop ventilatory undershoot, and hence, central apnea (48). An impaired vasodilator response to increasing arterial PaCO2 during apnea will have the opposite effect and hence promote ventilatory overshoot at apnea termination (48). Accordingly, compromised cerebrovascular blood flow responsiveness to CO2 may contribute to breathing instabilities during NREM sleep, and predispose to CSR-CSA. Several additional factors, such as metabolic alkalosis, low functional residual capacity, upper airway instability, and hypoxia, may further contribute to respiratory instability and CSRCSA. Metabolic alkalosis resulting from diuretic use in patients with HF could cause a decrease in the gap between prevailing and apneic threshold PaCO2. In sleeping dogs, metabolic alkalosis increases the apnea threshold to a greater degree than it increases eupneic PaCO2.As a result, dogs are more susceptible to periodic breathing during metabolic alkalosis (50). Indeed, Javaheri (51) showed in humans with HF that CSR-CSA improved in response to induction of metabolic acidosis by administration of acetazolamide even though it reduced PaCO2. Induction of metabolic acidosis therefore provides a constant drive to breathe through production of H1, and emphasizes that the effects of PaCO2 on ventilatory drive occur secondary to its effects on hydrogen ion concentration and pH. In the case of acetazolamide, the increased hydrogen ion concentration reduces prevailing pH and widens the gap between it and the higher pH threshold for apnea, and thus stabilizes breathing (49). Another way to look at this is that acetazolamide decreases prevailing PaCO2 to a lesser extent than it decreases the apnea threshold for PaCO2, and thus widens the difference between the two. Thus, in the genesis of CSR-CSA, a reduced difference between prevailing PaCO2 and apnea threshold for PaCO2 is more important than the prevailing PaCO2 itself. In any case, diuretic-induced metabolic alkalosis may facilitate CSR-CSA in a substantial number of patients, since a recent study by Milionis and coworkers demonstrated that 25% of patients with HF had metabolic alkalosis, either alone or with coexisting respiratory alkalosis. Patients with HF may have reduced functional residual capacity for several reasons, including cardiomegaly, pleural effusion, and pulmonary edema. Large functional residual capacity acts as anO2 and CO2 reservoir that dampens oscillations in PaO2 and PaCO2 that occur during apneas (53, 54), and therefore tends to stabilize respiration. A reduction in functional residual capacity reduces lung O2 and CO2 reservoirs such that, for a given apnea duration, the fall in PaO2 and rise in PaCO2 will be greater than they would if functional residual capacity was normal. This could contribute to post apneic ventilatory overshoot and instability of the respiratory control system. However, Naughton and colleagues (33) reported that lung volume in stable ambulatory patients with HF with CSR-CSA does not differ from that in patients without it. Thus, the role of reduced lung volume in the pathogenesis of CSR-CSA remains unclear. Upper airway instability may also play a role in the pathogenesis of CSR-CSA. Alex and coworkers (55) described upper airway occlusion at the onset and end of some central apneas in selected patients with HF. If upper airway resistance increases as ventilation decreases during the decrescendo phase of the hyperpneic segment of CSR-CSA, ventilatory undershoot is more likely to occur. The occasional occluded breath noted at the onset of central apnea during CSR-CSA is compatible with this (55). However, a decrease in resistance as ventilation increases during the crescendo phase of hyperpnea could facilitate ventilatory overshoot, making post-hyperventilation apnea more likely to occur. In addition, upper airway collapse itself may precipitate central apnea reflexively (56). Passive collapse of the upper airway after the onset of central apnea could also play a role in the pathogenesis of mixed apneas (57), such that once chemical drive increases above the apnea threshold, inspiratory efforts are then generated against an occluded pharynx. Therefore, one potential mechanism through which CPAP may attenuate CSR-CSA is by stabilizing the upper airway. However, CPAP exerts many other effects that could dampen periodic breathing, such as lung inflation, augmentation of cardiac output, and reductions in LV filling pressure and pulmonary edema (61). Hypoxia precipitates CSA at high altitude by causing hyperventilation and lowering PaCO2 below the apnea threshold (62). High-altitude periodic breathing can be abolished either byadministration of supplemental O2 or CO2 (62). However, patients with HF with CSR-CSA are generally not hypoxic, so that hypoxia is unlikely to be a primary cause of CSR-CSA in most. Nevertheless, hypoxic dips during apneas could accentuate the tendency to hyperventilate upon central apnea termination by amplifying the ventilatory overshoot in response to CO2 when PaCO2 increases above the ventilatory threshold (45). Ventilatory overshoot with propagation of CSR-CSA may therefore be facilitated by even mild apnea-related hypoxia. Several studies investigated the effects of supplemental oxygen in patients with HF and CSR-CSA (63–67). All consistently found small but significant reductions in the AHI. These data support the hypothesis that hypoxia plays a role in aggravating CSRCSA, but that it is not the major determinant of its development in patients with HF. Prolongation of circulation time secondary to reduced cardiac output with delayed transmission of alteration in arterial blood gas tensions from the lung to the peripheral and central chemoreceptors could theoretically contribute to the pathogenesis of CSR-CSA by facilitating ventilatory overshoot and undershoot. CSR-CSA was induced only when the lung to carotid body circulation time exceeded 1 minute, which was far greater than described in patients with HF. In addition, several studies have shown that cardiac output, LV ejection fraction (LVEF) and lung to chemoreceptor circulation time do not differ between patients with HF with and without CSR-CSA . Consequently, prolonged circulation time appears not to play a key role in initiating CSR-CSA in most patients with HF. Rather, its major influence appears to be on the durations of the hyperpneic phase and of the total periodic breathing cycle. Following central apnea, the length of the subsequent ventilatory phase is directly proportional to the lung to peripheral chemoreceptor circulation time and inversely proportional to cardiac output (28). Since the alteration in arterial blood gas tensions that occur in the pulmonary circulation in response to changes in ventilation arrive via the systemic arterial circulation in a graded fashion, once PaCO2 has risen above the apnea threshold, increases in tidal volumes and ventilation occur, gradually reaching a peak only several breaths after apnea termination. Similarly, as PaCO2 falls in response to the gradual increase in the preceding ventilation, tidal volumes diminish gradually until apnea ensues once PaCO2 has fallen below threshold. Thus, the prolonged transit time from the lungs to the chemoreceptors sculpts the classic crescendo-decrescendo pattern of tidal volumes during hyperpnea. However, apnea length appears not to be affected by prolonged circulation time, but rather is proportional to the preceding decrease in PaCO2 (28, 69). As shown in Figure 2, compared with patients with CSA but without HF, patients with HF and CSR-CSA have much longer hyperpnea with more gradual increases and decreases in tidal volume, but similar apnea duration (18, 28). Thus, differences in the total cycle duration of periodic breathing between patients with and without Fare primarily modulated by differences in hyperpnea, but not apnea duration. *Yumino D, Bradley TD Proc Am Thorac Soc 2008

KY’li Hastalarda CSR-CSA için Risk Faktörleri
İleri yaş (>60) Erkek cinsiyet Uyanıklık hipokapnisi (≤38 mmHg) With regard to risk factors for CSR-CSA, this was assessed in 450 patients with HF (382 men, 68 women) referred to a sleep laboratory because of a suspicion of sleep apnea, or because of HF refractory to therapy (14). Because this was a sleep clinic population, the prevalence of CSR-CSA may not have been representative of its prevalence in the general population with HF. Nevertheless, the prevalences of CSR-CSA at an AHI cutoff of greater than or equal to 10 (33%) and greater than or equal to 15 (29%) were similar to those reported in the epidemiologic cohort of Wang and coworkers (73) from the same laboratory 10 years later. Factors associated independently with the presence of CSR-CSA (with an AHI > 10) were older age (. 60 years), male sex, awake hypocapnia (PaCO2 < 38 mm Hg), and atrial fibrillation, but not LVEF. CSR-CSA varlığı

İleri yaş (>60) Erkek cinsiyet Uyanıklık hipokapnisi (≤38 mmHg) In the smaller studies in which cardiac and respiratory function were assessed in greater detail, the presence of CSR-CSA was associated with higher pulmonary capillary wedge pressure (35), and LV end-diastolic volume (29), and with greater peripheral and central chemosensitivity to CO2 (39) than in patients with HF without CSRCSA. CSR-CSA was also associated with induction of periodic breathing during exercise testing (2). CSR-CSA varlığı Yüksek PCWP Yüksek LV end-diastolik volümü Yüksek periferal ve santral kemoreseptör sensitivitesi

İleri yaş (>60) Erkek cinsiyet Uyanıklık hipokapnisi (≤38 mmHg) However, neither cardiac output nor LVEF differed between those with and without CSR-CSA. Taken together, these data indicate that the key clinically identifiable risk factors for CSR-CSA in patients with HF are older age, male sex, hypocapnia and factors that could contribute to hypocapnia such as elevated LV filling pressure and LV end-diastolic volume, atrial fibrillation, and increased chemosensitivity. However, lower LVEF and cardiac output have not been identified as independent risk factor for CSRCSA in patients with systolic HF. The reason why men are at higher risk for CSR-CSA remains to be elucidated. CSR-CSA varlığı Yüksek PCP Yüksek LV end-diastolik volümü Yüksek periferal ve santral kemoreseptör sensitivitesi LVEF

CSR-CSA’nın KV Etkileri
KY’li hastalarda PSG ile CSR-CSA %30-50 (+) CSR-CSA  KY’ne sekonder olarak ortaya çıkar, ancak bir kez başladıktan sonra kısır bir döngüyle KV fonksiyonlarda kötüleşmeye neden olur. CSR-CSA;  Basitçe bir sonuç mu?  Sorunlu olan myokard üzerinde bağımsız patolojik etkileri mi var? Although CSR-CSA appears to arise secondary to HF, once initiated it may participate in a pathophysiologic vicious cycle that contributes to deterioration in cardiovascular function. However, currently debated is whether CSR-CSA is simply a reflection of severely compromised cardiac function with elevated LV filling pressure (35), or whether CSR-CSA exerts unique and independent pathologic effects on the failing myocardium. Regardless of its etiology, there is evidence that CSR-CSA may have detrimental physiologic effects on the failing heart.

CSR-CSA  KY’ne sekonder olarak ortaya çıkar, ancak bir kez başladıktan sonra kısır bir döngüyle KV fonksiyonlarda kötüleşmeye neden olur. CSR-CSA;  Basitçe bir sonuç mu?  Sorunlu olan myokard üzerinde bağımsız patolojik etkileri mi var? Etyolojisinden bağımsız olarak  KY’i üzerinde zararlı etkileri (+)

Santral Apne Apne ilişkili hipoksi + PaC02’de Postapneik arousal Pulmoner gerim recp deaktive Santral sempatik sistem deşarjında disinhibe During central apnea, the absence of lung inflation deactivates pulmonary stretch receptors, and disinhibits central sympathetic nervous system outflow. This effect summates with apnea-related hypoxia and rises in PaCO2, and with post-apneic arousals to cause cyclical surges in sympathetic nervous system activity (SNA) in synchrony with the ventilatory oscillations of CSR-CSA (77). Ventilasyon ossilasyonu ile birlikte SNA’da siklik aktivasyon

As a consequence, blood pressure and heart rate oscillate in concert with Cheyne-Stokes cycles, very much as they do during OSA; peaks occur during hyperpneas and dips during apneas (66, 78). These effects cause a generalized increase in sympathetic activity manifest by higher overnight urinary norepinephrine concentration in patients with HF with than in those without CSR-CSA (77). However, Franklin and coworkers (66) and Leung and colleagues (79) found that administration of low flow oxygen at a rate sufficient to just abolish dips in SaO2, but not to eliminate CSR-CSA or fluctuations in PaCO2, did not influence blood pressure or heart rate oscillations during CSR-CSA. These data indicate that mechanisms other than hypoxic dips are involved in precipitating these surges in blood pressure and heart rate during CSR-CSA. Since there are direct connections between respiratory and cardiovascular sympathetic neurons in the brainstem, it is possible that these cardiovascular oscillations are driven by oscillations in outflow from central respiratory to cardiovascular sympathetic neurons (80).

CSR-CSA Tedavi I- Altta yatan kardiyak hastalığın optimal tedavisi
 Diüretik (PCWP’nı azaltarak, met alkaloza !!!)  ACE inhibitörleri (AHI ve NOD azaltır)  Beta-blokör (sempatik aktivasyon) II- C02 inhalasyonu III- Oksijen tedavisi IV- Solunum stimülanları (Asetazolamid,teofilin,…) V- NIMV Tüm bu ilaçlar ile CSA-CSR azalır ama, bu yöntemleri destekleyen ya da çürüten yeterli delil yok Tdv ile ilgili olarak randomize çalışmalar yok. Kimin tedavi edilmesi gerektiği ve optimal bir tdv stratejisi üzerinde bir konsensus yok. Diüretikler metabolik alkaloza yol açarak  kompansatuar hiperkapni yapar ve çevre PaC02 ile eşik PaC02 arasındaki farkın azalmasına neden olur

 Diüretik (PCWP’nı azaltarak, met alkaloza !!!)  ACE inhibitörleri (AHI ve NOD azaltır)  Beta-blokör (sempatik aktivasyon) II- C02 inhalasyonu III- Oksijen tedavisi IV- Solunum stimülanları (Asetazolamid,teofilin,…) V- NIMV Ölü boşluğu arttırarak veya CO2 solutarak, PaCO2 yi 1-3 mmHg arttırmak, Santral apneleri ortadan kaldırabilir Santral apnelerdeki belirgin azalmaya karşın; CO2 in artırılmasının uyku kalitesini düzeltmediği arousal indeksini düşürmediği belirgin sempatik eksitasyona yol açabileceği ve dakika ventilasyonunu arttırıp solunum kaslarında yorulma ile asidoza neden olabileceği bildirilmiştir

Hipoksi  hiperventilasyona yol açar. Hiperventilasyon  hipokapni ve intrapulmoner vagal recp’ler üzerinden solunum sıklığını azaltarak  SA oluşturur I- Altta yatan kardiyak hastalığın optimal tedavisi  Diüretik (PCWP’nı azaltarak, met alkaloza !!!)  ACE inhibitörleri (AHI ve NOD azaltır)  Beta-blokör (sempatik aktivasyon) II- C02 inhalasyonu III- Oksijen tedavisi IV- Solunum stimülanları (Asetazolamid,teofilin,…) V- NIMV Oksijen sık kullanılıyor, faydalı olduğu gösterilmiş, özellikle de yüksek flowlarda AHI’ni %50 oranında azalttığı gösterilmiş.. Ancak, yüksek flowda zararlı etkileri (+) Although the mechanism by which oxygen administration reduces central apneas has not yet been established, two explanations seem possible. One relates to the potential destabilizing influence of the hypoxic ventilatory response on respiratory control. As at altitude, an individual with hypoxia will hyperventilate, yielding hypocapnia and alkalosis. As previously stated, hypocapnia may inhibit respiration during sleep. Thus, cycling ventilation may develop, with central apneas occurring at the nadir of this periodic breathing. With the administration of oxygen, the hypoxic influence on ventilation may be reduced and breathing regularized. The other possible explanation relates to the fact that hypoxia can be a ventilatory depressant. If respiration is depressed by hypoxia, then central apneas may occur. Oxygen administration in this situation could reduce apneas. Regardless of the mechanism, low-flow oxygen may be an effective treatment for central sleep apnea.

 Diüretik (PCWP’nı azaltarak, met alkaloza !!!)  ACE inhibitörleri (AHI ve NOD azaltır)  Beta-blokör (sempatik aktivasyon) II- C02 inhalasyonu III- Oksijen tedavisi IV- Solunum stimülanları (Asetazolamid,teofilin,…) V- NIMV Hipoksi  hiperventilasyona yol açar. Hiperventilasyon  hipokapni ve intrapulmoner vagal recp’ler üzerinden solunum sıklığını azaltarak  SA oluşturur Oksijen sık kullanılıyor, faydalı olduğu gösterilmiş, özellikle de yüksek flowlarda AHI’ni %50 oranında azalttığı gösterilmiş.. Ancak, yüksek flowda zararlı etkileri (+) Although the mechanism by which oxygen administration reduces central apneas has not yet been established, two explanations seem possible. One relates to the potential destabilizing influence of the hypoxic ventilatory response on respiratory control. As at altitude, an individual with hypoxia will hyperventilate, yielding hypocapnia and alkalosis. As previously stated, hypocapnia may inhibit respiration during sleep. Thus, cycling ventilation may develop, with central apneas occurring at the nadir of this periodic breathing. With the administration of oxygen, the hypoxic influence on ventilation may be reduced and breathing regularized. The other possible explanation relates to the fact that hypoxia can be a ventilatory depressant. If respiration is depressed by hypoxia, then central apneas may occur. Oxygen administration in this situation could reduce apneas. Regardless of the mechanism, low-flow oxygen may be an effective treatment for central sleep apnea. Hipoksi solunumu deprese edebilir

 Diüretik (PCWP’nı azaltarak, met alkaloza !!!)  ACE inhibitörleri (AHI ve NOD azaltır)  Beta-blokör (sempatik aktivasyon) II- C02 inhalasyonu III- Oksijen tedavisi IV- Solunum stimülanları (Asetazolamid,teofilin,…) V- NIMV

CSR-CSA Tedavisinde NIMV
CPAP NOD SNA’da Naughton et al;Sempatik aktivitede azalma ile LVEF’da artmaya neden olduğu gösterilmiş. Ancak, CPAP’ın yararlı etkilerini nasıl gösterdiği tam olarak anlaşılamamıştır. Nasal CPAP has been shown to be an effective therapy for some patients with central sleep apnea.41,42 These patients probably fall into several groups. First, as stated previously, pharyngeal airway collapse or closure during sleep may initiate a reflex inhibition of ventilation in some patients and therefore a central apnea. With nasal CPAP, airway closure is prevented, and such apneas abolished. In obese, snoring patients in whom predominantly central apneas are observed, nasal CPAP may be an effective form of therapy. Second, an abstract suggests that CPAP may also be a viable form of therapy in idiopathic central sleep apnea.84 This efficacy was attributed primarily to a CPAP-induced increase in arterial PCO2. As a result, PCO2 was kept above the apnea threshold. Thus, some patients with central apnea may respond to CPAP, although the final role of this therapeutic modality in central apnea must await further investigation. CPAP has been shown to improve cardiovascular function in patients with heart failure who have central sleep apnea only when the treatment reduces the apnea–hypopnea index. Because CPAP does not attenuate central sleep apnea in patients with heart failure when the treatment is titrated over one night, we mandated a gradual upward-titration protocol. This resulted in a significant reduction in the apnea–hypopnea index, which was accompanied by an increase in nocturnal oxygen saturation that persisted for at least two years. Nonetheless, the reduction of 50 percent in the apnea–hypopnea index was less than had been achieved in previous trials with the use of similar upward titration and CPAP pressures, factors that may have contributed to the lack of a beneficial effect on clinical outcomes. Improvement in daytime LVEF may be due to several factors, including a reduction in cardiac sympathetic drive, left ventricular unloading resulting from an increase in intrathoracic pressure and reduced myocardial ischemia due to improvement in oxygen saturation.However, the increase of 2.2 percent in the LVEF was less than the increase of 7.7 percent observed in our first randomized trial. We attribute this difference to the higher initial LVEF (24.5 percent vs percent) and the greater proportion of patients receiving beta-blockers in the present trial (77 percent vs.<20 percent). Owing to the overlap in the effects of beta-blockade and CPAP on ventricular function, the potential for further improvement in the LVEF when CPAP is added may be limited. The high rate of use of beta-blockers may also have reduced the potential for a beneficial effect on clinical outcomes. One-night use of CPAP has been shown to eliminate central sleep apnea in 43% of the subjects with systolic heart failure.58 Typically, these CPAP-responsive patients had mild to moderate central sleep apnea, and the average AHI decreased from 36 to 4, with elimination of desaturation. An important observation was that the number of premature ventricular contractions, couplets, and ventricular tachycardias decreased. This effect was presumed to be due to decreased sympathetic activity because arousals decreased and saturation improved. Heart failure patients with severe central sleep apnea (57% of the patients) did not respond to CPAP, and use of CPAP had no significant effect on ventricular irritability in these patients.58 CPAP attenuated central sleep apnea and improved nocturnal oxygenation, left ventricular function, sympathetic nervous activity, and (at least initially) submaximal exercise performance. However, the CANPAP trial did not demonstrate a beneficial effect of CPAP on morbidity or mortality in these patients with central sleep apnea and heart failure. Ancak, CPAP’ın yararlı etkilerini nasıl gösterdiği tam olarak anlaşılamamıştır. Temel etkisi (primer) pre ve after loadu azaltmak (kalp çevresindeki basıncı arttırarak, transmural basıncı azaltır.) Ayrıca, plazma atriyal natriüretik peptid düzeyini düşürüp atrial duvar gerilimini önler. Tüm bu etkileriyle dispneyi düzeltir, yaşam kalitesini arttırır. Çalışmalar bir-üç aylık CPAP tedavisinin santral apne-hipopne indeksi (AHİ)’ni azalttığını, solunum sayısını düşürdüğünü, PaCO2’yi arttırdığını göstermiştir. KKY’lilerde santral uyku apnesine yol açan, uyku sırasında hiperventilasyonla birlikte hipokapnidir. Buna göre CPAP’ın solunumu düşürüp, PaCO2’yi apne eşiğinin üstüne kadar yükselttiği kabul edilebilir. Ayrıca CPAP, intratorasik basıncı arttırıp interstisyel sıvıyı ekstratorasik vasküler kompartımana çekerek pulmoner ödemi düzeltir. CPAP’la arousallar da azalır. PreLoad AfterLoad *Mortalite ? LVEF’da

CSR-CSA NIMV CPAP çoğu CSR-CSA’ları önlemede yeterli Ø.
Diğer yöntemler kullanılmalı BiPAP ASV BiPAP ile ventilasyonun daha fazla arttırılması zaten hiperventile olan bu bireylerde hipokapnik alkaloz ile glottik kapanmaya neden olacaktır. Bu konuda BiPAP’ın daha yeni bir formu olan ASV’de flow jeneratörü  ÜSY’daki obstrüktif olayları ortadan kaldırmaya titre edilen fiks bir end-ekspiratuar basınç üretir. İnspiratuar basınç desteği ise bir algoritmaya uygun olarak ventilasyonu; SON 3 DK İÇİNDEKİ bazal dakika ventilasyonunun yaklaşık olarak %80’ninde stabilize etmeyi amaçlayan bir şekilde değişir. Daha iyi sonuçları (+), uyum daha iyi. Adaptive servo-ventilation (ASV) utilizes an algorithm to analyze a patient’s ventilatory rhythm and estimates a minute ventilation with which to target support. While providing support during apneas and hypopneas, ASV is designed to avoid overventilation during the hyperpneic phase, promoting more uniform ventilation and reducing arousals from sleep. Previously available only outside of the U.S., the ASV mode recently received FDA approval and is targeted for U.S. distribution in ASV has been shown to effectively suppress CSA-CSR and may be preferred over CPAP by patients [51, 81]. A 1-month randomized trial comparing therapeutic ASV with subtherapeutic ASV showed significant improvements in daytime sleepiness and reductions in neurohormonal activity associated with active treatment in patients with stable HF and CSR-CSA [82]. A recent randomized crossover trial has demonstrated superiority of ASV over CPAP and NPPV in normalizing breathing and sleep parameters in patients with CSA syndromes with and without HF ASV, KY ve CSS olan hastaların tedavisinde son zamanlarda önerilen yeni bir NIMV tedavi modalitesidir. ASV, hedef ventilasyonu, hastaların son zamanlardaki ortalama ventilasyonunun % 90’ına eşit olarak ayarlar. Bu devamlı olarak güncellenen hedef, ASV’nin “adaptif” kısmıdır. ASV solunumdan solunuma, solunumsal desteği, hastaların ihtiyacına göre değişen miktarlarda verme kapasitesine sahiptir. CSS’nin kontrol altına alındığı kararlı durumda, düzleşmiş dalga formları kullanılarak, 5 cmH2O pozitif basıncın üzerine eklenen, 3 cmH2O basınç desteği verir. Küçük miktarlardaki pozitif basınç desteği; dispnenin, artmış önyükün ve pulmoner ödemin azaltılmasına yardım eder. Eğer hasta santral apne ya da hipopneye girerse, basıncın derecesi çok hızlı bir şekilde, solunum stabilize olana kadar (ya da ayarlanan maksimum 10 cmH2O’ya kadar) birkaç solunumda artırılır. Eğer hasta hiperpneye girerse ya da noktürnal solunum yeniden başlarsa, basıncın derecesi 3-4 solunumda azaltılır ve solunum stabilizasyonuna daha fazla yardım eder. Bu ASV’nin “servoventilasyon” kısmıdır. Özet olarak; ASV, ayarlanan bir solunum hızında, ekspiryum sonu pozitif basıncına ek olarak hastanın ihtiyacına göre (hiperpne-hipopne veya apnede olmasına göre) inspiryumda da uygun pozitif hava yolu basıncı vererek, CSS’ nu kontrol altına alır (77). Solunum stabilize olduktan sonra, ASV basıncın derecesini konforlu, minimum 3 cmH2O desteğe doğru, kademeli olarak azaltır ve böylece aşırı ventilasyon olasılığını azaltır. Basınç derecesinin otomatik olarak azaltılması önemlidir. Aşırı ventilasyon ve hipokapni vokal kord kapanmasına ve apnede artışa neden olur (77). ASV, KY olgularındaki uyku sırasında yaşanan santral apneleri, hipopneleri, arousalları, uyku bölünmelerini engelleyerek, aşırı yorgunluk ve uykululuk halini tedavi eder

Primer Santral Uyku Apnesi Medikal Sorunlara bağlı diğer Santral Uyku Apnesi  Cheyne-Stokes Solunumuna bağlı santral uyku apnesi  Yüksek irtifada periyodik solunuma bağlı santral uyku apnesi  Cheyne-Stokes ya da Yüksek İrtifa dışındaki hastalıklara bağlı santral uyku apnesi  İlaçlara bağlı santral uyku apne  Çocukluk çağı primer santral uyku apnesi 64

Santral Uyku Apnesi Ayırıcı Tanısı

Teşekkürler 69

HT + MI İlaçlar, kapaklar LV Tedavisiz OSA Hasarlanmış LV Naughton et al CQ’da azalma PCWP’da yükselme SNA’da yükselme Hiperventilasyon AC volümlerinde azalma Dolaşımda gecikme CSR-CSA

Santral Uyku Apne Sendromunda ICSD-2 sınıflamasında KY’de CSR-CSA Mekanizmaları
71

Santral Uyku Apne Sendromunda ICSD-2 sınıflamasında KY’de CSR-CSA Mekanizmaları
72

KY’de CSR-CSA Mekanizmaları
Asemptomatik LV disfonksiyonu + CSA’sı olan hastalarda CSA’sı olmayanlara kıyasla daha fazla kardiyak elektriksel instabilite vardır. Uyanıklıkta KY + CSA (+) olan hastalarda CSA olmayanlara kıyasla sempatik aktivasyon daha belirgin. Sempatik aktivasyon CSA’nın mı yoksa KY’nini bir sonucumu net değil.

İleri yaş (>60) Erkek cinsiyet Uyanıklık hipokapnisi (≤ 38 mmHg) Nopmaneejumruslers and associates (18) also observed that among 93 patients with stroke, 19% had CSA. The key factors associated with CSA were hypocapnia and asymptomatic LV systolic dysfunction (LVEF <40%), but not the location or type of stroke. Among those with Yumino and Bradley: Cheyne-Stokes Respiration with Central Sleep Apnea 231 LVEF less than or equal to 40%, hyperpnea had a waxing and waning pattern of tidal volume and a longer duration, characteristic of CSR, than in those with LVEF over 40%. These data suggest that the presence of CSR-CSA in a patient following a stroke is more likely due to underlying LV systolic dysfunction than the neurological damage caused by the stroke. They concluded that in patients with stroke, CSR-CSA is a sign of occult LV systolic dysfunction CSR-CSA varlığı Yüksek PCP Yüksek LV end-diastolik volümü Yüksek periferal ve santral kemoreseptör sensitivitesi CQ LVEF

KY’li hastaların bir kısmında CSR-CSA+OSA (+) OSA olarak başlar ve gecenin bitiminde CSA’ya shift olur [Sirkülasyon zamanı uzadıkça ve PaC02 düştükçe] In a small minority of patients with HF, OSA and CSR-CSA coexist. In one study, Tkacova and colleagues (75) demonstrated that in such patients, there was a shift from predominantly OSA at the beginning of the night to predominantly CSA at the end of the night. This shift in apnea type occurred in association with a prolongation of lung to peripheral chemoreceptor circulation time, a lengthening of hyperpnea and a fall in PaCO2 from the beginning to the end of the night. They concluded that the shift from predominantly OSA to CSR-CSA occurred in conjunction with an overnight deterioration of cardiac function. Since it has been shown that PaCO2 varies inversely with LV filling pressure, the implication was that OSA itself contributed to the deterioration of cardiac function, and that a rise in LV filling pressure contributed to the overnight decrease in PaCO2 that probably triggered CSR-CSA once PaCO2 fell below the apnea threshold. It has also been shown in patients with HF that the predominant type of sleep apnea can shift from obstructive to central in conjunction with an increase in circulation time and fall in nocturnal PaCO2, and vice versa over several months (76). These observations raise the possibility that in patients with HF, OSA and CSA can be part of a spectrum of periodic breathing whose predominant type can transform over time in response to alterations in cardiac function. Mechanisms involved in this transformation have not been identified, but may involve fluid displacement into and out of the upper airway and lungs, and alteration in chemosensitivity in relation to alteration in the severity of cardiac failure (40).

Tek başına HİPOKSİK stimulus ??? As a consequence, blood pressure and heart rate oscillate in concert with Cheyne-Stokes cycles, very much as they do during OSA; peaks occur during hyperpneas and dips during apneas (66, 78). These effects cause a generalized increase in sympathetic activity manifest by higher overnight urinary norepinephrine concentration in patients with HF with than in those without CSR-CSA (77). However, Franklin and coworkers (66) and Leung and colleagues (79) found that administration of low flow oxygen at a rate sufficient to just abolish dips in SaO2, but not to eliminate CSR-CSA or fluctuations in PaCO2, did not influence blood pressure or heart rate oscillations during CSR-CSA. These data indicate that mechanisms other than hypoxic dips are involved in precipitating these surges in blood pressure and heart rate during CSR-CSA. Since there are direct connections between respiratory and cardiovascular sympathetic neurons in the brainstem, it is possible that these cardiovascular oscillations are driven by oscillations in outflow from central respiratory to cardiovascular sympathetic neurons (80). Generalize Sempatik sinir aktivasyonunda

Tek başına HİPOKSİK stimulus ??? The sympathetic stimulatory effects of CSR-CSA are not isolated to sleep, but also carry over into wakefulness. Daytime plasma norepinephrine concentration and muscle sympathetic nerve burst frequency are significantly higher in patients with HF with CSR-CSA than in those without it, and they are directly related to the frequency of arousals from sleep and to the degree of apnea-related hypoxia, but not to LVEF. Treatment of CSR-CSA with either nocturnal oxygen or CPAP lowers SNA both during sleep and wakefulness (15, 65, 77). These data indicate that CSR-CSA contributes to sympathetic activation. Santral kaynaklı ? Generalize Sempatik sinir aktivasyonunda

Uykuda; İstemli (Davranışsal) kontrol ortadan kalkar Solunum merkezinin C02’a duyarlılığı azalır* Uyku sırasında normal C02 düzeyinde hafif artış olur (~ 2-4 mmHg) Solunum merkezinin apne eşiği yükselir (apneye neden olan en düşük PaC02 düzeyi) Uyku sırasında faringeal hava yolu kollapsı, solunumu inhibe eden refleksleri başlatarak santral apneye yol açabilir Normalde uykudaki eşik PaC02 değeri; uyanıklık PaC02’sinden yüksektir. Uykuya geçişte; Uykunun başlangıcında, solunum paterni yavaşlayıp PaCO2 hafif artış gösterene kadar, mevcut PaCO2 değeri apneik sınırın altına iner ve fizyolojik olarak birkaç santral apne görülebilir. Yani uyanıklık PaC02’si eşik değerin altında kalır ve birkaç adet santral apne gelişir. En belirgin instabilite uyanıklıktan uykuya geçiş anında yaşanmaktadır. Bu geçiş sırasında PaCO2 eşik değeri yükselmektedir ve uyanıklık arteryel PaCO2’si sıklıkla bu yeni eşik değerin altında kalmaktadır ve bu durum santral apneye yol açmaktadır. Non-REM’in yükselmiş PaCO2’si uyanıklığa göre rölatif olarak hiperkapni olarak algılanır ve böylece hiperpne ortaya çıkar. Sadece uykuya geçiş sırasında değil, arousal esnasında da solunum instabildir. Arousal ventilasyonu artırır, hipokapni ile santral apne oluşur

Santral apne; Tek bir klinik antite değildir Tek bir klinik sebepten kaynaklanmamaktadır. SA’ler farklı mekanizmalarla meydana gelmektedir. After tracheostomy for obstructive sleep apnea, many patients develop central apnea, which generally resolves over a period of months.4 This may also occur when continuous positive airway pressure (CPAP) is initiated to alleviate upper airway obstruction. In addition, it has been observed that the treatment of central apneas with either a respiratory stimulant (e.g., acetazolamide5) or diaphragmatic pacing6 can result in obstructive events. Finally, studies report objective evidence of pharyngeal airway narrowing during purely central apneas. These observations imply some commonality in the pathophysiology of the various types of apnea, so it is not surprising that central and obstructive apneas are frequently seen in the same individual. It should be recognized from the beginning that a central pause in breathing may result from a variety of physiologic or pathophysiologic events. The term central sleep apnea reflects several breathing patterns, all of which include pauses in inspiratory effort; it does not represent a single entity or result from a single cause. Examples include Cheyne-Stokes respiration, periodic breathing at altitude, and the idiopathic central sleep apnea observed at sea level. Each has a different pathogenesis but is manifested by central apneas during sleep. To understand central sleep apnea, the normal mechanisms controlling ventilation awake and asleep and pathologic influences on these mechanisms must be understood. All possible causes of central apnea must be considered in caring for patients with this disorder. Sonuç olarak; uyanıklık stimulusu olmadığı zaman ventilatuar ritm kritik olarak kemoreseptör stimülasyonuna bağlıdır. artmış TV hipokapni olmaksızın da solunumu inhibe eden bir mekanizma olabilir. Uyku başlangıcında disritmik bir solunum görülebilir. Uyanıklıktan evre 1-2’ye geçişte; uyanıklıkta ventilasyon için sorun oluşturmayan PaC02 düzeyi; uyku için apne eşiğinin altında kalır ve ventilasyonun devamı için yetersiz olur ve apne gelişir.

Santral apne; Tek bir klinik antite değildir Tek bir klinik sebepten kaynaklanmamaktadır.

Santral apne; Tek bir klinik antite değildir Tek bir klinik sebepten kaynaklanmamaktadır. Arousal from sleep is an integrated physiologic process that can serve as an important protective response. For example, during periods of compromised ventilation, arousal may be an important mechanism for restoring gas exchange when other compensatory mechanisms fail. However, arousal from sleep can also be deleterious to respiratory control stability. The propensity to develop central apnea is likely influenced by two important components of arousal sensitivity: arousal threshold and the ventilatory response to arousal. Arousal eşiği düşük olanlar (kolay uyananlar) ile arousala ventilatuar yanıtı hızlı olanlarda (PAC02’si hızlı düşenler) CA fazla.

CSR-CSA’nın KY üzerinde klinik etkileri
KY’li hastalarda PSG ile CSR-CSA %30-50 (+) CSR-CSA ile; Daha düşük LVEF Daha yüksek AF sıklığı Sık noktürnal aritmi varlığı Gündüz (Gece) hipokapni birlikteliği yüksek AHI yüksek ve sol atrial genişlemesi (+) olanlarda daha kötü sonuçlar (+) There are few data from well-designed epidemiologic studies on the prevalence of CSR-CSA in patients with HF. In one study involving 100 men with HF (LVEF < 45%) who underwent polysomnography within the last several years without regard to suspicion of sleep apnea, Javaheri found that the prevalence of CSR-CSA, defined as an AHI greater than or equal to 15 of which more than 50% were central, was 37% (17). Factors associated with the presence of CSR-CSA were worse New York Heart class (more class III than in patients without CSRCSA), lower LVEF, a higher prevalence of atrial fibrillation, increased nocturnal cardiac arrhythmias, and a lower awake PaCO2 compared with those without sleep apnea on univariate analyses. However, because this study included only men, it provided no data on the prevalence of CSR-CSA in women and therefore does not present an overall picture of the prevalence of CSR-CSA in the general population with HF. In addition because it was performed mainly before the widespread use of b-blockers for HF therapy, only a small minority of patients were on a b-blocker. Since CSR-CSA appears to arise from HF itself, and since there is some evidence that optimizing medical therapy for HF or heart transplantation attenuates CSR-CSA, the very high prevalence of CSR-CSA reported in that study (17) may not be representative of its prevalence in patients with HF on optimal contemporary medical therapy. Indeed, data from HF cohorts recruited more recently, in whom the great majority of patients were receiving b-blockers, indicate lower prevalences of CSR-CSA. For example, in 87 patients with HF (53 men, 34 women; LVEF < 45%), Ferrier and coworkers (42) reported that CSR-CSA was present in only 15%. In the largest cohort studied to date, Wang and colleagues performed sleep studies on 218 consecutive patients with HF (168 men and 50 women with LVEF < 45%) enrolled from a single HF clinic between 1997 and 2004 without regard to suspicion of sleep apnea. The prevalence of CSR-CSA, defined as an AHI greater than or equal to 15 of which more than 50% were central, was 21%. Because of the large number of subjects, and the inclusion of both men and women, the prevalence of CSR-CSA reported in this study may be more representative of its prevalence in the general HF population on optimal contemporary HF therapy.

*SNA’da RAS’de aktivasyon Periferal v.c Increased SNA has a number of adverse effects in patients with HF, including peripheral vasoconstriction, increased tubular reabsorption of sodium, and activation of the renin–angiotensin system (81). The increases in vascular resistance and in blood volume increase preload and afterload and, thus, work for the damaged myocardium. However, it is the increase in SNA itself that is probably the most damaging to the heart over time. Although the increase in SNA provides inotropic support that acts initially to increase cardiac output, in the longer term it promotes disease progression. This is demonstrated by the strong correlation between mortality risk and both plasma norepinephrine levels and cardiac norepinephrine production. Chronically elevated SNA is linked to abnormal calcium cycling and calcium leakage in the failing myocardium, contributing to a decrease in myocardial contractility over time. In addition, increases in SNA can enhance spontaneous inward currents through calcium channels, enhancing the likelihood of spontaneous repolarization, arrhythmia development, and sudden death (81). Indeed, ventricular arrhythmias are more common in patients with HF with CSR-CSA than in those without it (74). Furthermore, chronic exposure of the myocardium to excess SNA and circulating catecholamines increases cardiac myocyte injury, apoptosis, and necrosis, and contributes to hypertrophy and adverse remodeling (85). Suppression of SNA by long-term attenuation of CSR-CSA by CPAP in patients with HF may be one of the mechanisms that contributed to the associated improvement in LVEF and exercise performance (15). However, these effects were not accompanied by any improvement in survival. The main clinical significance of CSR-CSA in HF is its potential to adversely influence survival. However, there is controversy on this point. Sodyumun tübüler reabs’da *Vasküler R’da

As a consequence, blood pressure and heart rate oscillate in concert with Cheyne-Stokes cycles, very much as they do during OSA; peaks occur during hyperpneas and dips during apneas (66, 78). These effects cause a generalized increase in sympathetic activity manifest by higher overnight urinary norepinephrine concentration in patients with HF with than in those without CSR-CSA (77). However, Franklin and coworkers (66) and Leung and colleagues (79) found that administration of low flow oxygen at a rate sufficient to just abolish dips in SaO2, but not to eliminate CSR-CSA or fluctuations in PaCO2, did not influence blood pressure or heart rate oscillations during CSR-CSA. These data indicate that mechanisms other than hypoxic dips are involved in precipitating these surges in blood pressure and heart rate during CSR-CSA. Since there are direct connections between respiratory and cardiovascular sympathetic neurons in the brainstem, it is possible that these cardiovascular oscillations are driven by oscillations in outflow from central respiratory to cardiovascular sympathetic neurons (80). Generalize Sempatik sinir aktivasyonunda

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SANTRAL UYKU APNE SENDROMU

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