Central sleep related breathing disorders - diagnostic and therapeutic features.

THREE CLASSES OF CENTRAL SRBD ARE DISTINGUISHED: 1. Central sleep apnea (CSA), 2. Cheyne-Stokes Respiration as a subgroup of CSA and 3. central hypoventilation syndromes. Reduced or completely absent central respiratory drive without upper airway obstruction is the common feature of central SRBD. Hypoventilation syndromes most often occur secondary in patients with neuromuscular, pulmonary or sceletal diseases or in patients with massive obesity. In patients with hypoventilation during sleep nocturnal and exertional dyspnea and headaches are frequently reported symptoms. Excessive daytime sleepiness is the key symptom in patients with central sleep apnea syndrome. Cheyne-Stokes Respiration is frequent in heart failure patients but in many cases does not cause symptoms specific for the breathing disorder. If there are symptoms or if ambulatory recording of breathing during sleep suggests a sleep related breathing disorder, polysomnography is then performed to definitively rule out or confirm the diagnosis and to initiate treatment, if needed. The indication for treatment in asymptomatic patients with central sleep apnea and Cheyne-Stokes Respiration may be difficult, as there are very little data concerning the long-term benefit in these patients. Symptomatic patients and those with severe central sleep apnea should be treated. Oxygen and CPAP may be effective in 20-30% of patients each. If these treatment options are ineffective, non-invasive pressure support ventilaiton can be used. In patients suffering from hypoventilation syndromes the treatment of choice is non-invasive pressure support ventilaiton combined with supplemental oxygen, if required.

Introduction

Characteristics of central sleep related breathing disorders (SRBD)

Three classes of central SRBD are distinguished: 1. Central sleep apnea (CSA), 2. Cheyne-Stokes Respiration as a subgroup of CSA and 3. central hypoventilation syndromes. A central apnea is defined as a cessation of airflow for at least 10 seconds without respiratory efforts. Cheyne-Stokes Respiration as a subgroup of central apnea is characterized by a waxing and wanning pattern of tidal volume followed by a central apnea. Central hypoventilation presents as reduced tidal volume over several minutes without signs of upper airway obstruction leading to hypercapnia, hyoxia and tachycardia. During a period of central hypoventilation partial pressure of arterial carbon dioxide (PaCO2) per definition rises to more than 50 mmHg. Figures 1-3 (Fig. 1), (Fig. 2), (Fig. 3) demonstrate typical examples of the three different forms of central SRBD.

Figure 1

Example of central SRBD: central sleep apnea without any respiratory movements

Figure 2

Example of central SRBD: typical Cheyne-Stokes Respiration with waxing and wanning tidal volume followed by a central apnea

Figure 3

Example of central SRBD: central hypoventilation of several minutes. The increase in heart rate during hypoxia is the hallmark of central hypoventilation.

Definitions and epidemiology

The recently published revised „International Classification of Sleep Disorders“ (ICSD-2) [1] distinguishes three classes of central SRBD:

Central Sleep Apnea (CSA)

Congenital sleep related hypoventilation syndromes

sleep related hypoventilation syndromes due to other causes

Central apneas also occur in normal subjects, especially during the transition from wakefulness to sleep. If more than 5 central apneas occur per hour of sleep and if the patient reports symptoms of disturbed sleep (excessive daytime sleepiness, nocturnal awakening with dyspnea, frequent awakenings or insomia) central sleep apnea syndrom is diagnosed. In patients with Cheyne-Stokes Respiration ten or more respiratory disturbances per hour have been definded as pathological. In patients with hypoventilation syndromes it is not helpful to report the number of breathing disorders per hour of sleep, as there are only 2-5 phases per night. As oxygen saturation is an easily measureable parameter and as hypoventilation without supplemental oxygen always leads to desaturation, hypoventilation during polysomnography is often defined as a drop in SaO2 to 85% or lower for at least 5 minutes. Hypoventilation during sleep does not occur in healthy subjects and has in any case to be considered as pathological.

Symptoms

Central sleep apnea

Concerning symptoms there are considerable differences in patients with central sleep apnea syndromes and those with hypoventilation syndromes. In patients who suffer from central sleep apnea excessive daytime sleepiness is often present, similar to patients with obstructive sleep apnea. Insomnia and frequent awakening from sleep may be reported by a number of patients. Heart failure patients who demonstrate Cheyne-Stokes Respiration during sleep usually do not report excessive daytime sleepiness, probably due to the fact that they have short naps during daytime associated with heart failure. Soring is not a typical symptom in patients with all forms of central sleep related breathing disorders, however, snoring does not exclude central sleep apnea or Cheyne-Stokes Respiration.

Hypoventilation syndromes

In patients with hypoventilation syndromes the predominant symptoms consist in dyspnea on exertion, nocturnal awakening due to dyspnea and a reduced physical performance. Edema of the lower limb as an indicator of right heart failure and cyanosis as a sign of hypoxemia are often found. The frequently reported headaches are thought to be a consequence of hypercapnia. Excessive daytime sleepiness may also be present.

Diagnosis

In symptomatic patients, polysomnography is the diagnostic gold standard, as only polysomnography is able to determine if the patients is actually sleeping and if he has reached rapid eye movement (REM) sleep. However ambulatory monitoring devices may be used as valuable screening tools in patients without or little symptoms who are at risk of nocturnal hypoventilation to actually demonstrate the breathing disorders. The clinical suspicion often can be verified with these simple and low cost devices and can then lead to a referral to a sleep centre for further treatment.

Besides studying breathing during sleep daytime blood gases, lung function and muscle performance tests as well as chemosensitivity measurements are well established methods that should be included in the complete diagnostic workup in order to determine the severity of the disorder.

Central apneas cannot be differentiated from obstructiv events by the use of older 4 chanel recorders without respiratory movements. Newer devices however, have recently become available who also include inductive plethysmography which at least theoretically can differentiate central from obstructive apneas already by the use of an outpatient recording. Recording of thoracic and abdominal movements, however, also has its limitations and in some patients esophageal pressure measurement, oscillometric resistance or diaphragmatic EMG may be needed to differentiate central from obstructive events.

Pathophysiology

Even in healthy subjects the transition from wakefulness to sleep is characterized by profound changes in respiration, as summarized below:

Reduction of functional residual capacity by 10%

Reduction of minute ventilation by 10-15% both during “non-rapid eye movement “ (NREM) sleep and REM sleep [2], [3].

Increase in upper airway resistance by more than 200%

Reduction in hypoxic and hypercapnic ventilatory response

These changes cause an increase in arterial PCO2 by 2.4-4 mmHg and a decrease in PO2 between 3-6 mmHg and desaturation of up to 2%. Almost all changes mentioned are more pronounced during REM sleep.

These changes that do not cause relevant blood gas alterations in normals will cause hypoventilation initially during REM sleep in many patients with chronic obstructive lung disease, massive obesity, kyphoskoliosis or neuromuscular disorders. The most important cause of hypoventilation in patients is a massive reduction in minute ventilation especially during REM sleep [4]. During this sleep stage muscle tone is massively reduced in all muscles except the diaphragm. Accessory breathing muscles also do not work propperly in REM sleep, however, in contrast to healthy subjects, patients with hypoventilation syndromes depend on these muscles to maintain minute ventilation. Due to chronic REM sleep related hypoventilation hypercapnic ventilatory response decreases so that patients develop hypercapnia during daytime in the long run.

A complete cessation of central respiratory drive can be caused by the following mechanisms: disturbances of the respiratory controller, change in sleep stage, changes in respiratory drive and upper airway reflexes.

PCO2 plays a key role in the pathophysiology of central sleep apneas. Even a relatively small drop in PCO2 during sleep by 2-6 mmHg may induce central apneas. During sleep there is an apnea threashold for CO2 below which central apneas occur. Patients with a large response to CO2 seem to be more prone to develop central apneas.

A PCO2 level that is sufficient to sustain respiratory drive during wakefulness may be below the apnea threashold during NREM 1 and 2. The apnea that follows will icrease PCO2 until it is above the threashold when breathing resumes. An arousal is often seen at maximum ventilation and the mentioned process re-starts when the patient reaches NREM sleep again.

Nasal obstruction can lead to obstructive as well as central apneas. Mechanoreceptors in the nose are thought to be the cause of this phenomenon. Inhibitory reflexes of the upper airways (larynx and pharyns) also influence respiratory drive. Studies in sleeping dogs have shown central apneas following the stimulation of the larynx. In humans too, there is indirect evidencs that negative pressure or deformities of the upper airways may lead to central apneas. The pharynx tends to collaps more easily during wakefulness in patients with central apneas. Central apneas occur more frequently when subjects are in the suppine position and may be treated by the use of continuous positive airway pressure (CPAP) in 20-30% of patients.

Treatment

Central sleep apnea and Cheyne-Stokes Respiration

Due to the various causes of central sleep apnea it is not possible to say which treatment will be effective in which patient. A stepwise treatment concept has therefore evolved. Treatment of any disorder that might lead to central apneas – systolic and diastolic heart failure is certainly the most important disease in this respect – is the basis of therapy. Effective medical treatment of heart failure for example will lead to a reduction or even complete removal of central sleep apneas in heart failure patients. If central apneas in a relevant amount persist despite optimal treatment supplemental oxygen may be used. In approx. 20 to 30% of the patients oxygen will prevent central apneas. If oxygen is not effective, we use CPAP as the next step which again prevents apneas in approx. 20 to 30% of the patients. If central apneas still persist positive pressure ventilaiton either as conventional bilevel positive airway pressure (bi-level) in the assist control or controlled mode or alternatively as an automatic bi-level (adaptive servo ventilation) may be used.

However, it must be emphasized that none of these treatments has been shown to lower mortality or morbidity in heart failure patients with Cheyne-Stokes Respiration. An improved quality of life has been shown with treatment.

For both central apneas and Cheyne-Stokes Respiration the aim of treatment is to completely remove breathing disorders.

The aim of treatment in patients with hypoventilation syndromes is an increase in minute ventilation. This cannot be achieved by the use of medical therapy, as both chemosensitivity and muscle function are disturbed in these patients.

The gold standard therapy in patients with hypoventilation syndromes nowerdays is non-invasive ventilation, a treatment that mechanically increases ventilation without endotracheal tube or tracheostomy.

Two forms of non-invasive ventilation can be distinguished: 1. negative pressure ventilation and 2. positive pressure ventilation. Negative pressure ventilation was the predominantely used methods until the eighties which however has the serious disadvantage of severe upper airway obstruction in many patients [5]. The gold standard therapy today is non-invasive positive pressure ventilation. Pressure support is the most widely used mode of ventilation, in some cases volume cycled ventilators are used. Patients with neuromuscular diseases or kyphoskoliosis often find controlle ventilation very pleasant and this mode leads to maximal muscle rest. Patients with COPD usually prefer assisted pressure controlled ventilation.

We start non-invasive ventilation during daytime and find the ventilator setting that is well tolerated by the patient. During sleep the machine setting is adjusted so that periods of hypoventilation are completely prevented. After a few treatment nights the increased daytime PCO2 will decrease. If hypercapnia does not resolve or if PCO2 does not drop substantially, treatment is ineffective and the cause for treatment failure has to be determined. Often mask leak [6] or low treatment pressure is the cause of ineffective therapy. In patients with neuromuscular diseases or kyphoskoliosis both quality of life and life expectancy are dramatically improved by non-invasive ventilation [7], [8]. Evidence based studies in these patients do not seem ethically feasible. In patients with stable COPD treatment effect is less striking. The use of NIV and the effect is far from optimal in this group of patients. However, the few controlled studies that are available have not checked treatment efficiency during the night. Therefore, at this stage, NIV cannot be regarded as a standard treatment of stable severe COPD. An attempt to treat patients with NIV seems however warranted in hypercapnic patients, as NIV does not have adverse effects. If the patient does not use or profit NIV despite optimal technology NIV treatment should be ended. In a relevant number of patients however, a substantial improvement in symptoms and a reduction or complete removal of hypercapnia can be achieved in experienced centers [9]. Usually, nighttime NIV is sufficient.

The most relevant advantages of NIV compared to invasive ventilation are:

Early treatment to maintain muscle function

NIV does not negatively influence daily activity as it is usually performed during the night

Risk for infections is not increased

Humidification an heating of inhaled air is not necessary

Intermittent treatment is possible

The disadvantage of NIV are leaks and pressure marks by the mask. In volume cycled ventilators alarms due to small leaks may disrupt sleep.

Conclusion

We have now realized that central sleep related breathing disorders are much more frequent than previously thought. Over the past years it has been shown that many diseases (heart failure, COPD, neuromuscular diseases, kyphoskoliosis and severe obesity) may all cause hypoventilation syndromes or central apneas that may play an important role in the prognosis of these patients. In patients with suspected central sleep related breathig disorders amulatory screening devices can be very helpful. If screening shows a pathological test polysomnography is then performed to confirm or exclude SRBD. The use of non-invasive ventilation offers excellent treatment for many of these patients.