Pulmonary Medicine

Central Sleep Apnea Syndrome (Idiopathic CSA, Cheyne-Stokes Respiration, CSA due to a drug or substance, High-altitude Periodic breathing, CSA due to a medical condition other than Cheyne-Stokes)

What every physician needs to know:

A Central Sleep Apnea (CSA) is defined as a cessation of breathing of at least ten seconds duration in the absence of a ventilatory drive. This is in contrast with Obstructive Sleep Apnea, where the ventilatory drive persists but airflow ceases because of the obstruction of the upper airway. Central Sleep Apneas can be a normal occurrence or can have a pathologic etiology.

Central Sleep Apnea Syndrome (CSAS) is most commonly defined as the presence of five or more central apneas per hour of sleep.

It is commonly linked to an underlying disorder, such as congestive heart failure, stroke, renal failure, brainstem lesions or malformations (e.g., Arnold Chiari malformation), narcotic use, and endocrine disorders like hypothyroidism and acromegaly. It is important to look for such disorders, as treatment of the underlying condition will frequently result in improvement in the CSA.

Classification:

CSA can be a normal occurrence during sleep when it occurs during the transition from wakefulness to sleep or after an arousal from sleep.

The International Classification of Sleep Disorders (ICSD) classifies CSA disorders into several types, some with known pathophysiology and others with unclear mechanisms:

  • Idiopathic CSA: This is a rare disorder of unclear etiology. It is a diagnosis of exclusion, as other causes of central sleep apnea noted below are excluded. It occurs most commonly in older males.

  • Cheyne-Stokes Respiration (CSR): CSR is a breathing pattern characterized by cycles of crescendo-decrescendo changes in tidal volume followed by central sleep apneas. A complete cycle of apnea, hypopnea, hyperpnea, and hypopnea leading to the next apnea usually takes about 45 seconds but may be longer. At least ten consecutive minutes of these cycles should be recorded before CSR can be diagnosed.

  • CSA that is due to a drug or substance: CSA has been documented in 30 percent of people who take narcotics.

  • High Altitude Periodic Breathing: Characterized by periods of central apnea or hypopnea cycling with periods of hyperpnea during sleep on ascent to high altitudes, high altitude periodic breathing occurs in virtually everyone at altitudes higher than 7600 meters.

  • CSA that is due to a medical condition other than Cheyne-Stokes: CSA without CSR occurs in persons with an underlying medical condition like vascular, neoplastic, degenerative demyelinating or traumatic injury to the brainstem; brainstem malformation, such as Arnold Chiari; myopathies; endocrine disorders, such as hypothyroidism or acromegaly; and renal failure.

  • Primary CSA of the Newborn (not discussed here)

Are you sure your patient has central sleep apnea syndrome? What should you expect to find?

Symptoms of CSA symptoms are similar to symptoms of other sleep-disordered breathing: mainly fragmented sleep with frequent awakenings, unrefreshing sleep, fatigue, sleepiness, snoring, sleep onset or sleep maintenance insomnia, and poor concentration. Some patients with CSA can also be asymptomatic.

Beware: there are other diseases that can mimic central sleep apnea syndrome:

The main differential diagnosis of CSA syndrome is the much more prevalent obstructive sleep apnea syndrome. The two disorders can have similar presenting symptoms, but they have different underlying pathophysiologies. Obstructive sleep apnea primarily results from collapse of the upper airway, resulting in cessation or decrease in airflow despite continuous and even increased respiratory muscle effort. In contrast, CSA and hypopnea result from a cessation or decrease in the respiratory effort and respiratory drive, leading to the drop in airflow with a usually patent airway.

The only way to differentiate between the two is to perform an overnight polysomnogram during which both airflow and chest and abdominal respiratory efforts are recorded. A more sensitive way to measure respiratory efforts is by inserting an esophageal pressure probe during the polysomnography to measure intrathoracic pressure swings. However, this procedure is rarely done outside of research labs.

How and/or why did the patient develop central sleep apnea syndrome?

The pathophysiology of altitude induced CSA, CSA/CSR in heart failure, and possibly idiopathic CSA is thought to be due to hyperventilation during wakefulness with resultant hypocapnia (caused by different known or unknown factors in each disorder) that leads to central apneas during sleep.

To understand this pathophysiology, one must understand the normal control of ventilation. During wakefulness, ventilation is controlled by multiple parameters:

  • the wakefulness respiratory drive

  • emotional, behavioral and volitional cues

  • central and peripheral chemoreceptors

Peripheral chemoreceptors, which are located mainly in the carotid body, sense oxygen concentration and carbon dioxide concentrations, while central receptors, which are located in the medulla, sense changes in carbon dioxide. The ventilatory response is normally much more sensitive to carbon dioxide changes (which are maintained in a very tight range) than to changes in oxygen level, which have to vary much more to elicit a change in ventilation.

During sleep, there is a loss of the wakefulness drive to breathe and the emotional, volitional and behavioral inputs. Therefore, chemoreceptors become the main regulators of breathing, with the carbon dioxide level as the main stimulus. Sleep onset unmasks the apnea threshold, which is the carbon dioxide level below which the ventilatory drive ceases.

Patients with the CSA syndromes mentioned above have a relative hypocapnia while awake, which means that, when they fall asleep, their CO2 level is below the apneic threshold, and that generates a central sleep apnea event.

The reason for the hypocapnia is different in each disorder. In idiopathic CSA, the cause is not known, but it is thought to be due to an acquired increased sensitivity of the chemoreceptors.

In high altitude CSA, the hypoxia present at high altitude is thought to lead to hyperventilation and resultant hypocapnia.

In congestive heart failure, it is thought that the elevated left-side pressures result in some pulmonary congestion and stimulate pulmonary vagal afferent C fibers, which in turn stimulate respiration and drive the CO2 down. This generates central sleep apneas during sleep because of the unmasking of the apneic threshold. The typically long cycle time and alternation between central sleep apnea and hyperventilation typically seen in Cheyne Stokes breathing in congestive heart failure is a direct result of the prolonged circulation time that occurs in these patients. The change in circulating CO2 levels takes more time to reach the central chemoreceptors, which results in constant overshooting of the target CO2 levels and leads to cycles of central sleep apneas followed by crescendo-decrescendo ventilation.

In opioid-related CSA, there is a direct effect of the medication on the central respiratory centers thought to be mediated by the opioid μ receptor. This effect results in blunting of the respiratory drive. Opioids also change the chemoreceptor sensitivity by blunting the hypercapnic drive. The effect on the hypoxic drive has been controversial, with some studies showing blunting and others showing increased sensitivity to hypoxia.

Strokes and other neurologic disorders are thought to decrease respiratory drive by directly affecting the brainstem respiratory centers.

The mechanism for CSA in hypothyroidism and acromegaly is not known.

Which individuals are at greatest risk of developing central sleep apnea syndrome?

Risk Factors for CSA include:

  • Congestive Heart failure: 25-40 percent of patients with heart failure develop CSA/CSR.

  • Ascent to high altitude

  • Stroke patients: 10-28 percent of stroke patients have been reported to have CSA.

  • Narcotic use: 30 percent of opioid users develop CSA.

  • Age: CSA is more prevalent in older individuals.

  • Gender: Male hormones elevate the apneic threshold closer to eupneic levels and make males are more susceptible than females to developing CSA. In the general population, women's relative chance of developing CSA is 0.04 (95%, p=0.05).

  • Other medical conditions, including Arnold Chiari malformation, hypothyroidism, acromegaly, renal failure, myopathies, neurodegenerative disorders, brainstem disorders, and atrial fibrillation in CHF

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Three laboratory values can be useful in looking for conditions associated with CSA and determining the etiology of the disorder: serum TSH, serum creatinine, and serum or arterial carbon dioxide levels.

What imaging studies will be helpful in making or excluding the diagnosis of central sleep apnea syndrome?

If a central nervous system disorder is suspected, brain imaging can be useful in ruling out disorders like Arnold Chiari malformation, demyelinating diseases, and tumors.

An echocardiogram should be ordered to evaluate heart function in patients with Cheyne Stokes respiration in particular but also in those with otherwise unexplained CSA.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of central sleep apnea syndrome?

No non-invasive pulmonary diagnostic studies are helpful in making or excluding the diagnosis of CSA syndrome.

What diagnostic procedures will be helpful in making or excluding the diagnosis of central sleep apnea syndrome?

An overnight polysomonogram (PSG), the gold standard for the diagnosis of CSA, should be ordered in all patients. The PSG will help differentiate CSA from the more common obstructive sleep apnea, which can have a very similar presentation.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of central sleep apnea syndrome?

No pathology/cytology/genetic studies are helpful in making or excluding the diagnosis of CSA syndrome.

If you decide the patient has central sleep apnea syndrome, how should the patient be managed?

The goal of treatment in CSA is to normalize breathing patterns during sleep and to improve symptoms. With the exception of CSA/CSR in CHF, there is little long-term prognostic data about the different CSA syndromes, so symptomatic improvement is the most important goal.

Idiopathic Central Sleep Apnea: Because this is a rare disorder, there is little data on treatment, and available data is mostly derived from small series. After the diagnosis is made, a trial of CPAP is warranted that may result in improvement of the AHI in some patients. If this trial is not effective, supplemental oxygen can be attempted. A small series showed improvement in the AHI with the administration of oxygen by nasal cannula at 2 to 4 L/min. However, this approach is not uniformly successful. Other treatments that have been tried with variable success include acetazolamide administration, inhaled CO2, and zolpidem administration.

Cheyne-Stokes Respiration (CSR) and CSA associated with CHF: In comparison with the other types of CSA, when associated with CHF, CSA and CSR portend a worse prognosis. There is emerging data that treatment of CSA/CSR in CHF can improve cardiac function, quality of life, and transplant-free survival.

The mainstay of therapy in CHF is medical optimization of the underlying heart condition. If CSA persists despite optimized medical therapy for CHF, therapy with positive airway pressure (PAP) ventilation should be initiated. PAP therapy in CHF was first studied in the form of CPAP. An initial randomized controlled study performed in Canada showed no change in survival and possible harm with CPAP use, but in a post hoc analysis the subgroup of patients who had an effective reduction in AHI with CPAP appeared to have an improvement in transplant-free survival.

Another form of PAP has been better studied in CSA/CSR with CHF: adaptive servoventilation (ASV). ASV devices evaluate the patient's breathing pattern on a breath-to-breath basis and aim to maintain stable ventilation by varying the amount of pressure support and ventilatory rate support delivered. This approach is intended to stabilize the circulating CO2 levels and reduce both central apneas and ventilatory overshoots.

ASV has been shown to control CSA and CSR better than CPAP and to improve left ventricular ejection fraction, quality of life, and in some studies, six-minute walk distance. Therefore, it is reasonable to recommend treatment with ASV after an overnight titration study is done. However, some guidelines still require that failure of CPAP be demonstrated before ASV is initiated.

Other treatments of CSA/CSR include supplemental oxygen if other treatments have failed. Although theophylline and acetazolamide have been shown in small case series to improve CSA in CHF, their use cannot be recommended at this time. There are anecdotal reports that cardiac resynchronization therapy can result in improvement of CSA in CHF patients. Cardiac valve replacement in patients with CHF secondary to valvular disease is associated with an improved AHI.

Central Sleep Apnea that is due to a drug or substance, most commonly opioid medications: The mainstay of treatment is to discontinue or reduce the dose of narcotics used, which usually eliminates CSA. However. when this approach is not possible or is ineffective, treatment with PAP should be attempted using an overnight titration study. CPAP is not always effective, and it often fails to result in normalization of the AHI. In these cases, treatment with bilevel PAP with a back-up rate or ASV have been reported with variable success.

High Altitude Periodic Breathing: The best treatment for high-altitude-induced periodic breathing is to descend to sea level or to a lower altitude. Acetazolamide, supplemental oxygen and temazepam have also been reported to improve this condition.

Central Sleep Apnea that is due to a medical condition other than Cheyne-Stokes: Treatment if the underlying condition is the mainstay of treatment. Otherwise, the PAP therapies described above could be used.

What is the prognosis for patients managed in the recommended ways?

With the exception of CSA/CSR in congestive heart failure, there is no long-term data regarding the prognosis for the different types of CSA syndromes. Therefore, therapy is aimed at relieving symptoms.

In congestive heart failure, the presence of CSA/CSR portends a poor prognosis. Treatment with CPAP, when effective in reducing the AHI, can improve ejection fraction and transplant-free survival, but there is no definite proof for improved overall mortality rates.

Treatment with ASV can improve quality of life, hemodynamic parameters like left ventricular ejection fraction, and exercise capacity. There is no evidence of a mortality benefit.

What other considerations exist for patients with central sleep apnea syndrome?

No other considerations exist for patients with central sleep apnea syndrome.

What’s the evidence?

Dempsey, JA. "Crossing the apnoeic threshold: causes and consequences". Exp Physiol. vol. 90. 2005. pp. 13-24.

Review of the physiology of the control of breathing during non-REM sleep and the role of the apnea threshold in generating a central sleep apnea.

Javaheri, S. "Sleep disorders in systolic heart failure: a prospective study of 100 male patients. The final report". Int J Cardiol. vol. 106. 2006. pp. 21-8.

Prospective review of one hundred consecutive patients with heart failure showing a prevalence of CSA of 37 percent.

Oldenburg, O, Lamp, B, Faber, L, Teschler, H, Horstkotte, D, Topfer, V. "Sleep-disordered breathing in patients with symptomatic heart failure: a contemporary study of prevalence in and characteristics of 700 patients". Eur J Heart Fail. vol. 9. 2007. pp. 251-7.

Large prospective study of seven hundred patients with heart failure who were on medical therapy, including ACE inhibitors and beta blockers, and who underwent screening sleep studies. The prevalence of CSA was found to be 40 percent. Patients with CSA had more severe disease.

Nopmaneejumruslers, C, Kaneko, Y, Hajek, V, Zivanovic, V, Bradley, TD. "Cheyne-Stokes respiration in stroke: relationship to hypocapnia and occult cardiac dysfunction". Am J Respir Crit Care Med. vol. 171. 2005. pp. 1048-52.

Prospective study of 93 patients who had had a stroke. CSA was found to be associated with hypocapnia and occult cardiac dysfunction, but not with the location or type of stroke.

Sin, DD, Fitzgerald, F, Parker, JD, Newton, G, Floras, JS, Bradley, TD. "Risk factors for central and obstructive sleep apnea in 450 men and women with congestive heart failure". Am J Respir Crit Care Med. vol. 160. 1999. pp. 1101-6.

Observational study of 450 patients with heart failure referred to a sleep center. CSA was associated with male gender, age greater than sixty years, atrial fibrillation, and hypocapnia during wakefulness.

Hanly, PJ, Zuberi-Khokhar, NS. "Increased mortality associated with Cheyne-Stokes respiration in patients with congestive heart failure". Am J Respir Crit Care Med. vol. 153. 1996. pp. 272-6.

Prospective study of sixteen male patients with chronic CHF who underwent a polysomongram. Nine were found to have nocturnal Cheyne Stokes Respiration (CSR), and these nine had a higher mortality rate over a 3.1-4.5-year follow-up than did the group of patients who did not have CSR.

Lanfranchi, PA, Braghiroli, A, Bosimini, E. "Prognostic value of nocturnal Cheyne-Stokes respiration in chronic heart failure". Circulation. vol. 99. 1999. pp. 1435-40.

Prospective study of 62 patients with CHF followed for 28 months plus or minus 13 months that found that the AHI in CSR, as well as the left atrial area, were powerful independent predictors of mortality.

Sin, DD, Logan, AG, Fitzgerald, FS, Liu, PP, Bradley, TD. "Effects of continuous positive airway pressure on cardiovascular outcomes in heart failure patients with and without Cheyne-Stokes respiration". Circulation. vol. 102. 2000. pp. 61-6.

Randomized controlled study of 66 patients with CHF with and without CSR who received CPAP or were assigned to a control arm. CPAP treatment improved LVEF in patients with CSR but not in those without CSR. There was a suggestion that CPAP could reduce the combined mortality-cardiac transplantation rate in those CHF patients with CSR-CSA who comply with therapy.

Pepperell, JC, Maskell, NA, Jones, DR. "A randomized controlled trial of adaptive ventilation for Cheyne-Stokes breathing in heart failure". Am J Respir Crit Care Med. vol. 168. 2003. pp. 1109-14.

Thirty patients with CHF with CSR were randomized to adaptive servo ventilation (ASV) treatment or subtherapeutic ASV treatment. The therapeutic ASV arm showed improvement in excessive daytime sleepiness, circulating brain natriuretic peptide, and secretion of urinary metadrenaline.

Philippe, C, Stoica-Herman, M, Drouot, X. "Compliance with and effectiveness of adaptive servoventilation versus continuous positive airway pressure in the treatment of Cheyne-Stokes respiration in heart failure over a six month period". Heart. vol. 92. 2006. pp. 337-42.

Twenty-five patients with CHF and CSA-CSR were randomly assigned to ASV or CPAP. ASV was better at normalizing the AHI. At six months, compliance and improvement in quality of life were higher with ASV, and only ASV induced a significant increase in LVEF.

Andreas, S, Weidel, K, Hagenah, G, Heindl, S. "Treatment of Cheyne-Stokes respiration with nasal oxygen and carbon dioxide". Eur Respir J. vol. 12. 1998. pp. 414-9.

Cross-over, single-blind, placebo-controlled trial of nine patients with CHF and CSA-CSR: nocturnal O2 plus CO2 improved Cheyne-Stokes respiration but increased sympathetic activation.

Javaheri, S, Parker, TJ, Wexler, L, Liming, JD, Lindower, P, Roselle, GA. "Effect of theophylline on sleep-disordered breathing in heart failure". N Engl J Med. vol. 335. 1996. pp. 562-7.

Small cross-over, placebo-controlled series of fifteen men with CHF and CSR who received theophylline or placebo for five days. Theophylline therapy reduced the number of episodes of apnea and hypopnea and the duration of arterial oxyhemoglobin desaturation during sleep.

Hanly, PJ, Millar, TW, Steljes, DG, Baert, R, Frais, MA, Kryger, MH. "The effect of oxygen on respiration and sleep in patients with congestive heart failure". Ann Intern Med. vol. 111. 1989. pp. 777-82.

Randomized, single-blind, placebo-controlled crossover study of nine patients with heart failure and CSR who received oxygen at 2-3L/min. Nocturnal oxygen therapy reduced Cheyne-Stokes respiration, corrected hypoxemia, and consolidated sleep by reducing arousals caused by the hyperpneic phase of Cheyne-Stokes respiration.

Lorenzi-Filho, G, Rankin, F, Bies, I, Douglas Bradley, T. "Effects of inhaled carbon dioxide and oxygen on Cheyne-Stokes respiration in patients with heart failure". Am J Respir Crit Care Med. vol. 159. 1999. pp. 1490-8.

Small prospective study of ten patients with CHF and CSR showing that inhalation of CO2 increased circulating CO2 levels and reversed central apneas.

Javaheri, S. "Acetazolamide improves central sleep apnea in heart failure: a double-blind, prospective study". Am J Respir Crit Care Med. vol. 173. 2006. pp. 234-7.

Double-blind cross-over study of twelve male patients with CHF and CSA given acetazolamide or placebo prior to an overnight polysomnogram. Acetazolamide significantly improved CSA and related daytime symptoms.

Bradley, TD, Logan, AG, Kimoff, RJ. "Continuous positive airway pressure for central sleep apnea and heart failure". N Engl J Med. vol. 353. 2005. pp. 2025-33.

CANPAP study: Randomized controlled study of 258 patients with CHF and CSA randomized to CPAP therapy or no therapy. Although CPAP improved central sleep apneas, nocturnal oxygenation, ejection fraction, and six-minute walk distances, there were no differences between the control group and the CPAP group in terms of the number of hospitalizations, the quality of life, or atrial natriuretic peptide levels. An early divergence in survival rates without heart transplantation favored the control group, but after eighteen months the divergence favored the CPAP group so the overall event rates (death and heart transplantation) did not differ. There was no evidence of improved survival with CPAP.

Arzt, M, Floras, JS, Logan, AG. "Suppression of central sleep apnea by continuous positive airway pressure and transplant-free survival in heart failure: a post hoc analysis of the Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure Trial (CANPAP)". Circulation. vol. 115. 2007. pp. 3173-80.

This was a post-hoc analysis of the CANPAP study that divided a group of patients on CPAP into those who had an adequate suppression of the central apneas with CPAP to an AHI lower than 15 and those who did not. The two groups were compared them to a control arm. Despite similar CPAP pressure and hours of use in the two test groups, CPAP-CSA-suppressed subjects experienced a greater increase in left ventricular ejection fraction at three months (P=0.001) and significantly better transplant-free survival (hazard ratio at 95% confidence interval 0.371 [0.142 to 0.967], P=0.043) than control subjects did, whereas the CPAP-CSA-unsuppressed group did not (for left ventricular ejection fraction, P=0.984, and for transplant-free survival, hazard ratio 1.463 [95% confidence interval 0.751 to 2.850], P=0.260).

Kasai, T, Usui, Y, Yoshioka, T. "Effect of flow-triggered adaptive servo-ventilation compared with continuous positive airway pressure in patients with chronic heart failure with coexisting obstructive sleep apnea and Cheyne-Stokes respiration". Circ Heart Fail. vol. 3. 2010. pp. 140-8.

Randomized study of 31 patients with CHF and CSR who were randomized to be treated with CPAP or ASV. ASV resulted in significantly better control of the respiratory events, improved quality of life, and improved left ventricular ejection fraction than CPAP did.

Leung, RS, Huber, MA, Rogge, T, Maimon, N, Chiu, KL, Bradley, TD. "Association between atrial fibrillation and central sleep apnea". Sleep. vol. 28. 2005. pp. 1543-6.

Observational study that compared the prevalence of atrial fibrillation in sixty consecutive patients with idiopathic CSA, sixty patients with obstructive sleep apnea and sixty patients without sleep apnea (apnea-hypopnea index < 10), matched for age, sex, and body mass index. The prevalence was found to be much higher in idiopathic CSA than in the other two groups (27%, 1.7%, and 3.3%, respectively, P < .001).

Parra, O, Arboix, A, Bechich, S. "Time course of sleep-related breathing disorders in first-ever stroke or transient ischemic attack". Am J Respir Crit Care Med. vol. 161. 2000. pp. 375-80.

Prospective study of 161 patients with acute stroke. In the acute phase, there was a high prevalence of both obstructive and central apneic events. as well as Cheyne-Stokes respiration. Three months later the central events improved spontaneously, but the obstructive events remained unchanged, suggesting that OSA might have predated the stroke, whereas the central apneas might have been caused by the stroke.

Wang, D, Teichtahl, H, Drummer, O. "Central sleep apnea in stable methadone maintenance treatment patients". Chest. vol. 128. 2005. pp. 1348-56.

Prospective study of fifty patients on a stable methadone program compared to matched controls. Methadone patients had a prevalence of central sleep apnea of 30 percent versus 0 percent in the control group.

Javaheri, S, Malik, A, Smith, J, Chung, E. "Adaptive pressure support servoventilation: a novel treatment for sleep apnea associated with use of opioids". J Clin Sleep Med. vol. 4. 2008. pp. 305-10.

Small case study of five patients on chronic opioids with sleep-disordered breathing who failed CPAP because of an increase in central events. ASV resulted in a significant reduction in both central and obstructive events.

Farney, RJ, Walker, JM, Boyle, KM, Cloward, TV, Shilling, KC. "Adaptive servoventilation (ASV) in patients with sleep-disordered breathing associated with chronic opioid medications for non-malignant pain". J Clin Sleep Med. vol. 4. 2008. pp. 311-9.

Retrospective review of 22 patients on chronic opioids who underwent titration studies for sleep-disordered breathing with CPAP and ASV. ASV improved obstructive events but not central events or hypopneas. ASV did not improve oxygenation or Biot's breathing.

Luks, AM, van Melick, H, Batarse, RR, Powell, FL, Grant, I, West, JB. "Room oxygen enrichment improves sleep and subsequent day-time performance at high altitude". Respir Physiol. vol. 113. 1998. pp. 247-58.

Randomized, double-blind trial of eighteen subjects taken from sea level to 3800 meters of altitude. Supplementation with 24 percent oxygen improved apneas, periodic breathing, and sleep quality.

Nickol, AH, Leverment, J, Richards, P. "Temazepam at high altitude reduces periodic breathing without impairing next-day performance: a randomized cross-over double-blind study". J Sleep Res. vol. 15. 2006. pp. 445-54.

A double-blind, randomized, cross-over trial of 33 healthy volunteers who took 10 mg of temazepam and placebo in random order on two successive nights soon after arrival at five thousand meters of altitude, following a seventeen-day trek from 410 meters of altitude. Temazepam significantly reduced periodic breathing and resulted in a 2 percent drop in mean oxygen saturations overnight but did not affect next day performance levels.

Fischer, R, Lang, SM, Leitl, M, Thiere, M, Steiner, U, Huber, RM. "Theophylline and acetazolamide reduce sleep-disordered breathing at high altitude". Eur Respir J. vol. 23. 2004. pp. 47-52.

Randomized, double-blind, placebo-controlled study of thirty males at high altitude who were given theophylline, acetazolamide, or placebo. Both theophylline and acetazolamide normalized periodic breathing and improved oxygenation compared to placebo.

Franklin, KA, Eriksson, P, Sahlin, C, Lundgren, R. "Reversal of central sleep apnea with oxygen". Chest. vol. 111. 1997. pp. 163-9.

Prospective study of twenty patients with non-hypercapnic central sleep apnea, eighteen with Cheyne-Stokes associated with either heart failure or stroke, and two with idiopathic CSA. Administration of supplemental oxygen significantly reduced the number of central events and related arousals.

Thomas, RJ, Daly, RW, Weiss, JW. "Low-concentration carbon dioxide is an effective adjunct to positive airway pressure in the treatment of refractory mixed central and obstructive sleep-disordered breathing". Sleep. vol. 28. 2005. pp. 69-77.

Small series of six patients with mixed obstructive and central apneas without renal or heart failure. Administration of carbon dioxide with CPAP was effective at reducing the treatment-resistant mixed and central events during a titration night with no adverse events reported.

Xie, A, Rankin, F, Rutherford, R, Bradley, TD. "Effects of inhaled CO2 and added dead space on idiopathic central sleep apnea". J Appl Physiol. vol. 82. 1997. pp. 918-26.

Increasing PaCO2 by increasing dead space or rebreathing CO2 abolished central apneic events in patients with idiopathic CSA.

Quadri, S, Drake, C, Hudgel, DW. "Improvement of idiopathic central sleep apnea with zolpidem". J Clin Sleep Med. vol. 5. 2009. pp. 122-9.

Case series of twenty patients with idiopathic CSA who were treated with zolpidem 10 mg at bedtime. Overnight polysonogram showed a significant reduction in the AHI that was mainly due to a reduction in central events. Subjects also had improved sleep continuity and decreased subjective daytime sleepiness, in the majority of cases without a worsening of oxygenation or obstructive events.
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