Central Sleep Apnea in Congestive Heart Failure: Prevalence, Mechanisms, Impact, and Therapeutic Options

Shahrokh Javaheri, M.D.

Disclosures

Semin Respir Crit Care Med. 2005;26(1):44-55. 

In This Article

Treatment of Central Sleep Apnea

Treatment of central sleep apnea may be achieved in several ways (Fig. 4).[1,68] Because heart failure is the fundamental reason for development of periodic breathing with central sleep apnea, we first maximize the therapy of heart failure. If periodic breathing persists, several therapeutic options are available (Fig. 4).

Treatment of central sleep apnea-hypopnea in heart failure. With permission from Javaheri.[1]

Optimal pharmacological therapy of heart failure should improve or eliminate periodic breathing[1,68] by several mechanisms ( Table 1 ). Treatment of heart failure by reverse remodeling should improve both systolic and diastolic dysfunctions. Stroke volume should increase, whereas regurgitant murmur, pulmonary capillary pressure, congestion and edema, and pleural effusion should decrease. Due to decreased pulmonary capillary pressure and reduced lung water, which decrease J receptor stimulation, tachypnea should imrove and hypocapnia should revert to eucapnia. As stroke volume increases and cardiopulmonary blood volume decreases, effective arterial circulation time should decrease. Functional residual capacity shoud increase as cardiac size decreases and pleural effusion and intra- and extravascular lung water decrease. All these changes should decrease the likelihood of periodic breathing and central sleep apnea (see mechanisms).

After optimization of cardiopulmonary function, if periodic breathing persists, several therapeutic options are possible (Fig. 4). These include surgical (cardiac transplantation, which has a long waiting list) and medical approaches.

Studies[69,70,71,72] suggest that cardiac transplantation usually eliminates central sleep apnea. This is expected because cardiac transplantation results in the reversal of hemodynamic features of heart failure that mediate periodic breathing. However, obstructive sleep apnea may develop after cardiac transplantation.[73,74,75,76,77] Due to the use of steroids and improved quality of life, weight gain is common in transplant recipients, and obesity is the major risk factor for obstructive sleep apnea. A recent systematic study[77] of a relatively large number of cardiac transplant recipients revealed a high prevalence of obstructive sleep apnea. Forty-five of 60 consecutive eligible patients took part in the study. Thirty-six percent had an apnea-hypopnea index of ≥ 15 per hour. The average index was ~50 per hour. The presence of obstructive sleep apnea was related to the amount of weight gain after cardiac transplantation. Subjects with obstructive sleep apnea had gained the most weight after transplantation and had significantly higher body mass index, higher prevalence of hypertension, and a poorer quality of life than those without sleep apnea. Interestingly, the prevalence of periodic limb movement and restless leg syndrome is high in cardiac transplant recipients.[77]

Supplemental nasal oxygen administered during sleep is a potent therapy for central sleep apnea in systolic heart failure.[76] Several studies[78,79,80,81] have shown apnea-hypopnea index decreases significantly and arterial oxyhemoglobin desaturation is eliminated. In addition, a randomized, placebo-controlled, double-blind study reported that (1 week) administration of supplemental nocturnal oxygen improves maximum exercise capacity,[82] which perhaps is mediated by a reduction in ventilatory response to CO2.[83] Oxygen therapy also decreases sympathetic activity as measured by microneurography[84] and urinary norepinephrine excretion.[85] The latter was reported in a randomized, double-blind, placebo-controlled study[83] showing 50% reduction in urinary norepinephrine excretion after 4 weeks of nocturnal oxygen therapy.

Mechanisms of therapeutic effect of nasal O2 on central sleep apnea[78] include a small rise in PCO2,[86] reduction in ventilatory response to CO2,[83] and increasing body stores (e.g., lung contents) of O2. These mechanisms are briefly described following here.

Hypoxemia has been shown to increase the difference between eucapnic PCO2 minus the apneic PCO2 level, increasing the likelihood for development of central apnea.[35] It is therefore conceivable that O2 administration increases the PCO2 and also widens the difference between the two PCO2 set points. Furthermore, because heightened ventilatory response increases the likelihood of developing central sleep apnea, reduction in hypercapnic ventilatory response by administration of oxygen[83] should decrease the likelihood of developing periodic breathing and central apnea. Similarly, increased body stores of oxygen should increase underdamping and decrease periodic breathing.

In spite of several studies showing the therapeutic effects of oxygen on central sleep apnea, prospective, placebo-controlled, long-term studies are necessary to determine if nocturnal oxygen therapy has the potential to decrease morbidity and mortality of patients with systolic heart failure.[78]

Theophylline is a known respiratory stimulant. At therapeutic serum concentrations, theophylline competes with adenosine at some of its receptor sites. In the central nervous system, adenosine is a respiratory depressant and theophylline stimulates respiration by competing with adenosine. Open studies[87,88] and a double-blind study[89] have shown the efficacy of this drug in the treatment of central sleep apnea in heart failure. This effect is achieved at therapeutic plasma concentration. In a double-blind, randomized, placebo-controlled, crossover study of 15 patients with systolic heart failure,[89] administration of theophylline, twice daily by mouth for more than a week, decreased the apnea-hypopnea index by ~50% and improved arterial oxyhemoglobin saturation. Central apnea index decreased from 26/hr on placebo to 6/hr with theophylline.[89] Though the exact mechanisms remain to be established, conceivably, an increase in ventilation by theophylline could decrease the likelihood of developing central apnea during sleep. Furthermore, it is reasonable to hypothesize that theophylline should widen the difference between the prevailing PCO2 and the apneic threshold PCO2. However, this needs to be experimentally proven.

Potential arrhythmogenic effects and phosphodiesterase inhibition are common concerns with long-term use of theophylline in patients with heart failure. Therefore, further controlled studies of larger numbers of patients than our study[89] are necessary to assure its safety. Meanwhile, if theophylline is used to treat central sleep apnea, frequent and careful follow-ups are necessary.

Acetazolamide is a carbonic anhydrase inhibitor and is used as a diuretic and as a respiratory stimulant. Respiratory stimulation is mediated in part by metabolic acidosis stimulating the peripheral and central chemoreceptors. Acetazolamide has been effectively used in the treatment of idiopathic central sleep apnea[90,91] and periodic breathing at higher altitude.[92] Conceivably, acetazolamide may also be useful in the treatment of central sleep apnea in patients with heart failure, though no systematic study has been reported. This notion is substantiated by the observation that acetazolamide increases the difference between the prevailing PCO2 and PCO2 at the apneic threshold,[35] decreasing the likelihood of developing central apnea.

Overnight application of a nasal CPAP device has been shown to improve central sleep apnea in 43% of the subjects with systolic heart failure.[93] In this group, the apnea-hypopnea index decreased from 36 per hour to 4 per hour, and desaturation was virtually eliminated. CPAP level varied from 5 to 12 cm of H2O. In heart failure patients whose sleep apnea responded to CPAP, the number of premature ventricular contractions, couplets and ventricular tachycardias decreased. This effect was presumed to be due to decreased sympathetic activity and improved oxygenation. CPAP had no significant effect on ventricular irritability in patients whose disordered breathing did not improve.[93] This group accounted for 57% of heart failure patients. Characteristically, these patients had severe central sleep apnea with an average apnea-hypopnea index of 60/hr.

Chronic trials (1-3 months) of nasal positive airway pressure devices in subjects with heart failure show a reduction in apnea-hypopnea index, improved desaturation, decreased plasma and urinary norepinephrine, and an increase in left ventricular ejection fraction.[62,94,95] The results of a study of a small number of patients suggest that CPAP therapy may improve survival of heart failure patients.

However, I should emphasize that several negative studies[96,97,98] have also been reported. And, as noted earlier, in our study[93] most patients were nonresponsive to overnight use of CPAP. Furthermore, caution should be exercised with use of nasal CPAP. Because of increased intrathoracic pressure, cardiac output may decrease resulting in hypotension, particularly in patients with atrial fibrillation[99] and those in whom right ventricular volume pressure characteristics are on the ascending limb of the Frank-Starling curve. In such patients, right ventricular stroke volume is preload dependent, and a decrease in venous return could result in hypotension. A similar mechanism may result in hypotension in patients in whom left ventricular stroke volume is preload dependent. Such reduction in cardiac output could result in reduction in coronary blood flow and ischemia, particularly in patients with established coronary artery disease.

We also note that most CPAP studies of patients with central sleep apnea and heart failure with favorable results have been reported from Toronto. We are awaiting the results of a large, multicenter, control study on CPAP to substantiate the preliminary favorable effects of CPAP on survival of patients with systolic heart failure.

Another positive airway pressure device that has been used to treat central sleep apnea is adaptive pressure support servoventilation. This device provides variable amounts of ventilatory support during different phases of periodic breathing. The support is minimal during the hyperpneic phase of periodic breathing, and maximal during periods of diminished breathing and central apnea. In an acute (1-night) study[100] of 14 subjects with systolic heart failure and central sleep apnea, the apnea-hypopnea index decreased significantly from ~45 per hour to 6 per hour. The improvement by the adaptive pressure support servoventilation was better than that observed with either CPAP or oxygen. The adaptive pressure support servoventilation device may be particularly helpful in heart failure patients who are nonresponsive to[93] or noncompliant with CPAP. However, like CPAP, multicenter, long-term studies with this device are also necessary to prove its long-term safety in patients with heart failure.

In 15 subjects, some of whom had mild left ventricular systolic dysfunction, atrial overdrive pacing was shown to improve central and obstructive sleep apnea.[101] These subjects had permanent atrial-synchronized ventricular pacemakers placed for symptomatic sinus bradycardia. Atrial overdrive [nocturnal mean (± SD) spontaneous beats per minute 51 ± 8, vs 72 ± 4 with overdrive] moderately but significantly decreased the apnea-hypopnea index (from 28 ± 22 to 11 ± 14 per hour), improved arterial oxyhemoglobin desaturation, and decreased arousals. It is emphasized that in these patients, central apneas accounted for most of the disordered breathing events. Respective indices for central apneas, obstructive apneas, and hypopneas were 13, 6, and 9 per hour. With pacing, respective indices were 6, 3, and 3 per hour. Therefore the change in mean obstructive apnea index was 3/hour.[101] In any case the mechanisms of action of pacing improving central apnea remain unclear, and further trials are necessary to determine whether atrial pacing overdrive would be therapeutically helpful for sleep-related breathing disorders in the setting of congestive heart failure.

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