Recent studies show that central sleep apnea occur in about 40% of patients with heart failure and systolic dysfunction. The pathophysiological consequences of central sleep apnea may contribute to morbidity and mortality of heart failure, three treatment modalities, oxygen, continuous positive airway pressure and theophylline have been shown to decrease periodic breathing modestly with considerable improvement in arterial oxyhemoglobin desaturation, and variable effects on sleep characteristics. However, long-term effects of central sleep apnea and its treatment on the natural history of heart failure remain to be determined.

Background-Heart failure is a highly prevalent disorder that continues to be associated with repeated hospitalizations, high morbidity, and high mortality. Sleep-related breathing disorders with repetitive episodes of asphyxia may adversely affect heart function. The main aims of this study were to determine the prevalence, consequences, and differences in various sleep-related breathing disorders in ambulatory male patients with stable heart failure.Methods and Results-This article reports the results of a prospective study of 81 of 92 eligible patients with heart failure and a left ventricular ejection fraction <45%. There were 40 patients without (hourly rate of apnea/hypopnea, 4+/-4; group 1) and 41 patients with (51% of all patients; hourly rate of apnea/hypopnea, 44+/-19, group 2) sleep apnea. Sleep disruption and arterial oxyhemoglobin desaturation were significantly more severe and the prevalence of atrial fibrillation (22% versus 5%) and ventricular arrhythmias were greater in group 2 than in group 1. Forty percent of all patients had central sleep apnea, and 11% had obstructive sleep apnea. The latter patients had significantly greater mean body weight (112+/-30 versus 75+/-16 kg) and prevalence of habitual snoring (78% versus 28%). However, the hourly rate of episodes of apnea and hypopnea (36+/-10 versus 47+/-21), episodes of arousal (20+/-14 versus 23+/-11), and desaturation (lowest saturation, 72+/-11% versus 78+/-12%) were similar in patients with these different types of apnea.Conclusions-Fifty-one percent of male patients with stable heart failure suffer from sleep-related breathing disorders: 40% from central and 11% from obstructive sleep apnea, Both obstructive and central types of sleep apnea result in sleep disruption and arterial oxyhemoglobin desaturation. Patients with sleep apnea have a high prevalence of atrial fibrillation and ventricular arrhythmias.

A recent study [1] showed that about 45% of patients with stable, treated heart failure may have periodic breathing during sleep. These episodes of apnea and hypopnea are associated with severe arterial oxyhemoglobin desaturation and excessive arousals that disrupt sleep. Because heart failure is highly prevalent, performance of sleep studies on all patients with heart failure is not practical. However, it is difficult to predict which patients may develop periodic breathing during sleep [1]. Therefore, simple laboratory tests that could predict periodic breathing during sleep would be helpful screening tools. Arterial Pco 2 has a dominant influence on breathing. A carefully performed study [2] done during sleep in normal humans showed that central apnea may be induced when the Paco 2 is experimentally lowered by 1 to 3 mm Hg below the resting Paco 2 while patients are awake. Therefore, a low Paco 2 while awake may predispose to ventilatory instability and development of central sleep apnea. To examine the predictive value of resting Paco 2 while awake for central sleep apnea in heart failure, we studied patients with stable heart failure and no major comorbid conditions. Methods Ambulatory male patients with stable, medically treated left heart failure (left ventricular ejection fraction 45%) took part in this study. Details on these patients have been published elsewhere [1, 3]. Patients were clinically stable (symptoms or signs of heart failure had not changed in the preceding 4 weeks) and received standard therapy; no change had been made in cardiac medications in the preceding 4 weeks. Exclusion criteria were major comorbid disorders or use of morphine derivatives, benzodiazepines, or respiratory stimulants, such as theophylline and acetazolamide [1-3]. We studied only men because women are seldom referred to our center. After patients spent an adaptation night in the sleep laboratory, polysomnography was performed by using standard techniques, as detailed elsewhere [1, 3, 4]. Apnea was defined as cessation of inspiratory airflow for 10 seconds or more. Obstructive apnea was defined as the absence of airflow in the presence of rib cage and abdominal excursions. Central apnea was defined as the absence of rib cage and abdominal excursions and absence of airflow [1, 3, 4]. Hypopnea was defined as a reduction of airflow lasting 10 seconds or more associated with a decrease of 4% or more in arterial oxyhemoglobin saturation or an arousal [5]. In the absence of measurements of esophageal pressure, however, differentiation of central apnea and hypopnea from obstructive events can be difficult. We classified hypopnea as obstructive if paradoxical thoracoabdominal excursions occurred or if the airflow decreased out of proportion to the reduction in the thoracoabdominal excursion. The apneahypopnea index was the number of episodes of apnea and hypopnea per hour. Polysomnograms were scored in a blinded manner. Central sleep apnea was defined polysomnographically by the presence of 10 or more hourly episodes of apnea and hypopnea and 5 or more hourly episodes of central apnea. The number of hourly episodes of central disordered breathing had to be more than 50% of the overall total number of episodes of apnea and hypopnea. We defined absence of sleep apnea as fewer than 10 hourly episodes of apnea and hypopnea. Arterial blood samples were obtained with the patient in a sitting position after he had rested for 15 minutes. To minimize pain, we used 2% lidocaine to anesthetize the skin where the radial artery was punctured. Afterward, by touching the skin with a sterile needle, we assured the patient that the procedure was painless. Our intent was to minimize changes in Paco 2 caused by pain and anxiety. We performed pulmonary function tests, measured left ventricular ejection fraction, and did Holter monitoring as detailed elsewhere [1, 3, 6]. Patients were classified as eucapnic (Paco 2 > 35 and < 44 mm Hg [n = 41]) or hypocapnic (Paco 2 35 mm Hg [n = 18]). We used the Wilcoxon rank-sum test to assess significant differences between the two groups and chi-square analysis for proportions. Stepwise least-squares multiple regression analysis was used to determine the independent effects of certain variables on log transformation of the hourly rate of apnea and hypopnea. A two-sided P value less than 0.05 was considered statistically significant. Mean values SDs and percentages are reported as needed. We calculated 95% CIs by using t statistics. All calculations were done by using SAS software [7]. Results In eucapnic and hypocapnic patients, the mean Paco 2 and plasma concentrations of hydrogen and bicarbonate ions differed significantly, but demographic characteristics, results of pulmonary function tests, and left ventricular ejection fraction did not (Table 1). Table 1. Characteristics of Eucapnic and Hypocapnic Patients with Stable Heart Failure Arterial Pco 2 ranged from 35.2 to 43.6 mm Hg in eucapnic patients (mean, 39 mm Hg [95% CI, 38 to 40 mm Hg]) and 23.0 to 35.0 mm Hg in hypocapnic patients (mean, 32.5 mm Hg [CI, 30.8 to 34.2 mm Hg]). Of the 18 hypocapnic patients, 14 (78% [CI, 52% to 93%]) had central sleep apnea; this prevalence was significantly higher than that in eucapnic patients (16 of 41 [39%; CI, 25% to 55%]; P = 0.01). Although the prevalence of subjective habitual snoring was lower and the prevalence of excessive daytime sleepiness was higher in the hypocapnic patients than in the eucapnic patients, the differences were not significant (Table 1). In eucapnic patients and hypocapnic patients, the use of vasodilators (93% and 89%), digoxin (73% and 67%), isosorbide dinitrate (41% and 39%), and diuretics (80% and 89%) did not significantly differ. However, significantly more hypocapnic patients were New York Heart Association class III and fewer were class I and class II compared with eucapnic patients (Table 1). Hypocapnic patients had significantly more arousals and decreased sleep efficiency due to excessive periodic breathing (Table 2). The number of hourly episodes of apnea and hypopnea and central apnea was significantly greater in hypocapnic patients than in eucapnic patients (Table 2). Consistent with the difference in the number of hourly episodes of apnea and hypopnea, arterial oxyhemoglobin desaturation was more severe in hypocapnic patients than in eucapnic patients, although the differences were not statistically significant (Table 2). Hypocapnic patients had a significantly higher prevalence of ventricular irritability (Table 2). Ventricular tachycardia (defined as three premature ventricular depolarizations in a row) was 20 times more prevalent in hypocapnic patients than in eucapnic patients. The mean serum potassium level and concentrations of sodium and digoxin did not significantly differ between the two groups. Table 2. Sleep Characteristics of Eucapnic and Hypocapnic Patients with Stable Heart Failure* In a stepwise least-squares multiple regression analysis, we assessed the independent contribution of Paco 2, hydrogen ion concentration ( 35 or >35 nmol/L), and New York Heart Association functional classes (III or I and II) with the apneahypopnea index as the dependent variable. The P values for Paco 2 and hydrogen ion concentration were 0.014 and 0.034, respectively. When New York Heart Association functional classes were added, only Paco 2 remained significant (P = 0.04 [for hydrogen ion concentration, P = 0.06]). Discussion Among 59 patients with stable heart failure who did not have other comorbid disorders, 18 (31%) were hypocapnic while awake. Only 4 of the 18 patients did not have central sleep apnea. Therefore, given the prevalence of central sleep apnea in study patients, 78% of patients with heart failure and low Paco 2 had central sleep apnea. As shown by our results, most hypocapnic patients will develop relatively severe periodic breathing during sleep, with an average of 36 hourly episodes of apnea and hypopnea (Table 2). Furthermore, in stepwise multiple regression analysis, Paco 2 was associated with hourly episodes of apnea and hypopnea (although this may have been confounded by hydrogen ion concentrations). These episodes of apnea and hypopnea resulted in a moderate degree of arterial oxyhemoglobin desaturation, excessive arousals, and disrupted sleep (Table 2). However, our results also show that in patients with stable heart failure, a low Paco 2 while awake is not a prerequisite for development of central sleep apnea. Of 41 eucapnic patients, 16 (39%) had central sleep apnea. Because only 14 of the 30 patients with central sleep apnea were hypocapnic, the sensitivity [8] of a low Paco 2 was 47%. In the absence of systematic, large, longitudinal studies, we speculate that the degree of periodic breathing with associated arterial oxyhemoglobin desaturation and arousals, if left untreated, may adversely affect cardiac function and result in excessive illness and death [1, 9]. The results of our current study and two previous studies [10, 11] suggest that performing sleep studies on hypocapnic patients with heart failure may identify patients who require sleep apnea therapy. Another important finding was the significantly greater number of hourly episodes of ventricular arrhythmias during sleep in hypocapnic patients with heart failure (Table 2). The prevalence of ventricular tachycardia was 20 times greater in the hypocapnic patients than in the eucapnic patients. A low Paco 2 while awake may also indicate the need for Holter monitoring because detection and appropriate treatment of ventricular tachycardia may improve survival [12]. Although a previous report [13] suggested that hypocapnia may contribute to the development of arrhythmias in patients with coronary artery disease, our report describes the largest systematic study to date to show the relation between hypocapnia and ventricular tachycardia in patients with left heart failure. We could not determine

Neuropathological studies have shown increased cerebral spaces in alcoholics, yet, the effect of ethanol on cerebrospinal fluid (CSF) production is not known. We investigated the effects of ethanol on CSF production measured by ventriculocisternal perfusion (VCP) technique, in two groups (n=10 in each) of anesthetized, paralyzed and mechanically ventilated dogs. In group I, which served as control, VCP was performed with normal mock CSF. Ethanol (150 mg/dl of mock CSF, approximately 33 mM) was added to VCP in group II. Beginning 60 min after the start of VCP, CSF production was measured every 15 min for the next 4 h. In group I, mean (+/-S.D.) value for CSF production was 51+/-10 microliter/min initially and decreased significantly but slightly with time, to the lowest value of 44+/-11 microliter/min at the end of the experiment. In group II, values for CSF production were 41+/-8, 41+/-8, 41+/-8, 43+/-6, 43+/-8, 42+/-6, 42+/-8, 38+/-6, 37+/-6, 36+/-5, 36+/-5, microliter/min, respectively, from 15 to 165 min. These values were invariably significantly lower than their respective mean values in the control group. Furthermore, when ethanol was withdrawn at the trough of CSF production (at 165 min), production significantly increased by about 40%. We conclude that ethanol at a concentration of 150 mg/dl (far below lethal levels) is one of the most potent inhibitory drugs for decreasing CSF production. This effect is short-onset and is fully reversible within 15 min of ethanol withdrawal.

We investigated the effects of omeprazole and Sch 28080, a more specific and a more potent inhibitor of K+,H+-ATPase than omeprazole, in canine cerebrospinal fluid (CSF) production. CSF production was measured by ventriculocisternal perfusion (VCP) technique in three groups (n=10 in each group) of anesthetized, paralyzed and mechanically ventilated dogs. Group I served as control, Sch 28080 (10−4 mol/l of synthetic CSF) was added to VCP in group II, and omeprazole (10−5 mol/l of synthetic CSF) was added to VCP in group III, after baseline control CSF production had been determined at 15, 30, 45, and 60 min. Comparing the three groups, the mean baseline values for CSF production did not differ significantly. However, the percent decreases in CSF production in the omeprazole treated group were 26±17 and 24±13 at 210 and 225 min, which were significantly more than the respective values in the control group. Percent decrease in CSF production in Sch 28080 was not significantly different from that in the control group. We conclude that in the canine model, physiological doses of omeprazole decrease CSF production by about 26%. However, the effect is independent of the K+,H+-ATPase activity, since Sch 28080 which is more potent than omeprazole did not significantly affect CSF production.

NaCl cotransport carrier is known to be involved in transepithelial fluid absorption and secretion in various tissues. Recent studies indicate that Na-K-2Cl cotransport carrier also exists in the choroid plexus cells and that inhibition of the carrier decreases cerebrospinal fluid (CSF) production. In this study, we used large-dose intravenous furosemide, an inhibitor of Na-K-2Cl carrier, to determine the effects on cisternal CSF ionic composition in acute respiratory acidosis. In pentobarbital-anesthetized mechanically ventilated dogs, renal pedicles were ligated to prevent furosemide-induced diuresis. The experimental group (group II, n = 7) received 400 mg/kg of furosemide intravenously, and group I (control group, n = 7) received the vehicle. In group II, serial serum and CSF furosemide concentrations were approximately 10(-3) and 10(-5) mol/l, respectively. During 5 h of acute respiratory acidosis in both groups, the mean arterial PCO2 increased approximately 25 Torr, with comparable changes in CSF PCO2. In both groups, CSF [HCO3-] and [H+] rose approximately 3 meq/l and 20 neq/l, respectively. Changes in CSF [Na+], [K+], [Cl-], and [Na(+)-Cl-] were also similar and were not significantly different from each other when the two groups were compared. These data show that furosemide at the dose that inhibits NaCl cotransport carrier does not significantly alter ionic composition of cisternal CSF.

Data on canine cisternal cerebrospinal fluid (CSF) ions in acute respiratory alkalosis are limited and fragmentary We hypothesized that with the fall in arterial PCO2, (Pa-CO2) and in the face of normal osmoregulation, CSF [Na+] remains relatively constant and CSF [Na+ - Cl-] narrows to account in part for the fall in CSF [HCO3-]. We therefore measured blood and CSF acid-base variables and ions of two groups of pentobarbital-anesthetized, mechanically ventilated dogs (n = 10 in each group). In the control group, Pa-CO2 was kept constant and changes in serum and CSF ions were minimal. In Group II (acute respiratory alkalosis), both Pa-CO2 and cisternal CSF PCO2, decreased by 10 mm Hg. Five hours after induction of respiratory alkalosis, mean CSF [HCO3-] decreased significantly by 4.4 +/- 1.2 mEq/L (mean +/- SD). The fall in CSF [HCO3-] was similar to changes in CSF strong ion difference (SID = Na+ + K+ + Ca2+ + Mg2+ - Cl- lactate), which decreased 4.4 +/- 1.9 mEq/L. Concentrations of the four major CSF cations did not change significantly. Cisternal CSF lactate rose significantly by 1.2 +/- 0.9 mEq/L, accounting for 25% of the change in CSF [HCO3-]. The remaining (75%) change in CSF [HCO3-] was accounted for by changes in CSF [Cl-].