Shahrokh Javaheri

Sleep Apnea in 81 Ambulatory Male Patients With Stable Heart Failure Types and Their Prevalences, Consequences, and Presentations

BACKGROUNDnHeart 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.nnnMETHODS AND RESULTSnThis 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.nnnCONCLUSIONSnFifty-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.

Effects of Continuous Positive Airway Pressure on Sleep Apnea and Ventricular Irritability in Patients With Heart Failure

BACKGROUNDnPatients with heart failure and systolic dysfunction may develop disordered breathing during sleep. Repeated episodes of apnea and hypopnea may result in desaturation and arousals, which could adversely affect left ventricular function. The purpose of this study was to determine the short-term effects of continuous positive airway pressure (CPAP) on sleep-disordered breathing and its consequences in heart failure patients.nnnMETHODS AND RESULTSnThe author prospectively studied 29 male patients whose initial polysomnograms showed 15 or more episodes of apnea and hypopnea per hour (apnea-hypopnea index, AHI). Twenty-one patients had predominately central and 8 patients obstructive sleep apnea. All were treated with CPAP during the subsequent night. In 16 patients, CPAP resulted in virtual elimination of disordered breathing. In these patients, the mean AHI (36+/-12 [SD] versus 4+/-3 per hour, P=0.0001), arousal index due to disordered breathing (16+/-9 versus 2+/-2 per hour, P=0.0001), and percent of total sleep time below saturation of 90% (20+/-23% to 0.3+/-0.7%, P=0.0001) decreased, and lowest saturation (76+/-8% versus 90+/-3%, P=0.0001) increased with CPAP. In 13 patients who did not respond to CPAP, these values did not change significantly. In patients whose sleep apnea responded to CPAP, the number of hourly episodes of nocturnal premature ventricular contractions (66+/-117 versus 18+/-20, P=0.055) and couplets (3.2+/-6 versus 0.2+/-0.21, P=0.031) decreased. In contrast, in patients whose sleep apnea did not respond to CPAP, ventricular arrhythmias did not change significantly.nnnCONCLUSIONSnIn 55% of patients with heart failure and sleep apnea, first-night nasal CPAP eliminates disordered breathing and reduces ventricular irritability.

Effect of Theophylline on Sleep-Disordered Breathing in Heart Failure

BACKGROUNDnTheophylline has been used to treat central apnea associated with Cheyne-Stokes respiration (periodic breathing). We studied the effect of short-term oral theophylline therapy on periodic breathing associated with stable heart failure due to systolic dysfunction.nnnMETHODSnFifteen men with compensated heart failure (left ventricular ejection fraction, 45 percent or less) participated in the study. Their base-line polysomnograms showed periodic breathing, with more than 10 episodes of apnea and hypopnea per hour. In a double-blind crossover study, the patients received theophylline or placebo orally twice daily for five days, with one week of washout between the two periods.nnnRESULTSnAfter five days of treatment, the mean (+/-SD) plasma theophylline concentration was 11 +/- 2 microgram per milliliter. Theophylline therapy resulted in significant decreases in the number of episodes of apnea and hypopnea per hour (18 +/- 17, vs. 37 +/- 23 with placebo and 47 +/- 21 at base line; P<0.001), the number of episodes of central apnea per hour (6 +/- 14, vs. 26 +/- 21 and 26 +/- 20, respectively; P<0.001), and the percentage of total sleep time during which the arterial oxyhemoglobin saturation was less than 90 percent (6 +/- 11 percent, vs., 23 +/- 37 and 14 +/- 14 percent, respectively; P<0.04). There were no significant differences in the characteristics of sleep, the frequency of ventricular arrhythmias, daytime arterial-blood gas values, or the left ventricular ejection fraction during the base-line, placebo, and theophylline phases of the study.nnnCONCLUSIONSnIn patients with stable heart failure, oral theophylline therapy reduced the number of episodes of apnea and hypopnea and the duration of arterial oxyhemoglobin desaturation during sleep.

Occult Sleep-Disordered Breathing in Stable Congestive Heart Failure

Despite recent advances in its treatment, congestive heart failure associated with depressed left ventricular function is highly prevalent and continues to be associated with excess morbidity and mortality. Multiple factors may contribute to the progressively declining course of congestive heart failure. Severe nocturnal arterial oxyhemoglobin desaturation caused by sleep-disordered breathing could be a contributing factor, particularly because it has been associated with excess mortality in patients with chronic obstructive pulmonary disease [1]. Cheyne and Stokes were the first to observe periodic breathing in patients with heart failure (Cheyne-Stokes respiration). In a subsequent systematic study, Harrison and colleagues [2] reported that periodic breathing characterized by repeated episodes of apnea and hypopnea during sleep occurred in patients with congestive heart failure. Since this early observation, several investigators have used standard polysomnography to study periodic breathing during sleep in patients with congestive heart failure [3-7]. The differences in prevalence rates in these studies (36% to 100%) might have been caused by several factors, including the few patients studied (4 to 11), the varying inclusion of patients with risk factors predisposing them to sleep apnea (such as loud snoring, witnessed apnea, and obesity), the varying severity of heart failure and systolic dysfunction, the inclusion of patients with unstable (as opposed to stable, maximally treated) congestive heart failure, and the presence of other factors that may influence periodic breathing. These important factors, which were not considered in most of previous studies, could considerably affect the prevalence and the severity of sleep apnea. We determined the prevalence and effect of sleep-disordered breathing in a relatively large group of clinically well-defined patients with stable, optimally treated congestive heart failure. We also determined the predictors of sleep-disordered breathing in these patients. Methods Entry Criteria Forty-two ambulatory patients with stable congestive heart failure (no change in signs or symptoms of congestive heart failure and no change in medications for at least 4 weeks before polysomnography) and systolic dysfunction (left ventricular ejection fraction 45%) participated in the study. Patients were recruited from the cardiology and medical clinics of the Department of Veterans Affairs Medical Center, Cincinnati, Ohio. The cardiologist coinvestigator evaluated all patients to confirm that their condition was stable and that they were receiving optimal therapy, which included digoxin (26 patients), diuretics (38 patients), angiotensin-converting enzyme inhibitors (37 patients), or hydralazine (2 patients). At the time of recruitment, no information was sought about symptoms or risk factors for sleep apnea. The following were the exclusion criteria: unstable angina; unstable congestive heart failure; acute pulmonary edema; congenital heart disease; primary valvular heart disease; use of benzodiazepines or theophylline; intrinsic pulmonary diseases, including interstitial lung disease, moderate to severe chronic obstructive lung defect (percentage of the ratio of the predicted forced expiratory volume in 1 second and forced vital capacity < 68%); intrinsic renal and liver disorders; untreated hypothyroidism; and kyphoscoliosis. For uniformity, we studied only male patients (female patients are rarely referred to this center). Only 6 of the 48 patients who met the entry criteria and were asked to participate in the study refused. The main reasons for refusal were an unwillingness to stay in the hospital or an unwillingness to travel to the hospital because of distance. The study was approved by the Research and Development Committee of the Veterans Affairs Medical Center, Cincinnati, Ohio, and the Institutional Review Board at the University of Cincinnati College of Medicine. Baseline Studies After giving written informed consent, the patients were hospitalized for 2 consecutive nights. On the first day, a detailed history was obtained and physical examination and screening tests were done, including complete blood count; tests for serum electrolytes, digoxin, thyroid, and renal function; radionuclide ventriculography; determinations of arterial blood gases and pH; and pulmonary function tests. Strict criteria described elsewhere [8, 9] were used for doing pulmonary function tests and for obtaining arterial blood samples and their measurements. Because some studies [10] have suggested that a low baseline Paco 2 is a risk factor for periodic breathing, skin over the radial artery was anesthetized with 2% lidocaine to minimize pain (which could potentially induce hyperventilation during arterial blood sampling). While the patient was sitting, arterial blood was collected anaerobically in heparinized syringes during several breath cycles. Duplicate determinations of arterial blood gases and pH were immediately made with appropriate electrodes [9]. Polysomnography On the first night, patients were taken to the sleep laboratory. Surface electrodes were attached, but no recording was obtained. This adaptation night was used to minimize the first-night effect of sleeping in the laboratory. On the next night, polysomnography was done using standard techniques described previously [11-13]. For staging sleep, we recorded electroencephalograms (two channels), chin electromyograms (one channel), and electro-oculograms (two channels). Thoracoabdominal excursions were measured qualitatively by respiratory inductance plethysmography (Respitrace; Ambulatory Monitoring, Inc., Ardsley, New York) or by pneumatic respiration transducers (Grass Instrument Company, Quincy, Massachusetts) placed over the rib cage and abdomen. Airflow was qualitatively monitored using an oral-nasal thermocouple (Model TCT1R; Grass Instrument Company). Arterial oxyhemoglobin saturation was recorded using an ear oximeter (Biox IIA; BT, Inc., Boulder, Colorado). These variables were recorded on a multichannel polygraph (Model 78D; Grass Instrument Company). An apnea was defined as cessation of inspiratory airflow lasting 10 seconds or longer. An obstructive apnea was defined as the absence of airflow in the presence of rib cage and abdominal excursions. A central apnea was defined as the absence of airflow and of rib cage and abdominal excursions [11-13]. However, a central apnea may not be easily distinguished from an obstructive apnea if esophageal pressure is not measured. Hypopnea was defined as a reduction of airflow lasting 10 seconds or more that was associated with at least a 4% decrease in arterial oxyhemoglobin saturation or an arousal. An arousal was defined as the appearance of waves on an electroencephalogram that were at least 3 seconds in duration [14]. The number of episodes of apnea and hypopnea per hour is referred to as the apneahypopnea index. Scoring of polysomnograms was blinded. The prevalence of sleep-disordered breathing in patients with congestive heart failure was determined using an apneahypopnea index of more than 20 episodes per hour. In a retrospective study of patients with the sleep apnea syndrome [15], an index of more than 20 apneas per hour was associated with excess mortality. Because this study was done before hypopnea was recognized, the investigators did not include it in their calculation of the index. Lower thresholds (for example, an apneahypopnea index of 10 episodes per hour) have been used in other studies; however, the clinical importance, particularly of low cutoff points, has not been adequately determined. Other Studies Holter monitoring was done during polysomnography. Three electrocardiographic channels (leads V1, V3, and V5) were recorded using a Laser SxP Holter monitor system (Marquett Electronics Inc., Milwaukee, Wisconsin). The tapes were analyzed by computer and were manually overread by the cardiologist coinvestigator. Using standard techniques [16], we calculated right and left ventricular ejection fractions from gated first-pass and multigated radionuclide ventriculograms, respectively [16]. Statistical Analysis We used the Wilcoxon rank-sum test to assess the significance of differences between the two groups because the common variance assumption required by the t-test was not appropriate for many of the measurements. A P value of less than 0.05 was considered significant. We calculated 95% CIs using the approximate degrees of freedom for the t-statistic [17]. The relations between certain pathophysiologically important variables and the apneahypopnea index were examined by regression analysis and stepwise multiple regression analysis. Calculations were done using SAS software [17]. Results The apneahypopnea index varied from 0.3 to 82.2 episodes per hour. The frequency histogram of the index is shown in Figure 1. In 23 patients (group I), the apneahypopnea indexes varied from 0.3 to 13.4 episodes per hour (mean SD, 4.4 4 episodes per hour [CI, 2.7 to 6.0 episodes per hour; median, 3.2 episodes per hour]). In the 19 patients in group II (45%), the apneahypopnea index varied from 26.5 to 82.2 episodes per hour (mean, 44 13 episodes per hour [CI, 37.6 to 50.6 episodes per hour; median, 40.4 episodes per hour]. Figure 1. Frequency distribution of the apneahypopnea index in 10-unit intervals in 42 patients with stable, optimally treated congestive heart failure. The two groups did not differ significantly in demographic and historical data (Table 1). Congestive heart failure was caused by ischemic cardiomyopathy (16 patients in group I and 13 patients in group II), idiopathic cardiomyopathy (5 patients in group I and 6 patients in group II), and alcohol-related cardiomyopathy (2 patients in group I). Table 1. Demographics, Historical Data, and Physical Examination Findings in Patients without (Group I) or with (Group II) Sleep-Disordered Breathing* The mean values for s

Association of Low PaCO2 with Central Sleep Apnea and Ventricular Arrhythmias in Ambulatory Patients with Stable Heart Failure

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

Reversible Orthodeoxia and Platypnea Due to Right-to-Left Intracardiac Shunting Related to Pericardial Effusion

Excerpt The rare phenomena of platypnea (dyspnea exacerbated by upright posture and relieved by recumbency) and orthodeoxia (hypoxemia exacerbated by upright posture and relieved by recumbency) hav...

The Performance of Two Automatic Servo-Ventilation Devices in the Treatment of Central Sleep Apnea

INTRODUCTIONnThis study was conducted to evaluate the therapeutic performance of a new auto Servo Ventilation device (Philips Respironics autoSV Advanced) for the treatment of complex central sleep apnea (CompSA). The features of autoSV Advanced include an automatic expiratory pressure (EPAP) adjustment, an advanced algorithm for distinguishing open versus obstructed airway apnea, a modified auto backup rate which is proportional to subjects baseline breathing rate, and a variable inspiratory support. Our primary aim was to compare the performance of the advanced servo-ventilator (BiPAP autoSV Advanced) with conventional servo-ventilator (BiPAP autoSV) in treating central sleep apnea (CSA).nnnSTUDY DESIGNnA prospective, multicenter, randomized, controlled trial.nnnSETTINGnFive sleep laboratories in the United States.nnnPARTICIPANTSnThirty-seven participants were included.nnnMEASUREMENTS AND RESULTSnAll subjects had full night polysomnography (PSG) followed by a second night continuous positive airway pressure (CPAP) titration. All had a central apnea index ≥ 5 per hour of sleep on CPAP. Subjects were randomly assigned to 2 full-night PSGs while treated with either the previously marketed autoSV, or the new autoSV Advanced device. The 2 randomized sleep studies were blindly scored centrally. Across the 4 nights (PSG, CPAP, autoSV, and autoSV Advanced), the mean ± 1 SD apnea hypopnea indices were 53 ± 23, 35 ± 20, 10 ± 10, and 6 ± 6, respectively; indices for CSA were 16 ± 19, 19 ± 18, 3 ± 4, and 0.6 ± 1. AutoSV Advanced was more effective than other modes in correcting sleep related breathing disorders.nnnCONCLUSIONSnBiPAP autoSV Advanced was more effective than conventional BiPAP autoSV in the treatment of sleep disordered breathing in patients with CSA.

Heart failure and sleep apnea: emphasis on practical therapeutic options

Heart failure is a highly prevalent problem associated with excess morbidity and mortality and economic impact. Because of increased average life span, improved therapy of ischemic coronary artery disease and hypertension, the incidence and prevalence of heart failure will continue to rise into the twenty-first century. Multiple factors may contribute to the progressively declining course of heart failure. One such cause could be the occurrence of repetitive episodes of apnea, hypopnea, and hyperpnea, which frequently occur in patients with heart failure. Episodes of apnea, hypopnea, and hyperpnea cause sleep disruption, arousals, intermittent hypoxemia, hypercapnia, hypocapnia, and changes in intrathoracic pressure. These pathophysiologic consequences of sleep-related breathing disorders have deleterious effects on cardiovascular system, and the effects may be most pronounced in the setting of established heart failure and coronary artery disease. Diagnosis and treatment of sleep-related breathing disorders may improve morbidity and mortality of patients with heart failure [34]. Large-scale, carefully executed therapeutic studies are needed to determine if treatment of sleep-related breathing disorders changes the natural history of left ventricular failure.

Effects of domperidone and medroxyprogesterone acetate on ventilation in man

If endogenous dopamine acts as an inhibitory neurotransmitter in the carotid bodies in man, domperidone (DP), a selective dopamine D-2 receptor antagonist should stimulate carotid bodies and augment ventilation. Furthermore, the combination of a central ventilatory stimulant, medroxyprogesterone acetate (MPA), with a peripheral ventilatory stimulant, DP, may produce an additive/synergistic ventilatory effect. We conducted a double-blind, placebo-controlled (P), cross-over trial comparing MPA 20 mg three times daily (TID) and DP (20 mg TID) alone and together in 8 healthy male human subjects. Drug effects were measured after 7 days, and a two-week drug washout period was allowed. MPA significantly increased alveolar ventilation (VA), and slopes of hypercapnic and hypoxic ventilatory responses. Domperidone alone significantly increased the slope of the hypoxic response; however, VA and PaCO2 did not change significantly. The combination of MPA and DP resulted in ventilatory changes similar to MPA alone. We conclude that in man endogenous dopamine acts as a modulator of chemoreception during hypoxemia, but plays no major role tonically in control of ventilation during normoxemia and normocapnia. Lack of additive effect with combined DP and MPA suggests that these drugs may share the same final common pathway in the process of chemoreception.

Acetazolamide attenuates Hunter-Cheyne-Stokes breathing but augments the hypercapnic ventilatory response in patients with heart failure.

RATIONALEnAcetazolamide has been used to attenuate Hunter-Cheyne-Stokes breathing with central sleep apnea (CSA) associated with heart failure. However, the mechanisms underlying this improvement remain to be fully elucidated.nnnOBJECTIVESnWe hypothesized that acetazolamide stabilizes CSA by attenuating the ventilatory sensitivity to CO2, which is increased in patients with heart failure and is thought to be the major mechanism mediating CSA.nnnMETHODSnSix consecutive male patients with stable systolic heart failure and CSA (apnea-hypopnea index [AHI] ≥ 15 episodes/h) were randomized to a double-blind crossover protocol with acetazolamide or placebo received 1 hour before bedtime for six nights with 2 weeks of wash-out. Under both conditions, we measured the hypercapnic ventilatory response (HCVR), arterial blood Pco2, steady-state metabolic CO2 production, overnight attended polysomnography, and also assessed cardiac and pulmonary function.nnnMEASUREMENTS AND MAIN RESULTSnCompared with placebo, acetazolamide significantly decreased the AHI (65 ± 32 vs. 31 ± 19 events/h, mean ± SD). Acetazolamide increased the HCVR slope by 55% (3.3 ± 1.7 vs. 5.1 ± 2.4 L/min/mm Hg; P = 0.03), an increase that far exceeded the 12% fall in arterial Pco2 (P = 0.02). The acetazolamide-induced change in the balance of these effects (ΔHCVR × Pco2) was inversely associated with the reduction in AHI (r = 0.8; P = 0.045).nnnCONCLUSIONSnThis placebo-controlled study indicates that acetazolamide improves CSA in patients with heart failure despite an increase in the slope of the HCVR. However, because the degree of HCVR elevation inhibits the improvement in unstable breathing, an increased CO2 chemosensitivity may be a key mechanism underlying an incomplete resolution of CSA with acetazolamide.