Reversal of Ticagrelor-Induced Arrhythmias and Cheyne-Stokes Respiration With Aminophylline Infusion.

Dyspnea and bradyarrhythmias are frequent adverse effects (AEs) of ticagrelor. AEs commonly occur within the first week of therapy, are dose related and usually mild, but sometimes they may cause drug discontinuation. Currently, the exact mechanisms of ticagrelor-related AEs have not been definitively explained. In addition to the prevalent theory of adenosine overload, other reasonable mechanism like a direct central stimulation hypothesis was suggested. We present a case of incessant Cheyne-Stokes respiration associated with heart rate instability in patient with congestive heart failure and non-ST-segment elevation myocardial infarction, supporting the use of aminophylline as a potential reversal agent of ticagrelor-related AEs.

Acute improvement of pulmonary hemodynamics does not alleviate Cheyne-Stokes respiration in chronic heart failure-a randomized, controlled, double-blind, crossover trial.

OBJECTIVES: This randomized, controlled trial aimed to investigate whether acute improvement of pulmonary congestion would reduce the severity of Cheyne-Stokes respiration (CSR) in patients with chronic heart failure (CHF). METHODS: Twenty-one consecutive patients with CHF and CSR (apnea-hypopnea index [AHI] ≥15/h) underwent right heart catheterization with titration of intravenous (IV) glyceryltrinitrate (GTN) to a maximum tolerable dosage and inhalation of iloprost 10 µg/mL after a washout phase. Maximum tolerable dosages of GTN and iloprost were randomly applied during full cardiorespiratory polysomnography within two split-night procedures and compared with IV or inhaled sodium chloride (NaCl) 0.9 %, respectively. RESULTS: GTN (6.2 ± 1.5 mg/h) and iloprost significantly lowered \mean pulmonary artery pressure (20.1 ± 9.0 to 11.6 ± 4.2 mmHg, p < 0.001 and 16.9 ± 7.9 to 14.2 ± 6.4 mmHg, p < 0.01, respectively). Pulmonary capillary wedge pressure was only reduced by GTN (14.0 ± 5.6 to 7.2 ± 3.9 mmHg, p < 0.001), and there was no significant change in the cardiac index. Sleep studies revealed no significant improvement in markers of CSR severity, including AHI, central apnea index, and CSR cycle length following GTN or iloprost treatment. Significant decreases in blood pressure, mean oxygen saturation, and S3 sleep were documented during GTN infusion. CONCLUSIONS: Acute improvement of pulmonary congestion by GTN had no immediate impact on CSR severity. Future investigations must therefore include longer treatment periods and treatment regimens that have positive, rather than negative, additional effects on peripheral and central chemoreceptors and sleep structure. TRIAL REGISTRATION: German Clinical Trial Registry-ID:DRKS00000467 ( www.germanctr.de ).

Aminophylline increases cerebral metabolic rate and decreases anoxic survival in young mice.

In weanling mice treated with pharmacologic doses of aminophylline, the concentrations of adenosine 3',5'-monophosphate and guanosine 3',5'-monophosphate in the brain increased 44 and 36 percent, respectively, and the cerebral metabolic rate was three times that in controls. In neonatal mice, therapeutic doses of aminophylline greatly decreased the rate of anoxic survival in vivo and the duration of gasping of the isolated head. The findings suggest caution in the use of this drug and other methylxanthines in hypoxic human newborns.

Effect of inhaled 3% CO2 on Cheyne-Stokes respiration in congestive heart failure.

Cheyne-Stokes respiration (CSR) in severe stable congestive heart failure (CHF) may be associated with significant nocturnal arterial oxygen desaturation and sleep disruption. Previous investigations of inhaled CO2 in CSR have been uncontrolled and of short duration, sleep has not been monitored electroencephalographically, and most patients studied have had neurological disease with or without cardiac disease. The purpose of our study was to document the effects of inhaled CO2 on CSR in patients with severe stable CHF (left ventricular ejection fraction < 35% and NYHA class 3 or 4 dyspnea) in controlled all-night polysomnographic studies. Six patients were studied for 3 nights and days: adaptation, control and inhalation of CO2. These patients received a constant F1CO2 = 0.03 in air (with a 4-5 mm Hg increase in PaCO2) on night 3. This caused virtual abolition of CSR as reflected by CSR duration/total sleep time (62-2.2%; p = 0.0012) and CSR duration/nonrapid eye movement (NREM) sleep time (73-2.4%; p = 0.00064), and NREM apnea index was reduced from 33.5 to zero (p = 0.026). The apparatus used to accurately control F1CO2, however, was intrusive and some features of sleep structure such as sleep latency were adversely affected. We conclude that inhalation of CO2 with a constant F1CO2 = 0.03 virtually eradicates CSR in all-night polysomnographically monitored studies in patients with severe stable CHF. The clinical significance of these findings remains to be determined.

Benzodiazepines in congestive heart failure: effects of temazepam on arousability and Cheyne-Stokes respiration.

We studied seven male patients with moderate to severe congestive heart failure (CHF) [left ventricular ejection fraction (LVEF) = 22.4 +/- 6.7; mean +/- SD] in a double-blind crossover trial to determine the effects of temazepam 15 mg on arousability, sleep architecture, Cheyne-Stokes respiration (CSR) and nighttime oxygen saturation. Sleep architecture was not markedly improved with temazepam. There was no significant change in total sleep time (TST) (383.1 +/- 14.1 minutes to 396.6 +/- 15.4 minutes, p = ns) (mean +/- SE, placebo vs. temazepam) or total wake time (TWT) (96.9 +/- 14.0 vs. 81.4 +/- 14.0 minutes, p = ns). Sleep stage proportions did not change appreciably except for a reduction in stage 1 sleep (6.7 +/- 1.2% vs. 4.0 +/- 1.0%, p < 0.05). Microarousals per hour of sleep decreased with temazepam (21.1 +/- 2.7/hour vs. 13.9 +/- 2.1/hour placebo, p < 0.05), with the largest change occurring in stage 2 (24.9 +/- 5.4/hour vs. 15.0 +/- 3.1/hour, p < 0.05). Wake time during sleep (WDS) was reduced from 82.5 +/- 11.7 minutes to 54.5 +/- 9.4 minutes, p < 0.03. Daytime alertness was improved with temazepam as was indicated by an increase in mean latency to sleep [multiple sleep latency test (MSLT) = 7.1 +/- 2.4 vs. 5.7 +/- 2.0 minutes, p < 0.04) on days following treatment with temazepam. There was no significant change in CSR as a percentage of TST (38.7 +/- 13.6% vs. 32.5 +/- 11.8%, p = ns). However, the apnea/hypopnea index (AHI) (10% filter) was decreased in stage 1 (28.1 +/- 9.7/hour vs. 15.6 +/- 8.2/hour). Overnight oxygen saturation did not change with temazepam (95.1 +/- 0.6% both nights) and the percentage of TST spent below 90% oxygen saturation was minimal for both conditions (1.5 +/- 1.1% vs. 2.2 +/- 1.7%, p = ns). We conclude that CHF patients with CSR experience frequent arousals and that these arousals can be reduced with temazepam. There was an improvement in daytime somnolence. There was no worsening of nighttime oxygen saturation.

Hemodynamics, cerebral circulation, and oxygen saturation in Cheyne-Stokes respiration.

Because cardiovascular disorders and stroke may induce Cheyne-Stokes respiration, our purpose was to study the interaction among cerebral activity, cerebral circulation, blood pressure, and blood gases during Cheyne-Stokes respiration. Ten patients with heart failure or a previous stroke were investigated during Cheyne-Stokes respiration with recordings of daytime polysomnography, cerebral blood flow velocity, intra-arterial blood pressure, and intra-arterial oxygen saturation with and without oxygen administration. There were simultaneous changes in wakefulness, cerebral blood flow velocity, and respiration with accompanying changes in blood pressure and heart rate approximately 10 s later. Cerebral blood flow velocity, blood pressure, and heart rate had a minimum occurrence in apnea and a maximum occurrence during hyperpnea. The apnea-induced oxygen desaturations were diminished during oxygen administration, but the hemodynamic alterations persisted. Oxygen desaturations were more severe and occurred earlier according to intra-arterial measurements than with finger oximetry. It is not possible to explain Cheyne-Stokes respiration by alterations in blood gases and circulatory time alone. Cheyne-Stokes respiration may be characterized as a state of phase-linked cyclic changes in cerebral, respiratory, and cardiovascular functions probably generated by variations in central nervous activity.

Beneficial effect of inhaled CO2 in a patient with non-obstructive sleep apnoea.

A 63-year-old man with severe non-obstructive sleep apnoea (apnoea index 28; apnoea duration 45-60s; O2 saturation between 72% and 98%), who did not respond to common modes of treatment, was successfully treated with CO2. A tent was perfused with compressed air (6 1/min) and increasing amounts of CO2. A concentration of 3% CO2 (180 ml/min) was sufficient to raise the PaCO2 above apnoea threshold and to suppress apnoeas completely. As a result, O2 saturation remained normal throughout the whole night and the symptoms of sleep apnoea disappeared. We hypothesize that the PCO2 ventilatory drive was intact in our patient and that hypocapnia was the major factor causing the non-obstructive sleep apnoea syndrome. Administration of CO2 with a constant flow system could be a safe and easy alternative for patients with non-obstructive sleep apnoea syndrome who present with hypocapnia and an intact respiratory feedback control system.

[Theophylline in the treatment of sleep-related breathing disorders]. / Theophyllin in der Therapie schlafbezogener Atmungsstörungen.

The methylxanthine derivates are known to have respiratory stimulant properties. Therefore theophylline is used in sleep related disturbances of breathing. Theophylline reduces central apneas and periodic breathing in infants. The efficiency of theophyllin is confirmed in reducing central apneas in patients with neurologic diseases or Cheyne Stokes breathing in patients with congestive heart failure. In patients with obstructive sleep apnoea the effect of theophylline is doubtful. An effect of therapy exists in some mild forms of sleep apnoea (apnoea index < 20/h total sleep time). Further studies are necessary to investigate the precise mechanism of of theophylline in obstructive sleep apnoea.

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

RATIONALE: Acetazolamide 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. OBJECTIVES: We 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. METHODS: Six 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. MEASUREMENTS AND MAIN RESULTS: Compared 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). CONCLUSIONS: This 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.

Theophylline therapy for Cheyne-Stokes respiration during sleep in a 41-year-old man with refractory arterial hypertension.

We report a case of a 41-year-old man who was noted to have position-dependent Cheyne-Stokes respiration with central sleep apnea (CSA) during sleep. The patient had multiple cardiovascular risk factors and target organ damages, including a history of two myocardial infarctions, transient ischemic attack, and chronic kidney disease. His hypertension was refractory to a number of antihypertensive medicines, however, a complete elimination of sleep-disordered breathing with oral theophylline treatment was paralleled by a significant BP fall with a subsequent need for reduction of antihypertensive drugs. Following these surprising observations we decided to withdraw theophylline from treatment (in-clinic). Theophylline discontinuation resulted in a gradual increase in BP and an urgent call for antihypertensive treatment modification. These observations suggest a potent hypotensive action of oral theophylline via Cheyne-Stokes respiration with CSA elimination. Our data suggest that CSA may be a mechanism that raises BP even during the daytime.

Effect of acetazolamide on chemosensitivity, Cheyne-Stokes respiration, and response to effort in patients with heart failure.

Increased chemosensitivity to hypoxia and hypercapnia, together with a prolonged circulatory time, are the main determinants of Cheyne-Stokes (C-S) respiration in heart failure. To evaluate the effect of acetazolamide, a carbonic anhydrase inhibitor, on chemosensitivity and respiratory dynamics in patients with heart failure with C-S respiration, 12 patients (mean age 62 ± 9 years, mean left ventricular ejection fraction 24 ± 9%) and C-S respiration (mean apnea-hypopnea index 23 ± 13) who underwent 4 consecutive days of oral acetazolamide treatment (250 mg twice daily) were enrolled in this study. Assessment of chemosensitivity to hypoxia and hypercapnia, cardiopulmonary stress testing, 24-hour cardiorespiratory polygraphy, and neurohormonal characterization were performed at baseline and at the end of treatment. Acetazolamide improved central apneas (apnea-hypopnea index 23 ± 13 to 15 ± 9, p = 0.012) and the percentage of time spent below an arterial oxyhemoglobin saturation of 90% (16 ± 23% to 10 ± 18%, p = 0.005). Chemosensitivity to hypoxia was blunted (1.03 ± 0.69 to 0.78 ± 0.55 L/min/mm Hg, p = 0.032), while chemosensitivity to hypercapnia increased after acetazolamide (1.27 ± 0.71 to 1.54 ± 0.78 L/min/% arterial oxygen saturation, p = 0.023); patients achieved a lower workload (90 ± 30 to 81 ± 30 W, p <0.001), with no differences in peak oxygen consumption, while there was an increment in the regression slope relating minute ventilation to carbon dioxide output (39 ± 10 to 43 ± 9, p = 0.010). In conclusion, in patients with heart failure, acetazolamide diminishes C-S respiration and improves oxyhemoglobin saturation, likely by decreasing chemosensitivity to hypoxia. However, it is associated with reduced maximal workload achieved during effort and increased chemosensitivity to hypercapnia, inducing a reduction in the ventilatory efficiency.

Cheyne-Stokes breathing and systemic arterial pressure periodic pattern during sleep in central alveolar hypoventilation.

This report refers to a 51 year old man with the clinical features of central alveolar hypoventilation (CAH). Polysomnographic recordings showed periodic breathing and central apnoeas associated with abnormal oscillations of systemic arterial pressure and heart rate during all sleep stages. Oxygen administration during sleep reduced hypoxia, while the periodic breathing and arterial pressure oscillations persisted. The authors suggest that an impairment of the brain structures that play a role in homeostatic adjustment of autonomic functions in connection with the sleep-wake cycle, is responsible for the unusual sleep-related disturbances shown by this patient.

Apneas and oscillation of cardiac ectopy in Cheyne-Stokes breathing during sleep.

Previous investigators have described heart rate oscillations (1,2) and various arrhythmias (3-5) during Cheyne-Stokes breathing. To our knowledge, however, this is the first report describing cardiac ectopic beats oscillating with the identical frequency as ventilatory movement and SaO2 in Cheyne-Stokes breathing during sleep. This case is also the first to document with polygraphic sleep recordings the suggested efficacy of acetazolamide (26) in abolishing the apneas of Cheyne-Stokes breathing during sleep. However, generalizations regarding the impact of ventilation on cardiac ectopy and the therapeutic effect of acetazolamide will require prospective studies on multiple patients with Cheyne-Stokes breathing during sleep.

Theophylline therapy for near-fatal Cheyne-Stokes respiration. A case report.

BACKGROUND: Cheyne-Stokes respiration is characterized by periodic breathing that alternates with hypopnea or apnea. OBJECTIVE: To describe the effect of theophylline on near-fatal Cheyne-Stokes respiration. DESIGN: Case report. SETTING: Tertiary referral center. PATIENT: A 48-year-old diabetic woman with a history of three cardiorespiratory arrests, a normal coronary arteriogram, normal left ventricular function, and severe Cheyne-Stokes respiration. MEASUREMENTS: Oxygen saturation, intra-arterial blood pressure, central venous pressure, chest wall movement, electrocardiography, electromyography, electroencephalography, electro-oculography, minute ventilation, arterial blood gases, and serum theophylline levels. RESULTS: After intravenous administration of 1.2 mg of theophylline at 0.6 mg/kg per hour (serum level, 5.6 microg/mL), both Cheyne-Stokes respiration and oxygen desaturation were markedly attenuated. After infusion of 2.4 mg of theophylline (serum level, 11.6 microg/mL), Cheyne-Stokes respiration resolved completely. No change was seen with placebo. Cheyne-Stokes respiration did not recur during outpatient treatment with oral theophylline. CONCLUSION: Theophylline may be a rapid and effective therapy for life-threatening Cheyne-Stokes respiration.

Cheyne-Stokes respiration revisited: controversies and implications.

Investigation of the periodic crescendo-decrescendo alterations in tidal volume in Cheyne-Stokes respiration (CSR) has provided remarkable insight into the physiology of respiratory control. Many patients with periodic breathing have both cardiac and neurologic disease. Considerable controversy has surrounded determination of the relative importance of cardiac and neurologic mechanisms in the genesis of this breathing abnormality. Several investigators have considered the respiratory center as a chemostat model with three basic components: the controller system (chemoreceptors), the controlled system (gas tensions of O2 and CO2), and the feedback loop (arterial circulation from the lung to the brain). If the relationship between these cardiac and neurologic components is altered, stability of the respiratory control system is lost. Such disturbance in the control system may arise by prolongation of the circulation time, or by the system becoming more dependent on its O2, rather than the CO2 component. Earlier investigators considered periodic breathing as a forewarning of ominous developments. In recent studies, mild degrees of periodic breathing, easily missed on physical examination, are often found in otherwise normal subjects, particularly during sleep. Generally no therapy is required, although aminophylline, O2 or CO2 administration has been shown to abolish periodic breathing.