Central Sleep Apnea in Patients With Coronary Heart Disease Taking P2Y12 Inhibitors.

ABSTRACT: Central sleep apnea (CSA) is common in patients with heart failure. Recent studies link ticagrelor use with CSA. We aimed to evaluate CSA prevalence in patients with coronary heart disease (CHD) and whether ticagrelor use is associated with CSA. We reviewed consecutive patients with CHD who underwent a polysomnography (PSG) test over a 5-year period from 3 sleep centers. We sampled patients who were on ticagrelor or clopidogrel during a PSG test at a 1:4 ticagrelor:clopidogrel ratio. Patients with an active opioid prescription during PSG test were excluded. Age, left ventricle (LV) dysfunction, and P2Y12 inhibitor use were included in a multivariate logistic regression. A total of 135 patients were included with 26 on ticagrelor and 109 on clopidogrel (age 64.1 ± 11.4, 32% male). High CSA burden (12%) and strict CSA (4.4%) were more common in patients on ticagrelor than in those on clopidogrel (27% vs. 8.3% and 10.0% vs. 1.8%). Ticagrelor use (vs. clopidogrel) was associated with high CSA burden (OR 3.53, 95% CI 1.04-12.9, P = 0.039) and trended toward significance for strict CSA (OR 6.32, 95% CI 1.03-51.4, P = 0.052) when adjusting for age and LV dysfunction. In an additional analysis also adjusting for history of atrial fibrillation, ticagrelor use and strict CSA became significantly associated (OR 10.0, 95% CI 1.32-117, P = 0.035). CSA was uncommon in patients with CHD undergoing sleep studies. Ticagrelor use (vs. clopidogrel) was associated with high CSA burden and trended toward significance for strict CSA.

Case of buprenorphine-associated central sleep apnea resolving with dose reduction.

Aside from respiratory suppression in overdose, full opioid agonist agents are known to cause sleep-disordered breathing (SDB). The increasing rates of opioid overdose in the United States have led to increasing use of medication-assisted treatments for opioid use disorders. Dose-dependent increase in SDB has been documented with methadone. There is emerging literature in the form of case reports providing evidence of buprenorphine and buprenorphine-naloxone contributing to sleep apnea. We report an additional case of a female patient developing central sleep apnea during initiation of buprenorphine-naloxone treatment. The condition resolved with dose reduction.

Incidence and Nature of Respiratory Events in Patients Undergoing Bronchoscopy Under Conscious Sedation.

BACKGROUND: During diagnostic bronchoscopies, conscious sedation improves patient tolerance, but it can contribute to hypercapnia and hypoxia by various mechanisms including depression of ventilatory drive. This prospective study was undertaken to determine the frequency of respiratory events and associated oxygen desaturations during bronchoscopy with conscious sedation. PATIENTS AND METHODS: The Nox-T3 monitoring system was placed before starting the bronchoscopy and remained in place for 30 minutes following the procedure. The primary endpoint was the occurrence of obstructive and central apneic events during bronchoscopy under conscious sedation. RESULTS: Obstructive events (apnea and hypopnea) occurred in 100% of patients (n=31), and central apneas occurred in 58% of patients (n=18) during the procedure with a median of 9 and 2 events per patient, respectively. During recovery, a significant proportion of patients had detectable obstructive (86%) and central (36%) events. Higher body mass index was associated with oxygen desaturation to <90% and with the need for escalation of care. Furthermore, a conscious sedation regimen that included propofol was significantly associated with central apneic events. CONCLUSION: Respiratory events are common during and immediately postprocedure after conscious sedation for bronchoscopy. Most events are obstructive, and the use of propofol predisposes to central apneas during the procedure. Both types of events are associated with a higher body mass index. Oxygen desaturation to <90% triggers escalation of care. A further prospective study will be required to determine the clinical significance of these apneic events and whether alleviating these events will improve the safety and outcomes of bronchoscopic procedures performed under conscious sedation.

Chronic Opioid Use and Central Sleep Apnea, Where Are We Now and Where To Go? A State of the Art Review.

Opioids are commonly used for pain management, perioperative procedures, and addiction treatment. There is a current opioid epidemic in North America that is paralleled by a marked increase in related deaths. Since 2000, chronic opioid users have been recognized to have significant central sleep apnea (CSA). After heart failure-related Cheyne-Stokes breathing (CSB), opioid-induced CSA is now the second most commonly seen CSA. It occurs in around 24% of chronic opioid users, typically after opioids have been used for more than 2 months, and usually corresponds in magnitude to opioid dose/plasma concentration. Opioid-induced CSA events often mix with episodes of ataxic breathing. The pathophysiology of opioid-induced CSA is based on dysfunction in respiratory rhythm generation and ventilatory chemoreflexes. Opioids have a paradoxical effect on different brain regions, which result in irregular respiratory rhythm. Regarding ventilatory chemoreflexes, chronic opioid use induces hypoxia that appears to stimulate an augmented hypoxic ventilatory response (high loop gain) and cause a narrow CO2 reserve, a combination that promotes respiratory instability. To date, no direct evidence has shown any major clinical consequence from CSA in chronic opioid users. A line of evidence suggested increased morbidity and mortality in overall chronic opioid users. CSA in chronic opioid users is likely to be a compensatory mechanism to avoid opioid injury and is potentially beneficial. The current treatments of CSA in chronic opioid users mainly focus on continuous positive airway pressure (CPAP) and adaptive servo-ventilation (ASV) or adding oxygen. ASV is more effective in reducing CSA events than CPAP. However, a recent ASV trial suggested an increased all-cause and cardiovascular mortality with the removal of CSA/CSB in cardiac failure patients. A major reason could be counteracting of a compensatory mechanism. No similar trial has been conducted for chronic opioid-related CSA. Future studies should focus on (1) investigating the phenotypes and genotypes of opioid-induced CSA that may have different clinical outcomes; (2) determining if CSA in chronic opioid users is beneficial or detrimental; and (3) assessing clinical consequences on different treatment options on opioid-induced CSA.

Central sleep apnea after acute coronary syndrome and association with ticagrelor use.

STUDY OBJECTIVES: By modifying the apneic threshold, the antiplatelet agent ticagrelor could promote central sleep apnea hypopnea syndrome (CSAHS). We aimed to assess the association between CSAHS and ticagrelor administration. METHODS: Patients were prospectively included within 1 year after acute coronary syndrome (ACS), if they had no heart failure (and left ventricular ejection fraction ≥ 45%) and no history of sleep apnea. After an overnight sleep study, patients were classified as "normal" with apnea hypopnea index (AHI) < 15, "CSAHS patients" with AHI ≥ 15 mostly with central sleep apneas, and "obstructive sleep apnea hypopnea syndrome (OSAHS) patients" with AHI ≥ 15 mostly with obstructive sleep apneas. RESULTS: We included 121 consecutive patients (mean age 56.8 ± 10.8, 88% men, mean body mass index 28.3 ± 4.4 kg/m2, left ventricular ejection fraction 56 ± 5%, at a mean of 67 ± 60 days (median 40 days, interquartile range: 30-80 days) after ACS. In total, 49 (45.3%) patients had AHI ≥ 15 (27 [22.3%] CSAHS %, 22 [18.2%] OSAHS). For 80 patients receiving ticagrelor, 24 (30%) had CSAHS with AHI ≥ 15, and for 41 patients not taking ticagrelor, only 3 (7.3%) had CSAHS with AHI ≥ 15 (chi-square = 8, p = 0.004). On multivariable analysis only age and ticagrelor administration were associated with the occurrence of CSAHS, (p = 0.0007 and p = 0.0006). CONCLUSION: CSA prevalence after ACS is high and seems promoted by ticagrelor administration. Results from monocentric study suggest a preliminary signal of safety. CLINICAL TRIALS. GOV ID: NCT03540459.

Central apnoeas and ticagrelor-related dyspnoea in patients with acute coronary syndrome.

AIMS: Dyspnoea often occurs in patients with acute coronary syndrome (ACS) treated with ticagrelor compared with other anti-platelet agents and is a cause of drug discontinuation. We aimed to explore the contribution of central apnoeas (CA) and chemoreflex sensitization to ticagrelor-related dyspnoea in patients with ACS. METHODS AND RESULTS: Sixty consecutive patients with ACS, preserved left ventricular ejection fraction, and no history of obstructive sleep apnoea, treated either with ticagrelor 90 mg b.i.d. (n = 30) or prasugrel 10 mg o.d. (n = 30) were consecutively enrolled. One week after ACS, all patients underwent two-dimensional Doppler echocardiography, pulmonary static/dynamic testing, carbon monoxide diffusion capacity assessment, 24-h cardiorespiratory monitoring for hypopnoea-apnoea detection, and evaluation of the chemosensitivity to hypercapnia by rebreathing technique. No differences were found in baseline demographic and clinical characteristics, echocardiographic, and pulmonary data between the two groups. Patients on ticagrelor, when compared with those on prasugrel, reported more frequently dyspnoea (43.3% vs. 6.7%, P = 0.001; severe dyspnoea 23.3% vs. 0%, P = 0.005), and showed higher apnoea-hypopnoea index (AHI) and central apnoea index (CAI) during the day, the night and the entire 24-h period (all P < 0.001). Similarly, they showed a higher chemosensitivity to hypercapnia (P = 0.001). Among patients treated with ticagrelor, those referring dyspnoea had the highest AHI, CAI, and chemosensitivity to hypercapnia (all P < 0.05). CONCLUSION: Central apnoeas are a likely mechanism of dyspnoea and should be screened for in patients treated with ticagrelor. A drug-related sensitization of the chemoreflex may be the cause of ventilatory instability and breathlessness in this setting.

The influence of opioids and nonopioid central nervous system active medications on central sleep apnea: a case-control study.

STUDY OBJECTIVES: Opioids are known to contribute to central sleep apnea (CSA), but the influence of nonopioid central nervous system active medications (CNSAMs) on CSA remains unclear. In light of the hypothesized impact of nonopioid CNSAMs on respiration, we examined the relationships between the use of opioids only, nonopioid CNSAMs alone, and their combination with CSA. METHODS: Among all adults who underwent polysomnography testing at the University of Michigan's sleep laboratory between 2013 and 2018 (n = 10,606), we identified 212 CSA cases and randomly selected 300 controls. Participants were classified into four groups based on their medication use: opioids alone, nonopioid CNSAMs only, their combination, and a reference group, including those who did not use any of these medications. We defined CSA as a binary outcome and as a continuous variable using central apnea index data. Logistic and linear regression were used to examine associations between medication use, CSA diagnosis, and central apnea index. RESULTS: Study participants included 58% men, and mean age was 50 (± 14 standard deviation years. Nearly half of the study participants did not use opioids or nonopioid CNSAMs, 6% used opioids alone, 27% nonopioid CNSAMs alone, and 16% used a combination of these medications. In adjusted analyses, opioids-only users had a nearly twofold increase in CSA odds, whereas those who used a combination of opioids and nonopioid CNSAMs had fivefold higher odds of CSA relative to the reference group. In contrast, the use of nonopioid CNSAMs alone had protective associations with CSA. CONCLUSIONS: This report showed increased odds of CSA, particularly among patients with sleep complaints who were prescribed opioids in combination with nonopioid CNSAMs compared with those who did not use any of these medications.

Opioids and sleep.

PURPOSE OF REVIEW: Summarize the effects of opioids on sleep including sleep architecture, sleep disordered breathing (SDB) and restless legs syndrome. RECENT FINDINGS: Opioids are associated with the development of central sleep apnea (CSA) and ataxic breathing. Recent reports suggest that adaptive servo-ventilation may be an effective treatment for CSA associated with opioids. SUMMARY: Opioids have multiple effects on sleep, sleep architecture and SDB. Although originally described with methadone use, most commonly used opioids have also been shown to affect sleep. In patients on chronic methadone, sleep architecture changes include decreases in N3 and REM sleep. However, in patients with chronic nonmalignant pain, opioids improve sleep quality and sleep time. Opioids, generally at a morphine equivalent dose more than 100 mg/day, are associated with an increased incidence of CSA and ataxic breathing as well as obstructive sleep apnea. Other risk factors may include concomitant use of other medications such as antidepressants, gabapentinoids and benzodiazepines. Opioid-induced CSA can be potentially treated with adaptive servo-ventilation. Finally, opioids are a potential therapeutic option for restless legs syndrome unresponsive to dopamine agonists and other medications. However, use in patients with restless legs syndrome should proceed with caution, taking into account the risk for dependence and development of SDB.

Mechanism of central hypopnoea induced by organic phosphorus poisoning.

Whether central apnoea or hypopnoea can be induced by organophosphorus poisoning remains unknown to date. By using the acute brainstem slice method and multi-electrode array system, we established a paraoxon (a typical acetylcholinesterase inhibitor) poisoning model to investigate the time-dependent changes in respiratory burst amplitudes of the pre-Bötzinger complex (respiratory rhythm generator). We then determined whether pralidoxime or atropine, which are antidotes of paraoxon, could counteract the effects of paraoxon. Herein, we showed that paraoxon significantly decreased the respiratory burst amplitude of the pre-Bötzinger complex (p < 0.05). Moreover, pralidoxime and atropine could suppress the decrease in amplitude by paraoxon (p < 0.05). Paraoxon directly impaired the pre-Bötzinger complex, and the findings implied that this impairment caused central apnoea or hypopnoea. Pralidoxime and atropine could therapeutically attenuate the impairment. This study is the first to prove the usefulness of the multi-electrode array method for electrophysiological and toxicological studies in the mammalian brainstem.

The effect of acetazolamide on the improvement of central apnea caused by abusing opioid drugs in the clinical trial.

PURPOSE: Acetazolamide is utilized as a treatment which falls effective in treating some type of CSA. Hence, it might be effective as far as opium addicts who suffer from CSA are concerned. MATERIALS AND METHOD: The current study was a double-blind, placebo-controlled, cross-over study ( clinicalTrials.gov ID: NCT02371473). The whole procedures were identical for both placebo and acetazolamide phases of clinical research. There were 14 CSA more than 5/h and more than 50% of apnea-hypopnea index (AHI). Out of these 14 patients, 10 volunteered to participate in the study. Fast Fourier transformation was used to separate heart rate variability (HRV) into its component VLF (very low frequency band), LF (low frequency band), and HF (high frequency band) rhythms that operate within different frequency ranges. RESULT: There are significant results in terms of decreased mix apnea and central apnea together due to acetazolamide compared with placebo (P < 0.023). Time of SatO2 < 90% is decreased as well (P < 0.1). There is also decrease of SDNN and NN50 after treatment with acetazolamide respectively (P < 0.001). Regarding fast Fourier transformation, there is increase of pHF and decrease of pLF after acetazolamide treatment (P < 0.001). CONCLUSION: Acetazolamide seems to be effective in improving oxygenation and a decrease of mixed and central apnea events together. In HRV analysis section, LF power has decreased significantly, which may more likely improve prognosis of the patients.

Brainstem activity, apnea, and death during seizures induced by intrahippocampal kainic acid in anaesthetized rats.

OBJECTIVE: To investigate how prolonged seizure activity affects cardiorespiratory function and activity of pre-Bötzinger complex, leading to sudden death. METHODS: Urethane-anesthetized female Long-Evans rats were implanted with nasal thermocouple; venous and arterial cannulae; and electrodes for electrocardiography (ECG) and hippocampal, cortical, and brainstem recording. Kainic acid injection into the ventral hippocampus induced status epilepticus. RESULTS: Seizures caused hypertension, tachycardia, and tachypnea punctuated by recurrent transient apneas. Salivation increased considerably: in 11 of 12 rats, liquid with alkaline pH consistent with saliva was expelled from the mouth. Most transient apneas were obstructive: nasal airflow ceased, while, in 83%, efforts to breathe persisted as continued rhythmic activity of respiratory pre-Bötzinger neurons, inspiratory electromyography (EMG), and excursions of the chest wall and abdomen. Blood pressure oscillated in time with respiratory efforts. This pattern also occurred in a minority of cases (16%) of incomplete apnea, but not in rare cases (1%) of transient central apneas. During transient obstructive apneas, the frequency of all inspiratory efforts decreased abruptly by ~30%, suggesting a resetting of the central respiratory rhythm generator. Twenty-two of thirty-one rats died, due either to obstructive apnea (12) or central apnea following progressive slowing of respiration (10). Most rats dying of central apnea had experienced several transient obstructive apneas. Negative DC field potential shifts of the brainstem followed the final breath, consistent with previous reports on spreading depolarization in mouse models. Timing suggests that the DC shift is a consequence rather than cause of respiratory collapse. Cardiac activity continued for tens of seconds. SIGNIFICANCE: Seizure activity in forebrain induces pronounced autonomic activation and disrupts activity in medullary respiratory centers, resulting in death from either obstructive or central apnea. These results directly inform mechanisms of death in status epilepticus, and indirectly provide clues to mechanisms of sudden unexpected death in epilepsy (SUDEP).

Ticagrelor-Associated Shift From Obstructive to Central Sleep Apnea: A Case Report.

None: Ticagrelor, a P2Y12 receptor antagonist, is used in combination with aspirin in patients with coronary artery disease. Recent reports suggest that ticagrelor might induce central sleep apnea (CSA) by increasing chemosensitivity to hypercapnia. We herein describe the case of a patient with positive airway pressure (PAP)-treated obstructive sleep apnea (OSA), in whom PAP-telemonitoring revealed the emergence of CSA and Cheyne-Stokes respiration (CSR) after initiation of ticagrelor for an acute coronary syndrome with preserved left ventricular ejection fraction. Ticagrelor-associated shift from OSA to CSA was confirmed by respiratory polygraphy after PAP withdrawal, and was associated with an increased chemosensitivity to hypercapnia. Ticagrelor discontinuation was associated with the recurrence of pure OSA and the normalization of hypercapnic ventilatory response. A transient recurrence of CSA and CSR was identified by PAP-telemonitoring after accidental reintroduction of the drug. Further studies are required to determine the mechanisms, incidence, and consequences of ticagrelor-associated CSA. CITATION: Paboeuf C, Priou P, Meslier N, Roulaud F, Trzepizur W, Gagnadoux F. Ticagrelor-associated shift from obstructive to central sleep apnea: a case report. J Clin Sleep Med. 2019;15(8):1179-1182.

More than Heart Failure: Central Sleep Apnea and Sleep-Related Hypoventilation.

Central sleep apnea (CSA) comprises a variety of breathing patterns and clinical entities. They can be classified into 2 categories based on the partial pressure of carbon dioxide in the arterial blood. Nonhypercapnic CSA is usually characterized by a periodic breathing pattern, while hypercapnic CSA is based on hypoventilation. The latter CSA form is associated with central nervous, neuromuscular, and rib cage disorders as well as obesity and certain medication or substance intake. In contrast, nonhypercapnic CSA is typically accompanied by an overshoot of the ventilation and often associated with heart failure, cerebrovascular diseases, and stay in high altitude. CSA and hypoventilation syndromes are often considered separately, but pathophysiological aspects frequently overlap. An integrative approach helps to recognize underlying pathophysiological mechanisms and to choose adequate therapeutic strategies. Research in the last decades improved our insights; nevertheless, diagnostic tools are not always appropriately chosen to perform comprehensive sleep studies. This supports misinterpretation and misclassification of sleep disordered breathing. The purpose of this article is to highlight unresolved problems, raise awareness for different pathophysiological components and to discuss the evidence for targeted therapeutic strategies.

Masking of obstructive sleep apnoea by drug induced central sleep apnoea.

Benzodiazepines are widely prescribed hypnotic agents which have multiple proven neurological and respiratory side effects. However, literature is sparse with regards to the incidence and occurrence of new onset central sleep apnoea in individuals being treated with benzodiazepines for insomnia. We present a case report of a patient presenting with new onset central sleep apnoea secondary to long term usage of benzodiazepines, with resultant masking of his pre-existing obstructive sleep apnoea.

Central Sleep Apnea With Sodium Oxybate in a Pediatric Patient.

ABSTRACT: A 12-year-old girl with normal neurodevelopment and narcolepsy type 1 presented with unexpected central apneas in response to sodium oxybate (SO). The patient underwent overnight polysomnography on SO (2.75 + 2.5 grams) which showed an apnea-hypopnea index of 4.3 events/h, and all the events were central apneas. A majority of central apneas clustered at about 1.5 hours after the first dose of SO. Remarkably, after a second dose of SO that was 0.25 grams smaller, she did not exhibit clusters of central sleep apneas. However, she did experience similar but milder breathing abnormalities that did not meet criteria to be scored as central apneas or hypopneas. Based on this observation, there may be an association between SO treatment and the development of central apnea. Further polysomnographic research on pediatric patients taking SO would help determine if there is a significant association between SO treatment and the development of central apnea in the pediatric population.

Polysomnographic Analysis of a Pediatric Case of Baclofen-Induced Central Sleep Apnea.

ABSTRACT: Respiratory disorders may follow brain injury and may also occur because of comorbidities and drug use, especially central depressants or muscle relaxants. Sleep can precipitate respiratory disorders, thus polysomnography can be a powerful diagnostic tool. By revealing breathing patterns that identify specific sleep disorders, polysomnography may unmask adverse pharmacological effects, for instance connecting central depressant drugs with central sleep apneas. We describe the case of a pediatric patient in rehabilitation from brain injury who developed a central sleep apnea following a baclofen dose increase within the therapeutic range, while assuming an under-dosed benzodiazepine. Polysomnography identified a typical respiration pattern, previously observed in adults treated with baclofen and other central depressants. Baclofen tapering resolved the central sleep apnea. Polysomnography, and this specific pattern, may be proposed as diagnostic tools in patients with high dose baclofen that can be used to prevent potential respiratory disorders in children.