RESUMO
Questionnaire-based studies have suggested genetic differences in sleep symptoms in chronic opioid users. The present study aims to investigate if there is a genetic effect on sleep architecture and quantitative electroencephalogram (EEG) in response to acute morphine. Under a randomized, double-blind, placebo-controlled, crossover design, 68 men with obstructive sleep apnea undertook two overnight polysomnographic studies conducted at least 1 week apart. Each night they received either 40 mg of controlled-release morphine or placebo. Sleep architecture and quantitative EEG were compared between conditions. Blood was sampled before sleep and on the next morning for genotyping and pharmacokinetic analyses. We analysed three candidate genes (OPRM1 [rs1799971, 118 A > G], ABCB1[rs1045642, 3435 C > T] and HTR3B [rs7103572 C > T]). We found that morphine decreased slow wave sleep and rapid eye movement sleep and increased stage 2 sleep. Those effects were less in subjects with HTR3B CT/TT than in those with CC genotype. Similarly, sleep onset latency was shortened in the ABCB1 CC subgroup compared with the CT/TT subgroup. Total sleep time was significantly increased in ABCB1 CC but not in CT/TT subjects. Sleep apnea and plasma morphine and metabolite concentration were not confounding factors for these genetic differences in sleep. With morphine, patients had significantly more active/unstable EEG (lower delta/alpha ratio) during sleep. No genetic effects on quantitative EEG were detected. In summary, we identified two genes (HTR3B and ABCB1) with significant variation in the sleep architecture response to morphine. Morphine caused a more active/unstable EEG during sleep. Our findings may have relevance for a personalized medicine approach to targeted morphine therapy.
Assuntos
Analgésicos Opioides/farmacologia , Morfina/farmacologia , Apneia Obstrutiva do Sono/fisiopatologia , Sono/efeitos dos fármacos , Adulto , Analgésicos Opioides/administração & dosagem , Método Duplo-Cego , Humanos , Masculino , Pessoa de Meia-Idade , Morfina/administração & dosagem , Polissonografia , Adulto JovemRESUMO
In 2019, the first multi-source registry of sudden cardiac arrest and death for patients aged 1-50 years launched in Victoria, Australia. Sudden cardiac arrest (SCA) affects approximately fifteen hundred younger Victorians per year. The End Unexplained Cardiac Death (EndUCD) Registry enrols SCA/death (D) cases aged 1-50 years, providing family screening, access to psychological support through clinical sites and creating a genetic biorepository for whole-genome sequencing. The registry will support clear pathways of cardiac assessment, epidemiological profiling and routine family screening and psychological support.
Assuntos
Morte Súbita Cardíaca , Parada Cardíaca , Morte Súbita Cardíaca/epidemiologia , Morte Súbita Cardíaca/etiologia , Humanos , Sistema de Registros , VitóriaRESUMO
This study sought to explore the feasibility and utility of post-mortem coronary artery calcium (CAC) scoring in identifying patients with ischemic heart disease as cause of sudden death. 100 deceased patients aged 18-50 years underwent post-mortem examination in the setting of sudden death. At post-mortem, fifty cases were determined to have ischemic heart disease, and fifty had death attributed to trauma or unascertained causes. The CAC score was calculated in a blinded manner from post-mortem CTs performed on all cases. CAC scores were assessable in 97 non-decomposed cases (feasibility 97%). The median CAC score was 88 Agatston units [IQR 0-286] in patients deceased from ischemic heart disease vs 0 [IQR 0-0] in patients deceased from other causes (p < 0.0001). Presence of any coronary calcification differed significantly between ischemic heart disease and non-ischemic groups (adjusted odds ratio 10.7, 95% CI 3.2-35.5). All cases with a CAC score > 100 (n = 22) had ischemic heart disease as the cause of death. Fifteen cases had a CAC score of zero but severe coronary disease at post-mortem examination. Post-mortem CAC scoring is highly feasible. An elevated CAC score in cases 18-50 years old with sudden death predicts ischemic heart disease at post-mortem examination. However, a CAC score of zero does not exclude significant coronary artery disease. Post-mortem CAC score may be considered as a further assessment tool to help predict likely cause of death when there is an objection to or unavailability of post-mortem examination.
Assuntos
Vasos Coronários/diagnóstico por imagem , Morte Súbita/etiologia , Isquemia Miocárdica/diagnóstico , Calcificação Vascular/diagnóstico por imagem , Adolescente , Adulto , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/mortalidade , Valor Preditivo dos Testes , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X , Adulto JovemRESUMO
Accidental opioid-related deaths are increasing. These often occur during sleep. Opioids such as morphine may worsen obstructive sleep apnoea (OSA). Thus, people with OSA may be at greater risk of harm from morphine. Possible mechanisms include respiratory depression and reductions in drive to the pharyngeal muscles to increase upper airway collapsibility. However, the effects of morphine on the four key phenotypic causes of OSA (upper airway collapsibility (pharyngeal critical closure pressure; P crit), pharyngeal muscle responsiveness, respiratory arousal threshold and ventilatory control (loop gain) during sleep) are unknown.21 males with OSA (apnoea-hypopnoea index range 7-67â events·h-1) were studied on two nights (1-week washout) according to a double-blind, randomised, cross-over design (ACTRN12613000858796). Participants received 40â mg of MS-Contin on one visit and placebo on the other. Brief reductions in continuous positive airway pressure (CPAP) from the therapeutic level were delivered to induce airflow limitation during non-rapid eye movement (REM) sleep to quantify the four phenotypic traits. Carbon dioxide was delivered via nasal mask on therapeutic CPAP to quantify hypercapnic ventilatory responses during non-REM sleep.Compared to placebo, 40â mg of morphine did not change P crit (-0.1±2.4 versus -0.4±2.2â cmH2O, p=0.58), genioglossus muscle responsiveness (-2.2 (-0.87 to -5.4) versus -1.2 (-0.3 to -3.5) µV·cmH2O-1, p=0.22) or arousal threshold (-16.7±6.8 versus -15.4±6.0â cmH2O, p=0.41), but did reduce loop gain (-10.1±2.6 versus -4.4±2.1, p=0.04) and hypercapnic ventilatory responses (7.3±1.2 versus 6.1±1.5â L·min-1, p=0.006).Concordant with recent clinical findings, 40â mg of MS-Contin does not systematically impair airway collapsibility, pharyngeal muscle responsiveness or the arousal threshold in moderately severe OSA patients. However, consistent with blunted chemosensitivity, ventilatory control is altered.
Assuntos
Morfina , Apneia Obstrutiva do Sono , Pressão Positiva Contínua nas Vias Aéreas , Humanos , Masculino , Fenótipo , SonoRESUMO
Background: Sudden cardiac death (SCD) is a major global health problem, accounting for up to 20% of deaths in Western societies. Clinical quality registries have been shown in a range of disease conditions to improve clinical management, reduce variation in care and improve outcomes. Aim: To identify existing cardiac arrest (CA) and SCD registries, characterising global coverage and methods of data capture and validation. Methods: Biomedical and public search engines were searched with the terms 'registry cardio*'; 'sudden cardiac death registry' and 'cardiac arrest registry'. Registries were categorised as either CA, SCD registries or 'other' according to prespecified criteria. SCD registry coordinators were contacted for contemporaneous data regarding registry details. Results: Our search strategy identified 49 CA registries, 15 SCD registries and 9 other registries (ie, epistries). Population coverage of contemporary CA and SCD registries is highly variable with registries densely concentrated in North America and Western Europe. Existing SCD registries (n=15) cover a variety of age ranges and subpopulations, with some enrolling surviving patients (n=8) and family members (n=5). Genetic data are collected by nine registries, with the majority of these (n=7) offering indefinite storage in a biorepository. Conclusions: Many CA registries exist globally, although with inequitable population coverage. Comprehensive multisource surveillance SCD registries are fewer in number and more challenging to design and maintain. Challenges identified include maximising case identification and case verification. Trial registration number: CRD42019118910.
Assuntos
Confiabilidade dos Dados , Mineração de Dados , Morte Súbita Cardíaca/epidemiologia , Medicina Baseada em Evidências , Saúde Global , Parada Cardíaca/mortalidade , Sistema de Registros , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Morte Súbita Cardíaca/prevenção & controle , Feminino , Parada Cardíaca/diagnóstico , Parada Cardíaca/terapia , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Prognóstico , Reprodutibilidade dos Testes , Fatores de Risco , Adulto JovemRESUMO
Opioid-related deaths from respiratory depression are increasing but there is only limited information on the effect of morphine on breathing during sleep. This study aimed to detect and quantify opioid-induced cardiorespiratory pattern changes during sleep in obstructive sleep apnea (OSA) patients using novel automated methods and correlate these with conventional polysomnography (PSG) measures. Under a randomized double-blind placebo-controlled crossover design, 60 male OSA patients attended two one-night visits to the sleep laboratory, at least a week apart. Either a 40-mg controlled-release oral morphine dose or placebo was administered. Breathing during sleep was measured by standard in-laboratory PSG. We analysed the inter-breath interval (IBI) from the PSG flow channel to quantify breathing irregularity. Cardiopulmonary coupling (CPC) was analysed using the PSG electrocardiogram (ECG) channel. Following the consumption of morphine, the 60 OSA patients had fewer breaths (p = .0006), a longer inter-breath interval (p < .0001) and more irregular breathing with increased IBI coefficient of variation (CV) (p = .0015) compared to the placebo night. A higher CPC sleep quality index was found with morphine use. The change of key IBI and CPC parameters was significantly correlated with the change of key PSG sleep-disordered breathing parameters. In conclusion, 40 mg controlled-release morphine resulted in a longer breathing cycle and increased breathing irregularity but generally more stable sleep in OSA patients. The significant links between the IBI and CPC techniques and a range of PSG sleep-disordered breathing parameters may suggest a practical value as surrogate overnight cardiorespiratory measurements, because both respiratory flow and ECG can be detected by small portable devices.
Assuntos
Analgésicos Opioides/efeitos adversos , Morfina/efeitos adversos , Polissonografia/métodos , Respiração/efeitos dos fármacos , Apneia Obstrutiva do Sono/fisiopatologia , Adolescente , Adulto , Idoso , Analgésicos Opioides/farmacologia , Estudos Cross-Over , Método Duplo-Cego , Humanos , Masculino , Pessoa de Meia-Idade , Morfina/farmacologia , Sono/efeitos dos fármacos , Adulto JovemRESUMO
OBJECTIVE: Anaesthesiology guidelines suggest that opioids worsen obstructive sleep apnoea (OSA) despite no randomised controlled trial evidence. We therefore conducted a randomised controlled trial to evaluate the effects of a common clinical dose of morphine on OSA, and to identify clinical phenotype and genotype vulnerability to opioid-respiratory depression. METHODS: Under a double-blind, randomised, crossover design, 60 male patients with OSA attended two visits to the hospital sleep laboratory, at least 1 week apart. Either 40 mg controlled-release oral morphine or placebo was administered. Awake ventilatory chemoreflex tests were performed post dose and prior to overnight polysomnography monitoring. Blood was sampled before sleep and the next morning for toxicology and genotype analyses. Sleep time with oxygen saturation (SpO2) <90% (T90) was the primary outcome. RESULTS: Despite a large inter-individual variability, 40 mg morphine did not worsen T90 and apnoea-hypopnoea index, and only decreased the SpO2 nadir by 1.3%. In patients with severe OSA, a lower baseline CO2ventilatory response threshold correlated with the worsening of T90, apnoea-hypopnoea index and oxygen desaturation index with morphine use. Patients with OSA and the A118G OPRM1 polymorphism of A/A and A/G had a significantly different morphine effect on awake ventilatory chemosensitivity and T90 during sleep. CONCLUSIONS: 40 mg oral controlled-release morphine did not worsen OSA in men, challenging traditional thinking that OSA will be worsened by opioids. Individual opioid response in patients with OSA may relate to baseline CO2 response threshold and OPRM1 genotype. Our study findings may pave the way for a precision medicine approach to avoid opioid-related risks. TRIAL REGISTRATION NUMBER: The Australian and New Zealand Clinical Trial Registry, ACTRN12613000858796.
Assuntos
Morfina/administração & dosagem , Entorpecentes/administração & dosagem , Apneia Obstrutiva do Sono/tratamento farmacológico , Sono/efeitos dos fármacos , Adulto , Estudos Cross-Over , Método Duplo-Cego , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Morfina/efeitos adversos , Entorpecentes/efeitos adversos , Oxigênio/sangue , Fenótipo , Polimorfismo Genético , Polissonografia/métodos , Receptores Opioides mu/genética , Apneia Obstrutiva do Sono/genética , Apneia Obstrutiva do Sono/fisiopatologiaRESUMO
There is no satisfactory treatment for obstructive sleep apnoea (OSA). Supplemental low-flow oxygen therapy (LFO2) has been shown to reduce hypoxaemia and is well tolerated by patients with OSA. However, oxygen therapy may be beneficial only to certain subsets of patients with OSA. In this study, we evaluated a 10-min awake ventilatory chemoreflex test in predicting individual OSA response to 2â months of LFO2 therapy.At baseline, patients with OSA underwent ventilatory chemoreflex testing in the afternoon, prior to the overnight polysomnography. Subjects were reassessed with polysomnography after 2â months of nocturnal oxygen treatment.20 patients with OSA completed the study. After 2â months of O2 treatment, changes in the apnoea-hypopnoea index (AHI) were significantly correlated with baseline CO2 ventilatory response threshold (VRT) and chemosensitivity (p<0.05). In predicting a fall in AHI, the area under the receiver operating characteristic curve (AUC) was 0.79 for VRT and 0.89 for chemosensitivity. When these two variables were combined in a logistic regression model, the prediction effect became stronger with an AUC of 0.97, sensitivity of 0.92 and specificity of 0.83.Our awake ventilatory chemoreflex test could be considered a simple potential clinical tool to predict individual OSA response to oxygen therapy. It could provide a novel personalised medicine approach to OSA treatment.
Assuntos
Polissonografia/métodos , Apneia Obstrutiva do Sono/fisiopatologia , Vigília , Idoso , Reações Falso-Positivas , Feminino , Humanos , Hipóxia , Masculino , Pessoa de Meia-Idade , Oxigênio/uso terapêutico , Oxigenoterapia , Apneia Obstrutiva do Sono/terapia , Fatores de TempoAssuntos
Hipóxia/complicações , Transtornos Neurocognitivos/etiologia , Síndromes da Apneia do Sono/complicações , Privação do Sono/complicações , Diagnóstico Diferencial , Hipóxia/diagnóstico , Transtornos Neurocognitivos/diagnóstico , Fatores de Risco , Síndromes da Apneia do Sono/diagnóstico , Privação do Sono/diagnósticoRESUMO
BACKGROUND: The key determinants of daytime drowsiness in sleep disordered breathing (SDB) are unclear. Hypercapnia has not been examined as a potential contributor due to the lack of reliable measurement during sleep. To overcome this limitation, we studied predominantly hypercapnic SDB patients to investigate the role of hypercapnia on EEG activation and daytime sleepiness. METHODS: We measured overnight polysomnography (PSG), arterial blood gases, and Epworth Sleepiness Scale in 55 severe SDB patients with obesity hypoventilation syndrome or overlap syndrome (COPD+ obstructive sleep apnea) before and â¼3 months after positive airway pressure (PAP) treatment. Quantitative EEG analyses were performed, and the Delta/ Alpha ratio was used as an indicator of EEG activation. RESULTS: After the PAP treatment, these patients showed a significant decrease in their waking pCO(2), daytime sleepiness, as well as all key breathing/oxygenation parameters during sleep. Overnight Delta/Alpha ratio of EEG was significantly reduced. There is a significant cross-correlation between a reduced wake pCO(2), a faster (more activated) sleep EEG (reduced Delta/Alpha ratio) and reduced daytime sleepiness (all p < 0.05) with PAP treatment. Multiple regression analyses showed the degree of change in hypercapnia to be the only significant predictor for both ESS and Delta/ Alpha ratio. CONCLUSIONS: Hypercapnia is a key correlate of EEG activation and daytime sleepiness in hypercapnic SDB patients. The relationship between hypercapnia and sleepiness may be mediated by reduced neuro-electrical brain activity.