Pharmacological treatment for central sleep apnoea in adults.

BACKGROUND: The term central sleep apnoea (CSA) encompasses diverse clinical situations where a dysfunctional drive to breathe leads to recurrent respiratory events, namely apnoea (complete absence of ventilation) and hypopnoea sleep (insufficient ventilation) during sleep. Studies have demonstrated that CSA responds to some extent to pharmacological agents with distinct mechanisms, such as sleep stabilisation and respiratory stimulation. Some therapies for CSA are associated with improved quality of life, although the evidence on this association is uncertain. Moreover, treatment of CSA with non-invasive positive pressure ventilation is not always effective or safe and may result in a residual apnoea-hypopnoea index. OBJECTIVES: To evaluate the benefits and harms of pharmacological treatment compared with active or inactive controls for central sleep apnoea in adults. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 30 August 2022. SELECTION CRITERIA: We included parallel and cross-over randomised controlled trials (RCTs) that evaluated any type of pharmacological agent compared with active controls (e.g. other medications) or passive controls (e.g. placebo, no treatment or usual care) in adults with CSA as defined by the International Classification of Sleep Disorders 3rd Edition. We did not exclude studies based on the duration of intervention or follow-up. We excluded studies focusing on CSA due to periodic breathing at high altitudes. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were central apnoea-hypopnoea index (cAHI), cardiovascular mortality and serious adverse events. Our secondary outcomes were quality of sleep, quality of life, daytime sleepiness, AHI, all-cause mortality, time to life-saving cardiovascular intervention, and non-serious adverse events. We used GRADE to assess certainty of evidence for each outcome. MAIN RESULTS: We included four cross-over RCTs and one parallel RCT, involving a total of 68 participants. Mean age ranged from 66 to 71.3 years and most participants were men. Four trials recruited people with CSA associated with heart failure, and one study included people with primary CSA. Types of pharmacological agents were acetazolamide (carbonic anhydrase inhibitor), buspirone (anxiolytic), theophylline (methylxanthine derivative) and triazolam (hypnotic), which were given for between three days and one week. Only the study on buspirone reported a formal evaluation of adverse events. These events were rare and mild. No studies reported serious adverse events, quality of sleep, quality of life, all-cause mortality, or time to life-saving cardiovascular intervention. Carbonic anhydrase inhibitors versus inactive control Results were from two studies of acetazolamide versus placebo (n = 12) and acetazolamide versus no acetazolamide (n = 18) for CSA associated with heart failure. One study reported short-term outcomes and the other reported intermediate-term outcomes. We are uncertain whether carbonic anhydrase inhibitors compared to inactive control reduce cAHI in the short term (mean difference (MD) -26.00 events per hour, 95% CI -43.84 to -8.16; 1 study, 12 participants; very low certainty). Similarly, we are uncertain whether carbonic anhydrase inhibitors compared to inactive control reduce AHI in the short term (MD -23.00 events per hour, 95% CI -37.70 to 8.30; 1 study, 12 participants; very low certainty) or in the intermediate term (MD -6.98 events per hour, 95% CI -10.66 to -3.30; 1 study, 18 participants; very low certainty). The effect of carbonic anhydrase inhibitors on cardiovascular mortality in the intermediate term was also uncertain (odds ratio (OR) 0.21, 95% CI 0.02 to 2.48; 1 study, 18 participants; very low certainty). Anxiolytics versus inactive control Results were based on one study of buspirone versus placebo for CSA associated with heart failure (n = 16). The median difference between groups for cAHI was -5.00 events per hour (IQR -8.00 to -0.50), the median difference for AHI was -6.00 events per hour (IQR -8.80 to -1.80), and the median difference on the Epworth Sleepiness Scale for daytime sleepiness was 0 points (IQR -1.0 to 0.00). Methylxanthine derivatives versus inactive control Results were based on one study of theophylline versus placebo for CSA associated with heart failure (n = 15). We are uncertain whether methylxanthine derivatives compared to inactive control reduce cAHI (MD -20.00 events per hour, 95% CI -32.15 to -7.85; 15 participants; very low certainty) or AHI (MD -19.00 events per hour, 95% CI -30.27 to -7.73; 15 participants; very low certainty). Hypnotics versus inactive control Results were based on one trial of triazolam versus placebo for primary CSA (n = 5). Due to very serious methodological limitations and insufficient reporting of outcome measures, we were unable to draw any conclusions regarding the effects of this intervention. AUTHORS' CONCLUSIONS: There is insufficient evidence to support the use of pharmacological therapy in the treatment of CSA. Although small studies have reported positive effects of certain agents for CSA associated with heart failure in reducing the number of respiratory events during sleep, we were unable to assess whether this reduction may impact the quality of life of people with CSA, owing to scarce reporting of important clinical outcomes such as sleep quality or subjective impression of daytime sleepiness. Furthermore, the trials mostly had short-term follow-up. There is a need for high-quality trials that evaluate longer-term effects of pharmacological interventions.

Effect of Zolpidem on nocturnal arousals and susceptibility to central sleep apnea.

PURPOSE: Arousals may contribute to the pathogenesis of sleep-disordered breathing (SDB) and central sleep apnea (CSA). We aimed to determine the effect of the nonbenzodiazepine hypnotic zolpidem on the frequency of respiratory-related arousals and central apnea in patients with moderate-to-severe SDB. We hypothesized that zolpidem decreases the severity of SDB by decreasing the frequency of respiratory-related arousals. METHODS: Patients with apnea-hypopnea index ≥ 15 events/hour and central apnea-hypopnea index ≥ 5 events/hour underwent a sleep study on zolpidem 5 mg and a sleep study with no medication in a randomized order. The respiratory arousal index was compared between the two studies using a randomized crossover design. Sleep, respiratory, and physiologic parameters, including the CO2 reserve and the respiratory arousal threshold, were also compared. RESULTS: Eleven participants completed the study. Compared to no treatment, zolpidem reduced the respiratory arousal index (39.7 ± 7.7 vs. 23.3 ± 4.4 events/h, P = 0.031). Zolpidem also lowered the total apnea-hypopnea index (55.6 ± 8.5 vs. 41.3 ± 7.5 events/hour, P = 0.033) but did not affect other clinical and physiologic parameters. Compared to control, zolpidem did not widen CO2 reserve (- 0.44 ± 1.47 vs. - 0.63 ± 0.86 mmHg, P = 0.81). The respiratory arousal threshold did not show a significant change on zolpidem compared to control (- 8.72 ± 2.1 vs. - 8.25 ± 2.81 cmH2O, P = 0.41). CONCLUSION: Nocturnal arousals and overall SDB severity were reduced with a single dose of zolpidem in patients with moderate-to-severe sleep-disordered breathing with increased susceptibility for central apnea. Zolpidem did not widen the CO2 reserve or increase the arousal threshold. TRIAL REGISTRATION: Clinicaltrials.gov. Sleep and Breathing in the General Population - Chemical Stimuli (NCT04720547).

Effects of sacubitril-valsartan on central and obstructive apneas in heart failure patients with reduced ejection fraction.

OBJECTIVE: This study aimed to evaluate the effect of sacubitril-valsartan (SV) on central apneas (CA) and obstructive apneas (OA) in patients with heart failure with reduced ejection fraction (HFrEF). METHODS: In patients with HFrEF, SV initiation was titrated to the highest tolerable dosage. Patients were evaluated with portable apnea monitoring, echocardiography, and cardiopulmonary exercise testing at baseline and 3 months later. RESULTS: Of a total of 18 patients, 9 (50%) had OA, 7 (39%) had CA, and 2 (11%) had normal breathing. SV therapy was related to a reduction in NT-pro BNP and an improvement in LV function after 3 months. Portable apnea monitoring revealed a significant decrease of the respiratory event index (REI) after treatment with SV (20 ± 23 events/h to 7 ± 7 events/h, p = 0.003). When subgrouping according to type of apneas, REI, and time spent below 90% saturation (T90) decreased in patients with CA and OA (all p < 0.05). CONCLUSION: In this prospective study, SV treatment for 3 months in patients with CA and OA is associated with a significant decrease in REI.

The bioavailability and maturing clearance of doxapram in preterm infants.

BACKGROUND: Doxapram is used for the treatment of apnea of prematurity in dosing regimens only based on bodyweight, as pharmacokinetic data are limited. This study describes the pharmacokinetics of doxapram and keto-doxapram in preterm infants. METHODS: Data (302 samples) from 75 neonates were included with a median (range) gestational age (GA) 25.9 (23.9-29.4) weeks, bodyweight 0.95 (0.48-1.61) kg, and postnatal age (PNA) 17 (1-52) days at the start of continuous treatment. A population pharmacokinetic model was developed using non-linear mixed-effects modelling (NONMEM®). RESULTS: A two-compartment model best described the pharmacokinetics of doxapram and keto-doxapram. PNA and GA affected the formation clearance of keto-doxapram (CLFORMATION KETO-DOXAPRAM) and clearance of doxapram via other routes (CLDOXAPRAM OTHER ROUTES). For a median individual of 0.95 kg, GA 25.6 weeks, and PNA 29 days, CLFORMATION KETO-DOXAPRAM was 0.115 L/h (relative standard error (RSE) 12%) and CLDOXAPRAM OTHER ROUTES was 0.645 L/h (RSE 9%). Oral bioavailability was estimated at 74% (RSE 10%). CONCLUSIONS: Dosing of doxapram only based on bodyweight results in the highest exposure in preterm infants with the lowest PNA and GA. Therefore, dosing may need to be adjusted for GA and PNA to minimize the risk of accumulation and adverse events. For switching to oral therapy, a 33% dose increase is required to maintain exposure. IMPACT: Current dosing regimens of doxapram in preterm infants only based on bodyweight result in the highest exposure in infants with the lowest PNA and GA. Dosing of doxapram may need to be adjusted for GA and PNA to minimize the risk of accumulation and adverse events. Describing the pharmacokinetics of doxapram and its active metabolite keto-doxapram following intravenous and gastroenteral administration enables to include drug exposure to the evaluation of treatment of AOP. The oral bioavailability of doxapram in preterm neonates is 74%, requiring a 33% higher dose via oral than intravenous administration to maintain exposure.

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.

The association of serotonin reuptake inhibitors and benzodiazepines with ictal central apnea.

OBJECTIVE: Ictal (ICA) and postconvulsive central apnea (PCCA) have been implicated in sudden unexpected death in epilepsy (SUDEP) pathomechanisms. Previous studies suggest that serotonin reuptake inhibitors (SRIs) and benzodiazepines (BZDs) may influence breathing. The aim of this study was to investigate if chronic use of these drugs alters central apnea occurrence in patients with epilepsy. METHODS: Patients with epilepsy admitted to epilepsy monitoring units (EMUs) in nine centers participating in a SUDEP study were consented. Polygraphic physiological parameters were analyzed, including video-electroencephalography (VEEG), thoracoabdominal excursions, and pulse oximetry. Outpatient medication details were collected. Patients and seizures were divided into SRI, BZD, and control (no SRI or BZD) groups. Ictal central apnea and PCCA, hypoxemia, and electroclinical features were assessed for each group. RESULTS: Four hundred and seventy-six seizures were analyzed (204 patients). The relative risk (RR) for ICA in the SRI group was half that of the control group (p = 0.02). In the BZD group, ICA duration was significantly shorter than in the control group (p = 0.02), as was postictal generalized EEG suppression (PGES) duration (p = 0.021). Both SRI and BZD groups were associated with smaller seizure-associated oxygen desaturation (p = 0.009; p ≪ 0.001). Neither presence nor duration of PCCA was significantly associated with SRI or BZD (p ≫ 0.05). CONCLUSIONS: Seizures in patients taking SRIs have lower occurrence of ICA, and patients on chronic treatment with BZDs have shorter ICA and PGES durations. Preventing or shortening ICA duration by using SRIs and/or BZD in patients with epilepsy may play a possible role in SUDEP risk reduction.

Genetics and Extracellular Vesicles of Pediatrics Sleep Disordered Breathing and Epilepsy.

Sleep remains one of the least understood phenomena in biology, and sleep disturbances are one of the most common behavioral problems in childhood. The etiology of sleep disorders is complex and involves both genetic and environmental factors. Epilepsy is the most popular childhood neurological condition and is characterized by an enduring predisposition to generate epileptic seizures, and the neurobiological, cognitive, psychological, and social consequences of this condition. Sleep and epilepsy are interrelated, and the importance of sleep in epilepsy is less known. The state of sleep also influences whether a seizure will occur at a given time, and this differs considerably for various epilepsy syndromes. The development of epilepsy has been associated with single or multiple gene variants. The genetics of epilepsy is complex and disorders exhibit significant genetic heterogeneity and variability in the expressivity of seizures. Phenobarbital (PhB) is the most widely used antiepileptic drug. With its principal mechanism of action to prolong the opening time of the γ-aminobutyric acid (GABA)-A receptor-associated chloride channel, it enhances chloride anion influx into neurons, with subsequent hyperpolarization, thereby reducing excitability. Enzymes that metabolize pharmaceuticals including PhB are well known for having genetic polymorphisms that contribute to adverse drug-drug interactions. PhB metabolism is highly dependent upon the cytochrome P450 (CYP450) and genetic polymorphisms can lead to variability in active drug levels. The highly polymorphic CYP2C19 isozymes are responsible for metabolizing a large portion of routinely prescribed drugs and variants contribute significantly to adverse drug reactions and therapeutic failures. A limited number of CYP2C19 single nucleotide polymorphisms (SNPs) are involved in drug metabolism. Extracellular vesicles (EVs) are circular membrane fragments released from the endosomal compartment as exosomes are shed from the surfaces of the membranes of most cell types. Increasing evidence indicated that EVs play a pivotal role in cell-to-cell communication. Theses EVs may play an important role between sleep, epilepsy, and treatments. The discovery of exosomes provides potential strategies for the diagnosis and treatment of many diseases including neurocognitive deficit. The aim of this study is to better understand and provide further knowledge about the metabolism and interactions between phenobarbital and CYP2C19 polymorphisms in children with epilepsy, interplay between sleep, and EVs. Understanding this interplay between epilepsy and sleep is helpful in the optimal treatment of all patients with epileptic seizures. The use of genetics and extracellular vesicles as precision medicine for the diagnosis and treatment of children with sleep disorder will improve the prognosis and the quality of life in patients with epilepsy.

Inhibitory respiratory responses to progesterone and allopregnanolone in newborn rats chronically treated with caffeine.

KEY POINTS: In premature newborns, recurrent apnoea is systematically treated with caffeine to prevent long-term neurocognitive disorders, but a substantial percentage of apnoea persists particularly in neonates born before 28 weeks of gestation. Progesterone has been proposed as a respiratory stimulant potentially suitable for the treatment of newborn apnoea persistent to caffeine. Accordingly we asked whether acute progesterone administration reduces apnoea frequency in newborn rats treated with caffeine. Surprisingly our results show that in newborn rats treated with caffeine, administration of progesterone inhibits breathing and increases apnoea frequency. Additional experiments showed an enhanced GABAergic inhibitory drive on breathing after caffeine treatment, and that progesterone is converted to allopregnanolone (an allosteric modulator of GABAA receptors) to inhibit breathing. We conclude that combining progesterone and chronic caffeine is not an option in preterm neonates, unless the effects of allopregnanolone can be counteracted. ABSTRACT: Caffeine is the main treatment for apnoea in preterm neonates, but its interactions with other respiratory stimulants like progesterone are unknown. We tested the hypothesis that the addition of progesterone to caffeine treatments further stimulates ventilation. Newborn rats were treated with water (control) or caffeine (15 mg kg(-1)) by daily gavage between postnatal day (P)3 and P12. At P4 and P12, we measured apnoea frequency, ventilatory responses and metabolic parameters under both normoxia and hypoxia (12% O2, 20 min) following an acute administration of either saline or progesterone (4 mg kg(-1); i.p.). Progesterone injection increased the serum levels of both progesterone and its neuroactive metabolite allopregnanolone. Progesterone had no effect on ventilation in control rats under normoxia. Progesterone depressed ventilation in P12 caffeine-treated rats under normoxia and hypoxia and increased apnoea frequency in both P4 and P12 rats. Because allopregnanolone is an allosteric modulator of GABAA receptors and caffeine may enhance GABAergic inhibition in newborns, we studied the effects of the GABAA receptor antagonist bicuculline at 0, 1, 2 and 3 mg kg(-1) doses and allopregnanolone (10 mg kg(-1) dose) in P12 rats. In caffeine-treated rats, bicuculline enhanced ventilation, while allopregnanolone decreased ventilation and increased total apnoea time. Progesterone had no effect on ventilation and apnoea frequency in caffeine-treated rats injected with finasteride, which blocks the conversion of progesterone to allopregnanolone. We conclude that combining progesterone and chronic caffeine therapy is not an option for the treatment of persistent apnoea in preterm neonates, unless the effects of allopregnanolone can be counteracted.

Central Sleep Apnea at High Altitude.

The discovery of central sleep apnea (CSA) at high altitude is usually attributed to Angelo Mosso who published in 1898. It can occur in susceptible individuals at altitude above 2000 m, but at very high altitude, say above 5000 m, it will occur in most subjects. Severity is correlated with ventilatory responsiveness, particularly to hypoxia. Theoretically, it should spontaneously improve with time and acclimatization. Although the time course of resolution is not well described, it appears to persist for more than a month at 5000 m.It occurs due to the interaction of hypocapnia with stages 1 and 2 NREM sleep, in the presence of increased loop-gain. The hypocapnia is secondary to hypoxic ventilatory drive. With acclimatization, one might expect that the increase in PaO2 and cerebral blood flow (CBF) would mitigate the CSA. However, over time, both the hypoxic and hypercapnic ventilatory responses increase, causing an increase in loop gain which is a counteracting force.The severity of the CSA can be reduced by descent, supplemental oxygen therapy, oral or intravenous acetazolamide. Recent studies suggest that acute further increases in cerebral blood flow will substantially, but temporarily, reduce central sleep apnea, without altering acid based balance. Very recently, bi-level noninvasive ventilation has also been shown to help (mechanism unknown). Sleep quality can be improved independent of the presence of CSA by the use of benzodiazepine sedation.

GAL-021 and GAL-160 are Efficacious in Rat Models of Obstructive and Central Sleep Apnea and Inhibit BKCa in Isolated Rat Carotid Body Glomus Cells.

GAL-021 and GAL-160 are alkylamino triazine analogues, which stimulate ventilation in rodents, non-human primates and (for GAL-021) in humans. To probe the site and mechanism of action of GAL-021 and GAL-160 we utilized spirometry in urethane anesthetized rats subjected to acute bilateral carotid sinus nerve transection (CSNTX) or sham surgery. In addition, using patch clamp electrophysiology we evaluated ionic currents in carotid body glomus cells isolated from neonatal rats. Acute CSNTX markedly attenuated and in some instances abolished the ventilatory stimulant effects of GAL-021 and GAL-160 (0.3 mg/kg IV), suggesting the carotid body is a/the major locus of action. Electrophysiology studies, in isolated Type I cells, established that GAL-021 (30 µM) and GAL-160 (30 µM) inhibited the BK(Ca) current without affecting the delayed rectifier K(+), leak K(+) or inward Ca(2+) currents. At a higher concentration of GAL-160 (100 µM), inhibition of the delayed rectifier K(+) current and leak K(+) current were observed. These data are consistent with the concept that GAL-021 and GAL-160 influence breathing control by acting as peripheral chemoreceptor modulators predominantly by inhibiting BK(Ca) mediated currents in glomus cells of the carotid body.

Sacubitril/valsartan has an underestimated impact on the right ventricle in patients with sleep-disordered breathing, especially central sleep apnoea syndrome.

BACKGROUND: Sacubitril/valsartan has been demonstrated to significantly improve left ventricular performance and remodelling in patients with heart failure. However, its effects on the right ventricle in patients with chronic heart failure and sleep-disordered breathing (SDB) have not been studied. AIM: To investigate the impact of sacubitril/valsartan treatment on right ventricular function in patients with SDB. METHODS: This was a subanalysis of an observational prospective multicentre study involving 101 patients. At inclusion, patients were evaluated by echocardiography and nocturnal ventilatory polygraphy, which allowed patients to be divided into three groups: "central-SDB"; "obstructive-SDB"; and "no-SDB". RESULTS: After 3 months of sacubitril/valsartan therapy, a positive impact on right ventricular function was observed. In the general population, tricuspid annular plane systolic excursion increased by +1.32±4.74mm (P=0.024) and systolic pulmonary artery pressure decreased by -3.1±10.91mmHg (P=0.048). The central-SDB group experienced the greatest echocardiographic improvement, with a significant increase in tricuspid annular plane systolic excursion of +2.1±4.9mm (P=0.045) and a significant reduction in systolic pulmonary artery pressure of -8.4±9.7mmHg (P=0.001). CONCLUSIONS: Sacubitril/valsartan improved right ventricular function in patients with heart failure and SDB after only 3 months of treatment. The greatest improvement in right ventricular function was observed in the central-SDB group.

High-altitude hypoxia and periodic breathing during sleep: gender-related differences.

High-altitude exposure is characterized by the appearance of periodic breathing during sleep. Only limited evidence is available, however, on the presence of gender-related differences in this breathing pattern. In 37 healthy subjects, 23 male and 14 female, we performed nocturnal cardio-respiratory monitoring in the following conditions: (1) sea level; (2) first/second night at an altitude of 3400 m; (3) first/second night at an altitude of 5400 m and after a 10 day sojourn at 5400 m. At sea level, a normal breathing pattern was observed in all subjects throughout the night. At 3400 m the apnea-hypopnea index was 40.3 ± 33.0 in males (central apneas 77.6%, central hypopneas 22.4%) and 2.4 ± 2.8 in females (central apneas 58.2%, central hypopneas 41.8%; P < 0.01). During the first recording at 5400 m, the apnea-hypopnea index was 87.5 ± 35.7 in males (central apneas 60.0%, central hypopneas 40.0%) and 41.1 ± 44.0 in females (central apneas 73.2%, central hypopneas 26.8%; P < 0.01), again with a higher frequency of central events in males as seen at lower altitude. Similar results were observed after 10 days. With increasing altitude, there was also a progressive reduction in respiratory cycle length during central apneas in males (26.9 ± 3.4 s at 3400 m and 22.6 ± 3.7 s at 5400 m). Females, who displayed a significant number of central apneas only at the highest reached altitude, were characterized by longer cycle length than males at similar altitude (30.1 ± 5.8 s at 5400 m). In conclusion, at high altitude, nocturnal periodic breathing affects males more than females. Females started to present a significant number of central sleep apneas only at the highest reached altitude. After 10 days at 5400 m gender differences in the apnea-hypopnea index similar to those observed after acute exposure were still observed, accompanied by differences in respiratory cycle length.

Intrathecal baclofen treatment in dystonic cerebral palsy: a randomized clinical trial: the IDYS trial.

BACKGROUND: Dystonic cerebral palsy is primarily caused by damage to the basal ganglia and central cortex. The daily care of these patients can be difficult due to dystonic movements. Intrathecal baclofen treatment is a potential treatment option for dystonia and has become common practice. Despite this widespread adoption, high quality evidence on the effects of intrathecal baclofen treatment on daily activities is lacking and prospective data are needed to judge the usefulness and indications for dystonic cerebral palsy. The primary aim of this study is to provide level one clinical evidence for the effects of intrathecal baclofen treatment on the level of activities and participation in dystonic cerebral palsy patients. Furthermore, we hope to identify clinical characteristics that will predict a beneficial effect of intrathecal baclofen in an individual patient. METHODS/DESIGN: A double blind placebo-controlled multi-center randomized clinical trial will be performed in 30 children with dystonic cerebral palsy. Patients aged between 4 and 25 years old with a confirmed diagnosis of dystonic cerebral palsy, Gross Motor Functioning Classification System level IV or V, with lesions in the cerebral white matter, basal ganglia or central cortex and who are eligible for intrathecal baclofen treatment will be included. Group A will receive three months of continuous intrathecal baclofen treatment and group B will receive three months of placebo treatment, both via an implanted pump. After this three month period, all patients will receive intrathecal baclofen treatment, with a follow-up after nine months. The primary outcome measurement will be the effect on activities of and participation in daily life measured by Goal Attainment Scaling. Secondary outcome measurements on the level of body functions include dystonia, spasticity, pain, comfort and sleep-related breathing disorders. Side effects will be monitored and we will study whether patient characteristics influence outcome. DISCUSSION: The results of this study will provide data for evidence-based use of intrathecal baclofen in dystonic cerebral palsy.

Nighttime Sleep and Respiratory Disturbances in Individuals Receiving Methadone to Treat Opioid Use Disorder.

ABSTRACT: Opioids are a leading cause of drug overdose deaths in the United States. Methadone used as medication for opioid use disorder (MOUD) reduces drug cravings and promotes abstinence. However, individuals in methadone-based MOUD treatment commonly report subjective sleep complaints and are at risk for respiratory depression from opioids. We investigated nighttime sleep and respiratory function in eight individuals (six women, two men; ages 31-68 years) in their first 90 days of methadone-based MOUD treatment. Participants underwent overnight cardiorespiratory polysomnography. Sleep and respiratory variables were characterized with descriptive statistics for comparison to reference data from similarly aged healthy adults. Although participants spent 8.1 ± 0.3 hours (mean ± SD ) in bed, their total sleep time was only 6.8 ± 1.3 hours. They exhibited longer sleep latency and intermittent wakefulness. Sleep structure was irregular, with disrupted sleep cycles. Participants also displayed a decreased amount of N1 sleep and an increased amount of N3 sleep, compared with reference data. Participants showed respiratory depression, with an average apnea-hypopnea index of 16.5 ± 8.9 events per hour. Central sleep apneas comprised 69.1% ± 20.9% of the respiratory events. A Cheyne-Stokes-like breathing pattern, consisting of 30-second cycles of three central sleep apneas, was observed in 75% of participants. Our results suggest that individuals early in methadone-based MOUD treatment experience disordered sleep and respiratory disturbances. Such nighttime physiological changes may have serious long-term health consequences and contribute to unintended overdose rates. Identifying and treating MOUD individuals with sleep apnea could reduce risk of death.

Effect of adaptive servoventilation on muscle sympathetic nerve activity in patients with chronic heart failure and central sleep apnea.

BACKGROUND: Adaptive servoventilation (ASV) improves cardiac function and sympathetic nerve activity in patients with heart failure (HF). However, the mechanisms underlying these improvements remain obscure. METHODS AND RESULTS: We compared muscle sympathetic nerve activity (MSNA) and cardiorespiratory polygraphy and echocardiography findings at baseline and at 3.5 ± 0.8 months' follow-up in 32 patients with HF (New York Heart Association functional class II or III; ejection fraction <45%) and central sleep apnea (CSA; apnea-hypopnea index [AHI] ≥15/h) who consented (n = 20; ASV group) or declined (n = 12; non-ASV group) to undergo ASV treatment. Compliance with ASV and changes in AHI were determined from data collected by integral counters in devices and from cardiorespiratory polygraphic findings, respectively. Ejection fraction and MSNA significantly changed in the ASV (both P < .001) but not the non-ASV group. Although changes in AHI and MSNA correlated, the average use of ASV did not. In contrast, changes in AHI and the average use of ASV were independent predictors of changes in ejection fraction (both P < .01). CONCLUSIONS: ASV decreases MSNA and improves cardiac function in association with suppression of CSA in patients with HF.

Effects of hydrogen sulfide synthesis inhibitors on posthypoxic ventilatory behavior in the C57BL/6J mouse.

BACKGROUND: H(2)S synthesis inhibitors (HSSI) have been shown to impact respiratory control. For instance, the HSSI hydroxylamine (HA) decreases the respiratory discharge rate from isolated medullary sections, and HA in addition to other HSSIs propargylglycine and amino-oxyacetic acid (AOAA) have been found to reduce hypoxic responsiveness. OBJECTIVES: The aim of this study was to determine if administration of HSSIs could improve respiratory stability in an intact organism prone to recurrent central apneas. METHODS: Saline and HSSI compounds were administered to C57BL/6J mice (n = 24), a strain predisposed to recurrent central apneas, prior to measurement of hypoxic and posthypoxic ventilatory behavior. RESULTS: Administration of HA and AOAA resulted in a significantly smaller percentage of animals expressing one or more apneas during reoxygenation compared to saline control, and animals given AOAA demonstrated a smaller coefficient of variation for frequency during reoxygenation, a marker suggesting greater respiratory stability. This occurred despite varying effects of the three HSSI compounds on hypoxic ventilatory response. CONCLUSIONS: Instability and pause expression are improved by targeting H(2)S synthesis, an effect not predicted by effects on hypoxic responsiveness.

Mirtazapine reduces susceptibility to hypocapnic central sleep apnea in males with sleep-disordered breathing: a pilot study.

Studies in humans and animal models with spinal cord injury (SCI) have demonstrated that medications targeting serotonin receptors may decrease the susceptibility to central sleep-disordered breathing (SDB). We hypothesized that mirtazapine would decrease the propensity to develop hypocapnic central sleep apnea (CSA) during sleep. We performed a single-blind pilot study on a total of 10 men with SDB (7 with chronic SCI and 3 noninjured) aged 52.0 ± 11.2 yr. Participants were randomly assigned to either mirtazapine (15 mg at bedtime) or a placebo for at least 1 wk, followed by a 7-day washout period before crossing over to the other intervention. Split-night studies included polysomnography and induction of hypocapnic CSA using a noninvasive ventilation (NIV) protocol. The primary outcome was CO2 reserve, defined as the difference between eupneic and end of NIV end-tidal CO2 ([Formula: see text]) preceding induced hypocapneic CSA. Secondary outcomes included controller gain (CG), other ventilatory parameters, and SDB severity. CG was defined as the ratio of change in minute ventilation (V̇e) between control and hypopnea to the change in CO2 during sleep. CO2 reserve was significantly widened on mirtazapine than placebo (-3.8 ± 1.2 vs. -2.0 ± 1.5 mmHg; P = 0.015). CG was significantly decreased on mirtazapine compared with placebo [2.2 ± 0.7 vs. 3.5 ± 1.9 L/(mmHg × min); P = 0.023]. There were no significant differences for other ventilatory parameters assessed or SDB severity between mirtazapine and placebo trials. These findings suggest that the administration of mirtazapine can decrease the susceptibility to central apnea by reducing chemosensitivity and increasing CO2 reserve; however, considering the lack of changes in apnea-hypopnea index (AHI), further research is required to understand the significance of this finding.NEW & NOTEWORTHY To our knowledge, this research study is novel as it is the first study in humans assessing the effect of mirtazapine on CO2 reserve and chemosensitivity in individuals with severe sleep-disordered breathing. This is also the first study to determine the potential therapeutic effects of mirtazapine on sleep parameters in individuals with a spinal cord injury.