Clinical and prognostic significance of central and obstructive apneas in patients with transthyretin cardiac amyloidosis.

AIMS: Central (CA) and obstructive apneas (OA) are highly prevalent in patients with chronic heart failure (HF) and transthyretin cardiac amyloidosis (ATTR-CA) is an increasingly recognized HF etiology. This study aimed to investigate the prevalence and impact of CA and OA in patients with ATTR-CA. METHODS: Consecutive patients with ATTR-CA underwent a 24-hour ambulatory cardiorespiratory monitoring to evaluate the prevalence and severity of breathing disorders. The severity of these disorders was quantified using the apnea-hypopnea index (AHI). Accordingly, patients were categorized as having normal breathing (NB, AHI <5 events/hour), obstructive apnea (OA, AHI ≥5 events/hour with >50% being obstructive), or central apnea (CA, AHI >5 events/hour with ≥50% being central). The primary endpoint at follow-up was all-cause mortality. RESULTS: Out of 142 patients enrolled (n=142, aged 77±7 years, 91% males, 96% wild-type ATTR-CA), considering the 24 hours, 20% had NB (39% at daytime, 8% at nighttime), while 35% had CA (45% at daytime, 39% at nighttime) and 45% had OA (25% at daytime, 54% at nighttime). After a median 2.3 (1.4-3.3) years follow-up, 24-hour, daytime, and nighttime AHI were higher in non-survivors vs. survivors (all p<0.05), independently of the prevalent apnea type (p=0.64). At multivariable regression analysis (adjusted for the possible clinical, echocardiographic, and biohumoral confounders), nighttime AHI ≥30 events/hour (hazard ratio 2.37 [95%CI 1.07-5.23], p=0.033) and hs-troponin T (hazard ratio 2.43 [95%CI 1.42-4.17], p=0.001) were predictors of mortality. CONCLUSION: CA and OA are highly prevalent both at daytime and nighttime in patients with ATTR-CA and are associated with higher mortality.

This study investigated the prevalence and prognostic significance of central (CA) and obstructive apneas (OA) in 142 patients with transthyretin cardiac amyloidosis (ATTR-CA). Both CA and OA were highly prevalent during the whole 24-hour period, with only 20% classified as having normal breathing (meant as an apnea-hypopnea-index <5 events/hour during the 24-hour). OA were more frequent than CA, particularly during the night, while the prevalence of CA increased with worsening left ventricular systolic and diastolic dysfunction. At follow-up, 24-hour, daytime, and nighttime AHI were higher in non-survivors vs. survivors, independently of the prevalent apnea type and, at multivariable regression analysis (adjusted for the possible clinical, echocardiographic, and biohumoral confounders), nighttime AHI ≥30 events/hour was an independent predictor of mortality.

Sleep state-dependent development of resting state functional connectivity during the preterm period.

STUDY OBJECTIVES: The brains of preterm infants exhibit altered functional connectivity (FC) networks, but the potential variation in sleep states and the impact of breathing patterns on FC networks are unclear. This study explores the evolution of resting-state FC from preterm to term, focusing on breathing patterns and distinguishing between active sleep and quiet sleep. METHODS: We recruited 63 preterm infants and 44 healthy-term infants and performed simultaneous electroencephalography and functional near-infrared spectroscopy. FC was calculated using oxy- and deoxyhemoglobin signals across eight channels. First, FC was compared between periodic breathing (PB) and non-PB segments. Then sleep state-dependent FC development was explored. FC was compared between active sleep and quiet sleep segments and between preterm infants at term and term-born infants in each sleep state. Finally, associations between FC at term, clinical characteristics, and neurodevelopmental outcomes in late infancy were assessed in preterm infants. RESULTS: In total, 148 records from preterm infants and 44 from term-born infants were analyzed. PB inflated FC values. After excluding PB segments, FC was found to be elevated during active sleep compared to quiet sleep, particularly in connections involving occipital regions. Preterm infants had significantly higher FC in both sleep states compared to term-born infants. Furthermore, stronger FC in specific connections during active sleep at term was associated with unfavorable neurodevelopment in preterm infants. CONCLUSIONS: Sleep states play a critical role in FC development and preterm infants show observable changes in FC.

Effects of Naltrexone on Sleep Quality and Periodic Breathing at High Altitude.

Foster, Katharine, James D. Anholm, Gary Foster, Suman Thapamagar, and Prajan Subedi. Effects of naltrexone on sleep quality and periodic breathing at high altitude. High Alt Med Biol. 00:000-000, 2024. Objective: This study examined the effects of naltrexone on breathing and sleep at high altitude. Mu-opioid receptor (MOR) agonists have a depressive effect on respiration. Naltrexone is known to block the MOR. We hypothesized that MOR blockade with naltrexone would result in higher nocturnal oxygen saturations, fewer apneas, and improved sleep at high altitude. Methods: This double-blind, placebo-controlled, crossover study included nine healthy volunteers (four females, five males) aged 27.9 (4.6) (mean [standard deviation]) years. Two overnight trips spaced at least 2 weeks apart took participants from Loma Linda, CA (355 m) to the Barcroft Laboratory, CA (3,810 m) for each arm. Participants ingested either 50 mg naltrexone or matching placebo at bedtime. Sleep metrics were recorded using an ambulatory physiological sleep monitor (APSM). Subjective data were measured with the Groningen Sleep Quality Scale, Stanford Sleepiness Scale, and the 2018 Lake Louise Score (LLS) for acute mountain sickness (AMS). Results: Mean overnight SpO2 was lower after taking naltrexone, 81% (6) versus 83% (4) (mean difference 1.9% [2.1, 95% confidence interval or CI = 0.1-3.6, p = 0.040]). The lowest overnight SpO2 (nadir) was lower on naltrexone 70% (6) versus 74% (4) (dif. 4.6% [4.3], CI = 1.0-8.2, p = 0.020). Total sleep time and total apnea-hypopnea index were unchanged. Subjective sleep quality was significantly worse on naltrexone measured via the Groningen Sleep Quality Scale (p = 0.033) and Stanford Sleepiness Scale (p = 0.038). AMS measured via LLS was significantly worse while taking naltrexone (p = 0.025). Conclusion: Contrary to our hypothesis, this study demonstrated a significant decrease in nocturnal oxygen saturation, worse sleep quality, and AMS scores. Further characterization of the MOR's effects on sleep and AMS is needed to evaluate potential exacerbating mechanisms for AMS and poor sleep quality at altitude.

Effects of vanilla odor on hypoxia-related periodic breathing in premature newborns: A pilot study.

BACKGROUND: Periodic breathing (PB)-related intermittent hypoxia can have long-lasting deleterious consequences in preterm infants. Olfactory stimulation using vanilla odor is beneficial for apnea of prematurity in the first postnatal days/weeks. We aimed to determine for the first time whether vanilla odor can also decrease PB-related intermittent hypoxia. METHOD: This pilot study was a balanced crossover clinical trial including 27 premature infants born between 30 and 33+6 weeks of gestation. We performed 12-h recordings on two nights separated by a 24-h period. All infants were randomly exposed to vanilla odor on the first or second study night. The primary outcome was the desaturation index, defined as the number per hour of pulse oximetry (SpO2) values <90 % for at least 5 s, together with a drop of ≥5 % from the preceding value. Univariate mixed linear models were used for the statistical analysis. RESULTS: Overall, exposure to vanilla odor did not significantly decrease the desaturation index (52 ± 22 events/h [mean ± SD] on the intervention night vs. 57 ± 26, p = 0.2); furthermore, it did not significantly alter any secondary outcome. In a preliminary post hoc subgroup analysis, however, the effect of vanilla odor was statistically significant in infants with a desaturation index of ≥70/h (from 86 ± 12 to 65 ± 23, p = 0.04). CONCLUSION: In this pilot study, vanilla odor overall did not decrease PB-related intermittent hypoxia in infants born at 30-33+6 weeks of gestation, which is when they are close to term. Preliminary results suggesting a beneficial effect in infants with the highest desaturation index, however, justify further studies in the presence of PB-related intermittent hypoxia as well as in infants born more prematurely.

Short apneas and periodic breathing in preterm infants in the neonatal intensive care unit-Effects of sleep position, sleep state, and age.

This observational study investigated the effects of sleep position and sleep state on short apneas and periodic breathing in hospitalized preterm infants longitudinally, in relation to postmenstrual age. Preterm infants (25-31 weeks gestation, n = 29) were studied fortnightly after birth until discharge, in prone and supine positions, and in quiet sleep and active sleep. The percentage of time spent in each sleep state (percentage of time in quiet sleep and percentage of time in active sleep), percentage of total sleep time spent in short apneas and periodic breathing, respectively, the percentage of falls from baseline in heart rate, arterial oxygen saturation and cerebral tissue oxygenation index during short apneas and periodic breathing, and the associated percentage of total sleep time with systemic (arterial oxygen saturation < 90%) and cerebral hypoxia (cerebral tissue oxygenation index < 55%) were analysed using a linear mixed model. Results showed that the prone position decreased (improved) the percentage of falls from baseline in arterial oxygen saturation during both short apneas and periodic breathing, decreased the proportion of infants with periodic breathing and the periodic breathing-associated percentage of total sleep time with cerebral hypoxia. The percentage of time in quiet sleep was higher in the prone position. Quiet sleep decreased the percentage of total sleep time spent in short apneas, the short apneas-associated percentage of falls from baseline in heart rate, arterial oxygen saturation, and proportion of infants with systemic hypoxia. Quiet sleep also decreased the proportion of infants with periodic breathing and percentage of total sleep time with cerebral hypoxia. The effects of sleep position and sleep state were not related to postmenstrual age. In summary, when sleep state is controlled for, the prone sleeping position has some benefits during both short apneas and periodic breathing. Quiet sleep improves cardiorespiratory stability and is increased in the prone position at the expense of active sleep, which is critical for brain maturation. This evidence should be considered in positioning preterm infants.

Longitudinal effects of early exposure to intermittent hypoxia on autonomic cardiovascular control in very preterm infants.

INTRODUCTION: Cardiorespiratory control is immature in infants born preterm compared to those born at term. Animal studies have shown that repetitive hypoxia associated with periodic breathing can alter autonomic control. We aimed to elucidate if the amount of time spent with apnoea and periodic breathing in the neonatal unit was associated with longitudinal changes in autonomic control assessed using heart rate variability. METHODS: Twenty-nine very preterm infants (10 M 19F) were studied during supine daytime sleep on 4 occasions. Study 1: 32-36 weeks post menstrual age (PMA) (n = 29), Study 2: 36-40 weeks PMA (n = 27), Study 3: 3-months corrected age (CA) (n = 20) and Study 4: 6-months CA (n = 26). The percentage total sleep time (%TST) spent having apnoeas in active (AS) and quiet sleep (QS) at each study was calculated. Total power, low frequency (LF, sympathetic + parasympathetic activity) high frequency (HF, parasympathetic activity), and LF/HF (sympathovagal balance) were calculated. Infants were divided into two groups based on the %TST spent with apnoeas above and below the median in AS and QS at Study 1. Data were normalised and compared with two-way ANOVA with Bonferroni post-hoc tests. RESULTS: When apnoeas were included in the analysis, in QS Total power and HF power were higher, and when apnoeas were excluded HF power was higher in QS but lower in AS in the above median group at Study 4. CONCLUSION: This study provides new evidence that short apnoeas, particularly periodic breathing, which is currently not detected or treated in the neonatal unit can affect autonomic cardiovascular control.

Persistent and symptomatic periodic breathing beyond the neonatal period in full-term infants: A case series.

INTRODUCTION: Periodic breathing (PB) is considered physiological in the neonatal period and usually disappears in the first months of life. There are few data available on persistent PB after the neonatal period. The objective of this study was to characterize infants born at term with persistent PB after the age of 1 month through polysomnography (PSG) performed during symptoms. METHODS: This retrospective case series included infants born at term between 2012 and 2021, without an underlying disease, who presented with symptoms of persistent PB during a PSG. Persistent PB was defined as more than 1 % of total sleep time (TST) of PB after 1 month of life, and PB was defined as a succession of at least three episodes of central apnea lasting more than 3 s and separated by less than 20 s of normal breathing. RESULTS: A total of 10 infants born at term were included. They underwent PSG for brief resolved unexplained events, desaturation, pauses in breathing, cyanosis, and/or signs of respiratory distress. The percentage of TST spent with PB was 18.1 % before 3 months of age (n = 7), and 4.7 % between 3 and 6 months of age (n = 10). During the first PSG, ≥3 % of desaturation events were observed in 77-100 % of the PB episodes. At the first PSG, nine of the 10 infants had an obstructive apnea-hypopnea index of >10/h and five of 10 infants had a central apnea index of >5/h. Gastroesophageal reflux (GER) was suspected in eight infants. All infants showed improvement in the initial symptoms during the first year of life. CONCLUSION: This study presents cases of persistent and symptomatic PB after 1 month of life in infants born at term. The interesting finding was the presence of obstructive sleep apnea syndrome and/or central apnea syndrome in the majority of children, along with GER.

A narrative review of periodic breathing during sleep at high altitude: From acclimatizing lowlanders to adapted highlanders.

Periodic breathing during sleep at high altitude is almost universal among sojourners. Here, in the context of acclimatization and adaptation, we provide a contemporary review on periodic breathing at high altitude, and explore whether this is an adaptive or maladaptive process. The mechanism(s), prevalence and role of periodic breathing in acclimatized lowlanders at high altitude are contrasted with the available data from adapted indigenous populations (e.g. Andean and Tibetan highlanders). It is concluded that (1) periodic breathing persists with acclimatization in lowlanders and the severity is proportional to sleeping altitude; (2) periodic breathing does not seem to coalesce with poor sleep quality such that, with acclimatization, there appears to be a lengthening of cycle length and minimal impact on the average sleeping oxygen saturation; and (3) high altitude adapted highlanders appear to demonstrate a blunting of periodic breathing, compared to lowlanders, comprising a feature that withstands the negative influences of chronic mountain sickness. These observations indicate that periodic breathing persists with high altitude acclimatization with no obvious negative consequences; however, periodic breathing is attenuated with high altitude adaptation and therefore potentially reflects an adaptive trait to this environment.

Preterm infants experience a nadir in cerebral oxygenation during sleep three months after hospital discharge.

AIM: Preterm infants are at increased risk of Sudden Infant Death Syndrome (SIDS) and frequently experience short central apnoeas which can occur in isolation or a repetitive pattern (periodic breathing). We investigated the relationship between central apnoeas experienced before and over the 6 months after hospital discharge and cerebral oxygenation. METHODS: Preterm infants born between 28 and 32 weeks gestational age (GA) were studied during supine daytime sleep at 32-36 weeks post menstrual age (PMA) (n = 40), 36-40 weeks PMA (n = 27), 3-months corrected age (CA) (n = 20) and 6-months CA (n = 26). Cerebral tissue oxygenation (TOI), peripheral oxygenation (SpO2) and heart rate were recorded continuously. The percentage total sleep time (%TST) spent having central apnoeas at each study and cerebral fractional oxygen extraction (SpO2-TOI/SpO2) were calculated. RESULTS: %TST spent with central apnoeas decreased with increasing age in both active sleep (AS) and quiet sleep (QS). TOI tended to be lower and cerebral fractional oxygen extraction higher at 3 months compared to the other studies and this reached statistical significance compared to 32-36 weeks in QS. CONCLUSION: The nadir in cerebral tissue oxygenation at 3 months of age coincides with the peak risk period for SIDS and this may contribute to increased risk in these infants.

Infant periodic breathing and apneic threshold.

A mathematical model was proposed to predict the role played by apneic threshold in periodic breathing in preterm infants. Prior models have mainly applied linear control theory which predicted instability but could not explain sustained periodic breathing. Apneic threshold to CO2 which has been postulated to play a major role in infant periodic breathing is a nonlinear effect and cannot be described by linear theory. Another previously unexplored nonlinear factor affecting instability is brain vascular volume change with CO2 which affects time delay to chemoreceptors. The current model explored the influences of apneic threshold, central and peripheral chemoreceptor gains, cardiac output, lung volume, and circulatory time delay on periodic breathing. Apneic threshold was found to play a major role in ventilatory responses to spontaneous sighs. Sighs led to apneic pauses followed by periods of periodic breathing with peripheral chemoreceptor CO2 gain, cardiac output, and lung volume were at reported normal levels. Apneic threshold when exceeded was observed to cause an asymmetry in the periodic breathing cycling and an increased periodic breathing frequency. Sighs in infants occur frequently enough to lead to repeated stimulation within the epoch duration of periodic breathing for a single sigh. Multiple sighs may then play a major role in promoting continuous periodic breathing in infants. Peripheral chemoreceptor gain estimated using endogenous CO2 led to validated predicted periodic breathing cycle duration as a function of age. Brain vascular volume increase with CO2 contributes to periodic breathing in very young (1-2 day old) preterm infants.

Neuromedin B-Expressing Neurons in the Retrotrapezoid Nucleus Regulate Respiratory Homeostasis and Promote Stable Breathing in Adult Mice.

Respiratory chemoreceptor activity encoding arterial Pco2 and Po2 is a critical determinant of ventilation. Currently, the relative importance of several putative chemoreceptor mechanisms for maintaining eupneic breathing and respiratory homeostasis is debated. Transcriptomic and anatomic evidence suggests that bombesin-related peptide Neuromedin-B (Nmb) expression identifies chemoreceptor neurons in the retrotrapezoid nucleus (RTN) that mediate the hypercapnic ventilatory response, but functional support is missing. In this study, we generated a transgenic Nmb-Cre mouse and used Cre-dependent cell ablation and optogenetics to test the hypothesis that RTN Nmb neurons are necessary for the CO2-dependent drive to breathe in adult male and female mice. Selective ablation of ∼95% of RTN Nmb neurons causes compensated respiratory acidosis because of alveolar hypoventilation, as well as profound breathing instability and respiratory-related sleep disruption. Following RTN Nmb lesion, mice were hypoxemic at rest and were prone to severe apneas during hyperoxia, suggesting that oxygen-sensitive mechanisms, presumably the peripheral chemoreceptors, compensate for the loss of RTN Nmb neurons. Interestingly, ventilation following RTN Nmb -lesion was unresponsive to hypercapnia, but behavioral responses to CO2 (freezing and avoidance) and the hypoxia ventilatory response were preserved. Neuroanatomical mapping shows that RTN Nmb neurons are highly collateralized and innervate the respiratory-related centers in the pons and medulla with a strong ipsilateral preference. Together, this evidence suggests that RTN Nmb neurons are dedicated to the respiratory effects of arterial Pco2/pH and maintain respiratory homeostasis in intact conditions and suggest that malfunction of these neurons could underlie the etiology of certain forms of sleep-disordered breathing in humans.SIGNIFICANCE STATEMENT Respiratory chemoreceptors stimulate neural respiratory motor output to regulate arterial Pco2 and Po2, thereby maintaining optimal gas exchange. Neurons in the retrotrapezoid nucleus (RTN) that express the bombesin-related peptide Neuromedin-B are proposed to be important in this process, but functional evidence has not been established. Here, we developed a transgenic mouse model and demonstrated that RTN neurons are fundamental for respiratory homeostasis and mediate the stimulatory effects of CO2 on breathing. Our functional and anatomic data indicate that Nmb-expressing RTN neurons are an integral component of the neural mechanisms that mediate CO2-dependent drive to breathe and maintain alveolar ventilation. This work highlights the importance of the interdependent and dynamic integration of CO2- and O2-sensing mechanisms in respiratory homeostasis of mammals.

Sex-related Differences in Loop Gain during High-Altitude Sleep-disordered Breathing.

Rationale: Central sleep apnea (CSA) is pervasive during sleep at high altitude, disproportionately impacting men and associated with increased peripheral chemosensitivity. Objectives: We aimed to assess whether biological sex affects loop gain (LGn) and CSA severity during sleep over 9-10 days of acclimatization to 3,800 m. We hypothesized that CSA severity would worsen with acclimatization in men but not in women because of greater increases in LGn in men. Methods: Sleep studies were collected from 20 (12 male) healthy participants at low altitude (1,130 m, baseline) and after ascent to (nights 2/3, acute) and residence at high altitude (nights 9/10, prolonged). CSA severity was quantified as the respiratory event index (REI) as a surrogate of the apnea-hypopnea index. LGn, a measure of ventilatory control instability, was quantified using a ventilatory control model fit to nasal flow. Linear mixed models evaluated effects of time at altitude and sex on respiratory event index and LGn. Data are presented as contrast means with 95% confidence intervals. Results: REI was comparable between men and women at acute altitude (4.1 [-9.3, 17.5] events/h; P = 0.54) but significantly greater in men at prolonged altitude (23.7 [10.3, 37.1] events/h; P = 0.0008). Men had greater LGn than did women for acute (0.08 [0.001, 0.15]; P = 0.047) and prolonged (0.17 [0.10, 0.25]; P < 0.0001) altitude. The change in REI per change in LGn was significantly greater in men than in women (107 ± 46 events/h/LGn; P = 0.02). Conclusions: The LGn response to high altitude differed between sexes and contributed to worsening of CSA over time in men but not in women. This sex difference in acclimatization appears to protect females from high altitude-related CSA. These data provide fundamental sex-specific physiological insight into high-altitude acclimatization in healthy individuals and may help to inform sex differences in sleep-disordered breathing pathogenesis in patients with cardiorespiratory disease.

Neural bases for the genesis and CO2 therapy of periodic Cheyne-Stokes breathing in neonatal male connexin-36 knockout mice.

Periodic Cheyne-Stokes breathing (CSB) oscillating between apnea and crescendo-decrescendo hyperpnea is the most common central apnea. Currently, there is no proven therapy for CSB, probably because the fundamental pathophysiological question of how the respiratory center generates this form of breathing instability is still unresolved. Therefore, we aimed to determine the respiratory motor pattern of CSB resulting from the interaction of inspiratory and expiratory oscillators and identify the neural mechanism responsible for breathing regularization induced by the supplemental CO2 administration. Analysis of the inspiratory and expiratory motor pattern in a transgenic mouse model lacking connexin-36 electrical synapses, the neonatal (P14) Cx36 knockout male mouse, with a persistent CSB, revealed that the reconfigurations recurrent between apnea and hyperpnea and vice versa result from cyclical turn on/off of active expiration driven by the expiratory oscillator, which acts as a master pacemaker of respiration and entrains the inspiratory oscillator to restore ventilation. The results also showed that the suppression of CSB by supplemental 12% CO2 in inhaled air is due to the stabilization of coupling between expiratory and inspiratory oscillators, which causes the regularization of respiration. CSB rebooted after washout of CO2 excess when the inspiratory activity depressed again profoundly, indicating that the disability of the inspiratory oscillator to sustain ventilation is the triggering factor of CSB. Under these circumstances, the expiratory oscillator activated by the cyclic increase of CO2 behaves as an "anti-apnea" center generating the crescendo-decrescendo hyperpnea and periodic breathing. The neurogenic mechanism of CSB identified highlights the plasticity of the two-oscillator system in the neural control of respiration and provides a rationale base for CO2 therapy.

Ventilatory response and stability of oxygen saturation during a hypoxic challenge in very preterm infants.

BACKGROUND: Preterm infants have immature control of breathing and impaired pulmonary gas exchange. We hypothesized that infants with bronchopulmonary dysplasia (BPD) have a blunted ventilatory response and peripheral oxygen saturation (SpO2 ) instability during a hypoxic challenge. METHODS: We evaluated the response to hypoxia in 57 very preterm infants (38 no BPD, 10 mild BPD, 9 moderate-to-severe BPD) at 36 weeks' postmenstrual age. The fraction of inspired oxygen (FI O2 ) was reduced stepwise at 5-min intervals to achieve peripheral SpO2 between 86% and 95%. The lowest permissible FI O2 and SpO2 were 0.14% and 86%. We recorded SpO2 , FI O2 , and the respiratory signal (respiratory inductive plethysmography). We calculated respiratory rate (RR), tidal volume (VT ), minute ventilation (VE ), and respiratory drive (ratio between VT and inspiratory time, VT /TI ). SpO2 variability was expressed as the interquartile range (IQR). RESULTS: FI O2 was reduced from a median (Q1, Q3) of 0.21 (0.21, 0.21) to 0.17 (0.17, 0.18). We observed a marked individual variability in the ventilatory response to the hypoxic challenge, regardless of BPD severity. At the lowest permissible FI O2 , 37 (65%) infants reduced their VE , and 20 (35%) increased minute ventilation; 20 infants (35%) developed periodic breathing associated with increased SpO2 IQR and lower SpO2 minima, and 16 (28%) exhibited an oscillatory pattern in VE and SpO2 without end-expiratory pauses, regardless of BPD severity. CONCLUSION: In very preterm infants, a mild hypoxic challenge reduced ventilation, increased SpO2 variability and periodic breathing regardless of BPD severity.

Software development to standardize the clinical diagnosis of exercise oscillatory ventilation in heart failure.

BACKGROUND: Exercise oscillatory ventilation (EOV) is characterized by periodic oscillations of minute ventilation during cardiopulmonary exercise testing (CPET). Despite its prognostic value in chronic heart failure (HF), its diagnosis is complex due to technical limitations. An easier and more accurate way of EOV identification can contribute to a better approach and clinical diagnosis. This study aims to describe a software development to standardize the EOV diagnosis from CPET's raw data in heart failure patients and test its reliability (intra- and inter-rater). METHODS: The software was developed in the "drag-and-drop" G-language using LabVIEW®. Five EOV definitions (Ben-Dov, Corrà, Kremser, Leite, and Sun definitions), two alternative approaches, one smoothing technique, and some basic statistics were incorporated into the interface to visualize four charts of the ventilatory response. EOV identification was based on a set of criteria verified from the interaction between amplitude, cycle length, and oscillation time. Two raters analyzed the datasets. In addition, repeated measurements were verified after six months using about 25% of the initial data. Cohen's kappa coefficient (κ) was used to investigate the reliability. RESULTS: Overall, 391 tests were analyzed in duplicate (inter-rater reliability) and 100 tests were randomized for new analysis (intra-rater reliability). High inter-rater (κ > 0.80) and intra-rater (κ > 0.80) reliability of the five EOV diagnoses were observed. CONCLUSION: The present study proposes novel semi-automated software to detect EOV in HF, with high inter and intra-rater agreements. The software project and its tutorial are freely available for download.

The Association between Low CO2 Production and Central Sleep Apnea in Men with Heart Failure.

Rationale: Hunter-Cheyne-Stokes breathing with central sleep apnea (CSA) is prevalent in some patients with heart failure with reduced ejection fraction (HFrEF). Theoretical models of Hunter-Cheyne-Stokes breathing predict that a low metabolic rate (MR) predisposes one to CSA. Objectives: In this study, we examined the role of MR in the pathogenesis of CSA. Methods: A physiological study was conducted in a sleep laboratory at a U.S. Department of Veterans Affairs medical center. Patients were 28 consecutive male Veterans with stable HFrEF. After an adaptation night, polysomnography, left ventricular ejection fraction, pulmonary function tests, carbon dioxide production ([Formula: see text]), and arterial blood samples were obtained under strict standardized conditions. Physiological variables were then entered into regression models to examine the association with CSA. Results: Body mass index varied from 20 to 40 kg/m2, and [Formula: see text] ranged from 167 to 434 ml/min. In the final regression model, low [Formula: see text] and low body mass index were associated with CSA index. [Formula: see text] had the strongest association (95% confidence interval, -0.36 to -0.06; P = 0.007). Conclusions: In patients with HFrEF, a low MR and related low [Formula: see text], but not low oxygen consumption, were associated with CSA. Mechanistically, in the face of low MR and [Formula: see text], a given change in ventilation results in large swings in partial pressure of CO2, thus promoting CSA. To our knowledge, this is the first study in humans that shows this association.

High nocturnal periodic breathing reported by PAP adherence data predicts decompensation of heart failure.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) often coexists with heart failure (HF) and is commonly treated with positive airway pressure (PAP) therapy. Periodic breathing (PB) may be present in HF and is an indicator of poor prognosis, but there is no easy way to detect PB in an outpatient setting. However, it can be detected by analyzing PAP usage data. The study aimed to assess if high PB% detected by PAP machine could predict impending HF exacerbation and if better PAP adherence is associated with reduced hospitalization and mortality. METHODS: We retrospectively reviewed medical records of 115 patients with OSA from the sleep clinic of our VA Medical Center. The cross-sectional data on demographics, labs, PAP adherence, PB% in the previous 30 days, echocardiogram in the previous 6 months, and hospitalizations and mortality in the subsequent 180 days were extracted. Based on left ventricular ejection fraction (LVEF), patients were classified into (1) HF with normal-midrange LVEF (LVEF ≥40%, n = 74) and (2) HF with reduced LVEF (LVEF < 40%, n = 41). Pairwise correlation and linear regressions were done to assess predictors of PB%. Binomial and logistic regressions assessed the relationship of PB% and PAP adherence with hospitalization from HF and all-cause mortality. RESULTS: In the HF with reduced LVEF group, the mean PB% was 2.6 times higher (P < .001) and PAP adherence was 29% lower (P < .001). PB% positively correlated with brain natriuretic peptide level (r = .447, P < .01) and number of hospitalizations (r = .331, P < .01). Higher PB% negatively correlated with LVEF (r = -.423, P < .01) and estimated glomerular filtration rate (r = -.246, P < .01). Every 10% increase in PAP adherence decreased odds of hospitalization by 0.78 times (P < .001) and odds of death by 0.86 (P = .043). CONCLUSIONS: High PB% detected by PAP machine data is a predictor of impending HF exacerbation and hospitalization. Improved PAP adherence and optimization of medical therapy may reduce hospitalization and all-cause mortality. CITATION: Ullah MI, Tamanna S, Bhagat R. High nocturnal periodic breathing reported by PAP adherence data predicts decompensation of heart failure. J Clin Sleep Med. 2023;19(3):431-441.

Periodic breathing in clinically stable very preterm infants.

OBJECTIVE: We aimed to investigate the frequency and severity of periodic breathing (PB) in clinically stable very preterm infants and identify infant and maternal factors associated with increased time spent and severity of PB in these infants. METHOD: Thirty-eight infants (28-32 weeks gestational age) who were ≥3 days off noninvasive respiratory support, were studied for 2-3 h with a daytime sleep study at 31-36 weeks postmenstrual age. Percent total sleep time spent in PB (%TSTPB) and time spent with SpO2 <90%, <80%, and cerebral oxygenation <55% during PB were calculated. Infant and maternal characteristics were correlated with %TSTPB and hypoxia during PB. RESULTS: The majority of infants (92%) had at least one episode of PB and infants spent a median 9.1 [interquartile range: 1.2, 15.5] %TSTPB. 80%, 37%, and 37% of infants experienced SpO2 <90%, <80% and cerebral oxygenation <55%, respectively, during PB. Shorter duration of respiratory support, multigravida, multiparity, and maternal vitamin D deficiency were associated with higher %TSTPB. Multigravida, shorter duration on respiratory support, apnea of prematurity, and resuscitation at birth were associated with hypoxia during PB. CONCLUSIONS: The majority of very preterm infants exhibited PB when they were off respiratory support and considered clinically stable. The time spent in PB was very variable between infants and was associated with significant hypoxia in some infants. Fewer days spent on respiratory support was associated with both increased frequency and severity of PB. However, the potential contribution of PB to neurocognitive outcomes remains uncertain and warrants further investigations.

Primum non nocere; It's time to consider altitude training as the medical intervention it actually is!

Sleep is one of the most important aspects of recovery, and is known to be severely affected by hypoxia. The present position paper focuses on sleep as a strong moderator of the altitude training-response. Indeed, the response to altitude training is highly variable, it is not a fixed and classifiable trait, rather it is a state that is determined by multiple factors (e.g., iron status, altitude dose, pre-intervention hemoglobin mass, training load, and recovery). We present an overview of evidence showing that sleep, and more specifically the prolonged negative impact of altitude on the nocturnal breathing pattern, affecting mainly deep sleep and thus the core of physiological recovery during sleep, could play an important role in intra- and interindividual variability in the altitude training-associated responses in professional and recreational athletes. We conclude our paper with a set of suggested recommendations to customize the application of altitude training to the specific needs and vulnerabilities of each athlete (i.e., primum non nocere). Several factors have been identified (e.g., sex, polymorphisms in the TASK2/KCNK5, NOTCH4 and CAT genes and pre-term birth) to predict individual vulnerabilities to hypoxia-related sleep-disordered breathing. Currently, polysomnography should be the first choice to evaluate an individual's predisposition to a decrease in deep sleep related to hypoxia. Further interventions, both pharmacological and non-pharmacological, might alleviate the effects of nocturnal hypoxia in those athletes that show most vulnerable.

A neonatal case of an elongated soft palate.

The development of stridor and periodic desaturation in a 2-day-old neonate born at term lead to the suspicion of upper airway obstruction. The patient underwent flexible fiberoptic laryngo-tracheo-bronchoscopy and was diagnosed as having an elongated soft palate and secondary mild pharyngomalacia. Early intervention with high PEEP therapy using nasal CPAP led to improvement in the patient condition.