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.

Duration and Consequences of Periodic Breathing in Infants Born Preterm Before and After Hospital Discharge.

OBJECTIVE: To investigate the amount of time spent in periodic breathing and its consequences in infants born preterm before and after hospital discharge. METHODS: Infants born preterm between 28-32 weeks of gestational age were studied during daytime sleep in the supine position at 32-36 weeks of postmenstrual age (PMA), 36-40 weeks of PMA, and 3 months and 6 months of corrected age. The percentage of total sleep time spent in periodic breathing (% total sleep time periodic breathing) was calculated and infants were grouped into below and above the median (8.5% total sleep time periodic breathing) at 32-36 weeks and compared with 36-40 weeks, 3 and 6 months. RESULTS: Percent total sleep time periodic breathing was not different between 32-36 weeks of PMA (8.5%; 1.5, 15.0) (median, IQR) and 36-40 weeks of PMA (6.6%; 0.9, 15.1) but decreased at 3 (0.4%; 0.0, 2.0) and 6 months of corrected age 0% (0.0, 1.1). Infants who spent above the median % total sleep time periodic breathing at 32-36 weeks of PMA spent more % total sleep time periodic breathing at 36-40 weeks of PMA (18.1%; 7.7, 23.9 vs 2.1%; 0.6, 6.4) and 6 months of corrected age 0.9% (0.0, 3.3) vs 0.0% (0.0, 0.0). CONCLUSIONS: Percentage sleep time spent in periodic breathing did not decrease as infants born preterm approached term corrected age, when they were to be discharged home. High amounts of periodic breathing at 32-36 weeks of PMA was associated with high amounts of periodic breathing at term corrected age (36-40 weeks of PMA), and persistence of periodic breathing at 6 months of corrected age.

Autonomic cardiovascular control is altered by intermittent hypoxia in preterm infants.

AIM: Preterm infants frequently experience short apnoeas and periodic breathing. Animal studies have shown that repetitive hypoxia associated with periodic breathing can alter autonomic control. We aimed to elucidate if apnoea and periodic breathing were associated with changes in autonomic control assessed using heart rate variability, thus exacerbating the consequences of respiratory disturbance. METHODS: Forty very preterm infants (15 M/25 F) were studied at 34.3 weeks post-menstrual age with daytime polysomnography. Total power, low frequency (LF, sympathetic+parasympathetic activity) high frequency (HF, parasympathetic activity) and LF/HF (sympathovagal balance) were calculated. RESULTS: Infants were divided into those with above and below the median total sleep time spent with respiratory events: Active sleep (AS) 13%, Quiet sleep (QS) 10%. In AS, including respiratory events, Total power (p < 0.05) and HF power (p < 0.05) were higher in the above median group. During AS excluding respiratory events, Total power (p < 0.05) and HF power (p = 0.061) were higher and LF power (p < 0.01) and LF/HF (p < 0.05) were lower in the above median group. There were no differences in HRV parameters in QS. 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.

Ventilatory control instability as a predictor of persistent periodic breathing in preterm infants.

BACKGROUND: Periodic breathing (PB) is common in preterm infants. We aimed to characterize the contribution of ventilatory control instability to the presence and persistence of PB longitudinally. METHODS: Infants born between 28 and 32 weeks of gestation were studied using daytime polysomnography at: 32-36 weeks postmenstrual age (PMA) (N = 32), 36-40 weeks PMA (N = 20), 3 months corrected age (CA) (N = 18) and 6 months CA (N = 19). Loop gain, a measure of sensitivity of the ventilatory control system, was estimated by fitting a mathematical model to ventilatory patterns associated with spontaneous sighs. RESULTS: The time spent in PB decreased from 32-36 weeks PMA to 6 months CA (P = 0.005). Across all studies, studies with PB (N = 62) were associated with higher loop gain compared to those without PB (N = 23) (estimated marginal mean ± SEM: 0.445 ± 0.01 vs 0.388 ± 0.02; P = 0.020). A threshold of loop gain >0.415 (measured at 32-36 weeks PMA) provided a sensitivity of 86% and a specificity of 75% to detect the presence of PB at 6 months CA. CONCLUSIONS: The course of PB in preterm infants is related to changes in loop gain. Higher loop gain at 32-36 weeks PMA was associated with a greater risk of persistent PB at 6 months CA. IMPACT: The developmental trajectory of periodic breathing and its relationship to ventilatory control instability is currently unclear. Unstable ventilatory control is a determinant of periodic breathing in preterm infants up to 6 months corrected age. Infants who display greater ventilatory control instability at 32-36 weeks postmenstrual age may be at increased risk of persistent periodic breathing at 6 months corrected age. Assessment of ventilatory control stability may assist in the early identification of infants at risk of persistent periodic breathing and its potential adverse effects.

Journey towards a personalised medicine approach for OSA: Can a similar approach to adult OSA be applied to paediatric OSA?

The concept of personalised medicine is likely to revolutionise the treatment of adult obstructive sleep apnoea as a result of recent advances in the understanding of disease heterogeneity by identifying clinical phenotypes, pathophysiological endotypes, biomarkers and treatable traits. Children with the condition show a similar level of heterogeneity and paediatric obstructive sleep apnoea would also benefit from a more targeted approach to diagnosis and management. This review aims to summarise the adult literature on the phenotypes and endotypes of obstructive sleep apnoea and assess whether a similar approach may also be suitable to guide the development of new diagnostic and management approaches for paediatric obstructive sleep apnoea.

Role of ventilatory control instability in children with sleep-disordered breathing.

BACKGROUND AND OBJECTIVE: The contribution of non-anatomical factors, such as ventilatory control instability (i.e. LG), to the pathogenesis of obstructive SDB in children is unclear. Therefore, we aimed to identify the relationship between LG and severity of SDB, demographic, anthropometric and anatomical characteristics in a clinically representative cohort of children. METHODS: Children (aged 3-18 years) with various severities of SDB (n = 110) and non-snoring controls (n = 36) were studied. Children were grouped according to their OAHI. Anthropometric and upper airway anatomical characteristics were measured. Spontaneous sighs were identified on polysomnography and LG, a measure of the sensitivity of the negative feedback loop that controls ventilation, was estimated by fitting a mathematical model of ventilatory control to the post-sigh ventilatory pattern. RESULTS: There was no difference in LG between controls and any of the SDB severity groups. However, LG was significantly lower in children with larger tonsils (tonsil grade 4) compared with children with smaller tonsils (tonsil grade 1) (median LG (range): 0.25 (0.20-0.42) vs 0.32 (0.25-0.44); P = 0.009) and in children with a modified Mallampati score of class III/IV compared with class I (0.28 (0.24-0.33) vs 0.37 (0.27-0.44); P = 0.009). CONCLUSION: A direct relationship was not found between the severity of paediatric SDB and LG. However, an altered ventilatory control sensitivity may contribute to SDB in a subgroup of children depending on their degree of anatomical compromise of the airway.

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.

Developmental consequences of short apneas and periodic breathing in preterm infants.

OBJECTIVE: We investigated the relationship between respiratory events experienced before and after hospital discharge and developmental outcomes at 6 months corrected age (CA). STUDY DESIGN: Preterm infants born between 28-32 weeks gestational age (GA) were studied at 32-36 weeks postmenstrual age (PMA), 36-40 weeks PMA, 3- and 6-months CA. Percentage total sleep time (%TST) with respiratory events (isolated apneas, sequential apneas and periodic breathing (PB)) at each study was calculated. Stepwise multiple linear regressions determined significant predictors of developmental outcomes at 6 months. RESULT: %TST with respiratory events at term were significant predictors of language (R2 = 0.165, ß = -0.416) and motor (R2 = 0.180, ß = -0.485) composite scores of the Bayley Scales of Infant Development at 6 months, independent of GA, birth weight and sex. CONCLUSIONS: In clinically stable very preterm infants at term equivalent age, time spent having respiratory events, was related to a reduction in language and motor outcomes at 6 months.

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.

Children with down syndrome and sleep disordered breathing display impairments in ventilatory control.

OBJECTIVES: To investigate the role of ventilatory control instability (i.e. loop gain) in children with Down syndrome and sleep disordered breathing. METHODS: Children (3-19 years) with Down syndrome and sleep disordered breathing (n = 14) were compared with typically developing children (n = 14) matched for age, sex and sleep disordered breathing severity. All children underwent overnight polysomnography. Spontaneous sighs were identified and a 180s analysis window (60s pre-sigh to 120s post-sigh) containing flow measurements and oxygen saturation were created. Loop gain, a measure of the sensitivity of the negative feedback loop that controls ventilation, was estimated by fitting a mathematical model of ventilatory control to the post-sigh ventilatory pattern. Results; Loop gain was significantly higher in children with Down syndrome compared to matched typically developing children (median loop gain [interquartile range]: 0.36 [0.33, 0.55] vs 0.32 [0.24, 0.38]; P = 0.0395). While children with Down syndrome also had significantly lower average oxygen saturation associated within each analysis window compared to typically developing children (mean ± standard deviation: 96.9 ± 1.3% vs 98.0 ± 1.0%; P = 0.0155), loop gain was not related to polysomnographic measures of hypoxia. CONCLUSIONS: Higher loop gain in children with Down syndrome and sleep disordered breathing indicates that these children have more unstable ventilatory control, compared to age, sex and sleep disordered breathing severity matched typically developing children. This may be due to an inherent impairment in ventilatory control in children with Down syndrome contributing to their increased risk of sleep disordered breathing which may inform alternative treatment options for this population.