Sleep Arousal and Cardiovascular Dynamics

Sleep arousal conventionally refers to any temporary intrusions of wakefulness into sleep. Arousals are usually considered as a part of normal sleep and rarely result in complete awakening. However, once their frequency increases, they may affect the sleep architecture and lead to sleep fragmentation, resulting in fatigue, poor executive functioning and excessive daytime sleepiness. In the electroencephalogram, arousals mostly appear as a shift of power in frequency to values greater than 16 Hz lasting 3-15 seconds. The general objective of this thesis was to investigate on the nature of sleep arousal and study arousal interaction and association with cardiovascular dynamics. At the first step of this research, an algorithm was developed and evaluated for automatic detection of sleep arousal. The polysomnographic (PSG) data of 9 subjects were analysed and 32 features were derived from a range of biosignals. The extracted features were used to develop kNN classifier model in to differentiate arousal from non-arousal events. The developed algorithm can detect arousal events with the average sensitivity and accuracy of 79% and 95.5%, respectively. The second aim was to investigate cardiovascular dynamics once an arousal occurs. Overnight continuous systolic and diastolic blood pressure (SBP and DSP), spectral components of heart rate variability (HRV) and the pulse transit time of 10 subjects (average arousal number of 51.5 +/- 21.1 per person) were analysed before and after arousal occurrence. Whether each cardiovascular variable increases or decreases was evaluated in different types of arousals through slpoe index (SI). The analysis indicated a post-arousal SBP and DBP elevation and PTT dropping. High frequency component of HRV (HF) dropped at arousal onset whilst low frequency (LF) component shifted. HRV spectral components extracted from ECG, lead I alongside with PTT were utilised for sleep staging in 22 healthy and insomnia subjects using linear and non-linear classifier models. Obtained result shows that developed model by DW-kNN classifier could detect sleep stages with mean accuracy of 73.4% +/- 6.4. An empirical curve fitting model for overnight continuous blood pressure estimation was developed and evaluated using the first and second derivatives of fingertip PPG (VPG, APG) along with ECG. The VPG-based model could estimate systolic and diastolic blood pressure with mean error of 3:96 mmHg with standard deviation of 1.41 mmHg and DBP with 6:88 mmHg with standard deviation of 3.03 mmHg. The QT and RR time intervals are two cardiac variables which represent beat to beat variability and ventricular repolarisation, respectively. PSG dataset of 2659 men aged older than 65 (MrOS Sleep Study) was analysed to compare on RR and QT interval variability pre- and post-arousal onset. The cardiac interval gradients were developed to monitor instantaneous changes pre-and post-onset. Analysis of gradients demonstrated that both RR and QT are likely to start shortening several second prior to onset by average probability of 73% and 64%. The QT/RR linear correlation was significantly rising after arousal inducing regardless of arousal type and associated pathological events (Rpost = 0.218 vs Rpre = 0.047). ANOVA test and Tukey’s honest post-hoc analysis indicated a significant difference between cardiac intervals variability between respiratory, movements and spontaneous arousals. In addition, respiratory disturbance index (RDI) as a measure of sleep apnoea severity was reversely correlated with both QT (RVarQT = -0.251, p 1:1 ms) and greater frequency of sleep arousal, less physical activity and medical history of several cardiovascular disease. Similarly participants in quartile DRR> - 8:8 were likelier to be obese with less physical activity, medical history of COPD and stroke and suffered from severer degree of sleep apnoea (RDI = 28:7 20:4 vs RDI = 25:5 +/- 17:6, p < 0:001). Kaplan-Meier analysis showed that the distribution DRR at arousal onset was significantly associated with cardiovascular (CV) mortality (p < 0:001). Cox proportional hazard regression models also indicated the effect of arousal duration in prediction of CV mortality, where longer arousals had more prognostic value for CV mortality than shorter arousals.Thesis (Ph.D.) -- University of Adelaide, School of Electrical and Electronic Engineering, 202

Arousal, Sleep and Cardiovascular Responses to Intermittent Hypercapnic Hypoxia in Piglets

Clinical studies have demonstrated an arousal deficit in infants suffering Obstructive Sleep Apnoea (OSA), and that treatment to alleviate the symptoms of OSA appears to reverse the deficit in arousability. Some sudden infant deaths are thought to be contingent upon such an arousal deficit. This research utilised young piglets during early postnatal development, and exposed them to intermittent hypercapnic hypoxia (IHH) as a model of clinical respiratory diseases. Arousal responses of control animals were compared to the animals exposed to IHH. Comparisons were also made between successive exposures on the first and the fourth consecutive days of IHH. Time to arouse after the onset of the respiratory stimulus, and frequency of arousals during recovery, demonstrated that arousal deficits arose after successive exposures and that these were further exacerbated on the fourth study day. After an overnight recovery period, the arousal deficit was apparently dormant, and only triggered by HH exposure. These studies confirm that both acute and chronic deficits can be induced on a background of otherwise normal postnatal development, suggesting that deficits observed in the clinical setting may be a secondary phenomenon

Arousal, Sleep and Cardiovascular Responses to Intermittent Hypercapnic Hypoxia in Piglets

Clinical studies have demonstrated an arousal deficit in infants suffering Obstructive Sleep Apnoea (OSA), and that treatment to alleviate the symptoms of OSA appears to reverse the deficit in arousability. Some sudden infant deaths are thought to be contingent upon such an arousal deficit. This research utilised young piglets during early postnatal development, and exposed them to intermittent hypercapnic hypoxia (IHH) as a model of clinical respiratory diseases. Arousal responses of control animals were compared to the animals exposed to IHH. Comparisons were also made between successive exposures on the first and the fourth consecutive days of IHH. Time to arouse after the onset of the respiratory stimulus, and frequency of arousals during recovery, demonstrated that arousal deficits arose after successive exposures and that these were further exacerbated on the fourth study day. After an overnight recovery period, the arousal deficit was apparently dormant, and only triggered by HH exposure. These studies confirm that both acute and chronic deficits can be induced on a background of otherwise normal postnatal development, suggesting that deficits observed in the clinical setting may be a secondary phenomenon

Sleep-Related Arousal and Spontaneous Movement Properties in Methadone-Exposed Neonates: A Videographic Assessment On the First or Second Postnatal Night

Prenatal substance exposure such as alcohol, nicotine, and opiates is known to modulate autonomic regulatory function during sleep, and to decrease arousability and spontaneous movements (SM). SM during sleep may reflect a protective mechanism for immature patterns of arousals. Neurodevelopmental compromise in sleep and arousal systems may underlie sudden infant death syndrome (SIDS) risk in which infants expire during sleep. Previous studies from our laboratory found abnormal patterns of neonatal arousal, sleep fragmentation, and deficits in sleep-related SM in infants with prenatal alcohol exposure. In this study, prenatal exposure to methadone was hypothesized to disrupt the development of sleep and arousal neural circuitry, which have been found for other high-risk samples. Neonatal Abstinence Syndrome (NAS) is a common consequence of prenatal methadone exposure that may appear within 24 - 72 hours postbirth, and is known to disrupt sleep due to hyperarousability. As a secondary hypothesis, the neonatal age (day 1 or 2 of life) was expected to affect infant sleep and arousal outcomes in methadone-exposed neonates particularly on day 2 when NAS symptoms increase. Additionally, single nucleotide polymorphism (SNP) in the catechol-O-methyltransferase (COMT) gene was found to associate with the severity of NAS in our previous study. NAS severity has been associated with sleep disorders. Therefore, the second hypothesis of this thesis study is that the minor allelic variants (AG/GG) of the COMT gene previously identified as protective of NAS severity may also associate with better sleep organization and more robust SM than the carriers of the AA genotype. Rural, disadvantaged Caucasian mothers and infants (N=58 dyads: methadone=37, comparison=21) were recruited from multiple narcotic treatment sites and prenatal clinic at Eastern Maine Medical Center (EMMC). Mothers were interviewed to determine demographics, psychiatric status, and substance abuse history during the 3rd trimester. Biweekly maternal urinalysis screens and neonatal meconium were applied to verify comorbid alcohol, tobacco, and other drug use. Finnegan scores determined symptoms of withdrawal in opioid exposed newborns. Videosomnographic recordings of behavioral states were collected in the newborn nursery of EMMC overnight, and recordings between 2400-0500h were analyzed for frequency and duration of sleep, wake, arousal, and SM. Saliva samples for genetic study was collected using OrageneTM kits. Results from behavioral state analysis (n=50) showed that methadone-exposed neonates were significantly hyper-aroused and crying more on both day 1 and 2 of life (p\u3c.05); and both the frequency and duration of these parameters increased significantly in the methadoneexposed neonates on day 2 of life, as expected. In the genetic study (n=20), neonates with NAS protective AG/GG genotypes showed better behavioral sleep, fewer arousals, and robust SM than infants with NAS risk AA genotype (p\u3c.05). These findings support evidence of sleep fragmentation in the exposed neonates that is exacerbated by the passage of time since birth when withdrawal symptoms compound the intensity of sleep disturbance and infant distress. Consistent with other findings from other SIDS-risk samples, these findings indicate that arousal and SM regulation may be disrupted in methadone-exposed neonates, suggesting that prenatal methadone may increase risk for SIDS

Sleep and Breathing in Preterm Infants : Polysomnography Studies on the Effects of Caffeine and Supplemental Oxygen

Sleep-disordered breathing in preterm infants is common and is a prominent issue in neonatal care. Preterm infants express breathing pauses called apneas, and periodic breathing (PB) consisting of repetitive intervals of short apneas and periods of hyperpnea. Apneas are commonly divided into central, obstructive, and mixed depending on the presence of absence of breathing effort. Central apneas show no airflow nor any breathing attempts. Obstructive apneas show breathing attempts in which airflow is restricted due to collapsed upper airways. Mixed apneas are a combination of these two, usually commencing as a central apnea, followed by obstructive breaths. In clinical neonatal practice, apneas are commonly not divided into central, obstructive, or mixed. Apneas in these infants are considered pathologic if they cause significant hypoxia, or bradycardia, or last for over 15 to 20 seconds. These respiratory pauses are called apnea of prematurity (AOP) irrespective of the presence or absence of upper airway obstruction. The use of the concept of AOP is not necessarily relevant as varying apnea types respond to different treatment methods. The significance of PB in preterm infants is disputed. PB causes intermittent hypoxia, which can, for example, lead to increased appearance of apneas and can impair preterm infants’ development. The approach of treatment depends on the degree of sleep-disordered breathing and on the treating center. Treatment modalities vary: invasive ventilatory support, high-flow nasal cannulas, continuous positive airway pressure, oxygen therapy, and methylxanthines such as caffeine or theophylline. In preterm infants, caffeine reduces the number of apneas and PB, and reduces the need for mechanical ventilation. It also promotes development. Supplemental oxygen stabilizes breathing and enhances oxygenation. Whereas the effect of supplemental oxygen is mediated through the peripheral chemoreceptors, the effect of caffeine as a breathing stimulant is most likely mediated through the stimulation of the central respiratory centers. Despite caffeine’s routine use in clinical practice, its effects on sleep and respiratory control in preterm infants are yet to be well established. Caffeine has a general stimulative effect on the central nervous system, and in adults and older children it increases alertness and prevents falling asleep; in preterm infants such an effect is not evident. Sleep in preterm infants differs significantly from sleep in older infants, children, and adults. Preterm infants spend most of their time asleep without any circadian rhythm. In contrast to later in life, their sleep is occupied by 40 to 60% of rapid-eye movement (REM) sleep compared, later in life, to around 15%. REM sleep is susceptible to disturbance, and in premature infants, respiratory disorders and intensive care with medical equipment and procedures interfere with sleep, especially with REM sleep. The development of sleep, sleep stages, and especially REM sleep are fundamental for normal development. Thus, knowledge about the effect of treatments on sleep in preterm infants is vital. This thesis study is based on polysomnographic data in late-preterm infants. We studied 21 preterm infants cared for in the neonatal wards of Helsinki University Hospital between 2013 and 2018. These infants were estimated by the pediatrician in charge of their care to need commencing of caffeine treatment for apneas or the presence of long periods of PB. We performed full polysomnography (PSG) studies in three phases: 1) at baseline prior to any intervention, 2) on supplemental oxygen, and 3) on the day after initiation of caffeine citrate treatment The analysis of the PSG studies comprised explicit sleep analysis, analysis of breathing disorders such as apneas and PB, arousals, and heart rate, and the effects of supplemental oxygen and of caffeine on these events. The results of this thesis study showed that sleep of preterm infants was fragmented by frequent arousal-type phenomena. Apneas seemed to have no disturbing effect on sleep and apneas rarely ended in an arousal from sleep. Therefore, apnea termination seems to be independent from arousal in preterm infants. Supplemental oxygen appeared to mildly increase arousal in response to AOP-defined apneas. Hypoxia did not effectively cause arousals in preterm infants. However, caffeine increased the rate of arousal in response to hypoxia. Caffeine and supplemental oxygen did not affect sleep, and despite acting as a respiratory stimulant, caffeine caused no notable central nervous system stimulation. The infants presented with long, AOP-defined apneas mainly in REM sleep, independent of their PB. These AOP-defined apneas were mostly of a mixed type with a considerably long central apnea before obstructive breathing efforts commenced, and they were to some degree affected by caffeine treatment. PB emerged as a state of mild hyperventilation, it appeared dominantly in non-REM sleep, and it caused intermittent hypoxia. Conventional oxygen saturation measurement with long averaging intervals may often miss this intermittent hypoxia. PB and subsequent intermittent hypoxia showed effective dampening with caffeine, and even greater dampening with supplemental oxygen. In conclusion, in preterm infants, sleep-disordered breathing consisted of PB in NREM sleep and long apneas either during falling asleep or in REM sleep. Long apneas were most often mixed apneas commencing as central apneas but continuing as upper airway obstruction. PB shared characteristics similar to those evident later in life. It appeared as a state of mild hyperventilation and responded both to supplemental oxygen and to caffeine. Caffeine did not appear to be a general central nervous system stimulant in preterm infants, which should further reassure us as to its use in such infants.Ennenaikaisesti syntyneillä lapsilla eli keskosilla unenaikaiset hengityshäiriöt ovat yleisiä ja ne ovat yksi keskosten hoidon keskeisistä ongelmista. Näitä hengityshäiriöitä ovat mm. hengityskatkokset eli apneat sekä jaksottainen eli periodien hengitys, joka koostuu toistuvista lyhyiden sentraalisen apneoiden ja niiden välissä olevien ylihengitysjaksojen sykleistä. Apneat jaetaan yleisesti sentraalisiin, tukoksellisiin (obstruktiivisiin) ja sekamuotoisiin sen perusteella, liittykö niihin hengitysyrityksiä vai ei. Kliinisessä käytännössä keskosilla ja vastasyntyneillä apneatyyppien jakoa ei tavanomaisesti tehdä. Heillä apneat arvioidaan merkittäviksi, jos niihin liittyy hapetustason tai syketason merkittävää laskua tai niiden kesto on yli 15–20 sekuntia. Kuitenkin eri apneatyyppien hoitoon tehoavat parhaiten eri hoitomenetelmät. Keskosilla esiintyvän jaksottaisen hengityksen merkitys on kiistelty ja sen normaalivaihtelua ei varmuudella tunneta. Jaksottaiseen hengitykseen on todettu liittyvän lyhyitä intermittoivia hapenpuutejaksoja. Tällaisen intermittoivan hapenpuutteen on todettu liittyvän keskosilla mm. apneoiden lisääntymiseen sekä heikompaan kehitykseen. Kuitenkin sen merkityksestä keskosten kehitykseen on eriäviä arvioita. Keskosten hengityshäiriöiden yleisiä hoitomuotoja ovat vaikeusasteen mukaan hengityskonehoito, ylipainehengityshoito, korkeavirtausviiksihoito, happihoito ja kofeiinilääkitys. Keskosilla kofeiini vähentää apneoiden määrää, tasoittaa hengitystä, vähentää hengityskonehoidon tarvetta sekä parantaa keskosten kehitystä. Myös lisähappi tasoittaa keskosten hengitystä. Lisähappi vaikuttaa hengitykseen perifeeristen hapen ja hiilidioksidin aistinelimen, karotiskerästen, toiminnan lamaamisen kautta. Kofeiini puolestaan tehostaa hengitystä ja sen vaikutus välittyy ilmeisesti pääosin keskushermoston hengityskeskusten kautta. Aikuisilla ja vanhemmilla lapsilla kofeiini aktivoi keskushermostoa ja lisää valvetta. Kofeiinin rutiininomaisesta käytöstä huolimatta tietomme sen vaikutuksista keskosten nukkumiseen ja unen laatuun on vähäistä. Keskoset nukkuvat suurimman osan ajastaan, ja heidän unestaan valtaosa on vilke- eli REM-unta. REM-uni on herkkä häiriintymään ja keskoskaudella hengityshäiriöt sekä tehohoito häiritsevät unta, etenkin REM-unta. Unen ja sen eri vaiheiden, etenkin REM-unen, häiriintyminen haittaa normaalia kehitystä. Siten tieto keskosilla käytettävien hoitojen vaikutuksesta uneen on tärkeää. Tämä väitöskirjatyö pohjautuu keskosilla tehtyihin laajoihin unitutkimuksiin (polysomnografia, PSG). Tutkimme HUS Helsingin Yliopistollisen sairaalan Jorvin ja Kätilöopiston sairaaloiden vastasyntyneiden osastoilla 21 keskosta vuosina 2013–2018. Näillä lapsilla oli todettu merkittäviä apneoita tai taipumus runsaaseen periodiseen hengitykseen, minkä vuoksi heille suunniteltiin kliinisin perustein kofeiinihoidon aloitusta. Teimme näille lapsille laajat unitutkimukset kolmessa vaiheessa: 1) lähtötilanteessa ennen interventiota, 2) lisähapen annon aikana ja 3) kofeiinihoidon aloittamista seuraavana päivänä. Rekisteröintien pohjalta arvioimme tutkittavien unta ja sen eri vaiheita, hengityshäiriöitä (apneoita ja jaksottaista hengitystä) ja niiden esiintymistä eri univaiheissa sekä lisähapen ja kofeiinin vaikutusta. Tämän väitöskirjatyön tulokset osoittavat, että keskoslasten uni oli toistuvien spontaanien havahtumisten vuoksi huomattavan paljon pirstaleisempaa kuin silminnähden arvioituna. Apneoilla ei näyttänyt olevan unta häiritsevää vaikutusta, ja apneat ja hapenpuutejaksot päättyivät harvoin havahtumiseen. Apneoiden päättyminen vaikuttaa olevan keskosilla havahtumisesta riippumatonta, mikä johtunee ensisijaisesti keskosille ominaisista alhaisista vasteista hapenpuutteeseen. Lisähappi vaikutti hieman lisäävän havahtumisia pidempiin apneoihin. Hapenpuute ei ollut tehokas herättäjä, mutta kofeiini lisäsi siihen havahtumista. Kofeiini ja lisähappi eivät vaikuttaneet uneen. Johtopäätöksenä toteamme, että vaikka kofeiini toimi hengitystä stimuloivana lääkkeenä, se ei aiheuttanut merkittävää keskushermoston stimulaatiota näillä keskosilla, mikä edelleen vahvistaa kofeiinin turvallisuutta keskosten hengityshäiriöiden hoidossa. Tutkituilla keskosilla esiintyi yksittäisiä pitkiä keskosten apneoiksi määriteltyjä apneoita (apnea of prematurity, AOP) pääosin REM-unen aikana, erillään jaksottaisesta hengityksestä. Nämä apneat olivat pääosin sekamuotoisia, mutta usein niiden obstruktiivista osiota edelsi pitkä sentraalisen apnean osio. Kofeiini vähensi hieman näitä sekamuotoisia apneoita. Periodinen hengitys näyttäytyi hyperventilaatiotilana ja esiintyi pääosin rauhallisessa (NREM) unessa, ollen samankaltaista kuin myöhemmällä iällä. Siihen liittyi säännönmukaisesti toistuvat hapenpuutejaksot. Nämä jaksot jäävät huomaamatta, jos veren happikyllästeisyyden mittalaitteessa (pulssioksimetri) käytetään kliinisessä käytössä tavanomaista, pitkää keskiarvoistusaikaa. Kofeiini ja erityisesti lisähappi vähensivät huomattavasti periodista hengitystä ja niihin liittyneitä hapenpuutejaksoja