Lisa M. Walter

Elevated Blood Pressure During Sleep and Wake in Children With Sleep-Disordered Breathing

OBJECTIVE: Sleep-disordered breathing (SDB) in adults has been associated with elevated blood pressure (BP); however, the effects of severity of SDB on BP in children are uncertain. We addressed this issue by measuring BP noninvasively and continuously during sleep in children with a range of severities of SDB and in a group of nonsnoring control children. METHODS: A total of 105 children referred for assessment of SDB and 36 nonsnoring controls were studied. Routine polysomnography (PSG) was performed with continuous BP monitoring. Children were assigned to groups according to obstructive apnea/hypopnea index (OAHI). BP data were categorized as quiet awake (recorded before sleep onset), non–rapid eye movement sleep 1 and 2 combined, slow-wave sleep, and rapid eye movement sleep. RESULTS: BP during awake before sleep onset and during overnight sleep was elevated by 10 to 15 mm Hg in the 3 SDB groups compared with the control group; this finding was independent of SDB severity. BP during stable sleep (with respiratory events and movements excluded) was also elevated in the children with OSA compared with the control group. BP was elevated in rapid eye movement sleep compared with the non–rapid eye movement sleep, and heart rate was higher during wake state than in all sleep states. CONCLUSIONS: We recorded BP continuously overnight and found that SDB, regardless of the severity, was associated with increased BP during sleep and wake compared with nonsnoring control children. These findings highlight the importance of considering the cardiovascular effects of SDB of any severity in children, and the need to review current clinical management that focuses primarily on more severe SDB.

Endometrial Angiogenesis, Vascular Maturation, and Lymphangiogenesis

Angiogenesis, arteriogenesis or vessel maturation, and lymphangiogenesis comprise a continuum of vascular development, with overlap and interaction between the mechanisms by which they are controlled. These processes are of clinical interest because they play roles in endometrial repair, placental development, and in gynecological disorders including endometrial cancer, endometriosis and abnormal uterine bleeding. Using mouse models we have shown that estrogen can be either proangiogenic or antiangiogenic in endometrium. Progesterone alone is proangiogenic, although this can be moderated by pretreatment with estrogen. Arteriogenesis also increases in response to progesterone, and this effect is not inhibited by estrogen. Lymphatics account for 13% of all vessels in the human functionalis compared to 57% in the basalis. Many of the basalis lymphatic vessels are closely associated with spiral arterioles and this intimate connection may provide a mechanism for paracrine communication between the functionalis and the arteries supplying the endometrium.

Autonomic dysfunction in children with sleep disordered breathing

PurposeSleep disordered breathing (SDB) has adverse effects on cardiovascular health in adults, partly due to changes in autonomic activity. However, there have been limited studies in children. We analysed the impact of SDB and sleep stage on autonomic control of heart rate in 7–12-year-old children, utilizing spectral heart rate variability (HRV) as a measure of autonomic activity.MethodsEighty children underwent overnight polysomnography. Subjects were grouped according to their obstructive apnoea–hypopnoea index (OAHI): controls, OAHI ≤1 event/h and no history of snoring; primary snorers (PS) OAHI ≤1, Mild (OAHI 1–5) and moderate/severe (MS) OAHI >5. HRV was analysed during Wake, nonrapid eye movement (NREM) 1&2, slow wave sleep (SWS) and REM.ResultsCompared with controls, total power, low (LF) and high frequency (HF) power were reduced in all SDB severities during REM. LF/HF ratio was less in MS SDB (medianu2009=u20090.34; range, 0.20–0.49; pu2009<u20090.05) versus controls (0.38; 0.26–0.55; pu2009<u20090.05) and PS (0.39; 0.23–0.57; pu2009<u20090.05) during SWS. In all groups, total power, LF and HF power were highest during NREM 1&2 while LF/HF ratio was lowest during SWS. Blood pressure was elevated in SDB in all sleep states.ConclusionsHRV was altered in 7–12-year-old children with SDB, which may signify an overall depression of autonomic tone, perhaps a consequence of their elevated blood pressure during sleep coupled with repeated exposure to SDB event-related cardiovascular disturbance. Further research is warranted to elucidate the long-term effects on the cardiovascular system of subjects exhibiting impaired HRV and elevated BP in childhood.

Long-Term Cognitive and Behavioral Outcomes following Resolution of Sleep Disordered Breathing in Preschool Children

This study aimed to determine the long term effects of resolution of SDB in preschool children, either following treatment or spontaneous recovery, on cognition and behavior. Children diagnosed with SDB at 3-5y (N = 35) and non-snoring controls (N = 25), underwent repeat polysomnography (PSG) and cognitive and behavioral assessment 3 years following a baseline study. At follow-up, children with SDB were grouped into Resolved and Unresolved. Resolution was defined as: obstructive apnea hypopnea index (OAHI) ≤1 event/h; no snoring detected on PSG; and no parental report of habitual snoring. 57% (20/35) of children with SDB received treatment, with SDB resolving in 60% (12/20). 43% (15/35) were untreated, of whom 40% (6/15) had spontaneous resolution of SDB. Cognitive reduced between baseline and follow-up, however this was not related to persistent disease, with no difference in cognitive outcomes between Resolved, Unresolved or Control groups. Behavioral functioning remained significantly worse in children originally diagnosed with SDB compared to control children, regardless of resolution. Change in OAHI did not predict cognitive or behavioral outcomes, however a reduction in nocturnal arousals, irrespective of full resolution, was associated with improvement in attention and aggressive behavior. These results suggest that resolution of SDB in preschool children has little effect on cognitive or behavioral outcomes over the long term. The association between sleep fragmentation and behavior appears independent of SDB, however may be moderated by concomitant SDB. This challenges the assumption that treatment of SDB will ameliorate associated cognitive and behavioural deficits and supports the possibility of a SDB phenotype.

The impact of recent changes to the respiratory scoring rules in pediatrics.

STUDY OBJECTIVESnIn 2007 the American Academy of Sleep Medicine (AASM) published polysomnography (PSG) scoring guidelines, which were updated in 2012. A key change in terms of scoring respiratory events in children was the threshold for reduction in airflow (50% vs 30%) for the definition of hypopnea. This study aimed to determine the impact of different scoring rules on the assessment of severity of obstructive sleep apnea (OSA) in children.nnnMETHODSnForty-two children (mean age 4.3 y, 16 F) underwent PSG. An obstructive apnea-hypopnea index (OAHI) was determined using three scoring rules: (1) ATS 1996 rules with minor modifications (modified ATS 1996); (2) AASM 2007 rules (AASM 2007); and (3) AASM 2007 rules with respiratory event related arousals included in the OAHI (AASM+RERA).nnnRESULTSnThe AASM 2007 OAHI (median 0.4 events/h, range 0, 14) was lower than the modified ATS 1996 OAHI (median 0.8 range 0, 26.1, p < 0.001), underestimating severity of disease in 24% of cases. The AASM+RERA OAHI (median 0.8, range 0, 19.1) was also lower than the modified ATS 1996 OAHI (p = 0.02), but the difference was not clinically significant except at very high OAHIs.nnnCONCLUSIONnThe AASM 2007 rules lead to a lower OAHI and lesser OSA severity when compared to the previous standard. Inclusion of RERAs in the AASM 2007 OAHI leads to a comparable OAHI to the previous rules. Given that morbidity has been demonstrated even in mild OSA, these results support the inclusion of events with a reduction in airflow of less than 50% as included in the updated AASM rules in 2012.

Sleep and fatigue in pediatric oncology: A review of the literature

Cancer in children has detrimental effects on sleep patterns and sleep quality, which in turn impacts on the perception of, and the ability to cope with, the emotional and physical challenges associated with both the disease and its treatment. This places an added burden on their quality of life that can last many years beyond diagnosis and treatment. In addition to the effect of the cancer itself, surgery, chemotherapy and radiotherapy can all contribute both short and long term to sleep disruption. Sleep disorders have also been associated with pain, fatigue, medication and hospitalisation in children suffering from cancer. This review will explore the relationship between childhood cancer and associated sleep disorders, in the acute stage of diagnosis, during treatment and in the years following. We will discuss the possible causes and the current treatment modalities used to treat sleep disorders in children with cancer, and in childhood cancer survivors. It has been estimated that the recent advances in treatment have improved the overall five year survival rate for all childhood cancers to over 80%, with some cancers achieving a near 100% cure rate such as early stage Wilms tumour. Thus, recognition and appropriate treatment of associated sleep disorders is essential to optimise long term quality of life.

Improved long-term autonomic function following resolution of sleep-disordered breathing in preschool-aged children

PurposeSleep-disordered breathing (SDB) prevalence peaks in preschool children and is associated with deficits in cardiovascular functioning during sleep. No long-term studies have investigated the effects of SDB resolution in mitigating these outcomes. We hypothesized that following 3xa0years, normalization of alterations to heart rate (HR), pulse transit time (PTT), heart rate variability (HRV), and urinary catecholamines identified at the initial diagnosis would be associated with resolution of SDB.MethodsForty-five children with SDB and 28 non-snoring controls underwent polysomnography at baseline (3–5xa0years) and follow-up (6–9xa0years). Children were classified into control, resolved, and unresolved SDB. Resolution was defined as an obstructive apnea–hypopnea index (OAHI) ≤1 event/h, no snoring on polysomnography (PSG), or indicated by parents. PTT is an inverse surrogate measure of blood pressure change. HRV was assessed using power spectral analysis.ResultsThere was no change in PTT or HR between studies for any group. Our HRV data suggest reduced parasympathetic activity in children whose SDB resolved and increased parasympathetic activity in children whose SDB remained the same or worsened at follow-up. We identified a significant correlation between low frequency power and urinary dopamine and adrenaline levels at follow-up in the unresolved group, suggesting increased sympathetic activity in children with unresolved SDB.ConclusionOur findings suggest an association between resolution of SDB and normalization of HRV in the long term in these preschool children and an augmented sympathetic activity in the children with residual SDB. This highlights the autonomic impact of SDB in young children and the importance of detection and treatment.

Vascular endothelial growth factor-A isoform and (co)receptor expression are differentially regulated by 17β-oestradiol in the ovariectomised mouse uterus

The angiogenic effects of 17beta-oestradiol (E(2)) in the mouse endometrium are mediated by vascular endothelial growth factor-A (VEGFA). We analysed the temporal and spatial changes in VEGFA isoform and (co)receptor expression in ovariectomised mouse uteri following E(2) treatment. VEGFA isoform and receptor mRNA were quantified in whole uterine tissue collected 2, 6, 12 and 24 h after E(2) or vehicle treatment. Laser capture microdissection was used to investigate mRNA expression in epithelial, stromal and myometrial tissues separately. Endothelial cell proliferation, VEGFA and VEGF receptor-2 (VEGFR2) protein were visualised using immunohistochemistry. Endometrial endothelial cell proliferation was only observed 24 h after E(2) treatment. In whole uterine tissue, total Vegfa, Vegfa(164) and Vegfa(120) mRNA expression increased 2 h post E(2) treatment, and then decreased by 24 h. Vegfa(188) expression was lower in E(2)-treated animals at all time points relative to control animals. Vegfr2 and neuropilin-1 (Nrp1) mRNA expression did not change following E(2) treatment; Nrp2 expression decreased by 24 h. When uterine compartments were considered separately at 24 h post E(2) or vehicle, stromal Vegfa(120), Vegfa(188) and Vegfr2 mRNA expression and myometrial Vegfa(120) and Vegfa(188) mRNA expression were reduced in E(2)-treated mice relative to controls, whereas epithelial Vegfa(188) mRNA expression increased. The highest VEGFA immunoexpression was observed in luminal epithelium; expression increased at 24 h relative to other time points. No changes were noted in VEGFR2 immunoexpression among treatment groups. We have provided the first evidence that VEGFA isoform and receptor mRNA expression are differentially regulated by E(2) in different uterine cell compartments.

How Well Do Children with Cystic Fibrosis Sleep? An Actigraphic and Questionnaire-Based Study

Objective To measure sleep patterns and quality, objectively and subjectively, in clinically stable children with cystic fibrosis (CF) and healthy control children, and to examine the relationship between sleep quality and disease severity. Study design Clinically stable children with CF and healthy control children (7‐18 years of age) were recruited. Sleep patterns and quality were measured at home with actigraphy (14 days). Overnight peripheral capillary oxygen saturation was measured via the use of pulse oximetry. Daytime sleepiness was evaluated by the Pediatric Daytime Sleepiness Scale (PDSS) and subjective sleep quality by the Sleep Disturbance Scale for Children and Obstructive Sleep Apnea‐18. Results A total of 87 children with CF and 55 control children were recruited with no differences in age or sex. Children with CF had significantly lower total sleep time and sleep efficiency than control children due to frequent awakenings and more wake after sleep onset. In children with CF, forced expiratory volume in 1 second and overnight peripheral capillary oxygen saturation nadir correlated positively with total sleep time and sleep efficiency and negatively with frequency of awakenings and wake after sleep onset. Patients with CF had significantly greater Sleep Disturbance Scale for Children (45 vs 35; P < .001), Obstructive Sleep Apnea‐18 (35 vs 24; P < .001), and PDSS scores (14 vs 11; P < .001). There was a negative correlation between PDSS and forced expiratory volume in 1 second (r = −0.23; P < .05). Conclusions Even in periods of clinical stability, children with CF get less sleep than their peers due to more time in wakefulness during the night rather than less time spent in bed. Objective measures of sleep disturbance and subjective daytime sleepiness were related to disease severity. In contrast, parents of children with CF report high levels of sleep disturbance unrelated to disease severity.

Long-term improvements in sleep and respiratory parameters in preschool children following treatment of Sleep Disordered Breathing

STUDY OBJECTIVEnSleep disordered breathing (SDB) in preschool-aged children is common, but long-term outcomes have not been investigated. We aimed to compare sleep and respiratory parameters in preschool children to examine the effects of treatment or non-treatment after 3 years.nnnMETHODSnChildren (3-5 years) diagnosed with SDB (n = 45) and non-snoring controls (n = 30) returned for repeat overnight polysomnography (39% of original cohort), 3 years following baseline polysomnography. Children with SDB were grouped according to whether they had received treatment or not. SDB resolution was defined as an obstructive apnea hypopnea index (OAHI) ≤ 1 event/h, no snoring detected on polysomnography and habitual snoring not indicated by parents on questionnaire.nnnRESULTSnFifty-one percent (n = 23) of the children with SDB were treated. Overall, SDB resolved in 49% (n = 22), either spontaneously (n = 8) or with treatment (n = 14). SDB remained unresolved in 39% (n = 9) of those treated and 64% (n = 14) of the children who were untreated. Two of the non-snoring controls developed SDB at follow-up. The treated group had significantly lower OAHI (p < 0.01), respiratory disturbance index (p < 0.001), total arousal and respiratory arousal indices (p < 0.01 for both) at follow-up compared with baseline. There were no differences between studies for the untreated group.nnnCONCLUSIONSnAlthough treatment resulted in an improvement in indices related to SDB severity, 39% had SDB 3 years following diagnosis. These findings highlight that parents should be made aware of the possibility that SDB may persist or recur several years after treatment. This is relevant regardless of the severity of SDB at baseline and the treatment given.