The unfolded protein response and apoptotic regulation in the human placenta due to maternal cigarette smoking and pre-eclampsia.

Maternal cigarette smoking (CS) and pre-eclampsia (PE) alter placental function and expression of important proteins which maintain homeostasis. Two interlinked pathways of interest are the unfolded protein response (UPR) and apoptosis. The UPR is upregulated in the PE placenta, but no data is available on the effects of CS and how it correlates with apoptotic expression. Samples of human placental tissue from normotensive non-smokers (n = 8), women with PE (n = 8), and CS (n = 8) were analysed using immunohistochemistry for 3 UPR markers (phosphorylated PKR-like endoplasmic reticulum (ER) kinase (pPERK), inositol-requiring enzyme 1 (IRE1), activating transcription factor 6 (ATF6)), and an antibody microarray for 19 apoptotic and stress regulating markers. For the PE group compared to the normotensive group, staining for pPERK was increased in decidual tissue and villi, and for IRE1, the overall percentage of stained villi per field of view was increased. There were no differences in UPR expression comparing CS to controls. Of the apoptotic markers, only IκBα (Ser32/36), which is part of an inhibitory pathway, showed a significant decrease in the PE and CS groups compared to controls. These findings suggest UPR regulation is more evident in PE with a general increase in ER stress due to decreased inhibition of apoptosis as compared to CS for which UPR was not altered.

The α7 and ß2 nicotinic acetylcholine receptor subunits regulate apoptosis in the infant hippocampus, and in sudden infant death syndrome (SIDS).

Apoptosis is increased in the hippocampus of infants who died of sudden infant death syndrome (SIDS), yet it is not known via which mechanism this has occurred. Following existing support for a role of the α7 and ß2 nicotinic acetylcholine receptor (nAChR) subunits in apoptotic regulation, we aimed to determine whether these subunits are altered in the SIDS hippocampus and if they are correlated with cell death markers of active caspase-3 (Casp-3) and TUNEL. Further analyses were run according to the presence of major SIDS risk factors related to hypoxia (bed-sharing and prone sleeping), infection (presence of an upper respiratory tract infection (URTI)), cigarette smoke exposure and gender. Immunohistochemical expression of the markers was studied in 4 regions of the hippocampus (Cornu Ammonis (CA)1, CA2, CA3, CA4) and subiculum amongst 52 infants (aged 1-7 months) who died suddenly and unexpectedly (SUDI) and for whom the cause of death was explained (eSUDI; n = 9), or not and characterised as SIDS I (n = 8) and SIDS II (n = 35) according to the San Diego diagnostic criteria. Results showed that SIDS II infants had widespread increases in TUNEL compared with eSUDI and SIDS I infants, as well as increased α7 and Casp-3 in CA2 compared to eSUDI infants, although these changes were predominant amongst infants who did not bed-share. Cigarette smoke exposure had minimal effects on the markers, while an URTI was associated with changes in all markers (after accounting for bed-sharing). Our findings support the role of nAChRs in regulating apoptosis in the SIDS hippocampus, and highlight the need for separate analysis according to risk factors.

Hypoxia and nicotine effects on Pituitary adenylate cyclase activating polypeptide (PACAP) and its receptor 1 (PAC1) in the developing piglet brainstem.

Pituitary adenylate cyclase activating polypeptide (PACAP) and its cognate receptor 1 (PAC1), have been implicated in the pathophysiology of the Sudden Infant Death Syndrome (SIDS). Two main risk factors for SIDS are prone sleeping and cigarette smoke exposure. Using piglet models of these risk factors, intermittent hypercapnic hypoxia (IHH-mimicking rebreathing in prone position) and nicotine (main reinforcing element of cigarettes), this study aimed to determine their effects on PACAP and PAC1 protein expression in the medulla. IHH was delivered for 1 (n=7), 2 (n=6), 3 (n=6) and 4 (n=7) days prior to euthanasia at 13-14days of age, while nicotine (n=7) was continuous for the first 14days of life. An additional group of combined nicotine and 1day IHH (1DIHH) was studied to determine the combined effects of the risk factors. Changes in expression were seen after the acute 1DIHH exposure (none after repeated daily exposures) and included a decrease in PACAP in the dorsal motor nucleus of vagus (DMNV; p=0.024), nucleus of the solitary tract (NTS; p=0.024) and the gracile nucleus (GRAC; p=0.001), and a decrease in PAC1 in the NTS (p=0.01). No PACAP change was noted in the nicotine-exposed piglets, however, a decrease in PAC1 was found in the DMNV (p=0.02). IHH exposure in piglets with pre-exposure to nicotine led to a significant decrease in PACAP in the Grac (p=0.04) but had no effect on PAC1. These findings show for the first time, the vulnerability of PACAP in the brainstem during early development to an acute hypercapnic hypoxic exposure and that those effects are greater than from nicotine exposure.

Pituitary adenylate cyclase activating polypeptide (PACAP) and its receptor 1 (PAC1) in the human infant brain and changes in the Sudden Infant Death Syndrome (SIDS).

Pituitary adenylate cyclase activating polypeptide (PACAP) and its complementary receptor, PAC1, are crucial in central respiratory control. PACAP Knockout (KO) mice exhibit a SIDS-like phenotype, with an inability to overcome noxious insults, compression of baseline ventilation, and death in the early post-neonatal period. PAC1 KO demonstrate similar attributes to PACAP-null mice, but with the addition of increased pulmonary artery pressure, consequently leading to heart failure and death. This study establishes a detailed interpretation of the neuroanatomical distribution and localization of both PACAP and PAC1 in the human infant brainstem and hippocampus, to determine whether any changes in expression are evident in infants who died of Sudden Infant Death Syndrome (SIDS) and any relationships to risk factors of SIDS including smoke exposure and sleep related parameters. Immunohistochemistry for PACAP and PAC1 was performed on formalin fixed and paraffin embedded human infant brain tissue of SIDS (n=32) and non-SIDS (n=12). The highest expression of PACAP was found in the hypoglossal (XII) of the brainstem medulla and lowest expression in the subiculum of the hippocampus. Highest expression of PAC1 was also found in XII of the medulla and lowest in the midbrain dorsal raphe (MBDR) and inferior colliculus. SIDS compared to non-SIDS had higher PACAP in the MBDR (p<0.05) and lower PAC1 in the medulla arcuate nucleus (p<0.001). Correlations were found between PACAP and PAC1 with the risk factors of smoke exposure, bed sharing, upper respiratory tract infection (URTI) and seasonal temperatures. The findings of this study show for the first time that some abnormalities of the PACAP system are evident in the SIDS brain and could contribute to the mechanisms of infants succumbing to SIDS.

A cross-sectional analysis of daytime versus nocturnal polysomnographic respiratory parameters in cystic fibrosis during early adolescence.

BACKGROUND: In Cystic Fibrosis (CF), early detection and treatment of respiratory disease is considered the standard for respiratory care. Overnight polysomnography (PSG) may help identify respiratory deterioration in young patients with CF. METHODS: A prospective cohort study of 46 patients with CF, aged 8-12years, from a specialist clinic in a tertiary paediatric hospital. Daytime pulmonary function, shuttle test exercise testing and overnight PSG were studied. RESULTS: Of 81 children aged 8-12years, 46 (57%) agreed to participate. FEV1 (% predicted, mean 74.6%) was normal in 23 (50%), mildly abnormal in 12 (26.1%), moderately abnormal in 10 (21.7%) and severely abnormal in 1 (2.2%). Amongst sleep study parameters, FEV1 (% predicted) showed significant correlation with the respiratory rate (RR) in slow wave sleep (SWS), CO2 change in REM, baseline SaO2, and the arousal index (h-1). Backward, stepwise linear regression modelling for FEV1 (% predicted) included the entire group with a wide spectrum of clinical severity. From sleep, variables remaining in the multivariate model for FEV1 (F=16.81, p<0.001) were the RR in SWS (min-1) and the CO2 change in REM (p=0.003, and 0.014, respectively). When daytime tests were included, the variables remaining were RR in SWS and SD score for BMI (BMIsds) (F=18.70, p<0.001). CONCLUSIONS: Respiratory abnormalities on overnight sleep studies included elevated respiratory rates during SWS and mild CO2 retention in REM sleep, and these incorporated into a model correlating with FEV1 (% predicted). Thus, mild mechanical impairment of ventilation is evident on overnight sleep studies in children with cystic fibrosis although the significance of this finding will require further investigation.

Cigarette smoking during pregnancy regulates the expression of specific nicotinic acetylcholine receptor (nAChR) subunits in the human placenta.

Smoking during pregnancy is associated with low birth weight, premature delivery, and neonatal morbidity and mortality. Nicotine, a major pathogenic compound of cigarette smoke, binds to the nicotinic acetylcholine receptors (nAChRs). A total of 16 nAChR subunits have been identified in mammals (9 α, 4 ß, and 1 δ, γ and ε subunits). The effect of cigarette smoking on the expression of these subunits in the placenta has not yet been determined, thus constituting the aim of this study. Using RT-qPCR and western blotting, this study investigated all 16 mammalian nAChR subunits in the normal healthy human placenta, and compared mRNA and protein expressions in the placentas from smokers (n = 8) to controls (n = 8). Our data show that all 16 subunit mRNAs are expressed in the normal, non-diseased human placenta and that the expression of α2, α3, α4, α9, ß2 and ß4 subunits is greater than the other subunits. For mRNA, cigarette smoke exposure was associated with increased expression of the α9 subunit, and decreased expression of the δ subunit. At the protein level, expression of both α9 and δ was increased. Thus, cigarette smoking in pregnancy is sufficient to regulate nAChR subunits in the placenta, specifically α9 and δ subunits, and could contribute to the adverse effects of vasoconstriction and decreased re-epithelialisation (α9), and increased calcification and apoptosis (δ), seen in the placentas of smoking women.

Evaluation of the pro-cognitive effects of the AMPA receptor positive modulator, 5-(1-piperidinylcarbonyl)-2,1,3-benzoxadiazole (CX691), in the rat.

RATIONALE: Positive allosteric modulators of the glutamatergic alpha-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA) receptor do not stimulate AMPA receptors directly but delay deactivation of the receptor and/or slow its desensitisation. This results in increased synaptic responses and enhanced long-term potentiation. Thus, it has been suggested that such compounds may have utility for the treatment of cognitive impairment. OBJECTIVES: The objective of the study was to investigate the effect of an AMPA positive modulator, CX691, (1) in three rodent models of learning and memory, (2) on neurochemistry in the dorsal hippocampus and medial prefrontal cortex following acute administration, and (3) on brain-derived neurotrophic factor (BDNF) messenger RNA (mRNA) expression in the rat hippocampus following acute and sub-chronic administration. RESULTS: CX691 attenuated a scopolamine-induced impairment of cued fear conditioning following acute administration (0.1 mg/kg p.o.) and a temporally induced deficit in novel object recognition following both acute (0.1 and 1.0 mg/kg p.o.) and sub-chronic (bi-daily for 7 days) administration (0.01, 0.03, 0.1 mg/kg p.o.). It also improved attentional set-shifting following sub-chronic administration (0.3 mg/kg p.o.). Acute CX691 (0.1, 0.3 and 1.0 mg/kg, p.o.) increased extracellular levels of acetylcholine in the dorsal hippocampus and medial prefrontal cortex and dopamine in the medial prefrontal cortex. Sub-chronic administration of CX691 (0.1 mg/kg, p.o.) elevated BDNF mRNA expression in both the whole and CA(1) sub-region of the hippocampus (P < 0.05). CONCLUSIONS: Collectively, these data support the pro-cognitive activity reported for AMPA receptor positive modulators and suggest that these compounds may be of benefit in treating disorders characterised by cognitive deficits such as Alzheimer's disease and schizophrenia.

The identification of children with cleft palate and sleep disordered breathing using a referral system.

BACKGROUND: Cleft palate is associated with an increased risk of sleep disordered breathing (SDB) but the magnitude of this risk and specific risk factors are unclear. A better understanding of these components of risk will aid the early identification of SDB in this group of children. OBJECTIVE: To describe the clinical characteristics and results of sleep studies undertaken in a cohort of children with cleft palate. Clinical features will be examined to determine potential associations with SDB in this group. METHOD: A retrospective chart review was undertaken to ascertain sleep study results and clinical data for all children with cleft palate. Clinical features of interest included age, gender, syndrome diagnosis, cleft classification, and surgical status. RESULTS: A total of 99 sleep studies were available from 62 children. The sample included a select group of children with cleft palate with features predictive of a high risk of SDB. Baseline sleep study results were consistent with SDB for 87% of children and 28% (15 of 54) of these children demonstrated severe SDB. Uni-variate analysis showed that age, syndrome, and surgical status had significant association with the severity of SDB. On multi-variate analysis only surgical status maintained this association, such that pre-palatoplasty/pharyngoplasty was associated with more severe SDB. Follow-up studies were completed in one-third of the cohort. CONCLUSION: Children with cleft palate appear to have a significant risk of SDB. A prospective study of a population of children with cleft palate is needed to further define the characteristics of this risk and important risk factors.

Active caspase-3 in the sudden infant death syndrome (SIDS) brainstem.

In a retrospective postmortem study, we examined the neuronal expression of active caspase-3, a specific apoptotic marker, in the brainstem of 67 infants dying from sudden infant death syndrome (SIDS), and 25 age-matched control infants (non-SIDS). Neuronal immunostaining for active caspase-3 was semi-quantitatively scored in nuclei from five brainstem levels: rostral, mid and caudal pons, and rostral and caudal medulla. Regardless of the cause of death (SIDS vs. non-SIDS), age-related differences in active caspase-3 expression were identified, predominantly in the medulla. No gender-related differences were identified. Comparing SIDS to non-SIDS cases, increased active caspase-3 expression was restricted to four nuclei in the caudal pons (abducens, facial, superior olivary, and pontine nuclei) and two nuclei in the rostral medulla (hypoglossal and dorsal motor nucleus of the vagus). We conclude that neuronal apoptosis is increased in the brainstem of SIDS compared to non-SIDS infants.

Outcome of noninvasive ventilation in children with neuromuscular disease.

OBJECTIVE: To assess the effect of institution of noninvasive ventilation (NIV) on clinical outcome and quality of life (QOL) in a cohort of children with severe neuromuscular disorders. METHODS: We reviewed records and obtained clinical data from the year prior to commencing NIV and annually thereafter. Data obtained included diagnosis, patient symptoms, mortality, NIV adverse effects, pulmonary function tests, polysomnographic data, length of hospitalizations, and health care costs. Patients and parents completed questionnaires assessing QOL with NIV and recalling QOL before NIV. RESULTS: Fourteen of 17 (82%) suitable patients were enrolled. Follow-up ranged from 6 to 84 months (median 30). Symptoms of daytime sleepiness (p = 0.003) and headache (p = 0.046) improved after initiation of NIV. Sleep quality assessed by polysomnography also improved. Hospitalization rates (p = 0.002) and health care costs (p = 0.003) decreased. QOL remained stable after NIV, despite disease progression. CONCLUSION: Treatment of respiratory failure, in children with neuromuscular disease, with noninvasive ventilation results in a reduction in symptoms, hospitalizations, and health care costs without adverse effects on quality of life.

N-methyl-D-aspartate receptor 1 changes in the piglet braintem after nicotine and/or intermittent hypercapnic-hypoxia.

Prone sleeping and cigarette smoke exposure are two major risk factors for the sudden infant death syndrome (SIDS). Utilizing piglet models of early postnatal nicotine and/or intermittent hypercapnic-hypoxia (IHH) exposure, we tested the hypothesis that these exposures, separately or combined, increase N-methyl-D-aspartate (NMDA) receptor 1 (NR1) expression in the brainstem medulla. We also tested for gender-specific effects. Three piglet exposure groups were compared against 14 controls; 1, nicotine [n = 14], 2, IHH [n = 10], and 3, nicotine+IHH [n = 14], with equal gender proportions in each group. Non-radioactive in situ hybridization and immunohistochemistry were performed for NR1 mRNA and protein expression, respectively, and were quantified in seven nuclei of the brainstem medulla. NR1 mRNA was significantly increased in the gracile and inferior olivary nucleus (ION) after nicotine exposure, in five of seven nuclei after IHH exposure, and in three of seven nuclei after nicotine+IHH. The increased mRNA changes were accompanied by increased protein only in the ION after IHH and nicotine+IHH (P = 0.019, and P = 0.008 respectively). By gender, control females had greater NR1 mRNA than males in the dorsal motor nucleus of vagus (P = 0.05) and for protein in the ION (P = 0.02). This gender difference was maintained after nicotine exposure in the ION with additional gender differences observed including greater mRNA in the cuneate nucleus (P = 0.04) and nucleus of the spinal trigeminal tract (P = 0.03) of males compared with females. Overall, more changes occurred at the mRNA level than protein, and IHH exposure induced more changes than nicotine or nicotine+IHH exposures. Together, these findings suggest that hypercapnic-hypoxic exposures (modeling prone sleeping or sleep apnea) are more likely to induce NMDA receptor changes in the developing brainstem than nicotine exposure alone.

Postnatal nicotine and/or intermittent hypercapnic hypoxia effects on apoptotic markers in the developing piglet brainstem medulla.

The most important risk factors currently identified for the sudden infant death syndrome (SIDS) are prone sleeping and cigarette smoke exposure. In this study, we investigated the neuropathological sequelae of these risk factors by exposing piglets to intermittent hypercapnic-hypoxia (IHH) and/or nicotine (nic) in the early postnatal period. Our hypothesis was that either nic or IHH exposure could increase neuronal cell death, and that combined exposure (nic+IHH) would be additive. Four exposure patterns were studied: controls (n=14), IHH (n=10), nic (n=14), and nic+IHH (n=14). All groups had equal gender ratios. Nic exposure via an implanted osmotic minipump commenced within 48 h of birth and continued until age 13-14 days when animals were killed and brains collected. A total of 48 min of hypercapnic-hypoxia was delivered on the day immediately prior to killing in a pattern comprising 6 min of HH (8% O(2), 7% CO(2), balance N(2)) alternating with 6 min of air. Immunohistochemistry was performed to identify neurons positive for active caspase-3 and DNA fragmentation (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, TUNEL) in seven nuclei of the caudal medulla. Staining quantification showed that: 1. IHH induced neuronal death (increased both TUNEL and casapse-3) in more brainstem nuclei than nicotine. 2. Females were more severely affected by IHH than males. 3. Where IHH and nicotine were combined, TUNEL expression was approximately 5% less than IHH alone, but changes in caspase-3 were variable. We conclude that acute exposure to IHH in the postnatal period is more neurotoxic than exposure to nicotine alone. Combined exposure to IHH and nicotine produced variable responses with some results suggesting that nicotine can be neuroprotective. These results indicate that environmental insults attributable to prone sleeping can produce neurotoxic sequelae in SIDS, with some regional specificity in the response. However, no consistent relationship is evident when combining the two insults.

Effects of postnatal nicotine exposure on apoptotic markers in the developing piglet brain.

Exposure to cigarette smoke is a risk factor for the sudden infant death syndrome (SIDS), but the ability to distinguish between the neuropathological effects of pre- versus postnatal exposure is limited in the clinical setting. To test whether postnatal nicotine exposure could contribute to the increased neuronal expression of apoptotic markers that we have previously observed in SIDS infants, as well as including study of gender influences, we developed a piglet model to mimic passive smoking in the early postnatal period. Piglets were exposed to nicotine (2 mg/kg/day infused via an implanted osmotic minipump) within 48 h of birth until the age of 13-14 days, when the brain was collected for study. Four piglet groups included: control females (n=7), control males (n=7), nicotine females (n=7), and nicotine males (n=7). Apoptotic markers included immunohistochemistry for activated caspase-3, and for DNA fragmentation or terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling (TUNEL) in seven nuclei of the brainstem caudal medulla and two subregions of the hippocampus (CA4 and dentate gyrus). Among control females compared with males, there was less active caspase-3 and less TUNEL in the dorsal motor nucleus of vagus (DMNV), and there was less TUNEL in the nucleus of the spinal trigeminal tract (NSTT). Compared with controls, nicotine-exposed male piglets had increased TUNEL staining in the cuneate nucleus (P=0.05), and increased active caspase-3 in the hypoglossal, gracile and dentate gyrus (P<0.05 for each). Nicotine-exposed females showed no change in TUNEL staining in any of the nuclei studied, but increased active caspase-3 in the hypoglossal, DMNV and NSTT (P<0.05 for each). These results show for the first time that postnatal nicotine exposure can lead to an increase in apoptotic markers in the brain. In piglets, these effects showed regional and gender-specific differences, suggesting that passive, postnatal nicotine exposure may be responsible for some neuropathological changes observed in infants dying from SIDS.

Correlations between brainstem NMDA receptor changes and active neuronal cell death after intermittent hypercapnic hypoxia in the developing piglet.

The role of the N-methyl-D-aspartate (NMDA) receptor in cell death was evaluated in the piglet brainstem after exposure to intermittent hypercapnic hypoxia (IHH). Study groups comprised controls (n=6) and piglets exposed to IHH on 2 (n=6) or 4 (n=5) successive days prior to euthanasia. All piglets had the caudal medulla evaluated at 13-14 days of age using double immunohistochemistry for TUNEL and the NMDA receptor 1 (NR1) subunit. The percent of TUNEL positive neurons amongst NR1 (% TUN in NR1) and non-NR1 neurons (% TUN in non-NR1) was determined in eight nuclei. After 2 days of IHH, %TUN in NR1 was increased in the dorsal motor nucleus of the vagus (DMNV, P=0.007) and the inferior olivary nucleus (ION, P=0.05). After 2 days IHH, %TUN in non-NR1 neurons was increased in the lateral reticular nucleus (LRt, P=0.05), nucleus of the solitary tract (NTS, P=0.004) and gracile nucleus (P=0.05). After 4days IHH, the increase of %TUN in NR1 was sustained in the ION (P=0.05), while %TUN in non-NR1 neurons was sustained in NTS (P=0.04) and LRt (P=0.006). Daily IHH exposure induces neuronal death within NR1 and non-NR1 neurons, but the neuronal phenotype is consistent within affected brainstem nuclei. Involvement of the NMDA receptor tended to occur in nuclei with higher basal NR1 expression, and thus occurred in nuclei relevant to cardiorespiratory function. We speculate that IHH exposures, such as occurs during obstructive apnea or facial entrapment in prone sleeping during infancy, can induce abnormalities of cardiorespiratory control.

Observer-blinded comparison of two nonopioid analgesics for postoperative pain in piglets.

Piglets are popular for studies of respiratory and cardiovascular function, but opioid analgesics are contraindicated in these studies because of central nervous system depression. We evaluated two nonopioid analgesics for postoperative pain relief following implantation of a central arterial catheter via an inguinal incision. Animals were randomly assigned to paracetamol-treated (n=8, rectal suppositories, 100 mg/kg) meloxicam-treated (n=8, 1 mg/kg meloxicam via the catheter) or untreated control group (n=8, placebo suppositories and normal saline). Additional controls received paracetamol or meloxicam, without pain (n=6 for both groups). Behavioral and physiological assessments, and blood sampling were undertaken at nine timed intervals until 24 h after surgery. Multifactorial numerical rating scale (NRS), behavioral and physiological pain scores (PPS) decreased over time for all groups (P<.001). On NRS and behavioral criteria, meloxicam was significantly better than paracetamol (P<.001), and both were better than control (p<.001 for each). Physiological parameters discriminated between the control and analgesia-treated groups, but not between paracetamol and meloxicam. Preliminary pharmacokinetics, determined by isocratic high-performance liquid chromatography (HPLC), revealed no difference in the half-life of paracetamol (2.5+/-0.3 h) vs. meloxicam (3.4+/-0.4 h). Paracetamol and meloxicam provided effective postoperative analgesia in piglets, with meloxicam superior to paracetamol on behavioral criteria.

Depression of ventilatory responses after daily, cyclic hypercapnic hypoxia in piglets.

Ventilatory responses (VRs) were measured via a sealed face mask and pneumotachograph in 30 unsedated, mixed-breed miniature piglets at 12.6 +/- 2.3 days of age (day 1) and then repeated after seven daily 24-min exposures to 10% O(2)-6% CO(2) [hypercapnic hypoxia (HH)]. Arterial blood was sampled at baseline, after 10 min of exposure, and after 10 min of recovery. VRs included hypoxia (10% O(2) in N(2)), hypercapnia (6% CO(2) in air), and HH (10% O(2)-6% CO(2)-balance N(2)). Treatment groups (n = 10 each) were exposed to 24 min of HH from day 2 to 8 as sustained HH (24 min of HH and then 24 min of air) or cyclic HH (4 min of HH alternating with 4 min of air). Day 1 and 9 data were compared in treatment and control groups. After cyclic HH, respiratory responses to CO(2) were reduced during hypercapnia and during HH (P < 0.001 vs. control for minute ventilation in both). In both treatment groups, time to peak minute ventilation was delayed in hypoxia (P = 0.02, ANOVA), and response amplitude was increased (P < 0.001 and P = 0.003, sustained and cyclic HH, respectively, vs. control). Respiratory pattern was also altered during the VRs and among treatment groups. Stimulus presentation characteristics exert effects on VRs that are independent of those elicited by daily HH.

Treatment of sleep-disordered breathing in children with myelomeningocele.

The prevalence of moderate to severe sleep-disordered breathing (SDB) in patients with myelomeningocele may be as high as 20%, but little information is available regarding treatment of these patients. To assess the efficacy and complications of treatments for these children, we collected data on 73 patients from seven pediatric sleep laboratories. Obstructive sleep apnea (OSA, n = 30) and central apnea (n = 25) occurred more frequently than central hypoventilation (n = 12). We also describe a sleep-exacerbated restrictive lung disease type of SDB in 6 patients who had hypoxemia during sleep without apnea or central hypoventilation. For each type of SDB, effective treatments were identified in a stepwise process, moving towards more complex and invasive therapies. For OSA, adenotonsillectomy was often ineffective (10/14), whereas nasal continuous positive airway pressure (CPAP) was usually successful (18/21). For central apnea, methylxanthines and/or supplemental oxygen proved sufficient in 2 of 9 and 3 of 6, respectively, but noninvasive positive pressure ventilation was required in 7 children. For central hypoventilation, supplemental oxygen (alone or with methylxanthines), noninvasive positive pressure ventilation, and tracheostomy with positive pressure ventilation were effective in 3, 2, and 2 patients, respectively. Sleep-exacerbated restrictive lung disease always required supplemental oxygen treatment, but in 2 cases also required noninvasive positive pressure ventilation; nutritional and orthopedic procedures also were helpful. Posterior fossa decompression was used for the first three types of SDB, but data were insufficient to delineate specific recommendations for or against its use. In summary, evaluation by an experienced, multidisciplinary team can establish an effective treatment regime for a child with myelomeningocele and SDB.

Site and mechanics of spontaneous, sleep-associated obstructive apnea in infants.

To examine the mechanics of infantile obstructive sleep apnea (OSA), airway pressures were measured using a triple-lumen catheter in 19 infants (age 1-36 wk), with concurrent overnight polysomnography. Catheter placement was guided by correlations between measurements of magnetic resonance images and body weight of 70 infants. The level of spontaneous obstruction was palatal in 52% and retroglossal in 48% of all events. Palatal obstruction predominated in infants treated for OSA (80% of events), compared with 38.6% from infants with infrequent events (P = 0.02). During obstructive events, successive respiratory efforts increased in amplitude (mean intrathoracic pressures -11.4, -15.0, and -20.4 cmH(2)O; ANOVA, P < 0.05), with arousal after only 29% of the obstructive and mixed apneas. The soft palate is commonly involved in the upper airway obstruction of infants suffering OSA. Postterm, infant responses to upper airway obstruction are intermediate between those of preterm infants and older children, with infrequent termination by arousal but no persisting "upper airway resistance" and respiratory efforts exceeding baseline during the event.

Nocturnal pulse oximetry as an abbreviated testing modality for pediatric obstructive sleep apnea.

OBJECTIVE: To determine the utility of pulse oximetry for diagnosis of obstructive sleep apnea (OSA) in children. METHODS: We performed a cross-sectional study of 349 patients referred to a pediatric sleep laboratory for possible OSA. A mixed/obstructive apnea/hypopnea index (MOAHI) greater than or equal to 1 on nocturnal polysomnography (PSG) defined OSA. A sleep laboratory physician read nocturnal oximetry trend and event graphs, blinded to clinical and polysomnographic results. Likelihood ratios were used to determine the change in probability of having OSA before and after oximetry results were known. RESULTS: Of 349 patients, 210 (60%) had OSA as defined polysomnographically. Oximetry trend graphs were classified as positive for OSA in 93 and negative or inconclusive in 256 patients. Of the 93 oximetry results read as positive, PSG confirmed OSA in 90 patients. A positive oximetry trend graph had a likelihood ratio of 19.4, increasing the probability of having OSA from 60% to 97%. The median MOAHI of children with a positive oximetry result was 16.4 (7.5, 30.2). The 3 false-positive oximetry results were all in the subgroup of 92 children who had diagnoses other than adenotonsillar hypertrophy that might have affected breathing during sleep. A negative or inconclusive oximetry result had a likelihood ratio of.58, decreasing the probability of having OSA from 60% to 47%. Interobserver reliability for oximetry readings was very good to excellent (kappa =.80). CONCLUSIONS: In the setting of a child suspected of having OSA, a positive nocturnal oximetry trend graph has at least a 97% positive predictive value. Oximetry could: 1) be the definitive diagnostic test for straightforward OSA attributable to adenotonsillar hypertrophy in children older than 12 months of age, or 2) quickly and inexpensively identify children with a history suggesting sleep-disordered breathing who would require PSG to elucidate the type and severity. A negative oximetry result cannot be used to rule out OSA.

Head turning and face-down positioning in prone-sleeping premature infants.

BACKGROUND: Term infants may die of sudden infant death syndrome (SIDS) when they assume the face-straight-down or the face-near-straight-down head positions. Preterm infants have a higher SIDS rate, but it is not known how often they assume the face-straight-down and face-near-straight-down positions. OBJECTIVES: To determine the frequency and cardiorespiratory consequences of head turning and face-down head positioning in prone-sleeping premature infants. STUDY DESIGN: Supervised overnight cardiorespiratory and audiovisual recordings were conducted in 15 prone-sleeping preterm infants nearing hospital discharge: birth weight, 1178 101 (SEM) g, postconceptional age, 40 1.0 weeks. RESULTS: The preterm infants, studied at a younger postconceptional age than previously reported term infants, seldom turned their heads during sleep; therefore they rarely assumed the face-straight-down position (6 episodes in 3 infants) or the face-near-straight-down position (30 episodes in 6 infants). CONCLUSIONS: Prematurely born infants, known to be at increased risk of SIDS, rarely assume face-down positions when sleeping prone at approximately 40 weeks' postconceptional age. These results suggest that head turning during sleep is developmentally regulated and may have relevance to understanding the age distribution of SIDS.