Ann C. Halbower

Effects of inhaled nitric oxide on pulmonary edema and lung neutrophil accumulation in severe experimental hyaline membrane disease.

To determine the effects of inhaled NO (iNO) on pulmonary edema and lung inflammation in experimental hyaline membrane disease (HMD), we measured the effects of iNO on pulmonary hemodynamics, gas exchange, pulmonary edema, and lung myeloperoxidase (MPO) activity in extremely premature lambs (115 d of gestation, 0.78 term). In protocol 1, we measured the effects of iNO (20 ppm) on lung vascular endothelial permeability to 125I-labeled albumin(indexed to blood volume using 57Cr-tagged red blood cells) during 1 h(n = 10) and 3 h (n = 14) of conventional mechanical ventilation with Fio2 = 1.00. In comparison with controls, iNO improved pulmonary hemodynamics and gas exchange, but did not alter lung weight-to-dry weight ratio or vascular permeability to albumin after 1 or 3 h of mechanical ventilation. To determine whether low dose iNO (5 ppm) would decrease lung neutrophil accumulation in severe HMD, we measured lung MPO activity after 4 h of mechanical ventilation with or without iNO (protocol 2). Low dose iNO improved gas exchange during 4 h of mechanical ventilation (Pao2 at 4 h: 119 ± 35 mm Hg iNO versus 41 ± 7 mm Hg control,p < 0.05), and reduced MPO activity by 79% (p < 0.05). We conclude that low dose iNO increases pulmonary blood flow, without worsening pulmonary edema, and decreases lung neutrophil accumulation in severe experimental HMD. We speculate that in addition to its hemodynamic effects, low dose iNO decreases early neutrophil recruitment and may attenuate lung injury in severe HMD.

Heterogeneous Pulmonary Phenotypes Associated With Mutations in the Thyroid Transcription Factor Gene NKX2-1

BACKGROUND Mutations in the gene encoding thyroid transcription factor, NKX2-1, result in neurologic abnormalities, hypothyroidism, and neonatal respiratory distress syndrome (RDS) that together are known as the brain-thyroid-lung syndrome. To characterize the spectrum of associated pulmonary phenotypes, we identified individuals with mutations in NKX2-1 whose primary manifestation was respiratory disease. METHODS Retrospective and prospective approaches identified infants and children with unexplained diffuse lung disease for NKX2-1 sequencing. Histopathologic results and electron micrographs were assessed, and immunohistochemical analysis for surfactant-associated proteins was performed in a subset of 10 children for whom lung tissue was available. RESULTS We identified 16 individuals with heterozygous missense, nonsense, and frameshift mutations and five individuals with heterozygous, whole-gene deletions of NKX2-1. Neonatal RDS was the presenting pulmonary phenotype in 16 individuals (76%), interstitial lung disease in four (19%), and pulmonary fibrosis in one adult family member. Altogether, 12 individuals (57%) had the full triad of neurologic, thyroid, and respiratory manifestations, but five (24%) had only pulmonary symptoms at the time of presentation. Recurrent respiratory infections were a prominent feature in nine subjects. Lung histopathology demonstrated evidence of disrupted surfactant homeostasis in the majority of cases, and at least five cases had evidence of disrupted lung growth. CONCLUSIONS Patients with mutations in NKX2-1 may present with pulmonary manifestations in the newborn period or during childhood when thyroid or neurologic abnormalities are not apparent. Surfactant dysfunction and, in more severe cases, disrupted lung development are likely mechanisms for the respiratory disease.

Effect of a High-Flow Open Nasal Cannula System on Obstructive Sleep Apnea in Children

OBJECTIVE: Obstructive sleep apnea syndrome in children is associated with significant morbidity. Continuous positive airway pressure (CPAP) treats obstructive apnea in children, but is impeded by low adherence. We, therefore, sought to assess the effect of warm humidified air delivered through an open nasal cannula (treatment with nasal insufflation [TNI]) on obstructive sleep apnea in children with and without adenotonsillectomy. METHODS: Twelve participants (age: 10 ± 1 years; BMI: 35 ± 14 kg/m2), with obstructive apnea-hypopnea syndrome ranging from mild to severe (2–36 events per hour) were administered 20 L/min of air through a nasal cannula. Standard sleep architecture, sleep-disordered breathing, and arousal indexes were assessed at baseline, on TNI, and on CPAP. Additional measures of the percentage of time with inspiratory flow limitation, respiratory rate, and inspiratory duty cycle were assessed at baseline and on TNI. RESULTS: TNI reduced the amount of inspiratory flow limitation, which led to a decrease in respiratory rate and inspiratory duty cycle. TNI improved oxygen stores and decreased arousals, which decreased the occurrence of obstructive apnea from 11 ± 3 to 5 ± 2 events per hour (P < .01). In the majority of children, the reduction in the apnea-hypopnea index on TNI was comparable to that on CPAP. CONCLUSIONS: TNI offers an alternative to therapy to CPAP in children with mild-to-severe sleep apnea. Additional studies will be needed to determine the efficacy of this novel form of therapy.

An Official American Thoracic Society Clinical Practice Guideline: Pediatric Chronic Home Invasive Ventilation.

BACKGROUND Children with chronic invasive ventilator dependence living at home are a diverse group of children with special health care needs. Medical oversight, equipment management, and community resources vary widely. There are no clinical practice guidelines available to health care professionals for the safe hospital discharge and home management of these complex children. PURPOSE To develop evidence-based clinical practice guidelines for the hospital discharge and home/community management of children requiring chronic invasive ventilation. METHODS The Pediatric Assembly of the American Thoracic Society assembled an interdisciplinary workgroup with expertise in the care of children requiring chronic invasive ventilation. The experts developed four questions of clinical importance and used an evidence-based strategy to identify relevant medical evidence. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to formulate and grade recommendations. RESULTS Clinical practice recommendations for the management of children with chronic ventilator dependence at home are provided, and the evidence supporting each recommendation is discussed. CONCLUSIONS Collaborative generalist and subspecialist comanagement is the Medical Home model most likely to be successful for the care of children requiring chronic invasive ventilation. Standardized hospital discharge criteria are suggested. An awake, trained caregiver should be present at all times, and at least two family caregivers should be trained specifically for the childs care. Standardized equipment for monitoring, emergency preparedness, and airway clearance are outlined. The recommendations presented are based on the current evidence and expert opinion and will require an update as new evidence and/or technologies become available.

Treatment alternatives for sleep-disordered breathing in the pediatric population

Purpose for review Childhood sleep-disordered breathing (SDB) is associated with a myriad of health problems that underscore the need for early diagnosis and treatment. Children with SDB present with behavior problems, deficits of general intelligence, learning and memory deficits, evidence of brain neuronal injury, increased cardiovascular risk, and poor quality of life. Children are in a rapid state of cognitive development; therefore, alterations of health and brain function associated with SDB could permanently alter a childs social and economic potential, especially if the disorder is not recognized early in life or is treated inadequately. Recent findings There is evidence that the majority of the problems associated with SDB improve with treatment. Treatment strategies are now being aimed at mechanisms underlying the disorder. There are multiple treatment options available to children; some are novel, with pending treatments on the horizon that may replace age-old therapies such as adenotonsillectomy or nasal positive pressure. Summary It is imperative that healthcare workers actively seek out signs and symptoms of SDB in patients to improve early detection and treatment for prevention of long-term morbidity.

A Lightweight and Inexpensive In-ear Sensing System For Automatic Whole-night Sleep Stage Monitoring

This paper introduces LIBS, a light-weight and inexpensive wearable sensing system, that can capture electrical activities of human brain, eyes, and facial muscles with two pairs of custom-built flexible electrodes each of which is embedded on an off-the-shelf foam earplug. A supervised non-negative matrix factorization algorithm to adaptively analyze and extract these bioelectrical signals from a single mixed in-ear channel collected by the sensor is also proposed. While LIBS can enable a wide class of low-cost self-care, human computer interaction, and health monitoring applications, we demonstrate its medical potential by developing an autonomous whole-night sleep staging system utilizing LIBSs outputs. We constructed a hardware prototype from off-the-shelf electronic components and used it to conduct 38 hours of sleep studies on 8 participants over a period of 30 days. Our evaluation results show that LIBS can monitor biosignals representing brain activities, eye movements, and muscle contractions with excellent fidelity such that it can be used for sleep stage classification with an average of more than 95% accuracy.

Continuous and fine-grained breathing volume monitoring from afar using wireless signals

In this work, we propose for the first time an autonomous system, called WiSpiro, that continuously monitors a persons breathing volume with high resolution during sleep from afar. WiSpiro relies on a phase-motion demodulation algorithm that reconstructs minute chest and abdominal movements by analyzing the subtle phase changes that the movements cause to the continuous wave signal sent by a 2.4 GHz directional radio. These movements are mapped to breathing volume, where the mapping relationship is obtained via a short training process. To cope with body movement, the system tracks the large-scale movements and posture changes of the person, and moves its transmitting antenna accordingly to a proper location in order to maintain its beam to specific areas on the frontal part of the persons body. It also incorporates interpolation mechanisms to account for possible inaccuracy of our posture detection technique and the minor movement of the persons body. We have built WiSpiro prototype, and demonstrated through a user study that it can accurately and continuously monitor users breathing volume with a median accuracy from 90% to 95.4% (or 0.0581 to 0.111 of error) to even in the presence of body movement. The monitoring granularity and accuracy are sufficiently high to be useful for diagnosis by clinical doctor.

Comparative meta-analysis of prazosin and imagery rehearsal therapy for nightmare frequency, sleep quality, and posttraumatic stress.

STUDY OBJECTIVE In this meta-analysis, we compare the short-term efficacy of prazosin vs. IRT on nightmares, sleep quality, and posttraumatic stress symptoms (PTSS). METHODS Reference databases were searched for randomized controlled trials using IRT or prazosin for nightmares, sleep disturbance, and/or PTSS. Effect sizes were calculated by subtracting the mean posttest score in the control group from the mean posttest score in the treatment group, and dividing the result by the pooled standard deviation of both groups. Mixed effects models were performed to evaluate effects of treatment characteristics, as well as sample characteristics (veteran vs. civilian) on treatment efficacy. RESULTS Four studies used prazosin, 10 used IRT alone or in combination with another psychological treatment, and 1 included a group receiving prazosin and another group receiving IRT. Overall effect sizes of both treatments were of moderate magnitude for nightmare frequency, sleep quality, and PTSS (p < 0.01). Effect size was not significantly different with type of treatment (psychological vs. pharmacological) on nightmare frequency (p = 0.79), sleep quality (p = 0.65), or PTSS, (p = 0.52). IRT combined with CBT for insomnia showed more improvement in sleep quality compared to prazosin (p = 0.03), IRT alone (p = 0.03), or IRT combined with another psychological intervention, (p < 0.01). CONCLUSION Although IRT interventions and prazosin yield comparable acute effects for the treatment of nightmares, adding CBT for insomnia to IRT seems to enhance treatment outcomes pertaining to sleep quality and PTSS. More randomized clinical trials with long-term follow-up are warranted. COMMENTARY A commentary on this article appears in this issue on page 9.

Heart rate variability during sleep in children with autism spectrum disorder

PurposeAutonomic dysfunction has been reported in autism spectrum disorders (ASD). Less is known about autonomic function during sleep in ASD. The objective of this study is to provide insight into the autonomic cardiovascular control during different sleep stages in ASD. We hypothesized that patients with ASD have lower vagal and higher sympathetic modulation with elevated heart rate, as compared to typical developing children (TD).MethodsWe studied 21 children with ASD and 23 TD children during overnight polysomnography. Heart rate and spectral parameters were calculated for each vigilance stage during sleep. Data from the first four sleep cycles were used to avoid possible effects of different individual sleep lengths and sleep cycle structures. Linear regression models were applied to study the effects of age and diagnosis (ASD and TD).ResultsIn both groups, HR decreased during non-REM sleep and increased during REM sleep. However, HR was significantly higher in stages N2, N3 and REM sleep in the ASD group. Children with ASD showed less high frequency (HF) modulation during N3 and REM sleep. LF/HF ratio was higher during REM. Heart rate decreases with age at the same level in ASD and in TD. We found an age effect in LF in REM different in ASD and TD.ConclusionOur findings suggest possible deficits in vagal influence to the heart during sleep, especially during REM sleep. Children with ASD may have higher sympathetic dominance during sleep but rather due to decreased vagal influence.

Respiratory and polysomnographic values in 3-to 5-year-old normal children at higher altitude

STUDY OBJECTIVES To determine polysomnographic parameter differences in children living at higher altitude to children living near sea level. DESIGN AND SETTING Prospective study of non-snoring, normal children recruited from various communities around Denver, CO. In-lab, overnight polysomnograms were performed at a tertiary care childrens hospital. All children required residence for greater than one year at an elevation around 1,600 meters. PARTICIPANTS 45 children (62% female), aged 3-5 years, 88.9% non-Hispanic white with average BMI percentile for age of 47.8% ± 30.7%. MEASUREMENTS AND RESULTS Standard sleep indices were obtained and compared to previously published normative values in a similar population living near sea level (SLG). In the altitude group (AG), the apnea-hypopnea index was 1.8 ± 1.2 and the central apnea-hypopnea index was 1.7 ± 1.1, as compared to 0.9 ± 0.8 and 0.8 ± 0.7, respectively, (P ≤ 0.005) in SLG. Mean end-tidal CO2 level in AG was 42.3 ± 3.0 mm Hg and 40.6 ± 4.6 mm Hg in SLG (P = 0.049). The ≥ 4% desaturation index was 3.9 ± 2.0 in AG compared to 0.3 ± 0.4 in SLG (P < 0.001). Mean periodic limb movement in series index was 10.1 ± 12.3 in AG and 3.6 ± 5.4 in SLG (P = 0.001). CONCLUSION Comparison of altitude and sea level sleep studies in healthy children reveals significant differences in central apnea, apneahypopnea, desaturation, and periodic limb movement in series indices. Clinical providers should be aware of these differences when interpreting sleep studies and incorporate altitude-adjusted normative values in therapeutic-decision making algorithms.