Raouf S. Amin

Sleep Apnea and Cardiovascular Disease

Sleep-related breathing disorders are highly prevalent in patients with established cardiovascular disease. Obstructive sleep apnea (OSA) affects an estimated 15 million adult Americans and is present in a large proportion of patients with hypertension and in those with other cardiovascular disorders, including coronary artery disease, stroke, and atrial fibrillation.1–14 In contrast, central sleep apnea (CSA) occurs mainly in patients with heart failure.15–19 The purpose of this Scientific Statement is to describe the types and prevalence of sleep apnea and its relevance to individuals who either are at risk for or already have established cardiovascular disease. Special emphasis is given to recognizing the patient with cardiovascular disease who has coexisting sleep apnea, to understanding the mechanisms by which sleep apnea may contribute to the progression of the cardiovascular condition, and to identifying strategies for treatment. This document is not intended as a systematic review but rather seeks to highlight concepts and evidence important to understanding the interactions between sleep apnea and cardiovascular disease, with particular attention to more recent advances in patient-oriented research. Implicit in this first American Heart Association/American College of Cardiology Scientific Statement on Sleep Apnea and Cardiovascular Disease is the recognition that, although holding great promise, this general area is in need of a substantially expanded knowledge base. Specific questions include whether sleep apnea is important in initiating the development of cardiac and vascular disease, whether sleep apnea in patients with established cardiovascular disease accelerates disease progression, and whether treatment of sleep apnea results in clinical improvement, fewer cardiovascular events, and reduced mortality. Experimental approaches directed at addressing these issues are limited by several considerations. First, the close association between obesity and OSA often obscures differentiation between the effects of obesity, the effects of OSA, and the effects of synergies between these conditions. Second, multiple comorbidities, …

Clinical Practice Guideline Tonsillectomy in Children

Objective Tonsillectomy is one of the most common surgical procedures in the United States, with more than 530 000 procedures performed annually in children younger than 15 years. Tonsillectomy is defined as a surgical procedure performed with or without adenoidectomy that completely removes the tonsil including its capsule by dissecting the peritonsillar space between the tonsil capsule and the muscular wall. Depending on the context in which it is used, it may indicate tonsillectomy with adenoidectomy, especially in relation to sleep-disordered breathing. This guideline provides evidence-based recommendations on the preoperative, intraoperative, and postoperative care and management of children 1 to 18 years old under consideration for tonsillectomy. In addition, this guideline is intended for all clinicians in any setting who interact with children 1 to 18 years of age who may be candidates for tonsillectomy. Purpose The primary purpose of this guideline is to provide clinicians with evidence-based guidance in identifying children who are the best candidates for tonsillectomy. Secondary objectives are to optimize the perioperative management of children undergoing tonsillectomy, emphasize the need for evaluation and intervention in special populations, improve counseling and education of families of children who are considering tonsillectomy for their child, highlight the management options for patients with modifying factors, and reduce inappropriate or unnecessary variations in care. Results The panel made a strong recommendation that clinicians should administer a single, intraoperative dose of intravenous dexamethasone to children undergoing tonsillectomy. The panel made a strong recommendation against clinicians routinely administering or prescribing perioperative antibiotics to children undergoing tonsillectomy. The panel made recommendations for (1) watchful waiting for recurrent throat infection if there have been fewer than 7 episodes in the past year or fewer than 5 episodes per year in the past 2 years or fewer than 3 episodes per year in the past 3 years; (2) assessing the child with recurrent throat infection who does not meet criteria in statement 2 for modifying factors that may nonetheless favor tonsillectomy, which may include but are not limited to multiple antibiotic allergy/intolerance, periodic fever, aphthous stomatitis, pharyngitis and adenitis, or history of peritonsillar abscess; (3) asking caregivers of children with sleep-disordered breathing and tonsil hypertrophy about comorbid conditions that might improve after tonsillectomy, including growth retardation, poor school performance, enuresis, and behavioral problems; (4) counseling caregivers about tonsillectomy as a means to improve health in children with abnormal polysomnography who also have tonsil hypertrophy and sleep-disordered breathing; (5) counseling caregivers that sleep-disordered breathing may persist or recur after tonsillectomy and may require further management; (6) advocating for pain management after tonsillectomy and educating caregivers about the importance of managing and reassessing pain; and (7) clinicians who perform tonsillectomy should determine their rate of primary and secondary posttonsillectomy hemorrhage at least annually. The panel offered options to recommend tonsillectomy for recurrent throat infection with a frequency of at least 7 episodes in the past year or at least 5 episodes per year for 2 years or at least 3 episodes per year for 3 years with documentation in the medical record for each episode of sore throat and 1 or more of the following: temperature >38.3°C, cervical adenopathy, tonsillar exudate, or positive test for group A β-hemolytic streptococcus.

A randomized trial of adenotonsillectomy for childhood sleep apnea.

BACKGROUND Adenotonsillectomy is commonly performed in children with the obstructive sleep apnea syndrome, yet its usefulness in reducing symptoms and improving cognition, behavior, quality of life, and polysomnographic findings has not been rigorously evaluated. We hypothesized that, in children with the obstructive sleep apnea syndrome without prolonged oxyhemoglobin desaturation, early adenotonsillectomy, as compared with watchful waiting with supportive care, would result in improved outcomes. METHODS We randomly assigned 464 children, 5 to 9 years of age, with the obstructive sleep apnea syndrome to early adenotonsillectomy or a strategy of watchful waiting. Polysomnographic, cognitive, behavioral, and health outcomes were assessed at baseline and at 7 months. RESULTS The average baseline value for the primary outcome, the attention and executive-function score on the Developmental Neuropsychological Assessment (with scores ranging from 50 to 150 and higher scores indicating better functioning), was close to the population mean of 100, and the change from baseline to follow-up did not differ significantly according to study group (mean [±SD] improvement, 7.1±13.9 in the early-adenotonsillectomy group and 5.1±13.4 in the watchful-waiting group; P=0.16). In contrast, there were significantly greater improvements in behavioral, quality-of-life, and polysomnographic findings and significantly greater reduction in symptoms in the early-adenotonsillectomy group than in the watchful-waiting group. Normalization of polysomnographic findings was observed in a larger proportion of children in the early-adenotonsillectomy group than in the watchful-waiting group (79% vs. 46%). CONCLUSIONS As compared with a strategy of watchful waiting, surgical treatment for the obstructive sleep apnea syndrome in school-age children did not significantly improve attention or executive function as measured by neuropsychological testing but did reduce symptoms and improve secondary outcomes of behavior, quality of life, and polysomnographic findings, thus providing evidence of beneficial effects of early adenotonsillectomy. (Funded by the National Institutes of Health; CHAT ClinicalTrials.gov number, NCT00560859.).

Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation

Background VX-809, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, has been shown to increase the cell surface density of functional F508del-CFTR in vitro. Methods A randomised, double-blind, placebo-controlled study evaluated the safety, tolerability and pharmacodynamics of VX-809 in adult patients with cystic fibrosis (n=89) who were homozygous for the F508del-CFTR mutation. Subjects were randomised to one of four VX-809 28 day dose groups (25, 50, 100 and 200 mg) or matching placebo. Results The type and incidence of adverse events were similar among VX-809- and placebo-treated subjects. Respiratory events were the most commonly reported and led to discontinuation by one subject in each active treatment arm. Pharmacokinetic data supported a once-daily oral dosing regimen. Pharmacodynamic data suggested that VX-809 improved CFTR function in at least one organ (sweat gland). VX-809 reduced elevated sweat chloride values in a dose-dependent manner (p=0.0013) that was statistically significant in the 100 and 200 mg dose groups. There was no statistically significant improvement in CFTR function in the nasal epithelium as measured by nasal potential difference, nor were there statistically significant changes in lung function or patient-reported outcomes. No maturation of immature F508del-CFTR was detected in the subgroup that provided rectal biopsy specimens. Conclusions In this study, VX-809 had a similar adverse event profile to placebo for 28 days in F508del-CFTR homozygous patients, and demonstrated biological activity with positive impact on CFTR function in the sweat gland. Additional data are needed to determine how improvements detected in CFTR function secondary to VX-809 in the sweat gland relate to those measurable in the respiratory tract and to long-term measures of clinical benefit. Clinical trial number NCT00865904

Activity-Adjusted 24-Hour Ambulatory Blood Pressure and Cardiac Remodeling in Children with Sleep Disordered Breathing

Questions remain as to whether pediatric sleep disordered breathing increases the risk for elevated blood pressure and blood pressure–dependent cardiac remodeling. We tested the hypothesis that activity-adjusted morning blood pressure surge, blood pressure load, and diurnal and nocturnal blood pressure are significantly higher in children with sleep disordered breathing than in healthy controls and that these blood pressure parameters relate to left ventricular remodeling. 24-hour ambulatory blood pressure parameters were compared between groups. The associations between blood pressure and left ventricular relative wall thickness and mass were measured. 140 children met the inclusion criteria. In children with apnea hypopnea index <5 per hour, a significant difference from controls was the morning blood surge. Significant increases in blood pressure surge, blood pressure load, and in 24-hour ambulatory blood pressure were evident in those whom the apnea hypopnea index exceeded 5 per hour. Sleep disordered breathing and body mass index had similar effect on blood pressure parameters except for nocturnal diastolic blood pressure, where sleep disordered breathing had a significantly greater effect than body mass index. Diurnal and nocturnal systolic blood pressure, diastolic blood pressure, and mean arterial blood pressure predicted the changes in left ventricular relative wall thickness. Therefore, sleep disordered breathing in children who are otherwise healthy is independently associated with an increase in morning blood pressure surge, blood pressure load, and 24-hour ambulatory blood pressure. The association between left ventricular remodeling and 24-hour blood pressure highlights the role of sleep disordered breathing in increasing cardiovascular morbidity.

Neuropsychological effects of pediatric obstructive sleep apnea.

Obstructive sleep apnea (OSA) is a fairly common nocturnal breathing disorder, affecting 2-4% of individuals. Although OSA is associated with medical morbidity, its most functionally disruptive effects in adults appear to be neuropsychological in nature. Research on the neuropsychological effects of pediatric OSA has been limited. This study compared the neuropsychological functioning of school-aged children with OSA to that of healthy children. The primary goal was to clarify the presence and pattern of neuropsychological morbidity associated with pediatric OSA. Sleep was assessed with parent-report questionnaires and laboratory sleep studies. Neuropsychological functioning was assessed by formal tests and parent- and teacher-report questionnaires. Data indicated OSA-related cognitive and behavioral impairment that was particularly marked on measures of behavior regulation and some aspects of attention and executive functioning. Minimal effects were observed on measures of intelligence, verbal memory, or processing speed. Exploratory analyses failed to indicate any clear relationship between neuropsychological functioning and objective indexes of hypoxia or sleep disruption, though the sample was small. These data add to a growing literature which suggests that significant neuropsychological deficits are associated with pediatric OSA. Findings suggest a pattern of neuropsychological morbidity that is similar but not identical to that seen in adult OSA.

Growth Velocity Predicts Recurrence of Sleep-disordered Breathing 1 Year after Adenotonsillectomy

RATIONALE Adenotonsillectomy, the first line of treatment of sleep-disordered breathing (SDB), is the most commonly performed pediatric surgery. Predictors of the recurrence of SDB after adenotonsillectomy and its impact on cardiovascular risk factors have not been identified. OBJECTIVES Demonstrate that gain velocity in body mass index (BMI) defined as unit increase in BMI/year confers an independent risk for the recurrence of SDB 1 year after adenotonsillectomy. METHODS Children with SDB and hypertrophy of the tonsils and a comparison group of healthy children were followed prospectively for 1 year. MEASUREMENTS AND MAIN RESULTS Serial polysomnographies, BMI, and blood pressure were obtained before adenotonsillectomy and 6 weeks, 6 months, and 1 year postoperatively. Gain velocity in BMI, BMI and being African American (odds ratios, 4-6/unit change/yr; 1.4/unit and 15, respectively) provided equal amounts of predictive power to the risk of recurrence of SDB. In the group that experienced recurrence, systolic blood pressure at 1 year was higher than at baseline and higher than in children who did not experience recurrence. CONCLUSIONS Three clinical parameters confer independent increased risk for high recurrence of SDB after adenotonsillectomy: gain velocity in BMI, obesity, and being African American. A long-term follow-up of children with SDB and monitoring of gain velocity in BMI are essential to identifying children at risk for recurrence of SDB and in turn at risk for hypertension.

The respiratory management of patients with duchenne muscular dystrophy: a DMD care considerations working group specialty article.

In 2001, the Muscular Dystrophy Community Assistance, Research and Education Amendments (MD‐CARE Act) was enacted, which directed federal agencies to coordinate the development of treatments and cures for muscular dystrophy. As part of the mandate, the Centers for Disease Control and Prevention (CDC) initiated surveillance and educational activities, which included supporting development of care considerations for Duchenne muscular dystrophy (DMD) utilizing the RAND/UCLA Appropriateness Method (RAM). This document represents the consensus recommendations of the projects 10‐member Respiratory Panel and includes advice on necessary equipment, procedures and diagnostics; and a structured approach to the assessment and management of the respiratory complications of DMD via assessment of symptoms of hypoventilation and identification of specific thresholds of forced vital capacity, peak cough flow and maximum expiratory pressure. The document includes a set of Figures adaptable as “pocket guides” to aid clinicians. This article is an expansion of the respiratory component of the multi‐specialty article originally appearing in Lancet Neurology, comprising respiratory recommendations from the CDC Care Considerations project. Pediatr. Pulmonol. 2010; 45:739–748.

Attention, learning, and arousal of experimentally sleep-restricted adolescents in a simulated classroom.

PURPOSE To experimentally test whether chronic sleep restriction, which is common among adolescents, is causally related to poor learning, inattentive behaviors, and diminished arousal in a classroom-like situation. METHODS Sixteen healthy adolescents underwent a sleep manipulation that included, in counterbalanced order, five consecutive nights of sleep deprivation (6½ hours in bed) versus five nights of healthy sleep duration (10 hours in bed). At the end of each condition, participants viewed educational films and took related quizzes in a simulated classroom. Eight participants also underwent video and electroencephalography monitoring to assess levels of inattentive behaviors and arousal, respectively. RESULTS As compared with the healthy sleep condition, sleep-deprived participants had lower quiz scores (p = .05), more inattentive behaviors (p < .05), and lower arousal (p = .08). CONCLUSIONS These pilot data complement previous correlational reports by showing that chronic sleep restriction during adolescence can cause inattention, diminished learning, and lowered arousal in a simulated classroom.

Feasibility and behavioral effects of an at-home multi-night sleep restriction protocol for adolescents.

BACKGROUND Sleep deprivation is common among adolescents and has been associated with adverse behavioral and educational outcomes. However, it is difficult to draw strong causal conclusions because of a dearth of experimental sleep research. In part, this appears related to methodological challenges when working with this population. This study tested the feasibility and behavioral effects of a multi-night, at-home experimental sleep restriction protocol in a sample of adolescents. METHODS Twenty healthy adolescents aged 13.9-16.9 years were enrolled in a three-week sleep manipulation protocol using a counterbalanced cross-over experimental design. The protocol included a baseline week, followed in random order by a short sleep week (Monday-Friday nights limited to 6.5 hours time in bed) and an extended sleep week (10 hours lights-out time in bed Monday-Friday nights). Sleep was monitored via self-report and objective actigraphy. These were reviewed with participants and parents on the Saturdays at the end of each week, when parents and participants also completed behavior rating questionnaires. RESULTS One participant dropped out of the study, but each of the remaining 19 displayed markedly less sleep in the short sleep condition than the extended sleep condition (average nightly gap approximately 2.5 hours). Data also reflected indirect effects of sleep deprivation that are consistent with an increase in homeostatic sleep drive. Compared to the extended sleep week, parents during the short sleep week reported that the participants displayed significantly greater problems with sleepiness, attention, oppositionality/irritability, behavior regulation, and metacognition. Participant self-report results were similar, though less robust. CONCLUSIONS A multi-night, at-home sleep manipulation protocol for use with adolescents is indeed feasible. This study also provided the first experimental evidence that chronic sleep restriction during adolescence is causally related to a wide range of behavioral deficits.