Iris A. Perez

Peripheral chemoreceptors in congenital central hypoventilation syndrome.

Congenital central hypoventilation syndrome is a rare disorder caused by a mutation in the PHOX2B gene resulting in hypoventilation that is worse during sleep. Human physiologic studies show that patients with CCHS have absent or decreased rebreathing ventilatory responses to hypercapnia and hypoxemia during sleep as well as during wakefulness. Some ventilatory responses to hypoxia and hyperoxia can be demonstrated using a step change in inspired oxygen. However, these suggest that both central and peripheral chemoreceptor functions are generally defective in all states in children with CCHS. The defect in CCHS may lie in central nervous system pathways regulating ventilation, whose development and function are controlled by PHOX2B. Moreover, the retrotrapezoid nucleus (RTN) may be the major defect in CCHS, where central and peripheral inputs converge. Human physiological studies predicted that the defect in CCHS lies in central integration of the central and peripheral chemoreceptor signals. New evidence suggests the RTN may be the respiratory controller where chemoreceptor inputs are integrated. In this review we present the clinical presentation of CCHS, revisit results of human physiologic studies, and discuss the findings in light of new knowledge about the role of PHOX2B and RTN in CCHS.

Diuretics and Chronic Lung Disease of Prematurity

Babies leaving today’s neonatal nurseries with chronic lung disease of prematurity (CLD) are very different to those initial survivors followed by Northway et al. The definition of the disease has changed; most now consider an oxygen requirement beyond 36 weeks post conceptional age to be a more important defining criterion than the 28 days of oxygen dependency used initially for bronchopulmonary dysplasia. Early stages of the disease are associated with alveolar and interstitial edema, which could reduce lung compliance as well as increase airway resistance by narrowing terminal airways. Diuretic administration could improve pulmonary mechanics by three mechanisms: (1) immediate diuresis independent reabsorption of lung fluid, (2) decrease in bronchospasm in patients with reactive airway disease, and (3) reabsorption of lung fluid mediated by a decrease in extracellular volume secondary to increased diuresis. – 6 The first two mechanisms may occur during systemic or aerosolized administration, whereas the third mechanism requires systemic absorption or administration. Potential complications of diuretic use – 6 include patent ductus arteriosus ( furosemide), nephrocalcinosis, osteopenia, hearing loss, hypovolemia, hypotension, and electrolyte and acid base disturbances. When treatment is given for CLD, the crucial clinical question is whether it will affect longterm prognosis. Key outcomes might include mortality, duration of ventilation, and overall duration of oxygen therapy. We have recently concluded three systematic reviews of the use of diuretics in infants with oxygen or ventilator dependency secondary to lung disease beyond 5 days of age. – 6 We only considered randomized trials that assessed effects of diuretics on one of predetermined outcome variables. Primary outcome variables included changes in need for respiratory support and oxygen supplementation, mortality, oxygen dependency at 28 days or 36 weeks, length of stay, and number of hospitalizations during the first year of life. The complete list of eligible randomized trials and details of selection criteria and methods of analyses are all available at {http: / /www.nichd.nih.gov/cochraneneonatal}. Despite the widespread use of diuretics in CLD, there have been surprisingly few randomised clinical trials of their clinical safety or efficacy. The 20 eligible studies used very variable outcome measures, and most concentrated on short term physiological measures such as pulmonary mechanics. Only three of the studies extended beyond 8 days duration: two compared thiazide and spironolactone to placebo, and a third evaluated the addition of spironolactone to thiazide treatment. The studies spanned a 16-year period, during which the pattern of disease and survival in preterm infants have changed, and the assumptions made to calculate summary statistics from the often limited data available may have underestimated real differences between treatments. Furthermore, virtually no data are available about longterm morbidity due to side effects, such as nephrocalcinosis and bone mineral washout.

The Snoring Child

Snoring is a common manifestation of obstructive sleep apnea and represents one end of the spectrum of sleep-related breathing disorders. Children with primary snoring initially may develop OSAS later, so inquiring about symptoms of OSAS should be part of each visit. Obstructive sleep apnea can result in serious cardiovascular and metabolic consequences and neurocognitive deficits. Adenotonsillar hypertrophy remains the most common cause of OSA although the rising prevalence of obesity is of increasing importance. Polysomnography remains the gold standard in the diagnoses of OSAS and in assessing the risks associated with surgery. Most children with OSAS can be treated with adenotonsillectomy in the ambulatory surgery center. However, there are children at risk for severe OSAS and for postoperative complications, who will need PICU care. In addition to adenotonsillectomy, OSAS can be treated successfully in referral centers with other surgical approaches and by the use of positive airway pressure. Children with obesity-related OSAS often require CPAP or BPAP for control of OSAS.

Diaphragm Pacing without Tracheostomy in Congenital Central Hypoventilation Syndrome Patients.

Background: Congenital central hypoventilation syndrome (CCHS) is a rare disorder affecting central control of breathing. Thus, patients require lifelong assisted ventilation. Diaphragm pacing (DP) may permit decannulation in those who are ventilator dependent only during sleep. Objective: The purpose of this study is to determine if patients with CCHS can be successfully ventilated by DP without tracheostomy. Methods: We reviewed the records of 18 CCHS patients (mean age 19.5 ± 10.1 years; 44% female) who were ventilated by DP only during sleep. Results: Prior to diaphragm pacer implantation surgery, 14 CCHS patients had been using home portable positive pressure ventilation (PPV) via tracheostomy, 1 had been on PPV via endotracheal tube, and 3 had been using noninvasive PPV (NPPV). Of the patients with tracheostomy prior to DP (n = 15), 11 (73%) were decannulated and ventilated successfully by DP without tracheostomy. Of all the patients reviewed (n = 18), 13 (72%) were successfully ventilated by DP without tracheostomy. Obesity prevented successful DP without tracheostomy in 1 patient, and upper airway obstruction prevented success in another patient. Snoring and/or obstructive apneas were present in some patients, but they were improved by diaphragm pacer changes, adenotonsillectomy, and/or use of nasal steroids. Conclusions: DP without tracheostomy can be successfully achieved in patients with CCHS. Snoring and obstructive apneas, when present, can be managed by diaphragm pacer changes and medical therapies. Obesity can pose a challenge to successful DP.

Thoracoscopic pneumonectomy for severe bronchiectasis in a 9-year-old female.

INTRODUCTION Thoracoscopic total pneumonectomy has not been previously described in the pediatric surgical literature. In this paper, we describe a case of pneumonectomy performed through a minimally invasive approach in a 9-year-old female with Downs syndrome and gastroesophageal reflux disease. CASE REPORT The patient suffered from multiple recurrent aspiration pneumonias, which progressed to bronchiectasis of the entire left lung. As a result, the patient was hypoxemic and required continuous supplemental oxygen. Preoperative perfusion scans showed diminished perfusion of the left lung. Thoracoscopy was performed by using 3-5 mm trocars and one 12-mm trocar. Insufflation pressure was maintained at 5 mm Hg. Dissection was performed at the hilum by using hook electrocautery and the LigaSure device (ValleyLab, Boulder, CO). The pulmonary artery, veins, and left mainstem bronchus were sequentially divided by using a 35-mm ENDO GIA vascular stapler (Ethicon Endo-Surgery, Cincinnati, OH). There were no intraoperative complications. Eight months following surgery, her health is improved and she no longer requires supplemental oxygen. CONCLUSION Thoracoscopic pneumonectomy is a safe, technically feasible approach for severe bronchiectasis in children.

Thoracoscopic placement of phrenic nerve pacers for diaphragm pacing in congenital central hypoventilation syndrome

PURPOSE Congenital central hypoventilation syndrome (CCHS), or Ondines curse, is a rare disorder affecting central respiratory drive. Patients with this disorder fail to ventilate adequately and require lifelong ventilatory support. Diaphragm pacing is a form of ventilatory support which can improve mobility and/or remove the tracheostomy from CCHS patients. Little is known about complications and long-term outcomes of this procedure. METHODS A single-center retrospective review was performed of CCHS patients undergoing placement of phrenic nerve electrodes for diaphragm pacing between 2000 and 2012. Data abstracted from the medical record included operation duration, ventilation method, number of trocars required, and postoperative and pacing outcomes. RESULTS Charts of eighteen patients were reviewed. Mean surgical time was 3.3±0.7 hours. In all cases except one, three trocars were utilized for each hemithorax, with no conversions to open procedures. Five patients (27.8%) experienced postoperative complications. The mean ICU stay was 4.3±0.5 days, and the mean hospital stay is 5.7±0.3days. Eleven patients (61.1%) achieved their daily goal pacing times within the follow-up period. CONCLUSIONS Thoracoscopic placement of phrenic nerve electrodes for diaphragmatic pacing is a safe and effective treatment modality for CCHS. Observed complications were temporary, and the majority of patients were able to achieve pacing goals.

Three-Generation Family With Congenital Central Hypoventilation Syndrome and Novel PHOX2B Gene Non-Polyalanine Repeat Mutation

ABSTRACT PHOX2B non-polyalanine repeat mutation (NPARM) in patients with congenital central hypoventilation syndrome (CCHS) is generally considered to be associated with full-time ventilator dependence and severe autonomic nervous system dysfunction. We report a three-generation family with four individuals possessing a novel PHOX2B NPARM (c.245C > T) with variable phenotypes. This mutation was inherited in an autosomal dominant pattern with variable penetrance. The affected family members with CCHS have a milder phenotype than is typically expected with a NPARM. Two family members are ventilator dependent only during sleep and do not have Hirschsprung disease or neural crest tumors. One family member was asymptomatic until systemic hypertension developed during adulthood and another family member remains asymptomatic as an adult. Our findings emphasize the importance of monitoring adults with a PHOX2B NPARM who are considered asymptomatic in childhood.

Obstructive Sleep Apnea in Patients With Congenital Central Hypoventilation Syndrome Ventilated by Diaphragm Pacing Without Tracheostomy

STUDY OBJECTIVES To determine presence of obstructive sleep apnea (OSA) in patients with congenital central hypoventilation syndrome (CCHS) ventilated by diaphragm pacing (DP) without tracheostomy, and to determine if OSA can be improved by DP setting changes. METHODS We reviewed polysomnography (PSG) results of 15 patients with CCHS from October 2001 to April 2014, age 15.4 ± 7.8 years, body mass index 22.0 ± 6.0 kg/m2, and 60% female. RESULTS Of the 22 PSG results obtained for the 15 patients with CCHS, 9 were performed with tracheostomy capped, and 13 were performed after patients underwent decannulation. OSA was present on 6 of 9 tests in patients with tracheostomy capped, including 3 patients with immediate, severe OSA necessitating that the studies be completed with tracheostomy uncapped. OSA was present on 2 of 13 tests in patients in whom decannulation had been performed. Hypoventilation was seen on only one test without OSA. On 2 of 5 tests showing OSA, OSA improved by decreasing DP amplitude settings; apnea-hypopnea index decreased from 11.1 ± 2.5 to 1.8 ± 2.5 events/h; PETCO2 decreased from 57.5 ± 3.5 to 38.5 ± 0.7 torr; SpO2 increased from 76.5 ± 0.7% to 93.0 ± 7.1%. OSA improved in one patient with slight increase in respiratory rate. Settings were manipulated in 4 tests showing OSA; no changes were attempted in the remaining study. One patient was placed on bilevel positive airway pressure with temporary suspension of DP. Age (P < .119), previous adenotonsillectomy (P < .211), and body mass index (P < .112) did not significantly contribute to OSA. CONCLUSIONS OSA occurs in patients with CCHS ventilated by DP. However, decreasing DP amplitude settings can lessen upper airway obstruction without compromising gas exchange.

Congenital central hypoventilation syndrome: diagnosis and management

ABSTRACT Introduction: Congenital central hypoventilation syndrome (CCHS) is a rare disorder defined by a failure in autonomic control of breathing secondary to mutations of the PHOX2B gene. Affected individuals demonstrate absent or diminished physiologic response to hypercapnia and hypoxia that is most severe during sleep as well as multi-system dysregulation of autonomic functions. Areas covered: In this review, we will discuss how evaluation of the disease-defining PHOX2B gene aids diagnosis and helps prognosticate disease severity, review disease physiology, describe clinical presentation and various aspects of autonomic nervous system dysregulation, review ventilatory strategies, and highlight current challenges in the care of these complex patients. Expert commentary: CCHS is a rare disorder that requires a high degree of vigilance. PHOX2B mutation is essential for diagnosis and also helps direct disease management. There is currently no pharmacologic treatment proven effective in improving disease-related hypoventilation and care is focused on providing adequate ventilatory support and managing autonomic dysfunction.

Disorders of Sleep and Ventilatory Control in Prader-Willi Syndrome

Prader-Willi syndrome (PWS) is an imprinted genetic disorder conferred by loss of paternal gene expression from chromosome 15q11.2-q13. Individuals with PWS have impairments in ventilatory control and are predisposed toward sleep disordered breathing due to a combination of characteristic craniofacial features, obesity, hypotonia, and hypothalamic dysfunction. Children with PWS progress from failure to thrive during infancy to hyperphagia and morbid obesity during later childhood and onward. Similarly, the phenotype of sleep disordered breathing in PWS patients also evolves over time from predominantly central sleep apnea in infants to obstructive sleep apnea (OSA) in older children. Behavioral difficulties are common and may make establishing effective therapy with continuous positive airway pressure (CPAP) more challenging when OSA persists after adenotonsillectomy. Excessive daytime sleepiness (EDS) is also common in patients with PWS and may continue after OSA is effectively treated. We describe here the characteristic ventilatory control deficits, sleep disordered breathing, and excessive daytime sleepiness seen in individuals with PWS. We review respiratory issues that may contribute to sudden death events in PWS patients during sleep and wakefulness. We also discuss therapeutic options for treating sleep disordered breathing including adenotonsillectomy, weight loss, and CPAP. Lastly, we discuss the benefits and safety considerations related to growth hormone therapy.