Diagnosis and Management of Acute Respiratory Failure.

Acute hypoxemic respiratory failure is defined by Pao2 less than 60 mm Hg or SaO2 less than 88% and may result from V/Q mismatch, shunt, hypoventilation, diffusion limitation, or low inspired oxygen tension. Acute hypercapnic respiratory failure is defined by Paco2 ≥ 45 mm Hg and pH less than 7.35 and may result from alveolar hypoventilation, increased fraction of dead space, or increased production of carbon dioxide. Early diagnostic maneuvers, such as measurement of SpO2 and arterial blood gas, can differentiate the type of respiratory failure and guide next steps in evaluation and management.

Characteristics and outcomes in children with congenital central hypoventilation syndrome on long-term mechanical ventilation in the Netherlands.

Congenital central hypoventilation syndrome (CCHS) is a rare condition characterized by central hypoventilation, leading to the majority of patients being dependent on ventilatory support during sleep. This condition is often accompanied by various associated symptoms, due to a PHOX2B gene variant involved in neuronal crest cell migration. This study is the first to review the characteristics and outcomes in children with CCHS on long-term mechanical ventilation in the Netherlands. We performed a retrospective study of all CCHS patients treated in the 4 Centers of Home Mechanical Ventilation of the University Medical Centers in the Netherlands from 2000 till 2022 by collecting information from the electronic medical records, documented during follow-up. We included 31 patients, out of which 27 exhibited a known genetic profile associated with CCHS, while no PHOX2B variant was identified in the remaining patients. Among the 27 patients with known genetic profiles, 10 patients had a non-polyalanine repeat expansion mutation (NPARM), followed by 20/27, 20/25, and 20/26 polyalanine repeat expansion mutations (PARMs) in descending order. The most common presentation involved respiratory failure or apneas during the neonatal period with an inability to wean off ventilation. The majority of patients required ventilatory support during sleep, with four patients experiencing life-threatening events related to this dependency. Daily use of ventilatory support varied among different genetic profiles. All genotypes reported comorbidities, with Hirschsprung's disease and cardiac arrhythmias being the most reported comorbidities. Notably, Hirschprung's disease was exclusively observed in patients with a 20/27 PHOX2B variant. CONCLUSION: Our study results suggest that in our cohort, the genotype is not easily associated to the phenotype in CCHS. Consistent with these findings and international literature, we recommend a thorough annual evaluation for all patients with CCHS to ensure optimal management and follow-up. WHAT IS KNOWN: • The majority of CCHS patients are dependent on ventilatory support. • Variants in the PHOX2B gene are responsible for the characteristics of CCHS. WHAT IS NEW: • This study provides insight into the clinical course and long-term outcomes of CCHS patients in the Netherlands. • In CCHS, the genotype is not easily associated with the phenotype, requiring a thorough life-long follow-up for all patients.

Images: Atypical presentation of congenital central hypoventilation syndrome in an infant with central and obstructive sleep apnea.

Congenital central hypoventilation syndrome (CCHS), a rare disease caused by paired-like homeobox 2B variants, affects control of breathing. We report on a 21-month-old boy with CCHS caused by a novel nonpolyalanine repeat mutation, neuroblastoma, severe obstructive and central sleep apnea, and sleep-related hypoxemia without hypoventilation. At 10 months, due to persistent central sleep apnea during serial polysomnography, bilevel positive airway pressure therapy was initiated despite the absence of hypoventilation. Nonpolyalanine repeat mutations are associated with severe phenotypes requiring continuous assisted ventilation, Hirschsprung's disease, and neural crest tumors; however, our patient had a relatively milder respiratory phenotype requiring sleep-only assisted ventilation without tracheostomy. Although alveolar hypoventilation is the hallmark of CCHS, our patient lacked hypoventilation. Bilevel positive airway pressure could be considered in some infants with CCHS requiring sleep-only assisted ventilation for tracheostomy avoidance. Our case demonstrates the expanding phenotypic spectrum in CCHS and the importance of formulating an individualized care plan. CITATION: Fain ME, Raghunandan S, Pencheva B, Leu RM, Kasi AS. Images: atypical presentation of congenital central hypoventilation syndrome in an infant with central and obstructive sleep apnea. J Clin Sleep Med. 2024;20(3):478-481.

Sleep in pediatric neuromuscular disorders.

Sleep disordered breathing (SDB) is prevalent among children with neuromuscular disorders (NMD). The combination of respiratory muscle weakness, altered drive, and chest wall distortion due to scoliosis make sleep a stressful state in this population. Symptomatology can range from absent to snoring, nocturnal awakenings, morning headaches, and excessive daytime sleepiness. Sequelae of untreated SDB includes cardiovascular effects, metabolic derangements, and neurocognitive concerns which can be compounded by those innate to the NMD. The clinician should have a low threshold for obtaining polysomnography and recognize the nuances of individual disorders due to disproportionately impacted muscle groups such as hypoventilation in ambulating patients from diaphragm weakness. Non-invasive or invasive ventilation are the mainstay of treatment. In this review we explore the diagnosis and treatment of SDB in children with various NMD.

Effect of Facemask in Congenital Central Hypoventilation Syndrome.

INTRODUCTION: Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder with a mutation in the PHOX2B gene. Patients need ventilatory support by noninvasive ventilation or tracheostomy to treat alveolar hypoventilation. Patients with CCHS have a defect in chemosensitivity signal integration. Recently, due to the COVID-19 pandemic, the entire world has had to get used to wearing medical masks (MM). OBJECTIVES: The aim of the study was to evaluate the effect of an MM on gas exchange and to determine the role of central and peripheral chemoresponsiveness on the partial pressure of transcutaneous carbon dioxide (PtcCO2) in patients with CCHS wearing an MM. METHODS: This study was based on the analysis of recordings obtained without and with an MM during hospitalization and was conducted to assess the impact of MM on PtcCO2 and SpO2 recordings with the SenTec Digital Monitor and their relationships with peripheral CO2 chemosensitivity obtained during tidal breathing measurement and with the hypercapnic hyperoxic ventilatory response. RESULTS: Sixteen patients were included (13 boys) and were 10.2 (7.5; 18.5) years old. The use of an MM had a negative impact on gas exchange in patients with CCHS. The median PtcCO2 increased significantly. Peripheral chemosensitivity correlated with MM-induced PtcCO2 changes (R = -0.72, p = 0.005), but central chemosensitivity (the hypercapnic ventilator response slope) did not (R = -0.22, p = 0.510). CONCLUSION: The use of an MM had a negative impact on gas exchange in patients with CCHS.

Indications and evidence for domiciliary noninvasive ventilation.

INTRODUCTION: Home noninvasive ventilation (HNIV) has expanded globally, with a greater evidence base for its use. HNIV improves multiple patient related outcomes in patients with chronic hypercapnic respiratory failure. Obesity hypoventilation syndrome (OHS) is rapidly taking over as the primary indication for HNIV and COPD patients who overlap with obstructive sleep apnea hypoventilation syndromes (OSAHS) and are increasingly recognized but add to the complexity of HNIV prescribing. Optimal settings vary for differing diseases, with higher inspiratory pressures often required in those with OHS and COPD, yet which settings translate into greatest patient benefit remains unknown. AREAS COVERED: We cover the evidence base underpinning the common indications for HNIV in COPD, OHS, neuromuscular disease (NMD), and chest wall disease (CWD) and highlight common HNIV modes used. EXPERT OPINION: Active screening for nocturnal hypoventilation in OHS and COPD may be important to guide earlier ventilation. Further research on which HNIV modalities best improve patient related outcomes and the right time for initiation in different patient phenotypes is rapidly needed. Worldwide, clinical research trials should aim to bridge the gap by reporting on patient-related outcomes and cost effectiveness in real-world populations to best understand the true benefit of HNIV amongst heterogenous patient populations.

[Two children with late-onset congenital central hypoventilation syndrome].

Two children with late-onset congenital central hypoventilation syndrome were reported, one of whom was male and had no abnormal manifestations after birth, respiratory failure occurs at the age of 1 year and 6 months. After being hospitalized, he was treated with oxygen inhalation and non-invasive ventilation, but carbon dioxide retention could not be corrected. After one month of tracheal intubation, he was failure to wean from ventilator, so tracheostomy was performed. He needs a ventilator to help breath while sleeping, and can breath autonomously during the day without ventilator. The other case was a female, with no abnormalities after birth. At the age of 11 months, she developed respiratory failure. During sleep, the child needs non-invasive assisted ventilation through a nasal mask, and during the day, she breathed autonomously.Two patients were followed up forever 2 years and their growth and development were normal.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD): a collaborative review of the current understanding.

PURPOSE: To provide an overview of the discovery, presentation, and management of Rapid-onset Obesity with Hypothalamic dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD). To discuss a search for causative etiology spanning multiple disciplines and continents. METHODS: The literature (1965-2022) on the diagnosis, management, pathophysiology, and potential etiology of ROHHAD was methodically reviewed. The experience of several academic centers with expertise in ROHHAD is presented, along with a detailed discussion of scientific discovery in the search for a cause. RESULTS: ROHHAD is an ultra-rare syndrome with fewer than 200 known cases. Although variations occur, the acronym ROHHAD is intended to alert physicians to the usual sequence or unfolding of the phenotypic presentation, including the full phenotype. Nearly 60 years after its first description, more is known about the pathophysiology of ROHHAD, but the etiology remains enigmatic. The search for a genetic mutation common to patients with ROHHAD has not, to date, demonstrated a disease-defining gene. Similarly, a search for the autoimmune basis of ROHHAD has not resulted in a definitive answer. This review summarizes current knowledge and potential future directions. CONCLUSION: ROHHAD is a poorly understood, complex, and potentially devastating disorder. The search for its cause intertwines with the search for causes of obesity and autonomic dysregulation. The care for the patient with ROHHAD necessitates collaborative international efforts to advance our knowledge and, thereby, treatment, to decrease the disease burden and eventually to stop, and/or reverse the unfolding of the phenotype.

Decannulation in congenital central hypoventilation syndrome.

RATIONALE: Patients with congenital central hypoventilation syndrome (CCHS) require long-term ventilation to ensure gas exchange and to prevent deleterious consequences for neurocognitive development. Two ventilation modes may be used for these patients depending on their tolerance, one invasive by tracheostomy and the other noninvasive (NIV). For patients who have undergone a tracheostomy, transition to NIV is possible when they meet predefined criteria. Identifying the conditions favorable for weaning from a tracheostomy is critical for the success of the process. OBJECTIVE: The aim of the study was to share our experience of decannulation in a reference center; we hereby describe the modality of ventilation and its effect on nocturnal gas exchange before and after tracheostomy removal. METHODS: Retrospective observational study at Robert Debré Hospital over the past 10 years. The modalities of decannulation and transcutaneous carbon dioxide recordings or polysomnographies before and after decannulation were collected. RESULTS: Sixteen patients underwent decannulation following a specific procedure for transition from invasive to NIV. All decannulations were successful. The median age at decannulation was 12.6 [9.4; 14.1] years. Nocturnal gas exchange was not significantly different before and after decannulation, while expiratory positive airway pressure and inspiratory time increased significantly. An oronasal interface was chosen in two out of three patients. The median duration of hospital stay for decannulation was 4.0 [3.8; 6.0] days. CONCLUSION: Our study underlines that decannulation and transition to NIV are achievable in CCHS children using a well-defined procedure. Patient preparation is crucial to the success of the process.

Permissive hypoventilation equally effective to maintain oxygenation as positive pressure ventilation after porcine class III hemorrhage and whole blood resuscitation.

BACKGROUND: Prehospital anesthesia may lead to circulatory collapse after severe hemorrhage. It is possible that permissive hypoventilation, refraining from tracheal intubation and accepting spontaneous ventilation, decreases this risk, but it is not known if oxygen delivery can be maintained. We investigated the feasibility of permissive hypoventilation after class III hemorrhage and whole blood resuscitation in three prehospital phases: 15 min on-scene, 30 min whole blood resuscitation, and 45 min after. STUDY DESIGN AND METHODS: 19 crossbred swine, mean weight 58.5 kg, were anesthetized with ketamine/midazolam and hemorrhaged to a mean (SD) 1298 (220) mL (33%) and randomized to permissive hypoventilation (n = 9) or positive pressure ventilation with FiO2 21% (n = 10). RESULTS: In permissive hypoventilation versus positive pressure ventilation, indexed oxygen delivery (DO2 I) decreased to mean (SD) 4.73 (1.06) versus 3.70 (1.13) mL min-1 kg-1 after hemorrhage and increased to 8.62 (2.09) versus 6.70 (1.56) mL min-1 kg-1 at completion of resuscitation. DO2 I, indexed oxygen consumption (VO2 I), and arterial saturation (SaO2 ) did not differ. Permissive hypoventilation increased the respiratory rate and increased pCO2 . Positive pressure ventilation did not deteriorate circulation. Cardiac index (CI), systolic arterial pressure (SAP), hemoglobin (Hb), and heart rate did not differ. DISCUSSION: Permissive hypoventilation and positive pressure ventilation were equally effective to maintain oxygen delivery in all phases. A respiratory rate of 40 was feasible, showing no signs of respiratory fatigue for 90 min, indicating that whole blood resuscitation may be prioritized in select patients with severe hemorrhage and spontaneous breathing.

Control of Breathing and Central Hypoventilation Syndromes.

Control of breathing in children varies with age and sleep state. There is overlap between central hypoventilation, autonomic dysfunction, and hypothalamic dysfunction in the rare disorders (congenital central hypoventilation syndrome and rapid-onset obesity, hypoventilation, hypothalamic dysfunction, and autonomic dysregulation). Other, more common disorders that typically present in childhood also include central hypoventilation and disordered ventilatory responses.

Congenital central hypoventilation syndrome without hypoventilation: is it congenital central hypoventilation syndrome?

Congenital central hypoventilation syndrome (CCHS) is a rare condition caused by pathogenic variants of the PHOX2B gene. There have been case reports describing variable phenotypes and mutations of the PHOX2B gene, not commonly tested for, that may challenge the classic definition of CCHS. We report on 3 family members with a rare heterozygous deletion encompassing the entire PHOX2B gene with variable phenotypes, including sleep-disordered breathing and autonomic nervous system involvement, but an unexpected lack of alveolar hypoventilation, which is usually a defining feature of CCHS. Our cases highlight the dilemmas in making a diagnosis of CCHS and emphasize the need for expanded genetic testing, including for PHOX2B gene deletion. More patients with variable phenotypes of CCHS may be identified through comprehensive genetic testing and warrant surveillance as they are still at risk for high-risk complications of CCHS. CITATION: Wo LL, Itani R, Keens TG, Marachelian A, Ji J, Perez IA. Congenital central hypoventilation syndrome without hypoventilation: is it congenital central hypoventilation syndrome? J Clin Sleep Med. 2023;19(6):1161-1164.

Chronic Neuromuscular Respiratory Failure and Home Assisted Ventilation.

Chronic respiratory failure is a common, important complication of many types of neuromuscular and chest wall disorders. While the pathophysiology of each disease may be different, these disorders can variably affect all muscles involved in breathing, including inspiratory, expiratory, and bulbar muscles, ultimately leading to chronic respiratory failure and hypoventilation. The use of home assisted ventilation through noninvasive interfaces aims to improve the symptoms of hypoventilation, improve sleep quality, and, when possible, improve mortality. An increasing variety of interfaces has allowed for improved comfort and compliance. In a minority of scenarios, noninvasive ventilation is either not appropriate or no longer effective due to disease progression, and a transition to tracheal ventilation should be considered.

Use of Positive Airway Pressure in the Treatment of Hypoventilation.

The treatment of chronic hypoventilation usually requires noninvasive ventilation. However, upper airway obstruction can lead to hypoventilation in conditions such as obesity-hypoventilation syndrome, or chronic obstructive lung diseases (overlap syndrome). In these situations, continuous positive airway pressure can be an effective therapeutic option. This article reviews the pathophysiology of sleep-related hypoventilation, discusses situations where treatment with continuous positive airway pressure is feasible and briefly outlines noninvasive ventilation modes and settings for the treatment of common sleep-related hypoventilation disorders.

Effect of Respiratory Events on Health-Related Quality of Life in Patients Treated with Long-Term Noninvasive Ventilation.

BACKGROUND: Long-term noninvasive ventilation (NIV) can increase or maintain health-related quality of life (HRQoL) for patients with chronic hypercapnic respiratory failure (CHRF). Evidence from studies systematically assessing how NIV-specific factors influence HRQoL is limited. OBJECTIVES: The objective of this study was to describe HRQoL measured by the Severe Respiratory Insufficiency Questionnaire (SRI) in patients with CHRF treated with long-term NIV and to analyze the associations between HRQoL and hypoxemia, hypercapnia, and respiratory events such as apneas, hypopneas (AHI), and patient ventilator asynchrony (PVA) occurring during long-term NIV. METHODS: We included sixty-seven stable patients with established long-term NIV due to neuromuscular disease or thoracic cage disorders in a prospective cross-sectional study at Oslo University Hospital. Patients answered the SRI and underwent daytime arterial blood gases, nocturnal pulse oximetry, sleep polygraphy, and nocturnal transcutaneous CO2. RESULTS: The mean global SRI for 62 patients was 64.8 ± 14.5, with the highest score in SRI Social Relationships (79.5 ± 15.6). There were no differences in HRQoL between the different patient groups. Compliant patients had a significantly higher score in SRI Attendant and Sleep. Residual nocturnal hypoxemia affected both the subscale SRI "Respiratory Complaints" and SRI "Attendant Symptoms and Sleep." Persisting daytime hypercapnia, nocturnal hypoventilation, and high AHI affected the subscale SRI "Anxiety" negatively, while frequent PVA was associated with a lower score in SRI "Physical Function." CONCLUSION: In a group of patients with long-term NIV, undesired respiratory events during NIV are associated with lower HRQoL in several of the SRI subscales. We suggest designing interventional studies to confirm the possible relationship between HRQoL and respiratory events during long-term NIV.

Hypoventilation and sleep hypercapnia in a case of congenital variant-like Rett syndrome.

BACKGROUND: Breathing disturbances are often a primary clinical concern especially during wakefulness of the classic form of Rett syndrome, but data for atypical forms are lacking. CASE PRESENTATION: We report the case of a 20-month-old female affected by Rett syndrome with congenital variant-like onset, characterized by severe hypotonia and neurodevelopment impairment. She presented hypoventilation, persistent periodic breathing, and sustained desaturation during sleep, without obstructive or mixed events. Pulse oximetry and capnography during wakefulness were strictly normal. To the best of our knowledge, this is the first case of a patient affected by a congenital variant of Rett syndrome presenting sleep hypercapnia. Hypotonia may play a major role in the genesis of hypoventilation and hypoxemia in our patient. Non-invasive ventilation led to quality-of-life improvements. CONCLUSIONS: Thus, we suggest screening patients with congenital-like Rett syndrome through transcutaneous bedtime carbon dioxide and oxygen monitoring. Moreover, assisted control mode was a breakthrough to achieve adequate ventilation in our case.

Successful Total Management of Multi-Causative Sleep-Disordered Breathing Complicated with Patient with Adult Congenital Heart Disease.

Sleep-disordered breathing is one of the complications commonly seen in patients with adult congenital heart disease (ACHD) due to multiple causes including complex underlying cardiac defects, cardiomegaly, previous thoracotomies, obesity, scoliosis, and paralysis of the diaphragm. It is often hard to determine its main cause and predict the efficacy of each treatment in its management. We herein report a 30-year-old woman after biventricular repair of pulmonary atresia with intact ventricular septum diagnosed as sleep-related hypoventilation disorder. Simultaneous treatment targeting obesity, paralysis of the diaphragm, and cardiomegaly followed by respiratory muscle reinforcement through non-invasive ventilation resolved her sleep-related hypoventilation disorder. Such management for each factor responsible for the hypoventilation is expected to provide synergetic therapeutic efficacy and increase daily activity in a patient with ACHD.