Showing papers on "Hypoventilation published in 2022"

Congenital Central Hypoventilation Syndrome: Optimizing Care with a Multidisciplinary Approach

Abstract: Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder affecting respiratory control and autonomic nervous system function caused by variants in the paired-like homeobox 2B (PHOX2B) gene. Although most patients are diagnosed in the newborn period, an increasing number of patients are presenting later in childhood, adolescence, and adulthood. Despite hypoxemia and hypercapnia, patients do not manifest clinical features of respiratory distress during sleep and wakefulness. CCHS is a lifelong disorder. Patients require assisted ventilation throughout their life delivered by positive pressure ventilation via tracheostomy, noninvasive positive pressure ventilation, and/or diaphragm pacing. At different ages, patients may prefer to change their modality of assisted ventilation. This requires an individualized and coordinated multidisciplinary approach. Additional clinical features of CCHS that may present at different ages and require periodic evaluations or interventions include Hirschsprung's disease, gastrointestinal dysmotility, neural crest tumors, cardiac arrhythmias, and neurodevelopmental delays. Despite an established PHOX2B genotype and phenotype correlation, patients have variable and heterogeneous clinical manifestations requiring the formulation of an individualized plan of care based on collaboration between the pulmonologist, otolaryngologist, cardiologist, anesthesiologist, gastroenterologist, sleep medicine physician, geneticist, surgeon, oncologist, and respiratory therapist. A comprehensive multidisciplinary approach may optimize care and improve patient outcomes. With advances in CCHS management strategies, there is prolongation of survival necessitating high-quality multidisciplinary care for adults with CCHS.

Cost-effectiveness of outpatient versus inpatient non-invasive ventilation setup in obesity hypoventilation syndrome: the OPIP trial

Abstract: Background Current guidelines recommend that patients with obesity hypoventilation syndrome (OHS) are electively admitted for inpatient initiation of home non-invasive ventilation (NIV). We hypothesised that outpatient NIV setup would be more cost-effective. Methods Patients with stable OHS referred to six participating European centres for home NIV setup were recruited to an open-labelled clinical trial. Patients were randomised via web-based system using stratification to inpatient setup, with standard fixed level NIV and titrated during an attended overnight respiratory study or outpatient setup using an autotitrating NIV device and a set protocol, including home oximetry. The primary outcome was cost-effectiveness at 3 months with daytime carbon dioxide (PaCO2) as a non-inferiority safety outcome; non-inferiority margin 0.5 kPa. Data were analysed on an intention-to-treat basis. Health-related quality of life (HRQL) was measured using EQ-5D-5L (5 level EQ-5D tool) and costs were converted using purchasing power parities to £(GBP). Results Between May 2015 and March 2018, 82 patients were randomised. Age 59±14 years, body mass index 47±10 kg/m2 and PaCO2 6.8±0.6 kPa. Safety analysis demonstrated no difference in ∆PaCO2 (difference −0.27 kPa, 95% CI −0.70 to 0.17 kPa). Efficacy analysis showed similar total per-patient costs (inpatient £2962±£580, outpatient £3169±£525; difference £188.20, 95% CI −£61.61 to £438.01) and similar improvement in HRQL (EQ-5D-5L difference −0.006, 95% CI −0.05 to 0.04). There were no differences in secondary outcomes. Discussion There was no difference in medium-term cost-effectiveness, with similar clinical effectiveness, between outpatient and inpatient NIV setup. The home NIV setup strategy can be led by local resource demand and patient and clinician preference. Trial registration numbers NCT02342899 and ISRCTN51420481.

Developmental disorders affecting the respiratory system: CCHS and ROHHAD

Abstract: Rapid-onset Obesity with Hypothalamic dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) and Congenital Central Hypoventilation Syndrome (CCHS) are ultra-rare distinct clinical disorders with overlapping symptoms including altered respiratory control and autonomic regulation. Although both disorders have been considered for decades to be on the same spectrum with necessity of artificial ventilation as life-support, recent acquisition of specific knowledge concerning the genetic basis of CCHS coupled with an elusive etiology for ROHHAD have definitely established that the two disorders are different. CCHS is an autosomal dominant neurocristopathy characterized by alveolar hypoventilation resulting in hypoxemia/hypercarbia and features of autonomic nervous system dysregulation (ANSD), with presentation typically in the newborn period. It is caused by paired-like homeobox 2B (PHOX2B) variants, with known genotype-phenotype correlation but pathogenic mechanism(s) are yet unknown. ROHHAD is characterized by rapid weight gain, followed by hypothalamic dysfunction, then hypoventilation followed by ANSD, in seemingly normal children ages 1.5-7 years. Postmortem neuroanatomical studies, thorough clinical characterization, pathophysiological assessment, and extensive genetic inquiry have failed to identify a cause attributable to a traditional genetic basis, somatic mosaicism, epigenetic mechanism, environmental trigger, or other. To find the key to the ROHHAD pathogenesis and to improve its clinical management, in the present chapter, we have carefully compared CCHS and ROHHAD.

Monitoring Long Term Noninvasive Ventilation: Benefits, Caveats and Perspectives

Abstract: Long term noninvasive ventilation (LTNIV) is a recognized treatment for chronic hypercapnic respiratory failure (CHRF). COPD, obesity-hypoventilation syndrome, neuromuscular disorders, various restrictive disorders, and patients with sleep-disordered breathing are the major groups concerned. The purpose of this narrative review is to summarize current knowledge in the field of monitoring during home ventilation. LTNIV improves symptoms related to CHRF, diurnal and nocturnal blood gases, survival, and health-related quality of life. Initially, patients with LTNIV were most often followed through elective short in-hospital stays to ensure patient comfort, correction of daytime blood gases and nocturnal oxygenation, and control of nocturnal respiratory events. Because of the widespread use of LTNIV, elective in-hospital monitoring has become logistically problematic, time consuming, and costly. LTNIV devices presently have a built-in software which records compliance, leaks, tidal volume, minute ventilation, cycles triggered and cycled by the patient and provides detailed pressure and flow curves. Although the engineering behind this information is remarkable, the quality and reliability of certain signals may vary. Interpretation of the curves provided requires a certain level of training. Coupling ventilator software with nocturnal pulse oximetry or transcutaneous capnography performed at the patient's home can however provide important information and allow adjustments of ventilator settings thus potentially avoiding hospital admissions. Strategies have been described to combine different tools for optimal detection of an inefficient ventilation. Recent devices also allow adapting certain parameters at a distance (pressure support, expiratory positive airway pressure, back-up respiratory rate), thus allowing progressive changes in these settings for increased patient comfort and tolerance, and reducing the requirement for in-hospital titration. Because we live in a connected world, analyzing large groups of patients through treatment of “big data” will probably improve our knowledge of clinical pathways of our patients, and factors associated with treatment success or failure, adherence and efficacy. This approach provides a useful add-on to randomized controlled studies and allows generating hypotheses for better management of HMV.

Leptin-mediated neural targets in obesity hypoventilation syndrome.

Abstract: Obesity hypoventilation syndrome (OHS) is defined as daytime hypercapnia in obese individuals in the absence of other underlying causes. In the United States OHS is present in 10-20% of obese patients with obstructive sleep apnea and is linked to hypoventilation during sleep. OHS leads to high cardiorespiratory morbidity and mortality, and there is no effective pharmacotherapy. The depressed hypercapnic ventilatory response plays a key role in OHS. The pathogenesis of OHS has been linked to resistance to an adipocyte-produced hormone, leptin, a major regulator of metabolism and control of breathing. Mechanisms by which leptin modulates the control of breathing are potential targets for novel therapeutic strategies in OHS. Recent advances shed light on the molecular pathways related to the central chemoreceptor function in health and disease. Leptin signaling in the nucleus of the solitary tract, retrotrapezoid nucleus, hypoglossal nucleus, and dorsomedial hypothalamus, and anatomical projections from these nuclei to the respiratory control centers, may contribute to OHS. In this review, we describe current views on leptin-mediated mechanisms that regulate breathing and CO2 homeostasis with a focus on potential therapeutics for the treatment of OHS.

Adherence Index: sleep depth and nocturnal hypoventilation predict long-term adherence with positive airway pressure therapy in severe obstructive sleep apnea.

Abstract: STUDY OBJECTIVES Treatment of obstructive sleep apnea (OSA) with positive airway pressure (PAP) devices is limited by poor long-term adherence. Early identification of individual patient's probability of long-term PAP adherence would help in their management. We determined if conventional polysomnogram (PSG) scoring and measures of sleep depth based on the Odds Ratio Product (ORP) would predict adherence with PAP therapy twelve months after it was started. METHODS Patients with OSA referred to an academic sleep center had split-night PSG, arterial blood gases (ABG) and a sleep questionnaire. Multiple linear regression analysis of conventional PSG scoring and the ORP both during diagnostic PSG and PAP titration provided an "Adherence Index" which was correlated with PAP use twelve months later. RESULTS Patients with OSA (n=236, AHI 72.2 ± 34.1) were prescribed PAP therapy (82% received CPAP, 18% received BPAP). Each patient's adherence with PAP therapy twelve months later was categorized as "Never used", "Quit using", "Poor adherence" and Good adherence". Polysomnography measures that were most strongly correlated with PAP adherence were AHI and ORP during non-rapid eye movement sleep; the additional contribution of nocturnal hypoxemia to this correlation was confined to those with chronic hypoventilation treated with BPAP. The Adherence Index derived from these measures, both during diagnostic PSG and PAP titration, was strongly correlated with PAP adherence twelve months later. CONCLUSIONS Long-term adherence with PAP therapy can be predicted from diagnostic PSG in patients with severe OSA which may facilitate a precision-based approach to PAP management.

Impaired ventilation during 6‐min walk test in congenital central hypoventilation syndrome

Abstract: Patients with congenital central hypoventilation syndrome (CCHS) can develop hypoxemia and hypercapnia during exercise. However, there is limited literature on cardiorespiratory responses during submaximal exercise and their correlation with paired‐like homeobox 2B (PHOX2B) genotype.

Evolution of physiologic and autonomic phenotype in rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation over a decade from age at diagnosis

Abstract: Free AccessCase reportsEvolution of physiologic and autonomic phenotype in rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation over a decade from age at diagnosis Ilya Khaytin, MD, PhD, Tracey M. Stewart, RRT, Frank A. Zelko, PhD, Mitsu A.L. Kee, MD, Jennifer N. Osipoff, MD, Susan M. Slattery, MD, MSc, Debra E. Weese-Mayer, MD Ilya Khaytin, MD, PhD Address correspondence to: Ilya Khaytin, MD, PhD, Ann & Robert H. Lurie Children’s Hospital of Chicago, Division of Autonomic Medicine, Center for Autonomic Medicine in Pediatrics, 225 East Chicago Avenue, Chicago, IL 60611; Tel: (312) 227-3300; Email: E-mail Address: [email protected] Division of Autonomic Medicine, Center for Autonomic Medicine in Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois Stanley Manne Children’s Research Institute, Chicago, Illinois Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois Search for more papers by this author , Tracey M. Stewart, RRT Division of Autonomic Medicine, Center for Autonomic Medicine in Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois Search for more papers by this author , Frank A. Zelko, PhD Stanley Manne Children’s Research Institute, Chicago, Illinois Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois Pritzker Department of Psychiatry and Behavioral Health, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois Search for more papers by this author , Mitsu A.L. Kee, MD Northwell Health, Islandia, New York Search for more papers by this author , Jennifer N. Osipoff, MD Division of Pediatric Endocrinology, Stony Brook University, East Setauket, New York Search for more papers by this author , Susan M. Slattery, MD, MSc Division of Autonomic Medicine, Center for Autonomic Medicine in Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois Stanley Manne Children’s Research Institute, Chicago, Illinois Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois Search for more papers by this author , Debra E. Weese-Mayer, MD Division of Autonomic Medicine, Center for Autonomic Medicine in Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois Stanley Manne Children’s Research Institute, Chicago, Illinois Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois Search for more papers by this author Published Online:March 1, 2022https://doi.org/10.5664/jcsm.9740Cited by:2SectionsAbstractPDF ShareShare onFacebookTwitterLinkedInRedditEmail ToolsAdd to favoritesDownload CitationsTrack Citations AboutABSTRACTRapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a rare cause of syndromic obesity with risk of cardiorespiratory arrest and neural crest tumor. No ROHHAD-specific genetic test exists at present. Rapid weight gain of 20–30 pounds, typically between ages 2–7 years in an otherwise healthy child, followed by multiple endocrine abnormalities herald the ROHHAD phenotype. Vigilant monitoring for asleep hypoventilation (and later awake) is mandatory as hypoventilation and altered control of breathing can emerge rapidly, necessitating artificial ventilation as life support. Recurrent hypoxemia may lead to cor pulmonale and/or right ventricular hypertrophy. Autonomic dysregulation is variably manifest. Here we describe the disease onset with “unfolding” of the phenotype in a child with ROHHAD, demonstrating the presentation complexity, need for a well-synchronized team approach, and optimized management that led to notable improvement (“refolding”) in many aspects of the child’s ROHHAD phenotype over 10 years of care.Citation:Khaytin I, Stewart TM, Zelko FA, et al. Evolution of physiologic and autonomic phenotype in rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation over a decade from age at diagnosis. J Clin Sleep Med. 2022;18(3):937–944.BRIEF SUMMARYCurrent Knowledge/Study Rationale: ROHHAD (rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation) is a rare cause of syndromic obesity with a risk of cardiorespiratory arrest and neural crest tumors. The natural progression of symptoms of this disorder is not well known.Study Impact: This case report documents natural progression of the disorder in a well-chronicled patient over a decade of optimized care. It offers sleep medicine providers and pediatricians an overview of the expected phenotypic “unfolding” and “re-folding” and guides the care plan. INTRODUCTIONObesity is at an unprecedented level among children in the United States,1,2 with a prevalence of 18.5% in 2016.1 Although complex and multifactorial, it is essential for practicing sleep physicians to distinguish nonsyndromic obesity from a rare condition known by the acronym ROHHAD (rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation)3–5 carrying a 40% risk for cardiorespiratory arrest and potential mortality. Because of its extreme rarity, there is limited awareness of the ROHHAD natural course despite introducing the acronym in Pediatrics in 2007.3 Here we present the history and objective phenotype of a highly chronicled child followed at our single pediatric center for over 10 years, beginning weeks after her initial rapid weight gain (the heralding feature of ROHHAD).REPORT OF CASEThe patient had a healthy and slim body habitus and normal neurodevelopment when at 4.2 years of age she gained 6 pounds within 6 weeks, then experienced urinary incontinence twice in a single day, despite successful toilet-training 2 years prior. Mild puffiness of extremities, face, and eyelids was described. Echocardiogram and dexamethasone suppression test were unremarkable. Blood work included elevated hematocrit (42%), sodium (152 mmol/L), chloride (113 mmol/L), cholesterol (234 mg/dL), triglycerides (512 mg/dL), lactate dehydrogenase (325 U/L), and am cortisol (28.3 μg/dL). Brain magnetic resonance imaging was unremarkable. A left adrenal maturing ganglioneuroma with intermixed ganglioneuroblastoma was excised laparoscopically. A sleep study at age 4.3 years demonstrated an apnea-hypopnea index (AHI) of 0 events/h with 0% of total sleep time (TST) with oxygen saturation (SpO2) below 90% or end-tidal carbon dioxide (ETCO2) above 50%.The unique constellation of rapid weight gain, neuroendocrine tumor, and endocrine abnormalities led the pediatric oncologist to propose a diagnosis of ROHHAD and referral to our Center for comprehensive physiologic testing/evaluation. Testing includes continuous in-laboratory physiologic monitoring of the patient’s respiratory effort (thoracic and abdominal inductance plethysmography), electrocardiogram and heart rate (HR), SpO2, ETCO2, and cerebral near-infrared spectroscopy over 4 days and 4 nights during varied activities of daily living when awake and asleep. Blood pressure is monitored continuously with a finger probe during sleep but every 5 minutes by arm cuff when awake. Tympanic temperature and room temperature are measured every 60 minutes.On initial Center evaluation at age 4.5 years, breathing spontaneously in room air, the child demonstrated adequate oxygenation with mild hypoventilation during quiet play but desaturation to 91% with an ETCO2 peak of 56 mm Hg during exertional activity. Asleep breathing spontaneously, the child maintained marginally adequate ventilation, without central or obstructive apneas, but without increased breathing depth with transient hypoventilation. The child’s peak ETCO2 was 57 mm Hg during wakefulness before sleep onset and 60 mm Hg (ETCO2 > 50 mm Hg for 12%–16% of TST) during sleep. The child did not demonstrate any apnea or obstructive events awake or asleep. Asleep, a respiratory rate was increased into the high 30s breaths per minute (bpm) range and, while awake and during rapid eye movement (REM) sleep, into the low 40s bpm range. Periods of prolonged exhalation during sleep were associated with increased ETCO2. There were no significant/consistent changes in HR or blood pressure in REM sleep compared with non-REM sleep. The family was alerted that the child’s asleep spontaneous breathing would likely deteriorate over the next 2–3 months, so interim sleep studies at their home institution would be essential.Over the next months, snoring and periods of irregular respiratory pattern were observed asleep. A serum lipid panel revealed elevated cholesterol at 215 mg/dL, triglycerides at 403 mg/dL, thyroid-stimulating hormone (TSH) of 4.86 uIU/mL, and reduced high-density lipoprotein cholesterol of 31 mg/dL. Weight gain continued despite calorie restriction, with a pediatrician-documented weight of 26.8 kg (> 95th percentile for age) at 4.6 years of age. Between the first (age 4.5 years) and the second evaluations at our Center (age 4.7 years) the child had 2 interim sleep studies at her home institution. The first was performed after the mother noted snoring and heavy breathing at night. After 1.5 hours of baseline, due to snoring and obstructive events associated with elevated ETCO2 levels (peak of low 50s mm Hg) and desaturations (SpO2 nadir in the high 80% range), mask continuous positive airway pressure treatment was introduced (start of 4 centimeters of water pressure (cwp) then titrated to 6 cwp). However, even at a continuous positive airway pressure of 6 cwp, periods of shallow breathing were noted. The overall-study AHI was 28.3 events/h, with a higher AHI before the intervention. The SpO2 nadir was 78%, with baseline values during sleep in the high 80% range. After this study, the bilevel positive airway pressure (BPAP) treatment was empirically introduced, beginning with pressures of 8/4 cwp, then increased to 10/5 cwp. The second sleep study was a titration study. Despite an initial BPAP of 12/6 cwp, numerous central apneas were documented (on average, one 4- to 8-second central apnea per 30-second epoch). Consequently, BPAP was gradually increased to 17/13 cwp, with improved oxygenation and ventilation (sleep-onset baseline SpO2 was 96%; asleep average SpO2 was 96%–97% but 2 transient drops to 80%; ETCO2 was consistently ≤ 50 mm Hg). After the second interim sleep study, a prescription for BPAP in Spontaneous Timed mode (ST) 12/6 cwp with rate of 18 bpm was provided. The child was later transitioned to the Trilogy (Philips-Respironics, Murrysville, PA, USA) ventilator (bi-level ST mode) with increased ventilatory support (15/6 cwp, rate 15 bpm) via face mask during all sleep time.The second Center comprehensive physiologic evaluation was 4 months after rapid weight gain onset (3.5 months after initial evaluation). After water intake regulation, sodium (142–155 mEq/L), total cholesterol (from 261 to 189 mg/dL), triglycerides (from 512 to 271 mg/dL), and prolactin (from 62 to 55 ng/mL) improved. Thyroid results were unremarkable (TSH 4.11 mIU/L; free T4 1.42 ng/dL). The most notable indication of the “unfolding” ROHHAD phenotype was the progression of respiratory insufficiency. The child transitioned from a normal sleep study and normal spontaneous breathing soon after rapid-onset weight gain to mild hypoventilation during the first comprehensive physiologic Center evaluation. Then, over 2 months, there was a progression from obstructive sleep apnea to severe central apnea with physiologic compromise necessitating BPAP. After the second Center comprehensive evaluation, the child was discharged requiring Trilogy ventilator bilevel pressure support in pressure control (PC) mode, 18/6 cwp with rate of 18 bpm with a full-face mask. However, home SpO2 and ETCO2 monitoring demonstrated that the child continued to have periods of desaturation and hypercarbia. Based on her escalating sleep-disordered breathing trajectory, she underwent tracheostomy placement in anticipation of the need for continuous artificial ventilation. At the child’s third Center evaluation (4 months after her first Center evaluation), the need for continuous artificial ventilation during wakefulness and sleep was confirmed and artificial ventilator settings to optimize oxygenation and ventilation were determined. Due to the innate control of breathing abnormality in an otherwise developmentally appropriate and mobile child, the ventilator settings had to include the optimal pressure and a range of respiratory rates to accommodate for varied age-appropriate activities of daily living. After the Center evaluation, the child was determined to need awake ventilator settings of PC mode, IPAP of 22 cwp, EPAP of 6 cwp, inspiratory time 1 second, rate 16 bpm (range 10–24 bpm), and asleep ventilator settings the same as awake, except for IPAP of 24 cwp and 1 L/minute oxygen. Notably, oxygen was added at night because, on optimal pressure, the child had low normal ETCO2 values in the mid-30- to low 40-mm Hg range, but still had desaturations below 90%. Therefore, over 4 months, the ROHHAD phenotype transitioned from the child’s ability to breathe spontaneously awake and asleep, to full ventilator dependence as life support, with intact volitional breathing but no perception of respiratory distress, shortness of breath, or physiologic response to the deteriorating spontaneous breathing requiring continuous ventilatory support (Figure 1).Figure 1: Evolution of child’s ability to breathe spontaneously.Evolution of ability to breathe without ventilatory support since time of ROHHAD diagnosis, indicating a rapid decline followed by gradual improvement. (A) Percentage of time during daytime physiologic testing Center evaluations when the child breathed spontaneously without artificial ventilatory support (shaded bars). Note: during the first 2 Center evaluations, the child did not have a tracheostomy (2 clear bars at 4.5 and 4.7 years of age). At the first Center evaluation the child breathed spontaneously 100% of a day (awake and asleep), without a need for artificial ventilation. At the second center evaluation, the child required mask ventilation via bilevel positive airway pressure only during sleep but breathed spontaneously 100% of her awake time. (B) Center recommendation for duration of spontaneous breathing time per day at end of each admission based on extensive SpO2 and ETCO2 monitoring in varied activities of daily living. ETCO2 = end-tidal carbon dioxide, ROHHAD = rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation, SpO2 = oxygen saturation.Download FigureOver the next decade in partnership with her pediatrician and subspecialists, the child had comprehensive physiologic testing every 3–12 months, with interval polysomnography in her home medical center. Each evaluation at our Center included the following: (1) comprehensive physiologic evaluation of cardiorespiratory regulation when awake in varied daytime age-appropriate activities of daily living, before bedtime, and during sleep; (2) cardiac evaluation for HR variability and evidence of right ventricular hypertrophy or cor pulmonale; (3) serial endocrine testing of a battery of hypothalamic and pituitary hormones and blood chemistries; (4) age-appropriate noninvasive measures of autonomic regulation; and (5) imaging for tumor re-emergence. Figure 1 demonstrates the percentage of time during each evaluation with successful spontaneous breathing, indicating apparent evolution with advancing age. At 6.3 years of age, the child tolerated 2-hour periods of spontaneous breathing while awake during sedentary play. During the most recent Center evaluation at age 14.3 years, the child breathed spontaneously during all awake time engaging in activities of daily living, including moderate exertion and before nighttime sleep, with SpO2 and ETCO2 consistently in the acceptable range. The child continues to require ventilatory support via tracheostomy during sleep.Weight was challenging to manage (Figure 2) despite caloric restriction and a steadfast fitness regimen. At each Center admission, the child and both parents met with our dietitian, adjusted calorie targets, and demonstrated target adherence with body mass index (BMI) stabilization between ∼5 and 8 years of age; then, at 8 years of age (3.5 years after initial weight gain and enuresis), sustained restricted dietary intake and exercise led to a decreasing BMI. Her weight stabilized coincident with recovery-onset of awake spontaneous breathing at age 11.3 years. At age 12.6 years, BMI declined to the 95th percentile for the first time since ROHHAD presentation. Importantly, as can be seen from Figure 1 and Figure 2, it appears that awake spontaneous breathing and changes in overall BMI percentile did not necessarily follow each other but were improving following different trajectories.Figure 2: Height, weight, and BMI over time.(A) Height, (B) weight, and (C) BMI with advancing age beginning before ROHHAD diagnosis was made to age 14.3 years. Height, weight, and BMI percentiles were calculated using published CDC growth charts and methods.13,14 Dots are individual measurements for the child described in the case report. Bold solid lines represent 3rd, 50th, and 97th percentiles. Nonbold solid lines represent 10th and 90th percentiles. The 2 dotted lines in the graphs of weight and BMI indicate the 125th and 150th of 95th percentiles. BMI = body mass index, CDC = Centers for Disease Control and Prevention, ROHHAD = rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation.Download FigureIn addition to the “refolding” of the ROHHAD phenotype as evidenced by the recovery of awake spontaneous breathing and weight control, we documented the evolution of several other autonomic measures. The initially elevated HR declined and by age 5.7 years was near-consistently below the 90th percentile for age.6 Objective peripheral skin temperatures were introduced to assess vasomotor tone in this child with ROHHAD-related ice-cold hands and feet. Despite improvement in many ROHHAD phenotype features, and peripheral skin temperature improvement with introduction of oral caffeine at age 8 years to improve vasomotor tone, peripheral skin temperatures of hands and feet did not normalize (Figure 3), with the tip of the child’s middle toes often equal to or colder than the ambient temperature. Introduction of caffeine resulted in mild improvements in the child’s carbon dioxide responsiveness, as evidenced by the development of sighs and yawns and reduced periodic breathing. However, causality cannot be confirmed as discontinuation of the caffeine was not considered by the family. Pupillometry, performed using the handheld NeurOptics PLR-2000 pupillometer (Irvine, CA), providing noninvasive electronic measurement of pupillary response to precise light and dark stimuli, consistently demonstrated increased dark-acclimated pupil diameters, even before caffeine was introduced, compared with similarly aged children.7 However, maximum constriction and redilation velocities and latency to constriction were similar to healthy controls.Figure 3: Peripheral skin temperature from initial diagnosis until last evaluation.Central Dorsal = center of dorsal hand/foot, Central Ventral = center of ventral hand/foot, Left TM = left tympanic membrane, Room T = room temperature, 3rd Tip = tip of third finger/toe.Download FigureMonitoring for and staging of pubertal development was done at each endocrinology visit. The child developed Tanner stage 3 pubic hair by the age of 9.5 years. At that time, she had contour to her chest, but this was primarily adipose tissue. Over the next 4 years, she continued to progress with adrenarche, including axillary hair and apocrine odor. By the time she was 13.25 years old, her gonadotropins and estradiol remained undetectable (luteinizing hormone [LH] < 0.1 IU/L, follicle stimulating hormone [FSH] 0.2 IU/L, and estradiol < 5 pg/mL). Concurrent prolactin level was 59.7 ng/mL. To keep up with her peers’ development, parents and the child started estrogen replacement therapy with estradiol transdermal patches, and the dose was titrated upwards. In-person examinations were not possible due to COVID-19, but the child reported increased breast development a few months after beginning the patches. Approximately 18 months after starting, breakthrough bleeding began and progestin was cycled in.Formal neurocognitive testing was completed during each Center admission. Table 1 documents indices of overall intelligence (Full-Scale IQ) in the mid-average range or higher. Performance on intellectual subscales measuring verbal comprehension and processing speed was consistently in the high average to superior range, a notably higher level than her performances in the low-average to mid-average range on perceptual reasoning and working memory measures. Her performance on visuomotor/visuographic skills was also at a lower level, ranging from borderline deficient to mid-average. For the most part, the patient’s cognitive test results were stable over time. Based on our Center experience with children with ROHHAD, these are typical neurocognitive results in a well-managed patient.Table 1 Neurocognitive assessment15--17 results throughout follow-up over 10 years from time of ROHHAD diagnosis.Age (y)4.55.76.47.07.88.59.610.611.612.613.6Wechsler Abbreviated Scales of Intelligence—2nd edition Full-Scale IQa109100116115108100108108 Verbal Comprehensiona130115140129121113132123 Performance IQ aka Perceptual Reasoninga9083879692879290 Vocabularyb121318151515131414 Similaritiesb1813181614121615 Block Designb977678666 Matrix Reasoningb77911991111Wechsler Intelligence Scale for Children—5th edition Working Memorya889199971009110097 Processing Speeda123128136116135116108105 Digit Spanb8681089797 Picture Spanb811121111101112 Codingb141416151215151212 Symbol Searchb1416171417111110Visuomotor/visuographic skills Beery VMIa959387908592798473 GrPeg Dominantc−0.81−1.19−1.1−1.10.10.4−0.4−0.6−0.6Wechsler Preschool & Primary Scale of Intelligence—3rd edition Verbala118114 Performancea121112 Processing Speeda131 Verbal (percentile)8882 Performance (percentile)9279 Processing Speed (percentile)98 Verbal Scales Informationb1411 Vocabularyb1112 Word Reasoningb1515 Performance Scales Block Designb1113 Matrix Reasoningb129 Picture Conceptsb1714 Processing Speed Scales Codingb1515 Symbol Searchb16aStandard score, mean = 100, standard deviation = 15. bZ-score, mean = 10, standard deviation = 3. cScaled score, mean = 0, standard deviation = 1. 8.5 years. Testing was < 1 year after prior testing, so all tests were not performed (hence missing values). ROHHAD = rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation.DISCUSSIONIze-Ludlow et al3 introduced the ROHHAD acronym, referring to a characteristic phenotype progression, to increase awareness for the pediatricians who would identify rapid-onset weight gain while preparing well-child visit growth charts, building on reports by Fishman et al8 and Katz et al.9 To date, fewer than 200 cases of ROHHAD have been reported, indicating that it is either ultra-rare or too often unrecognized or insufficiently treated, leading to severe morbidity and mortality.Unlike congenital central hypoventilation syndrome, a rare neurocristopathy-hypoventilation disorder caused by typically heterozygous mutations in the paired-like homeobox gene PHOX2B, ROHHAD lacks an identifiable genetic marker despite extensive inquiry,10–12 emphasizing the need for phenotype familiarity. With increased awareness, the pediatric sleep physician will be alert to ROHHAD-related rapid-onset obesity in a previously healthy/developmentally normal child and maintain heightened suspicion in the event of cyanosis with sleep or exertion, altered temperature regulation, or unexplained enuresis. Serial screening for evolving ROHHAD involves comprehensive testing, as shown in Table 2, and is highly recommended in any child who develops sudden onset of obesity between ages 1.5 and 7 years, and in whom a diagnosis of ROHHAD is considered. Especially with hypernatremia and hyperprolactinemia, suspicion for ROHHAD should be further heightened and prompt referral made for initial polysomnography and to a center with ROHHAD expertise. With the pediatrician as the first responder considering ROHHAD at well-child visits, there is an opportunity for earlier identification of hypoventilation and averting cardiorespiratory arrest. Any child with suspected ROHHAD needs to have polysomnography included in the initial evaluation. Timing of the repeat polysomnography may depend on the progression of weight gain, metabolic abnormalities, and sleep-disordered breathing. However, vigilance is essential along with anticipation of the sleep-disordered breathing trajectory. As this case highlights, the progression of respiratory symptoms can be very rapid but challenging to identify in a child without fully intact control of breathing. Therefore, family and home nursing observation and in-home oximetry and capnography plus monitoring for any respiratory pauses or other pertinent new observations would expedite timing of another sleep study. In our Center experience, it is often possible to convince insurance providers to cover more than once-a-year polysomnography by describing cardiovascular arrest risk of 40% in children with suboptimally managed ROHHAD. Vigilant and conservative airway and artificial ventilation management is essential, with polysomnography and daytime physiologic recordings initially up to every 3 months, then 6 months, and after the patient is stable, every 8–12 months, with the overriding aim to anticipate respiratory deterioration in asleep, then awake, and to determine optimal ventilatory support to maintain normoxia and normocapnia as the ROHHAD phenotype evolves. An in-home, highly trained registered nurse to monitor continuous ETCO2 and SpO2 and the ventilator, and to promptly intervene to maintain consistent management, is vital. Without shortness of breath and outward measures to indicate illness (body temperature reduced with rare temperature spikes during intercurrent illness), objective measures of breathing, pulse rate, ETCO2, and SpO2 allow for early identification before health deterioration becomes irreversible. In addition to serial physiologic assessments of breathing, Holter recordings, echocardiograms, and neural crest tumor screening (chest X-ray to look along the sympathetic chain and abdominal/pelvic ultrasound to image both adrenal glands) are advised (Table 2). Neural crest tumors should be identified early, especially since a subset may be neuroblastoma, although removal does not prevent “unfolding” of the ROHHAD phenotype. Although no cure has been identified to date, the child presented here indicates that early referral, aggressive management, and stable artificial ventilation, as needed, awake and asleep allow for normal neurocognitive development. Altogether, this case demonstrates the longitudinal “unfolding” and “refolding” of the ROHHAD phenotype over a decade in a child identified within weeks of rapid weight gain onset. With objective longitudinal testing and personalized management, and with extensive efforts coordinated in large part by the pediatrician and endocrinologist, this now adolescent girl is thriving neurocognitively and socially.Table 2 Recommended testing, rationale, and frequency for children and adolescents with suspected or confirmed ROHHAD (*Sleep medicine physician action items).Objective MeasureRationale and Testing Frequency*Growth charts of weight, height, and BMI (if < 36 months, include head circumference)• *Need for accurate measurements and on the same scale with every physician visit (every 3 months) to evaluate growth trajectory with advancing age.*Serial objective physiologic recording during sleep and quiet wakefulness before sleep and upon awakening with inclusion of continuously recorded inductance plethysmography of chest/abdomen/sum, air flow, ETCO2 and waveform, SpO2 and pulse waveform, ECG and HR, EEG, EOG, and EMG. Inclusion of intermittent temperature and room temperature, continuous blood pressure, and cerebral regional blood flow/oxygenation are highly desirable.*At first consideration of ROHHAD diagnosis (ideally at time of rapid-onset weight gain) to evaluate for hypoventilation and sleep-disordered breathing.*Repeat every 2–3 months depending on observed symptom progression trajectory.With advancing age watch for cardiorespiratory coupling and cerebrovascular coupling to assess phenotype progression.Parental and physician vigilance are essential as child will lack fully intact control of breathing.Progression of sleep-disordered breathing may be very rapid, with heightened risk of cardiopulmonary arrest.Serial objective physiologic recording during wakefulness in varied activities of daily living with inclusion of continuously recorded inductance plethysmography of chest/abdomen/sum, ETCO2 and waveform, SpO2 and pulse waveform, ECG, and HR at a minimum. Inclusion of intermittent blood pressure, temperature, and continuous cerebral regional blood flow/oxygenation are highly desirable.*At first consideration of ROHHAD diagnosis (ideally at time of rapid-onset weight gain) to evaluate for hypoventilation and sleep-disordered breathing.*Repeat every 2–3 months depending on observed symptom progression trajectory.With advancing age watch for cardiorespiratory coupling and cerebrovascular coupling to assess phenotype progression.Parental and physician vigilance are essential as child will lack fully intact control of breathing.Progression of sleep-disordered breathing may be very rapid, with heightened risk of cardiopulmonary arrest.*Echocardiogram• *At first consideration of ROHHAD diagnosis (ideally at time of rapid-onset weight gain) then every 6 months thereafter to evaluate for right ventricular hypertrophy and cor pulmonale indicative of recurrent hypoxemia.*Holter recording (ideally, 72 hours during typical daily schedule)• *At first consideration of ROHHAD diagnosis (ideally at time of rapid-onset weight gain) then every 6 months thereafter to evaluate for cardiac rhythm disturbance and HR variability.*MRI of brain and brainstem with hypothalamus/pituitary protocol (with and without contrast) ideally without sedation• *At first consideration of ROHHAD diagnosis (ideally at time of rapid-onset weight gain) and without sedation.*Neural crest tumor screen (chest X-ray to view along sympathetic chain and abdominal US to view both adrenal glands) ideally without sedation*At first consideration of ROHHAD diagnosis (ideally at time of rapid-onset weight gain), then every 3 months until tumor is found.After age 7 years if no tumor can widen interimaging intervals.Although most are ganglioneuroma or ganglioneuroblastoma, neuroblastoma has been reported.Aim is early identification and intervention while tumor is small enough to be excised.*Endocrine-related bloodwork Comprehensive metabolic profile Osmolality, urine Prolactin FT4 S-TSH, serum Insulin-like growth factor binding protein Insulin-like growth factor I, serum Cortisol, free, urine Cortisol, serum or plasma*At first consideration of ROHHAD diagnosis (ideally at time of rapid-onset weight gain), then every 2–3 months during first 3 years, then every 4–6 months for next 3 years, then every 6 months thereafter.Aim is to identify varied direct and indirect hormonal changes with advancing age, need for hormone replacement therapy, and personalization of medication/dosing.*Endocrine-related bloodwork if precocious or delayed puberty DHEA-s LH FSH Testosterone GN-RH*At first consideration of precocious or delayed puberty, then every 3 months thereafter.Aim is to identify varied hormonal changes with advancing age, need for hormone replacement therapy, and personalization of medication/dosing.*Other bloodwork CBC with differential Reticulocytes, blood Lipid, screen Leptin*At first consideration of ROHHAD diagnosis (ideally at time of rapid-onset weight gain), then every 3 months during first 3 years, then every 6 months for the next 3 years, then every 6 months thereafter.CBC and reticulocyte count to assess for polycythemia and reticulocytosis indicative of recurrent hypoxemia.Lipid screen and leptin to identify and intervene if hyperlipidemia and hypertriglyceridemia.BMI = body mass index, CBC = complete blood count, DHEA-s = dehydroepiandrosterone sulfate, ECG = electrocardiography, EEG = electroencephalography, EMG = electromyography, EOG = electrooculography, ETCO2 = end-tidal carbon dioxide, FSH = follicle-stimulating hormone, FT4 = free thyroxine, GN-RH = gonadotropin-releasing hormone, HR = heart rate, LH = luteinizing hormone, MRI = magnetic resonance imaging, ROHHAD = rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation, SpO2 = oxygen saturation, S-TSH = thyroid-stimulating hormone-sensitive, US = ultrasound.DISCLOSURE STATEMENTAll authors have seen and approved this manuscript. Work for this study was performed at the Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois. This study was funded by ROHHAD Fight Inc. and ROHHAD Association. The authors report no conflicts of interest.ABBREVIATIONSAHIapnea-hypopnea indexBPAPbilevel positive airway pressurebpmbreaths per minutecwpcentimeters of water pressureEPAPexpiratory positive airway pressureETCO2end-tidal carbon dioxideHRheart rateIPAPinspiratory positive airway pressureROHHADrapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulationSpO2oxygen saturationREFERENCES1. Hales CM, Carroll MD, Fryar CD, Ogden CL. Prevalence of obesity among adults and youth: United States, 2015-2016. NCHS Data Brief. 2017;288:1–8. Google Scholar2. Brown CL, Halvorson EE, Cohen GM, Lazorick S, Skelton JA. Addressing childhood obesity: opportunities for prevention. Pediatr Clin North Am. 2015;62(5):1241–1261 . CrossrefGoogle Scholar3. Ize-Ludlow D, Gray JA, Sperling MA, et al.. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation presenting in childhood. Pediatrics. 2007;120(1):e179–e188 . CrossrefGoogle Scholar4. Ibáñez-Micó S, Marcos Oltra AM, de Murcia Lemauviel S, Ruiz Pruneda R, Martínez Ferrández C, Domingo Jiménez R. Rapid-onset obesity with hypothalamic dysregulation, hypoventilation, and autonomic dysregulation (ROHHAD syndrome): a case report and literature review. Neurologia. 2017;32(9):616–622. Google Scholar5. Patwari PP, Rand CM, Berry-Kravis EM, Ize-Ludlow D, Weese-Mayer DE. Monozygotic twins discordant for ROHHAD phenotype. Pediatrics. 2011;128(3):e711–e715 . CrossrefGoogle Scholar6. Fleming S, Thompson M, Stevens R, et al.. Normal ranges of heart rate and respiratory rate in children from birth to 18 years of age: a systematic review of observational studies. Lancet. 2011;377(9770):1011–1018 . CrossrefGoogle Scholar7. Winston M, Zhou A, Rand CM, et al.. Pupillometry measures of autonomic nervous system regulation with advancing age in a healthy pediatric cohort. Clin Auton Res. 2020;30(1):43–51 . CrossrefGoogle Scholar8. Fishman LS, Samson JH, Sperling DR. Primary alveolar hypoventilation syndrome (Ondine’s Curse). Am J Dis Child. 1965;110(2):155–161 . CrossrefGoogle Scholar9. Katz ES, McGrath S, Marcus CL. Late-onset central hypoventilation with hypothalamic dysfunction: a distinct clinical syndrome. Pediatr Pulmonol. 2000; 29(1):62–68 . CrossrefGoogle Scholar10. Barclay SF, Rand CM, Borch LA, et al.. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD): exome sequencing of trios, monozygotic twins and tumours. Orphanet J Rare Dis. 2015;10(1):103 . CrossrefGoogle Scholar11. Barclay SF, Rand CM, Gray PA, et al.. Absence of mutations in HCRT, HCRTR1 and HCRTR2 in patients with ROHHAD. Respir Physiol Neurobiol. 2016;221: 59–63 . CrossrefGoogle Scholar12. Rand CM, Patwari PP, Rodikova EA, et al.. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation: analysis of hypothalamic and autonomic candidate genes. Pediatr Res. 2011;70(4):375–378 . CrossrefGoogle Scholar13. Centers for Disease Control and Prevention, National Center for Health Statistics. Clinical Growth Charts. https://www.cdc.gov/growthcharts/clinical_charts.htm. Accessed October 26, 2021. Google Scholar14. Gulati AK, Kaplan DW, Daniels SR. Clinical tracking of severely obese children: a new growth chart. Pediatrics. 2012;130(6):1136–1140 . CrossrefGoogle Scholar15. Wechsler D. Wechsler Abbreviated Scale of Intelligence, Second Edition (WASI-II). San Antonio, TX: NCS Pearson; 2011. Google Scholar16. Wechsler D. Wechsler Intelligence Scale for Children, Fifth Edition (WISC-V). San Antonio, TX: NCS Pearson; 2014. Google Scholar17. Wechsler D. Wechsler Preschool and Primary Scale of Intelligence, Third Edition (WPPSI-III). San Antonio, TX: NCS Pearson; 2002. Google Scholar Previous article Next article FiguresReferencesRelatedDetailsCited by Neurocognition as a biomarker in the rare autonomic disorders of CCHS and ROHHADZelko F, Welbel R, Rand C, Stewart T, Fadl-Alla A, Khaytin I, Slattery S and Weese-Mayer D Clinical Autonomic Research, 10.1007/s10286-022-00901-1 Ceccherini I, Kurek K and Weese-Mayer D Developmental disorders affecting the respiratory system: CCHS and ROHHAD Respiratory Neurobiology: Physiology and Clinical Disorders, Part II, 10.1016/B978-0-323-91532-8.00005-7, (53-91), . Volume 18 • Issue 3 • March 1, 2022ISSN (print): 1550-9389ISSN (online): 1550-9397Frequency: Monthly Metrics History Submitted for publicationMay 26, 2021Submitted in final revised formOctober 12, 2021Accepted for publicationOctober 15, 2021Published onlineMarch 1, 2022 Information© 2022 American Academy of Sleep MedicineKeywordscardiorespiratory arrestlongitudinal observationhypoventilationobesityROHHADPDF download

ROHHAD syndrome without rapid-onset obesity: A diagnosis challenge

Abstract: Background ROHHAD syndrome (Rapid-onset Obesity with Hypothalamic dysfunction, Hypoventilation and Autonomic Dysregulation) is rare. Rapid-onset morbid obesity is usually the first recognizable sign of this syndrome, however a subset of patients develop ROHHAD syndrome without obesity. The prevalence of this entity is currently unknown. Alteration of respiratory control as well as dysautonomic disorders often have a fatal outcome, thus early recognition of this syndrome is essential. Material and methods A retrospective, observational, multicenter study including all cases of ROHHAD without rapid-onset obesity diagnosed in France from 2000 to 2020. Results Four patients were identified. Median age at diagnosis was 8 years 10 months. Median body mass index was 17.4 kg/m2. Signs of autonomic dysfunction presented first, followed by hypothalamic disorders. All four patients had sleep apnea syndrome. Hypoventilation led to the diagnosis. Three of the four children received ventilatory support, all four received hormone replacement therapy, and two received psychotropic treatment. One child in our cohort died at 2 years 10 months old. For the three surviving patients, median duration of follow-up was 7.4 years. Conclusion ROHHAD syndrome without rapid-onset obesity is a particular entity, appearing later than ROHHAD with obesity. This entity should be considered in the presence of dysautonomia disorders without brain damage. Likewise, the occurrence of a hypothalamic syndrome with no identified etiology requires a sleep study to search for apnea and hypoventilation. The identification of ROHHAD syndrome without rapid-onset obesity is a clinical challenge, with major implications for patient prognosis.

Strategy of changing from tracheostomy and non‐invasive mechanical ventilation to diaphragm pacing in children with congenital central hypoventilation syndrome

Abstract: Congenital central hypoventilation syndrome (CCHS) is a rare disorder that affects central control of breathing, and paediatric treatment varies worldwide.1 One approach is diaphragm pacing (DP), by phrenic nerve stimulation or direct diaphragm muscle stimulation, with or without a tracheostomy.2 In Sweden, noninvasive ventilation (NIV) has been the firstline ventilator support for patients with CCHS.3 However, disadvantages such as midface hypoplasia and unintentional leakage have required assessment over time.4 Diaphragm pacing implants are provided at the National Reference Center for Diaphragm Pacing at Uppsala University Hospital, Sweden, at 3– 4 years of age, when the upper airways have become more stable. Some international centres wait until children are older.2 Our aim was to evaluate switching patients with CCHS from mechanical ventilation, namely tracheostomy or NIV, to DP. We retrospectively studied 23 patients with central hypoventilation conditions who underwent DP implantation at the Hospital between 1 January 1980 and 31 December 2020. They included 12 international referrals. CCHS was defined as central hypoventilation with failed respiratory control, mainly during sleep. This was confirmed by gene testing and included pairedlike homeobox 2b and other genetic mutations.1 A successful transition to DP was defined as a complete change to sleepassisted, nonmechanical ventilation. All patients accepted for DP implantation needed respiratory support, verified by cardiorespiratory and polygraphic monitoring and clinical observation. Upper airway patency was evaluated before surgery was performed. This study comprised 23 patients (13 female) with central hypoventilation conditions, who received DP at a mean age of 9.1 years (range 2.9– 31.2) (Table 1). They included 21 with CCHS, and 18/23 were using NIV at the time of implantation. Five patients had a tracheostomy before implantation, and they were all decannulated after surgery: one within 3 months and 4 after 3– 6 months. We found that 20/23 were successfully transferred to DP and 3 continued with NIV. Some patients have now been using DP for 30 years without needing replacement electrodes or receivers. Four Swedish patients with CCHS were not included because they were under 3 years of age and ineligible for DP implantation, but they will be considered when they reach 3 years of age. Of the 23 patients, 18 had PHOX2B gene mutations: one had a 20/24 polyalanine repeat expansion mutation (PARM), two had a 20/25 PARM, six had a 20/26 PARM, five had a 20/27 PARM, two had a 20/30 PARM, one had a 20/33 PARM and one had a nonPARM mutation. One had rapidonset obesity with hypothalamic dysregulation, hypoventilation and autonomic dysregulation. One tested negative for pairedlike homeobox 2b, and three tested positive, but with unknown genotypes (Table 1). Most patients were successfully ventilated with DP, in line with earlier studies.2,5 Our cervical approach to DP implantation was feasible and minimally invasive, with low morbidity. We believe this is the first study to demonstrate that ventilator support in children with CCHS may shift from NIV to DP at an early age. This could prevent midface deformation after longterm NIV use. In our experience, younger patients accept DP better and older patients need a longer adaptation period. The age limit of 3– 4 years has been set due to increased stability of the upper airways and larger patient size, which simplifies surgical access. Young children seem to be more sensitive to upper airway obstruction because they lack synchrony between upper airway skeletal muscles and the diaphragm.2 Upper airway collapses and obstructive apnoeas were prevented by applying lower DP amplitude settings and higher frequency rates. This even worked for patients with upper airway obstruction due to midface deformation prior to DP implantation. A novel observation was that all patients who had a tracheostomy were decannulated and able to exclusively rely on DP for ventilatory support. Decannulation was determined by the ear, nose and throat

Contribution of hypercapnia to cognitive impairment in severe sleep-disordered breathing

Abstract: Although cognitive impairment in obstructive sleep apnea (OSA) is primarily attributed to intermittent hypoxemia and sleep fragmentation, hypercapnia may also play a role in patients whose OSA is complicated by hypoventilation. This study investigated the impact of hypercapnia on cognitive function in severe sleep-disordered breathing (OSA accompanied by hypoventilation).Patients with severe OSA (apnea-hypopnea index >30 events/h; n = 246) underwent evaluation for accompanying hypoventilation with polysomnography that included continuous transcutaneous carbon dioxide (TcCO2) monitoring and awake arterial blood gas analysis. Patients were categorized as having no hypoventilation (n = 84), isolated sleep hypoventilation (n = 40), or awake hypoventilation (n = 122). Global cognitive function was evaluated using the Montreal Cognitive Assessment (MoCA), memory with the Rey Auditory Verbal Learning Test (RAVLT), and processing speed with the Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV), Digit Symbol Coding subtest (DSC).Apnea-hypopnea index was similar across groups (P = .15), but the sleep and awake hypoventilation groups had greater nocturnal hypoxemia compared with the no-hypoventilation group (P < .01). Within all groups, mean MoCA scores were < 26, which is the validated threshold to indicate mild cognitive impairment; RAVLT scores were lower than age-matched norms only in the awake-hypoventilation group (P ≤ .01); and DSC scores were lower than age-matched norms within all groups (P < .01). In multivariable regression analyses, higher arterial partial pressure of carbon dioxide (PaCO2) and TcCO2 during wakefulness were associated with lower MoCA and DSC scores (P ≤ .03), independent of confounders including overlap syndrome (OSA + chronic obstructive pulmonary disease).Awake hypoventilation is associated with greater deficits in cognitive function in patients with severe sleep-disordered breathing.Beaudin AE, Raneri JK, Ayas NT, Skomro RP, Smith EE, Hanly PJ; on behalf of Canadian Sleep and Circadian Network. Contribution of hypercapnia to cognitive impairment in severe sleep-disordered breathing. J Clin Sleep Med. 2022;18(1):245-254.

APAP, BPAP, CPAP, and New Modes of Positive Airway Pressure Therapy.

Abstract: Positive airway pressure (PAP) is the primary treatment of sleep-disordered breathing including obstructive sleep apnea, central sleep apnea, and sleep-related hypoventilation. Just as clinicians use pharmacological mechanism of action and pharmacokinetic data to optimize medication therapy for an individual, understanding how PAP works and choosing the right mode and device are critical to optimizing therapy in an individual patient. The first section of this chapter will describe the technology inside PAP devices that is essential for understanding the algorithms used to control the airflow and pressure. The second section will review how different comfort settings including ramp and expiratory pressure relief and modes of PAP therapy including continuous positive airway pressure (CPAP), autotitrating CPAP, bilevel positive airway pressure, adaptive servoventilation, and volume-assured pressure support control the airflow and pressure. Proprietary algorithms from several different manufacturers are described. This chapter derives its descriptions of algorithms from multiple sources including literature review, manufacture publications and websites, patents, and peer-reviewed device comparisons and from personal communication with manufacturer representatives. Clinical considerations related to the technological aspects of the different algorithms and features will be reviewed.

Sleep-related hypoventilation and hypercapnia in multiple system atrophy detected by polysomnography with transcutaneous carbon dioxide monitoring

Abstract: We aimed to evaluate sleep-related hypoventilation in multiple system atrophy (MSA) using polysomnography (PSG) with transcutaneous partial pressure of carbon dioxide (PtcCO2) monitoring. This prospective study included 34 patients with MSA. Motor and autonomic function, neuropsychological tests, PSG with PtcCO2 monitoring, and pulmonary function tests were performed. Sleep-related hypoventilation disorder (SRHD) was defined according to the International Classification of Sleep Disorders, third edition. Nine (27%) of the 34 patients met the diagnostic criteria of SRHD. Twenty-nine (85%) patients had sleep-related breathing disorders based on an Apnea–Hypopnea Index of ≥ 5/h. The patients with MSA and SRHD had a higher arousal index (p = 0.017) and obstructive apnea index (p = 0.041) than those without SRHD. There was no difference in the daytime partial pressure of carbon dioxide in arterial blood or respiratory function between MSA patients with and without SRHD. Sleep-related hypoventilation may occur in patients with MSA even with a normal daytime partial pressure of carbon dioxide. This can be noninvasively detected by PSG with PtcCO2 monitoring. SRBD and sleep-related hypoventilation are common among patients with MSA, and clinicians should take this into consideration while evaluating and treating this population.

Sex differences in patients with obesity hypoventilation syndrome: Do they really exist?

Abstract: The International Classification of Sleep Disorders (ICSD-3) defines obesity hypoventilation syndrome (OHS) as the triad of obesity (body mass index [BMI] >30 kg/m), daytime hypoventilation (PaCO2 levels >45 mmHg), and sleep-disordered breathing in the absence of other neuromuscular, mechanical, and metabolic reasons for hypoventilation. Several studies have assessed the differences between male and female OHS patients. A study involving 144 patients revealed that OHS was more prevalent in women. Moreover, women had significantly more comorbidities, such as diabetes mellitus, hypertension, and hypothyroidism, than men. In another large, longitudinal cohort study from Sweden involving 1527 OHS patients under home mechanical ventilation, the female patients were reportedly older, more obese, and more hypercapnic than males. Emergency noninvasive ventilation (NIV) was more frequently performed for female than male patients. The 5-year survival rates of both sexes were similar. However, 21% of the male patients and 28% of the female patients were initially diagnosed with chronic obstructive pulmonary disease (COPD). Ideally, they should have been excluded from the cohort (according to ICSD-3). This study aimed to assess the differences in clinical presentation, comorbidities, adherence to NIV, and prognosis between male and female OHS patients.

A pilot randomized trial comparing CPAP vs bilevel PAP spontaneous mode in the treatment of hypoventilation disorder in patients with obesity and obstructive airway disease

Abstract: Both obesity and airways disease can lead to chronic hypercapnic respiratory failure, which can be managed with positive airway pressure (PAP) therapy. The efficacy of PAP has been studied in obesity hypoventilation syndrome as well as in chronic hypercapnic chronic obstructive pulmonary disease patients, but not in patients where both obesity and airway obstruction coexist. This pilot study aims to compare the efficacy of continuous positive airway pressure vs bilevel positive airway pressure spontaneous mode in the treatment of hypoventilation disorder with obesity and obstructive airways disease.We sequentially screened PAP-naïve patients with stable chronic hypercapnic respiratory failure (PaCO2 > 45 mm Hg), obesity (body mass index > 30 kg/m2), and obstructive airways disease. Participants were randomized to continuous positive airway pressure or bilevel positive airway pressure spontaneous mode treatment for 3 months. Participants were blinded to their PAP allocation. Change in awake PaCO2 was the primary endpoint. Secondary endpoints included change in lung function, daytime sleepiness, sleep quality, quality of life, PAP adherence, and neurocognitive function.A total of 32 individuals were randomized (mean ± SD: age 61 ± 11 years, body mass index 43 ± 7 kg/m2, PaCO2 54 ± 7 mm Hg, forced expiratory volume in 1 second 1.4 ± 0.6L, apnea-hypopnea index 59 ± 35 events/h). Sixteen participants in each PAP group were analyzed. Bilevel positive airway pressure yielded a greater improvement in PaCO2 compared to continuous positive airway pressure (9.4 mm Hg, 95% confidence interval, 4.3-15 mm Hg). There were no significant differences in PAP adherence, sleepiness, sleep quality, or neurocognitive function between the two therapies.Although both PAP modalities improved hypercapnic respiratory failure in this group of individuals, bilevel positive airway pressure spontaneous mode showed greater efficacy in reducing PaCO2.Registry: Australian New Zealand Clinical Trials Registry; Name: Nocturnal ventilatory support in obesity hypoventilation syndrome; URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12605000096651; Identifier: ACTRN12605000096651.Zheng Y, Yee BJ, Wong K, Grunstein R, Piper A. A pilot randomized trial comparing CPAP vs bilevel PAP spontaneous mode in the treatment of hypoventilation disorder in patients with obesity and obstructive airway disease. J Clin Sleep Med. 2022;18(1):99-107.

Study of the relationship between regional cerebral saturation and pCO2 changes during mechanical ventilation to evaluate modifications in cerebral perfusion in a newborn piglet model

Abstract: Near-infrared spectroscopy (NIRS) could be a useful continuous, non-invasive technique for monitoring the effect of partial pressure of carbon dioxide (PaCO2) fluctuations in the cerebral circulation during ventilation. The aim of this study was to examine the efficacy of NIRS to detect acute changes in cerebral blood flow following PaCO2 fluctuations after confirming the autoregulation physiology in piglets. Fourteen piglets (<72 h of life) were studied. Mean arterial blood pressure, oxygen saturation, pH, glycemia, hemoglobin, electrolytes, and temperature were monitored. Eight animals were used to evaluate brain autoregulation, assessing superior cava vein Doppler as a proxy of cerebral blood flow changing mean arterial blood pressure. Another 6 animals were used to assess hypercapnia generated by decreasing ventilatory settings and complementary CO2 through the ventilator circuit and hypocapnia due to increasing ventilatory settings. Cerebral blood flow was determined by jugular vein blood flow by Doppler and continuously monitored with NIRS. A decrease in PaCO2 was observed after hyperventilation (47.6±2.4 to 29.0±4.9 mmHg). An increase in PaCO2 was observed after hypoventilation (48.5±5.5 to 90.4±25.1 mmHg). A decrease in cerebral blood flow after hyperventilation (21.8±10.4 to 15.1±11.0 mL/min) and an increase after hypoventilation (23.4±8.4 to 38.3±10.5 mL/min) were detected by Doppler ultrasound. A significant correlation was found between cerebral oxygenation and Doppler-derived parameters of blood flow and PaCO2. Although cerebral NIRS monitoring is mainly used to detect changes in regional brain oxygenation, modifications in cerebral blood flow following experimental PaCO2 changes were detected in newborn piglets when no other important variables were modified.

Long‐term mechanical ventilation of an 8‐week‐old dog with idiopathic polyradiculoneuritis

Abstract: A 2-month-old labrador retriever diagnosed with progressive polyradiculoneuritis was anaesthetised and mechanically ventilated with the aid of pressure control ventilation due to severe hypoventilation and hypoxaemia. Anaesthesia was maintained with propofol and midazolam constant-rate infusions (CRIs). Over time, once the patient was showing spontaneous breathing attempts and arterial partial pressure of carbon dioxide (PaCO2) was within normal range, ventilatory mode was switched to pressure support ventilation. The anaesthetic protocol was modified to maintain an appropriate level of anaesthesia with a minimum amount of fluid administered. The midazolam CRI was substituted by a sufentanil CRI, followed by a change to a dexmedetomidine CRI. An intensive nursing care protocol was established. Intermittent hyperthermia and peripheral oedema were the main complications observed. Ventilatory support was reduced until the patient was successfully weaned from the ventilator at the third attempt after 116 hours of ventilatory support.

Characterization of sleep-disordered breathing in children with Duchenne muscular dystrophy by the American Academy of Sleep Medicine criteria vs disease-specific criteria: what are the differences?

Abstract: Individuals with Duchenne muscular dystrophy (DMD) frequently develop sleep-disordered breathing. Noninvasive ventilation is often prescribed for sleep-disordered breathing treatment based on the American Academy of Sleep Medicine (AASM) criteria. In 2018, DMD disease-specific criteria for sleep-disordered breathing were established. Our study aimed to examine the clinical interpretation differences using these different criteria.We performed a multicenter, retrospective chart review of children with DMD followed at The Hospital for Sick Children, Toronto, Canada, and Rady Children's Hospital, San Diego, California, who underwent polysomnography from August 1, 2012, to February 29, 2020. Baseline characteristics and polysomnography data were summarized using descriptive statistics. Agreement for the diagnosis of sleep-disordered breathing evaluated by kappa statistics and sensitivity/specificity analysis was assessed.One hundred five male children with DMD (mean ± SD age: 12.1 ± 3.8 years; body mass index z score: 0.2 ± 2.3) were included. The proportions of children with DMD that met at least 1 AASM criterion and at least 1 DMD criterion were 45.7% and 67.6%, respectively. We found that 32.4% of children met neither AASM nor DMD criteria. Overall agreement between AASM and DMD criteria was moderate (k = 0.57). There was almost perfect agreement in sleep apnea diagnosis (k = 0.90); however, there was only slight agreement in hypoventilation diagnosis (k = 0.12) between AASM and DMD criteria.There were more children with DMD diagnosed with nocturnal hypoventilation and prescribed noninvasive ventilation using DMD criteria compared with AASM criteria. Future studies should address whether the prescription of noninvasive ventilation for children with DMD based on both criteria is associated with different clinical outcomes.Hurvitz MS, Sunkonkit K, Massicotte C, Li R, Bhattacharjee R, Amin R. Characterization of sleep-disordered breathing in children with Duchenne muscular dystrophy by the American Academy of Sleep Medicine criteria vs disease-specific criteria: what are the differences? J Clin Sleep Med. 2022;18(2):609-615.

Diaphragm pacing in congenital central hypoventilation syndrome: A safe and final tool

Abstract: We have read with great interest this article, describing the use of diaphragm pacing (DP) in patients with congenital central hypoven tilation syndrome (CCHS) who need tracheostomy and non- invasive ventilation (NIV). In this issue of Acta Paediatrica, Tsolakis et al. 1 take a step to wards bridging our knowledge gap on this subject by reporting a co hort of patients ( n = 23) treated with DP over a 40- year span at 12 centres mainly through international referrals. DP use in CCHS has been described for more than five decades ago. 2 Since then, several reports and case series showed its efficacy, short comings, compli cations 3 and different surgical techniques. In review of this brief report, we are interested to learn more about pulmonary function measurements (e.g. polysomnogram) and upper airway assessment 4 (e.g. capnography to evaluate nocturnal hypoventilation and direct laryngoscopy). It is quite unique the success the authors showed in tracheos tomy patients in this cohort who were successfully decannulated after DP implementation. We are interested to learn of the strate gies and criteria used to consider when removing the tracheostomy tubes, 5 the immediate post- operative complications. Finally, home mechanical ventilation quality of life and home care protocols in this study are essential since DP implementation. How did care givers at home adjust to these changes and what safety measurements were put in place to help families accommodate the new technology?

Effectiveness of CPAP vs. Noninvasive Ventilation Based on Disease Severity in Obesity Hypoventilation Syndrome and Concomitant Severe Obstructive Sleep Apnea

Abstract: Obesity hypoventilation syndrome (OHS) with concomitant severe obstructive sleep apnea (OSA) is treated with CPAP or noninvasive ventilation (NIV) during sleep. NIV is costlier, but may be advantageous because it provides ventilatory support. However, there are no long-term trials comparing these treatment modalities based on OHS severity.To determine if CPAP have similar effectiveness when compared to NIV according to OHS severity subgroups.Post hoc analysis of the Pickwick randomized clinical trial in which 215 ambulatory patients with untreated OHS and concomitant severe OSA, defined as apnoea-hypopnea index (AHI)≥30events/h, were allocated to NIV or CPAP. In the present analysis, the Pickwick cohort was divided in severity subgroups based on the degree of baseline daytime hypercapnia (PaCO2 of 45-49.9 or ≥50mmHg). Repeated measures of PaCO2 and PaO2 during the subsequent 3 years were compared between CPAP and NIV in the two severity subgroups. Statistical analysis was performed using linear mixed-effects model.204 patients, 97 in the NIV group and 107 in the CPAP group were analyzed. The longitudinal improvements of PaCO2 and PaO2 were similar between CPAP and NIV based on the PaCO2 severity subgroups.In ambulatory patients with OHS and concomitant severe OSA who were treated with NIV or CPAP, long-term NIV therapy was similar to CPAP in improving awake hypercapnia, regardless of the severity of baseline hypercapnia. Therefore, in this patient population, the decision to prescribe CPAP or NIV cannot be solely based on the presenting level of PaCO2.

HIDEA syndrome: A rare cause of congenital hypoventilation in a premature infant

Abstract: HIDEA (hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy and eye abnormalities) syndrome is a rare and novel disease. We describe a premature patient who required extensive work up for his hypoventilation with a diagnosis of HIDEA syndrome.

Partial update of the German S3 Guideline Sleep-Related Breathing Disorders in Adults

Abstract: 1 AbstractA review of the recommendations in the currently applicable version of the chapter “Sleep-related breathing disorders in adults” in the guideline “Non-restorative sleep/sleep disorders” conducted by the guideline steering group identified a number of recommendations and chapters requiring revision or updating in the light of new scientific or clinical evidence. These included selected chapters on diagnosis (clinical examination, polysomnography, respiratory polygraphy, and diagnosis with reduced and alternative systems) and treatment (positional therapy, surgical procedures) of sleep-related breathing disorders, as well as the chapters on obstructive sleep apnea (OSA) and dementia and on sleep-related hypoventilation/sleep-related hypoxemia. These chapters were updated according to the methodology of an S3 guideline. The remaining recommendations and chapters, on the other hand, retain their validity for the time being.With regard to the diagnosis of sleep apnea, a number of recommendations on clinical examinations, as well as on respiratory polygraphy and polysomnography, have been specified more precisely and modified. A chapter on diagnosis has been supplemented with alternative systems: tonometry-based diagnostics has been included as an alternative for the diagnosis of sleep apnea. Positional therapy for positional OSA and tonsillectomy with uvulopalatopharyngoplasty are given a higher level of recommendation based on new randomized trials. Recommendations on OSA and dementia can no longer be made due to a lack of evidence; the recommendations on sleep-related hypoventilation/sleep-related hypoxemia have been specified with greater precision.

Phox2b mutation mediated by Atoh1 expression impaired respiratory rhythm and ventilatory responses to hypoxia and hypercapnia

Abstract: Mutations in the transcription factor Phox2b cause congenital central hypoventilation syndrome (CCHS). The syndrome is characterized by hypoventilation and inability to regulate breathing to maintain adequate O 2 and CO 2 levels. The mechanism by which CCHS impact respiratory control is incompletely understood, and even less is known about the impact of the non-polyalanine repeat expansion mutations (NPARM) form. Our goal was to investigate the extent by which NPARM Phox2b mutation affect (a) respiratory rhythm; (b) ventilatory responses to hypercapnia (HCVR) and hypoxia (HVR); and (c) number of chemosensitive neurons in mice. We used a transgenic mouse line carrying a conditional Phox2b Δ8 mutation (same found in humans with NPARM CCHS). We crossed them with Atoh1 cre mice to introduce mutation in regions involved with respiratory function and central chemoreflex control. Ventilation was measured by plethysmograph during neonatal and adult life. In room air, mutation in neonates and adult did not greatly impact basal ventilation. However, Phox2b Δ8 , Atoh1 cre increased breath irregularity in adults. The HVR and HCVR were impaired in neonates. The HVR, but not HCVR, was still partially compromised in adults. The mutation reduced the number of Phox2b + /TH - -expressing neurons as well as the number of fos-activated cells within the ventral parafacial region (also named retrotrapezoid nucleus [RTN] region) induced by hypercapnia. Our data indicates that Phox2b Δ8 mutation in Atoh1 -expressing cells impaired RTN neurons, as well as chemoreflex under hypoxia and hypercapnia specially early in life. This study provided new evidence for mechanisms related to NPARM form of CCHS neuropathology.

A Comparative Study on the Effects of Ketofol, Dexmedetomidine, and Isofol in Anesthesia of Candidates for Dilatation and Curettage

Abstract: Dilatation and curettage (D & C) is one of the relatively common surgeries among women. Familiarity with the analgesics, along with their different uses and specific characteristics, can help to determine the best and most appropriate drug to control pain in the patients.This study aimed to compare the effects of ketofol, dexmedetomidine, and isofol in anesthesia of candidates for D & C.In this double-blind clinical trial, 150 candidates for D & C surgeries with ASA class 1 and 2 were included. Patients were randomly divided into three groups. The first group received ketamine + propofol, the second group received dexmedetomidine, and the third group received isofol (isoflurane + propofol). Any hemodynamic changes or respiratory disorders, including apnea or hypoventilation, drop in the level of blood oxygen saturation, and the need for respiratory support, were recorded and compared.Hypoventilation was observed in 47 patients in isofol group, 18 in the dexmedetomidine group, and 42 in ketofol group. Also, 48 patients in the isofol group, eight in the dexmedetomidine group, and 33 in the ketofol group experienced apnea. Moreover, 17 patients in the dexmedetomidine group, 35 in the ketofol group, and eight in the isofol group experienced bradycardia. The rate of bradycardia was significantly higher in the dexmedetomidine group (70%) compared to the other two groups, and the rate of hypotension was significantly higher in the isofol group (P = 0.001).According to the results, dexmedetomidine was associated with fewer complications during general anesthesia in D & C surgery.