Pathophysiology of Chronic Hypercapnic Respiratory Failure.

Chronic hypercapnic respiratory failure occurs in several conditions associated with hypoventilation. The mechanisms underlying the development of chronic hypercapnia include a combination of processes that increase metabolic CO2 production, reduce minute ventilation (V'e), or increase dead space fraction (Vd/Vt). Fundamental to the pathophysiology is a mismatch between increased load and a reduction in the capacity of the respiratory pump to compensate. Though neural respiratory drive may be decreased in a subset of central hypoventilation disorders, it is more commonly increased in attempting to maintain the load-capacity homeostatic balance.

Autism spectrum disorder in young patients with congenital central hypoventilation syndrome: role of the autonomic nervous system dysfunction.

BACKGROUND: Congenital central hypoventilation syndrome (CCHS) is a rare condition characterized by alveolar hypoventilation and autonomic nervous system (ANS) dysfunction requiring long-term ventilation. CCHS could constitute a risk factor of autism spectrum disorder (ASD) due to birth injury related to respiratory failure, which remains to be determined. ANS dysfunction has also been described in ASD and there are indications for altered contribution of ANS-central nervous system interaction in processing of social information; thus, CCHS could be a risk factor for ASD based on pathophysiological background also. Our study aimed to determine the prevalence of ASD among CCHS patients, identify risk factors, and explore the relationship between the ANS, evaluated by heart rate variability indices, and adaptative functioning. RESULTS: Our retrospective study, based on the analysis of records of a French national center of patients with CCHS under 20 years of age, determined that the prevalence of ASD (diagnosed by a psychiatrist, following the criteria of DSM-4 or DSM-5) was 6/69 patients, 8.7% (95% confidence interval: 3.3-18.0%). In a case (CCHS with ASD, n = 6) - control (CCHS without ASD, n = 12) study with matching on sex, longer neonatal hospitalization stay and glycemic dysfunction were associated with ASD. Adaptative functioning was assessed using Vineland Adaptative behavioral scales (VABS) and heart rate variability indices (including daytime RMSSD as an index of parasympathetic modulation) were obtained from ECG Holter performed the same day. In 19 young subjects with CCHS who had both ECG Holter and VABS, significant positive correlations were observed between RMSSD and three of four sub-domains of the VABS (communication: R = 0.50, p = 0.028; daily living skills: R = 0.60, p = 0.006; socialization: R = 0.52, p = 0.021). CONCLUSION: Our study suggests a high prevalence of ASD in patients with CCHS. Glycemic dysfunction and longer initial hospitalization stays were associated with ASD development. A defect in parasympathetic modulation was associated with worse adaptative functioning.

Congenital Central Hypoventilation Syndrome and Disorders of Control of Ventilation.

Congenital disorders of ventilatory control typically manifest as central apneas, periodic breathing, and hypoventilation in the neonatal period, but some may present at a later age. Obstructive apneas may be the initial presentation, and some may have associated autonomic nervous system dysfunction. Individuals with these disorders can have absent or impaired ventilatory and arousal responses to hypoxemia and hypercapnia. This article discusses the presentation, pathophysiology, evaluation, and management of congenital central hypoventilation syndrome, rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome, Prader-Willi syndrome, and myelomeningocele.

Brief apnea with hypoventilation reduces seizure duration and shifts seizure location for several hours in a model of severe traumatic brain injury.

OBJECTIVE: Seizures can be difficult to control in infants and toddlers. Seizures with periods of apnea and hypoventilation are common following severe traumatic brain injury (TBI). We previously observed that brief apnea with hypoventilation (A&H) in our severe TBI model acutely interrupted seizures. The current study is designed to determine the effect of A&H on subsequent seizures and whether A&H has potential therapeutic implications. METHODS: Piglets (1 week or 1 month old) received multifactorial injuries: cortical impact, mass effect, subdural hematoma, subarachnoid hemorrhage, and seizures induced with kainic acid. A&H (1 min apnea, 10 min hypoventilation) was induced either before or after seizure induction, or control piglets received subdural/subarachnoid hematoma and seizure without A&H. In an intensive care unit, piglets were sedated, intubated, and mechanically ventilated, and epidural electroencephalogram was recorded for an average of 18 h after seizure induction. RESULTS: In our severe TBI model, A&H after seizure reduced ipsilateral seizure burden by 80% compared to the same injuries without A&H. In the A&H before seizure induction group, more piglets had exclusively contralateral seizures, although most piglets in all groups had seizures that shifted location throughout the several hours of seizure. After 8-10 h, seizures transitioned to interictal epileptiform discharges regardless of A&H or timing of A&H. SIGNIFICANCE: Even brief A&H may alter traumatic seizures. In our preclinical model, we will address the possibility of hypercapnia with normoxia, with controlled intracranial pressure, as a therapeutic option for children with status epilepticus after hemorrhagic TBI.

An unusual ophthalmologic finding in a patient with congenital central hypoventilation syndrome.

INTRODUCTION: Congenital Central Hypoventilation Syndrome (CCHS) is a rare disease due to a severely impaired central control of breathing and dysfunction of the autonomic nervous system. Ophthalmologic abnormalities are common in patients with CCHS and include horizontal strabismus, pupil and iris abnormalities and ptosis. We report a unique case of CCHS in association with monocular elevation deficit (MED) in a boy diagnosed with CCHS at birth. CASE DESCRIPTION: We report a case of a boy with a confirmed diagnosis of CCHS (complete sequencing of the paired-like homeobox 2b (PHOX2B) gene) after presenting little respiratory effort and cyanosis at birth. The ophthalmological examination shows an impaired elevation of the left eye, both in adduction and abduction, associated with mild and variable left ptosis. His mother has observed that the left eyelid elevates when the child feeds. A deviation in the primary gaze position or a chin-up position are not present. The funduscopic examination is normal. Given that deviation is limited to upgaze, the ptosis is mild and the patient's age, observation is decided. CONCLUSIONS: Ophthalmologic abnormalities are common in patients with CCHS and include horizontal strabismus, pupil and iris abnormalities and ptosis. To the best of our knowledge, this is the first report of MED in association with CCHS. Further studies are needed to determine if an association between MED and CCHS exists or is just a casual finding in this case.

Alkalosis-induced hypoventilation in cystic fibrosis: The importance of efficient renal adaptation.

The lungs and kidneys are pivotal organs in the regulation of body acid-base homeostasis. In cystic fibrosis (CF), the impaired renal ability to excrete an excess amount of HCO3- into the urine leads to metabolic alkalosis [P. Berg et al., J. Am. Soc. Nephrol. 31, 1711-1727 (2020); F. Al-Ghimlas, M. E. Faughnan, E. Tullis, Open Respir. Med. J. 6, 59-62 (2012)]. This is caused by defective HCO3- secretion in the ß-intercalated cells of the collecting duct that requires both the cystic fibrosis transmembrane conductance regulator (CFTR) and pendrin for normal function [P. Berg et al., J. Am. Soc. Nephrol. 31, 1711-1727 (2020)]. We studied the ventilatory consequences of acute oral base loading in normal, pendrin knockout (KO), and CFTR KO mice. In wild-type mice, oral base loading induced a dose-dependent metabolic alkalosis, fast urinary removal of base, and a moderate base load did not perturb ventilation. In contrast, CFTR and pendrin KO mice, which are unable to rapidly excrete excess base into the urine, developed a marked and transient depression of ventilation when subjected to the same base load. Therefore, swift renal base elimination in response to an acute oral base load is a necessary physiological function to avoid ventilatory depression. The transient urinary alkalization in the postprandial state is suggested to have evolved for proactive avoidance of hypoventilation. In CF, metabolic alkalosis may contribute to the commonly reduced lung function via a suppression of ventilatory drive.

Respiratory depressant effects of fentanyl analogs are opioid receptor-mediated.

Opioid-related fatalities involving synthetic opioids have reached unprecedented levels. This study evaluated the respiratory depressant effects of seven fentanyl analogs that have either emerged in the illicit drug supply or been identified in toxicological analyses following fatal or non-fatal intoxications. Adult male Swiss Webster mice were administered fentanyl analogs (isobutyrylfentanyl, crotonylfentanyl, para-methoxyfentanyl, para-methoxybutyrylfentanyl, 3-furanylfentanyl, thiophenefentanyl, and benzodioxolefentanyl) and their effects on minute volume as compared to mu-opioid receptor (MOR) agonist standards (fentanyl, morphine, and buprenorphine) were measured using whole body plethysmography (WBP). All drugs elicited significant (p ≤ 0.05) hypoventilation relative to vehicle for at least one dose tested: morphine (1, 3.2, 10, 32 mg/kg), buprenorphine, (0.032, 0.1, 0.32, 1, 3.2 mg/kg), fentanyl (0.0032, 0.01, 0.032, 0.1, 1, 32 mg/kg), isobutyrylfentanyl (0.1, 0.32, 1, 3.2, 10 mg/kg), crotonylfentanyl (0.1, 0.32, 1, 3.2, 10 mg/kg), para-methoxyfentanyl (0.1, 0.32, 1, 3.2, 10 mg/kg), para-methoxybutyrylfentanyl (0.32, 1, 3.2, 10 mg/kg), 3-furanylfentanyl (0.1, 0.32, 1, 3.2, 10 mg/kg), thiophenefentanyl (1, 3.2, 10, 32, 100 mg/kg), and benzodioxolefentanyl (3.2, 10, 32, 100 mg/kg). The ED50 values for hypoventilation showed a rank order of potency as follows: fentanyl (ED50 = 0.96 mg/kg) > 3-furanylfentanyl (ED50 = 2.60 mg/kg) > crotonylfentanyl (ED50 = 2.72 mg/kg) > para-methoxyfentanyl (ED50 = 3.31 mg/kg) > buprenorphine (ED50 = 10.8 mg/kg) > isobutyrylfentanyl (ED50 = 13.5 mg/kg) > para-methoxybutyrylfentanyl (ED50 = 16.1 mg/kg) > thiophenefentanyl (ED50 = 18.0 mg/kg) > morphine (ED50 = 55.3 mg/kg) > benzodioxolefentanyl (ED50 = 10,168 mg/kg). A naloxone pretreatment (10 mg/kg) attenuated the hypoventilatory effects of all drugs. These results establish that the respiratory depressant effects of these fentanyl analogs are at least in part mediated by the MOR.

Cerebral Autoregulation during Orthostatic Challenge in Congenital Central Hypoventilation Syndrome.

Rationale: Congenital central hypoventilation syndrome (CCHS) is a rare autonomic disorder with altered regulation of breathing, heart rate (HR), and blood pressure (BP). Aberrant cerebral oxygenation in response to hypercapnia/hypoxia in CCHS raises the concern that altered cerebral autoregulation may contribute to CCHS-related, variably impaired neurodevelopment. Objectives: To evaluate cerebral autoregulation in response to orthostatic challenge in CCHS cases versus controls. Methods: CCHS and age- and sex-matched control subjects were studied with head-up tilt (HUT) testing to induce orthostatic stress. Fifty CCHS and 100 control HUT recordings were included. HR, BP, and cerebral oxygen saturation (regional oxygen saturation) were continuously monitored. The cerebral oximetry index (COx), a real-time measure of cerebral autoregulation based on these measures, was calculated. Measurements and Main Results: HUT resulted in a greater mean BP decrease from baseline in CCHS versus controls (11% vs. 6%; P < 0.05) and a diminished increase in HR in CCHS versus controls (11% vs. 18%; P < 0.01) in the 5 minutes after tilt-up. Despite a similar COx at baseline, orthostatic provocation within 5 minutes of tilt-up caused a 50% greater increase in COx (P < 0.01) and a 29% increase in minutes of impaired autoregulation (P < 0.02) in CCHS versus controls (4.0 vs. 3.1 min). Conclusions: Cerebral autoregulatory mechanisms appear to be intact in CCHS, but the greater hypotension observed in CCHS consequent to orthostatic provocation is associated with greater values of COx/impaired autoregulation when BP is below the lower limits of autoregulation. Effects of repeated orthostatic challenges in everyday living in CCHS necessitate further study to determine their influence on neurodevelopmental disease burden.

Gavage approach to oxygen supplementation with oxygen therapeutic Ox66™ in a hypoventilation rodent model of respiratory distress.

Acute respiratory distress syndrome (ARDS) features pulmonary dysfunction capable of causing life-threatening hypoxaemia. Ventilation and hyperoxic therapies force oxygen through dysfunctional alveoli but risk exacerbating damage. Ox66™ is an ingestible, solid-state oxygen product designed for oxygen supplementation. Eighteen anaesthetized, ventilated rats were subjected to a 40% reduction in tidal volume to produce a hypoventilatory simulation of the hypoxia in ARDS (HV-ARDS). After 60 min, animals were randomized to receive either normal saline (Saline; volume control) or Ox66™ gavage. Cardiovascular function and blood oximetry/chemistry were measured alongside interstitial oxygenation (PISFO2) of the peripheral spinotrapezius muscle. HV-ARDS reduced mean arterial pressure by ∼20% and PISFO2 by ∼35% for both groups. Ox66™ gavage treatment at 60 min improved PISFO2 over Saline (p < .0001), restoring baseline values, however, the effect was temporary. A second bolus at 120 min repeated the OX66™ PISFO2 response, which remained elevated over Saline (p < .01) until study end and was supported by systemic parameters of lactate, PaO2, SO2, and base deficit. Saline remained hypotensive, whereas Ox66™ became normotensive. Vasoconstriction was observed in the Saline, but not Ox66™ group. Supplemental oxygenation through Ox66™ gavage increased peripheral tissue oxygenation, warranting further study for disorders featuring dysfunction of pulmonary perfusion like ARDS.

Obstructive Apneas in a Mouse Model of Congenital Central Hypoventilation Syndrome.

Rationale: Congenital central hypoventilation syndrome (CCHS) is characterized by life-threatening sleep hypoventilation and is caused by PHOX2B gene mutations, most frequently the PHOX2B27Ala/+ mutation, with patients requiring lifelong ventilatory support. It is unclear whether obstructive apneas are part of the syndrome. Objectives: To determine if Phox2b27Ala/+ mice, which present the main symptoms of CCHS and die within hours after birth, also express obstructive apneas, and to investigate potential underlying mechanisms. Methods: Apneas were classified as central, obstructive, or mixed by using a novel system combining pneumotachography and laser detection of abdominal movement immediately after birth. Several respiratory nuclei involved in airway patency were examined by immunohistochemistry and electrophysiology in brainstem-spinal cord preparations. Measurements and Main Results: The median (interquartile range) of obstructive apnea frequency was 2.3 (1.5-3.3)/min in Phox2b27Ala/+ pups versus 0.6 (0.4-1.0)/min in wild types (P < 0.0001). Obstructive apnea duration was 2.7 seconds (2.3-3.9) in Phox2b27Ala/+ pups versus 1.7 seconds (1.1-1.9) in wild types (P < 0.0001). Central and mixed apneas presented similar significant differences. In Phox2b27Ala/+ preparations, the hypoglossal nucleus had fewer (P < 0.05) and smaller (P < 0.01) neurons, compared with wild-type preparations. Importantly, coordination of phrenic and hypoglossal motor activities was disrupted, as evidenced by the longer and variable delay of hypoglossal activity with respect to phrenic activity onset (P < 0.001). Conclusions: The Phox2b27Ala/+ mutation predisposed pups not only to hypoventilation and central apneas, but also to obstructive and mixed apneas, likely because of hypoglossal dysgenesis. These results thus demand attention toward obstructive events in infants with CCHS.

Hypoxia inducible factor 1-α is minimally involved in determining the time domains of the hypoxic ventilatory response in adult zebrafish (Danio rerio).

In the current study, adult zebrafish (Danio rerio) were exposed to 72 h hypoxia (90 mmHg) to assess the time domains of the hypoxia ventilatory response (HVR) and the consequence on a subsequent more severe (40 mmHg) bout of acute hypoxia. Experiments were performed on wild-type fish and mutants in which one or both paralogs of hypoxia inducible factor-1α (hif-1α) were knocked out. Although there were subtle differences among the wild-type and knockout fish, resting fV was reestablished after 2-8 h of continuous hypoxia in both groups, a striking example of hypoxic ventilatory decline (HVD). When fish were subsequently exposed to more severe hypoxia, a rapid increase in fV was observed, the magnitude of which was independent of genotype or prior exposure history. During recovery, fish that had been exposed to 72 h of 90 mmHg hypoxia exhibited a pronounced undershoot in fV, which was absent in the hif-1α double knockouts. Overall, the results revealed distinct time domains of the HVR in zebrafish that were largely Hif-1α-independent.

The Effect of Tonsillectomy and Adenoidectomy on Isolated Sleep Associated Hypoventilation in Children.

OBJECTIVE: Sleep associated hypoventilation (SAH) is diagnosed when more than 25% of total sleep time (%TST) is spent with end tidal carbon dioxide (EtCO2 ) > 50 mmHg. SAH in children occurs as a single entity or combined with obstructive sleep apnea. Outcomes of surgical treatment for isolated SAH in children have not been reported. METHODS: The medical charts of children who were diagnosed with isolated SAH and did not have OSA at a tertiary children's hospital between January 2013 and December 2019 were reviewed. Data collection included information on history and physical examination, past medical history, polysomnography (PSG) findings, and surgical management. RESULTS: Seventeen children (10 male, 7 female, age range: 3-14 years) were diagnosed with isolated SAH. Comorbid conditions included asthma in four children, Down syndrome in one, and seizure in two. Eight children were normal weight, four were overweight, and five were obese. Children did not have obstructive or central sleep apnea. Three children (18%) had persistent SAH as documented by PSG. All normal weight children had resolution of SAH whereas two obese children and one overweight child had residual SAH. %TST with CO2 > 50 mmHg after upper airway surgery (3.4% ± 1.6%) was significantly less than that of before TA (59.1% ± 5.5%) (P < .001). CONCLUSIONS: The majority of children with isolated SAH had normalization of hypercapnia after TA. Further studies in larger groups of children are needed to identify the risk factors for residual isolated SAH after TA. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E1380-E1382, 2021.

The severity of sleep hypoventilation in stable chronic obstructive pulmonary disease.

PURPOSE: An increase in PaCO2 is the element that defines sleep hypoventilation (SH). We queried if patients with SH, and those with PaCO2 increases during sleep for shorter time periods than SH (shamSH) differed from the patients without SH (noSH) in other ways. METHODS: This was a retrospective re-analysis of data from 100 stable inpatients with COPD with and without chronic hypercapnic respiratory failure. COPD was defined by criteria of the Global initiative for Chronic Obstructive Lung Disease (GOLD). For this study, SH was defined by an increase in PaCO2 ≥ 1.33 kPa to a value exceeding 6.7 kPa for ≥ 10 min (≥ 20 epochs of 30 s). Patients fulfilling the increase in PaCO2 for less than 10 min (1-19 epochs) were designated shamSH. All patients had daytime arterial blood gases, lung function tests, and polysomnography (PSG) with transcutaneous CO2 (PtcCO2). RESULTS: Of 100 patients, 25 had PtcCO2 increase ≥ 1.33 kPa. One never exceeded 6.7 kPa, 15 had SH, and 9 shamSH. SH and shamSH patients had extra CO2 load (= PtcCO2*time) both during and between the SH periods compared to the noSH group, the SH group more than the shamSH group. CONCLUSION: Using CO2 load as a measure of severity of sleep hypoventilation, SH patients have worse hypoventilation than the shamSH. Both shamSH and SH groups have extra CO2 load during and between SH periods, indicating that the SH/shamSH patients may represent a separate group of true hypoventilators during sleep.

Neonatal apneic phenotype in a murine congenital central hypoventilation syndrome model is induced through non-cell autonomous developmental mechanisms.

Congenital central hypoventilation syndrome (CCHS) represents a rare genetic disorder usually caused by mutations in the homeodomain transcription factor PHOX2B. Some CCHS patients suffer mainly from deficiencies in CO2 and/or O2 respiratory chemoreflex, whereas other patients present with full apnea shortly after birth. Our goal was to identify the neuropathological mechanisms of apneic presentations in CCHS. In the developing murine neuroepithelium, Phox2b is expressed in three discrete progenitor domains across the dorsal-ventral axis, with different domains responsible for producing unique autonomic or visceral motor neurons. Restricting the expression of mutant Phox2b to the ventral visceral motor neuron domain induces marked newborn apnea together with a significant loss of visceral motor neurons, RTN ablation, and preBötzinger complex dysfunction. This finding suggests that the observed apnea develops through non-cell autonomous developmental mechanisms. Mutant Phox2b expression in dorsal rhombencephalic neurons did not generate significant respiratory dysfunction, but did result in subtle metabolic thermoregulatory deficiencies. We confirm the expression of a novel murine Phox2b splice variant which shares exons 1 and 2 with the more widely studied Phox2b splice variant, but which differs in exon 3 where most CCHS mutations occur. We also show that mutant Phox2b expression in the visceral motor neuron progenitor domain increases cell proliferation at the expense of visceral motor neuron development. We propose that visceral motor neurons may function as organizers of brainstem respiratory neuron development, and that disruptions in their development result in secondary/non-cell autonomous maldevelopment of key brainstem respiratory neurons.

Sleep-disordered breathing, respiratory patterns during wakefulness and functional capacity in pediatric patients with rapid-onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysregulation syndrome.

OBJECTIVE: To characterize the clinical presentation of sleep-disordered breathing and respiratory patterns at rest and during a 6-min walk test (6MWT) in children with rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome. METHODS: Retrospective study of children with ROHHAD who had a diagnostic baseline polysomnography, daytime cardiorespiratory monitoring at rest and a 6MWT. Polysomnography data were also compared with body mass index-, age-, and sex-matched controls. RESULTS: Of the eight children with ROHHAD, all eight (100%) had obstructive sleep apnea (OSA) and 2/8 (25%) had nocturnal hypoventilation (NH) on their baseline polysomnography. Comparing the ROHHAD group to the control group, there were no significant differences in the median (interquartile range [IQR]) obstructive apnea-hypopnea index (11.1 [4.3-58.4] vs. 14.4 [10.3-23.3] events/h, respectively; p = .78). However, children with ROHHAD showed a significantly higher desaturation index compared to the control group (37.9 [13.7-59.8] vs. 14.7 [4.3-27.6] events/h; p = .05). While awake at rest, some children with ROHHAD experienced significant desaturations associated with central pauses. During the 6MWT, no significant desaturations were observed, but two children showed moderate functional limitation. CONCLUSIONS: Among children with ROHHAD, respiratory instability may be demonstrated by a significant number and severity of oxygen desaturations during sleep in the presence of OSA, with or without NH, and oxygen desaturations with central pauses at rest during wakefulness. Interestingly, during daily activities that require submaximal effort, children may not experience oxygen desaturations. Early recognition of respiratory abnormalities and targeted therapeutic interventions are important to limit associated morbidity and mortality in ROHHAD.

Trastorno de hipoventilación central del sueño en pediatría: causas poco frecuentes / Central hypoventilation disorders sleep-related in pediatrics: unusual causes

Congenital central hypoventilation syndrome (CCHS) and rapid-onset obesity syndrome with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) are rare causes of hypoventilation during sleep in the pediatric population. This group of disorders are characterized by the absence or decrease in the automatic control of ventilation, decreased sensitivity of chemoreceptors to CO2, causing hypoventilation during sleep and even in wakefulness, in the most severe cases. For these reasons it is important to diagnose and treat them promptly. The objective of this review is to provide current and complete literature, to be able to identify, treat and refer this group of children early, and thus reduce the complications and/or associated comorbidities in the short and long term, improving their quality of life.

El síndrome de hipoventilación central congénita (CCHS) y síndrome de obesidad de inicio rápido con disfunción hipotalámica, hipoventilación y desregulación autonómica (ROHHAD), son causas poco comunes de hipoventilación durante el sueño en la población pediátrica. Este grupo de trastornos se caracterizan por ausencia o disminución en el control automático de la ventilación, sensibilidad disminuida de los quimioreceptores al CO2, provocando hipoventilación durante el sueño e incluso en vigilia, en los casos más severos. Por estas razones es importante diagnosticarlos y tratarlos oportunamente. El objetivo de esta revisión es proporcionar literatura actual y completa, para poder identificar, tratar y referir a éste grupo de niños tempranamente, y así disminuir las complicaciones y/o comorbilidades asociadas a corto y largo plazo, mejorando su calidad de vida.