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.

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.

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

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

Nocturnal Hypoventilation as a Respiratory Complication of Acute Flaccid Myelitis.

Detailed accounts of long-term respiratory complications among children with acute flaccid myelitis have not been reported systematically. We describe respiratory complications and outcomes in a single-center cohort of 19 children with acute flaccid myelitis. Significantly, 3 of the 19 children had a prolonged course of nocturnal hypoventilation that required intervention.

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

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

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.

Mutation in LBX1/Lbx1 precludes transcription factor cooperativity and causes congenital hypoventilation in humans and mice.

The respiratory rhythm is generated by the preBötzinger complex in the medulla oblongata, and is modulated by neurons in the retrotrapezoid nucleus (RTN), which are essential for accelerating respiration in response to high CO2 Here we identify a LBX1 frameshift (LBX1FS ) mutation in patients with congenital central hypoventilation. The mutation alters the C-terminal but not the DNA-binding domain of LBX1 Mice with the analogous mutation recapitulate the breathing deficits found in humans. Furthermore, the mutation only interferes with a small subset of Lbx1 functions, and in particular with development of RTN neurons that coexpress Lbx1 and Phox2b. Genome-wide analyses in a cell culture model show that Lbx1FS and wild-type Lbx1 proteins are mostly bound to similar sites, but that Lbx1FS is unable to cooperate with Phox2b. Thus, our analyses on Lbx1FS (dys)function reveals an unusual pathomechanism; that is, a mutation that selectively interferes with the ability of Lbx1 to cooperate with Phox2b, and thus impairs the development of a small subpopulation of neurons essential for respiratory control.

COPD sleep phenotypes: Genesis of respiratory failure in COPD.

The chronic obstructive pulmonary disease (COPD) patients could have respiratory failure during sleep without daytime overt arterial blood gas (ABG) abnormality. We undertook a study first of its kind to attempt in distinguishing the underlying pathophysiological mechanisms.  It was a prospective observational study in stable COPD patients. The inclusion criterion was presence of day time PaO2>60 mmHg and PaCO2<45 mmHg. Twenty five out of 110 patients were excluded because of the ABG abnormality. The remaining 85 patients were subjected to overnight pulse oximetry and end-tidal (ET)-CO2 monitoring. The nocturnal oxygen desaturation was defined as per Fletcher's criteria. The nocturnal hypoventilation was defined as per American academy of sleep medicine (AASM) guidelines. Patients having saw-tooth pattern on pulse oximetry and/or snoring were subjected to polysomnography. 38/85(44.8%) patients had nocturnal gas exchange abnormality in absence of daytime respiratory failure and were identified into 3 different phenotypes: obstructive sleep apnoea (OSA), nocturnal hypoventilation and nocturnal oxygen desaturation. The isolated abnormality was seen in 24 patients: 10 patients had OSA, 9 had nocturnal hypoventilation and 5 had nocturnal oxygen desaturation. Overlap of two or more phenotypes was seen in 14 patients. As compared to the nocturnal hypoventilation and desaturation phenotypes, the OSA phenotype had a significantly higher BMI & FEV1. The nocturnal hypoventilation and the desaturation phenotypes did not have significant difference in FEV1 and BMI, but the daytime SpO2 and PaO2 differed significantly.  Such parameters could help in identifying the three distinct COPD-sleep phenotypes (OSA, nocturnal hypoventilation and nocturnal oxygen desaturation). A phenotype based nocturnal management may help in delaying the process of overt respiratory failure in COPD.

Effects of spinal immobilization at 20° on end-tidal carbon dioxide.

OBJECTIVE: The aim was to determine the effect on end-tidal carbon dioxide (ETCO2) of spinal immobilization (SI) at a conventional 0° angle and to investigate the usefulness of immobilization at a 20° angle for preventing possible hypoventilation. METHODS: The study included 80 healthy volunteers, randomly divided into two groups. Spinal backboards and cervical collars were applied in Group 1 using a 0° angle and in Group 2 using a 20° angle, with the head up. SI was continued for 1 h, and ETCO2 values were measured at the 0th, 30th and 60th minute. RESULTS: There were no significant differences between the groups in 0th and 30th minute ETCO2. However, after 60th minute, results showed a statistically significant increase in ETCO2 in Group 1 (35.5 mmHg [IQR 25-75:35-38]) compared to Group 2 (34 mmHg [IQR 25-75:33-36]) (p < 0.001). During SI, there was a statistically significant increase in ETCO2 in Group 1 (35 mmHg [IQR 25-75:34-36], 35.5 mmHg [IQR 25-75:34-37] and 36 mmHg [IQR 25-75:35-38] respectively at the 0th, 30th and 60th minute after SI) (p < 0.001) and no change in Group 2. Also, we found statistically significant differences between ΔETCO2 levels in Groups 1 and 2 at all 3 time intervals. CONCLUSION: Conventional SI with an angle of 0° led to an increase in ETCO2 while subjects immobilization at a 20° angle maintained their initial ETCO2 values. Immobilization at 20° may prevent decompensation in patients who have thoracic trauma or lung diseases or those who are elderly, pregnant, or obese.

Diaphragm pacing in a pediatric patient with Acquired Central Hypoventilation syndrome. / Marcapasos diafragmático en paciente pediátrico con síndrome de Hipoventilación Central Adquirido.

INTRODUCTION: Diaphragmatic pacemaker is a device that reduces or eliminates the need of mechanical ventilation in patients with chronic respiratory failure who keep the phrenic nerve-diaphragm axis intact, as long as they do not present intrinsic lung disease. Although its implantation has been practiced for deca des, its use is not widespread and to date, there is little published literature about it, mostly related to high spinal cord injury and congenital central hypoventilation syndrome. OBJECTIVE: To describe an experience of diaphragmatic pacemaker implantation in a pediatric patient with acquired cen tral hypoventilation syndrome. CLINICAL CASE: Female patient with central hypoventilation syndrome secondary to ischemic brainstem lesion as a result of ventriculoperitoneal shunt malfunction. For this reason, for 5 years she was supported by inpatient mechanical ventilation. At 7 years of age, a diaphragmatic pacemaker was implanted by thoracoscopic surgery, which allowed, after a period of rehabilitation and respiratory conditioning, mechanical ventilation withdrawal, and hospital dischar ge. CONCLUSIONS: Diaphragmatic pacemaker is a feasible, potentially safe, and cost-effective option for decreasing or eliminating mechanical ventilation dependence and improve life quality in patients with acquired central hypoventilation syndrome.

A model to predict ventilator requirement in myotonic dystrophy type 1.

INTRODUCTION: Respiratory failure is one of the most common causes of mortality in myotonic dystrophy type 1 (DM1). The variation in the DM1 phenotype causes difficulty in clinically predicting the severity of respiratory involvement, and variables such as daytime somnolence are insensitive for identifying patients who require continuous or bilevel nocturnal positive airway pressure (NPAP). METHODS: We retrospectively analyzed a cohort of 126 adult onset patients with DM1 at the point of their first respiratory assessment to identify significant factors in predicting ventilator requirement. RESULTS: Triplet repeat years score and Muscle Impairment Rating Scale were significantly linearly related to NPAP and, thus, formed the model. DISCUSSION: We devised a simple model to aid clinicians in predicting at first visit those patients with DM1 who are likely to require NPAP. We also describe the causes of failure to tolerate NPAP in DM1. Muscle Nerve 59:683-687, 2019.

More than Heart Failure: Central Sleep Apnea and Sleep-Related Hypoventilation.

Central sleep apnea (CSA) comprises a variety of breathing patterns and clinical entities. They can be classified into 2 categories based on the partial pressure of carbon dioxide in the arterial blood. Nonhypercapnic CSA is usually characterized by a periodic breathing pattern, while hypercapnic CSA is based on hypoventilation. The latter CSA form is associated with central nervous, neuromuscular, and rib cage disorders as well as obesity and certain medication or substance intake. In contrast, nonhypercapnic CSA is typically accompanied by an overshoot of the ventilation and often associated with heart failure, cerebrovascular diseases, and stay in high altitude. CSA and hypoventilation syndromes are often considered separately, but pathophysiological aspects frequently overlap. An integrative approach helps to recognize underlying pathophysiological mechanisms and to choose adequate therapeutic strategies. Research in the last decades improved our insights; nevertheless, diagnostic tools are not always appropriately chosen to perform comprehensive sleep studies. This supports misinterpretation and misclassification of sleep disordered breathing. The purpose of this article is to highlight unresolved problems, raise awareness for different pathophysiological components and to discuss the evidence for targeted therapeutic strategies.

Moderate and deep sedation training and pharmacology for nonanesthesiologists: recommendations for effective practice.

PURPOSE OF REVIEW: The purpose of this review is to discuss current drugs used for intravenous moderate and deep sedation by nonanesthesiologists in the United States. We also explore training expectations for moderate and deep sedation as they play key roles in anesthetic selection and preprocedural planning. RECENT FINDINGS: Although opioids and benzodiazepines are considered the standard for moderate sedation, increased interest in propofol, dexmedetomidine, and other sedative-hyptonic drugs require additional attention in terms of training providers and complying with current practice guidelines. SUMMARY: Moderate sedation providers should be familiar with titrating benzodiazepines and opioids to achieve targeted sedation. The use of propofol and ketamine is generally reserved for deep sedation by qualified professionals. However, the role of dexmedetomidine in procedural sedation continues to evolve as its use is explored in moderate sedation. Providers of all sedation types should be aware of hypotension, apnea, hypoventilation, and hypoxia that can develop and they should be able to manage the patient under these circumstances. Preprocedural planning is an integral training expectation to minimize patient risks.

Expanding the phenotype of congenital central hypoventilation syndrome impacts management decisions.

Congenital central hypoventilation syndrome (CCHS) is a neurocristopathy caused by pathogenic heterozygous variants in the gene paired-like homeobox 2b (PHOX2B). It is characterized by severe infantile alveolar hypoventilation. Individuals may also have diffuse autonomic nervous system dysfunction, Hirschsprung disease and neural crest tumors. We report three individuals with CCHS due to an 8-base pair duplication in PHOX2B; c.691_698dupGGCCCGGG (p.Gly234Alafs*78) with a predominant enteral and neural crest phenotype and a relatively mild respiratory phenotype. The attenuated respiratory phenotype reported here and elsewhere suggests an emergent genotype:phenotype correlation which challenges the current paradigm of invoking mechanical ventilation for all infants diagnosed with CCHS. Best treatment requires careful clinical judgment and ideally the assistance of a care team with expertise in CCHS.

Changing respiratory expectations with the new disease trajectory of nusinersen treated spinal muscular atrophy [SMA] type 1.

Spinal muscular atrophy [SMA] is the most common genetic cause of childhood mortality, primarily from the most severe form SMA type 1. It is a severe, progressive motor neurone disease, affecting the lower brainstem nuclei and the spinal cord. There is a graded level of severity with SMA children from a practical viewpoint described as "Non-sitters", "Sitters" and less commonly, "Ambulant" correlating with SMA Type 0/Type 1, Type 2 and Type 3 respectively. Children with SMA Type 0 have a severe neonatal form whilst those with SMA Type 1 develop hypoventilation, pulmonary aspiration, recurrent lower respiratory tract infections, dysphagia and failure to thrive before usually succumbing to respiratory failure and death before the age of 2 years. The recent introduction of the antisense oligonucleotide nusinersen into clinical practice in certain countries, following limited trials of less than two years duration, has altered the treatment landscape and improved the outlook considerably for SMN1 related SMA. Approximately 70% of infants appear to have a clinically significant response to nusinersen with improved motor function. It appears the earlier the treatment is initiated the better the response. There are other rarer genetic forms of SMA that are not treated with nusinersen. Clinical expectations will change although it is unclear as yet what the extent of response will mean in terms of screening initiatives [e.g., newborn screening], "preventative strategies" to maintain respiratory wellbeing, timing of introduction of respiratory supports, and prolonged life expectancy for the subcategory of children with treated SMA type 1. This article provides a review of the strategies available for supporting children with respiratory complications of SMA, with a particular emphasis on SMA Type 1.

Patterns of use, survival and prognostic factors in patients receiving home mechanical ventilation in Western Australia: A single centre historical cohort study.

Home mechanical ventilation (HMV) is used in a wide range of disorders associated with chronic hypoventilation. We describe the patterns of use, survival and predictors of death in Western Australia. We identified 240 consecutive patients (60% male; mean age 58 years and body mass index 31 kg m-2) referred for HMV between 2005 and 2010. The patients were grouped into four categories: motor neurone disorders (MND; 39%), pulmonary disease (PULM; 25%, mainly chronic obstructive pulmonary disease), non-MND neuromuscular and chest wall disorders (NMCW; 21%) and the obesity hypoventilation syndrome (OHS; 15%). On average, the patients had moderate ventilatory impairment (forced vital capacity: 51%predicted), sleep apnoea (apnoea-hypopnea index: 25 events h-1), sleep-related hypoventilation (transcutaneous carbon dioxide rise of 20 mmHg) and daytime hypercarbia (PCO2: 54 mmHg). Median durations of survival from HMV initiation were 1.0, 4.2, 9.9 and >11.5 years for MND, PULM, NMCW and OHS, respectively. Independent predictors of death varied between primary indications for HMV; the predictors included (a) age in all groups except for MND (hazard ratios (HRs) 1.03-1.10); (b) cardiovascular disease (HR: 2.35, 95% confidence interval (CI): 1.08-5.10) in MND; (c) obesity (HR: 0.28, 95% CI: 0.13-0.62) and oxygen therapy (HR: 0.33, 95% CI: 0.14-0.79) in PULM; and (d) forced expiratory volume in 1 s (%predicted; HR: 0.93, 95% CI: 0.88-1.00) in OHS.

Sedation for gastrointestinal endoscopy in Australia: what is the same and what is different?

PURPOSE OF REVIEW: The purpose of this article is to review the practice of sedation for adults having gastrointestinal endoscopy in Australia and to compare it with practice in other countries. RECENT FINDINGS: The practice of sedation for endoscopy in Australia is dominated by anaesthesiologists, who have a preference for deep propofol-based sedation. The recent literature includes a number of guidelines for sedation developed by multidisciplinary groups, anaesthesiologists and gastroenterologists in Australia and other countries. The appropriate health practitioner to provide deep sedation and general anaesthesia, to use propofol for sedation and to manage higher risk patients remains controversial. The estimated risks associated with endoscopy vary by provider, sedation technique and study design (prospective or retrospective, single- or multicentre). New airway management techniques are being investigated that may be useful in patients at high risk of hypoventilation and hypoxia. SUMMARY: Endoscopy sedation is safe but more high-quality, multicentre observer-blinded randomized controlled trials are required.

Definition, discrimination, diagnosis and treatment of central breathing disturbances during sleep.

The complexity of central breathing disturbances during sleep has become increasingly obvious. They present as central sleep apnoeas (CSAs) and hypopnoeas, periodic breathing with apnoeas, or irregular breathing in patients with cardiovascular, other internal or neurological disorders, and can emerge under positive airway pressure treatment or opioid use, or at high altitude. As yet, there is insufficient knowledge on the clinical features, pathophysiological background and consecutive algorithms for stepped-care treatment. Most recently, it has been discussed intensively if CSA in heart failure is a "marker" of disease severity or a "mediator" of disease progression, and if and which type of positive airway pressure therapy is indicated. In addition, disturbances of respiratory drive or the translation of central impulses may result in hypoventilation, associated with cerebral or neuromuscular diseases, or severe diseases of lung or thorax. These statements report the results of an European Respiratory Society Task Force addressing actual diagnostic and therapeutic standards. The statements are based on a systematic review of the literature and a systematic two-step decision process. Although the Task Force does not make recommendations, it describes its current practice of treatment of CSA in heart failure and hypoventilation.

Safety of unsedated PEG placement using transoral ultrathin endoscopy in patients with amyotrophic lateral sclerosis.

BACKGROUND AND AIMS: In patients with amyotrophic lateral sclerosis (ALS), percutaneous endoscopic gastrostomy (PEG) placement under sedation often causes apnea or hypoventilation. The aim of the present study was to assess whether unsedated PEG placement in ALS patients using ultrathin endoscopy (UTE) via the transoral route can improve safety. METHODS: Between 2003 and 2013, PEG placement was identified and reviewed in 45 patients with ALS. PEG was performed in 14 patients using transoral UTE without sedation (UTE group), 17 patients using conventional normal-diameter esophagogastroduodenoscopy (C-EGD) without sedation (unsedated C-EGD group) and 14 patients using C-EGD with sedation (sedated C-EGD group). We compared the clinical features, cardiopulmonary data before and during PEG placement, and complications related to PEG placement among the three groups. RESULTS: There were no significant differences in age, male/female ratio, forced vital capacity, blood pressure, oxygen saturation before and during PEG, or major complications among the three groups. No minor complications were observed in the UTE group, whereas apnea and/or hypoventilation were observed in the sedated C-EGD group and aspiration pneumonia was observed in the unsedated C-EGD group. CONCLUSIONS: Unsedated PEG placement using transoral UTE in ALS patients is a safe method.