Airway Obstruction during Sleep due to Diaphragm Pacing Precludes Decannulation in Young Children with CCHS.

Children with congenital central hypoventilation syndrome (CCHS) have a PHOX2B mutation-induced control of breathing deficit necessitating artificial ventilation as life support. A subset of CCHS families seek phrenic nerve-diaphragm pacing (DP) during sleep with the goal of tracheal decannulation. Published data regarding DP during sleep as life support in the decannulated child with CCHS and related airway dynamics in young children are limited. We report a series of 3 children, ages 3.3-4.3 years, who underwent decannulation. Sleep endoscopy performed during DP revealed varied (oropharynx, supraglottic, glottic, etc.) levels of complete airway obstruction despite modification of pacer settings. Real-time analysis of end tidal CO2 and SpO2 confirmed inadequate gas exchange. Because the families declined re-tracheostomy, all 3 patients rely on noninvasive mask ventilation as a means of life support while asleep. These results emphasize the need for extreme caution in proceeding with tracheal decannulation in young children with CCHS who expect to use DP during sleep as life support. Parents and patients should anticipate that they will depend on noninvasive mask ventilation (rather than DP) during sleep after undergoing decannulation. This information may improve management and guide expectations regarding potential decannulation in young paced children with CCHS.

Perioperative anesthetic management of children with congenital central hypoventilation syndrome and rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation undergoing thoracoscopic phrenic nerve-diaphragm pacemaker implantation.

BACKGROUND: Congenital Central Hypoventilation Syndrome and Rapid-Onset Obesity with Hypothalamic dysfunction, Hypoventilation, and Autonomic Dysregulation are rare neurocristopathies characterized by autonomic dysregulation including bradyarrhythmias, abnormal temperature control, and most significantly, abnormal control of breathing leading to tracheostomy and ventilator dependence as life support. Surgical advancements have made phrenic nerve-diaphragm pacemakers available, to eliminate the tether to a mechanical ventilator for 12-15 hours each day. The thoracoscopic approach to implantation has allowed for a less invasive approach which may have implications for pain control and recovery time. However, thoracoscopic implantation of these devices presents several challenges to the anesthesiologist in these complex ventilator-dependent patients, including, but not limited to, sequential lung isolation, prevention of hypothermia, and management of arrhythmias. Postoperative challenges may also include strategies to treat hemodynamic instability, managing the ventilator following lung derecruitment, and providing adequate pain control. AIMS: We aimed to describe the anesthetic management of Congenital Central Hypoventilation Syndrome and Rapid-Onset Obesity with Hypothalamic dysfunction, Hypoventilation, and Autonomic Dysregulation patients undergoing thoracoscopic phrenic nerve-diaphragm pacemaker implantation and the nature and incidence of perioperative complications. METHODS: A retrospective chart review was performed of 14 children with Congenital Central Hypoventilation Syndrome and Rapid-Onset Obesity with Hypothalamic dysfunction, Hypoventilation, and Autonomic Dysregulation undergoing phrenic nerve-diaphragm pacemaker implantation at a single academic pediatric hospital between 2009 and 2017. Demographic information, intraoperative management, and perioperative complications were analyzed from patient records. RESULTS: Twelve of 14 patients (86%) underwent an inhalational induction via tracheostomy. Lung isolation was achieved via fiberoptic guidance of a single lumen endotracheal tube sequentially into the right or left mainstem bronchi for 12 patients (86%). Double lumen endotracheal tubes were utilized in two patients (7%) and bronchial blockers in two patients (7%) for lung isolation. Anesthesia was maintained using a balanced technique of volatile agents (sevoflurane/isoflurane) and opioids (fentanyl). Bradyarrhythmias developed in six patients (43%) during surgery, 5 (36%) responded to anticholinergics and one patient (7%) required backup cardiac pacing using a previously implanted bipolar cardiac pacemaker. Intraoperative hypothermia (<35.5°C) was present in five patients (36%) despite the use of warming devices. Hypercarbia (>50 mm Hg) during lung isolation was present in eight patients (57%) and hemoglobin desaturation (<90%) in four patients (29%). Postoperatively, oxygen desaturation was a common complication with nine patients (64%) requiring supplemental oxygen administration via mechanical ventilator or manual bag ventilation. Opioids via patient-controlled analgesia devices (12 patients, 86%) or intermittent injection (two patients, 14%) were administered to all patients for postoperative pain control. Phrenic nerve-diaphragm pacemaker placement was successful thoracoscopically in all patients with no perioperative mortality. CONCLUSION: The main anesthetic challenges in patients with Congenital Central Hypoventilation Syndrome and Rapid-Onset Obesity with Hypothalamic dysfunction, Hypoventilation, and Autonomic Dysregulation include hemodynamic instability, the propensity to develop hypothermia, hypercarbia/hypoxemia, and the need to perform bilateral sequential lung isolation requisite to the thoracoscopic implantation technique. Most anesthetic agents can be used safely in these patients; however, adequate knowledge of the susceptibility to complications, coupled with adequate preparation and understanding of the innate disease characteristics, are necessary to treat anticipated complications.

Localizing Effects of Leptin on Upper Airway and Respiratory Control during Sleep.

STUDY OBJECTIVES: Obesity hypoventilation and obstructive sleep apnea are common complications of obesity linked to defects in respiratory pump and upper airway neural control. Leptin-deficient ob/ob mice have impaired ventilatory control and inspiratory flow limitation during sleep, which are both reversed with leptin. We aimed to localize central nervous system (CNS) site(s) of leptin action on respiratory and upper airway neuroventilatory control. METHODS: We localized the effect of leptin to medulla versus hypothalamus by administering intracerbroventricular leptin (10 µg/2 µL) versus vehicle to the lateral (n = 14) versus fourth ventricle (n = 11) of ob/ob mice followed by polysomnographic recording. Analyses were stratified for effects on respiratory (nonflow-limited breaths) and upper airway (inspiratory flow limitation) functions. CNS loci were identified by (1) leptin-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation and (2) projections of respiratory and upper airway motoneurons with a retrograde transsynaptic tracer (pseudorabies virus). RESULTS: Both routes of leptin administration increased minute ventilation during nonflow-limited breathing in sleep. Phrenic motoneurons were synaptically coupled to the nucleus of the solitary tract, which also showed STAT3 phosphorylation, but not to the hypothalamus. Inspiratory flow limitation and obstructive hypopneas were attenuated by leptin administration to the lateral but not to the fourth cerebral ventricle. Upper airway motoneurons were synaptically coupled with the dorsomedial hypothalamus, which exhibited STAT3 phosphorylation. CONCLUSIONS: Leptin relieves upper airway obstruction in sleep apnea by activating the forebrain, possibly in the dorsomedial hypothalamus. In contrast, leptin upregulates ventilatory control through hindbrain sites of action, possibly in the nucleus of the solitary tract.

Reversal of pulmonary hypertension after diaphragm pacing in an adult patient with congenital central hypoventilation syndrome.

INTRODUCTION: Patients with the congenital central hypoventilation syndrome (CCHS) suffer from life-threatening hypoventilation when asleep, making them dependent on mechanical ventilation (MV) at night or during naps. State-of-art respiratory management consists of intermittent positive-pressure ventilation via a tracheotomy or mask. In some patients hypoventilation is permanent, in which case ventilatory support must be extended to the waking hours. Diaphragm pacing can prove useful in such situations. 
 METHODS AND RESULTS: This report describes the case of a 26-year-old woman with CCHS in whom failure to achieve adequate MV led to life-threatening pulmonary hypertension (PH), with a systolic pulmonary artery pressure (PAP) of 80 mmHg and right ventricular hypertrophy, despite optimization of all possible measures and despite extensive therapeutic education efforts. Diaphragm pacing using laparoscopically implanted intradiaphragmatic phrenic nerve stimulation electrodes corrected alveolar hypoventilation and lastingly reversed PH (systolic PAP below 40 mmHg after 2 months, sustained after 2 years). Diaphragm pacing induced shoulder pain, however, involving the chronic use of analgesics. The pacing had to be stopped for tolerance reasons after two years, leading to PH worsening and the need for diurnal MV. 
 CONCLUSIONS: Diaphragm pacing appears likely effective to restore alveolar ventilation and reverse PH in adult CCHS patients.

Respiratory safety pharmacology: positive control drug responses in Sprague-Dawley rats, Beagle dogs and cynomolgus monkeys.

Rats are most frequently used to fulfill ICH S7A requirements for respiratory safety pharmacology. We hypothesized that the models used to assess respiratory safety pharmacology present different ventilatory responses to bronchoconstriction, bronchodilation and respiratory depression. Respiratory monitoring was performed with head-out plethysmographs for rats, masks for dogs and bias airflow helmets for monkeys. Respiratory rate (RR), tidal volume (TV) and minute volume (MV) were recorded. Forty rats, 18 dogs and 8 monkeys were acclimated to the respiratory monitoring equipment. Animals received saline (IV), albuterol (inhalation), methacholine (IV) and remifentanil (IV). Albuterol increased TV in all species. Methacholine decreased TV and MV in monkeys. In dogs, methacholine increased TV, RR and MV. In rats, methacholine increased TV and decreased RR. Remifentanil induced central respiratory depression in all species with decreased MV, except in rats. Dogs presented a biphasic response to remifentanil with hypoventilation followed by delayed hyperventilation. The monkeys presented similar responses to humans which may be due to biologic similarities. Dogs and rats presented clinically significant ventilatory alterations following positive control drugs. Although, the response to bronchoconstriction in dogs and rats was different from humans, the two species presented ventilatory changes that highlight the potential adverse effect of test articles.

Successful diaphragmatic pacing for idiopathic alveolar hypoventilation.

We describe the case of a 17-year-old woman noted to have idiopathic alveolar hypoventilation, with multiple Intensive Care Unit (ICU) admissions because of acute respiratory failure (ARF) due to respiratory infections. After two years of diaphragmatic pacing arterial blood gases have substantially improved, without obstructive apnoea. Signs of right ventricular enlargement and pulmonary hypertension have decreased. Morning headache and diurnal somnolence have disappeared, and she is also able to perform more physical and mental activity, allowing her to enjoy a better quality of life.

Conditioning of the diaphragm by phrenic nerve pacing in primary alveolar hypoventilation.

A patient with respiratory muscle weakness due to alveolar hypoventilation was treated with nocturnal bilateral phrenic nerve pacing for one year. Treatment was associated with a progressive increase in diaphragmatic strength and endurance.

Stimulus parameters for phrenic nerve pacing in infants and children.

Phrenic nerve pacing has been used since 1966 to support breathing in quadriplegics and patients with central hypoventilation syndrome (CHS). Recently, using low-frequency, long-inspiratory-time (Ti) stimulation, phrenic nerve pacing has been used successfully to support breathing 24 hours per day in adults and older children. However, no similar experience exists for infants and young children. Therefore, in 27 studies in 14 infants and children we determined the effects of changing Ti and interpulse interval (the inverse of stimulus frequency) on ventilation. Diaphragmatic action potentials, airflow, tidal volume, PACO2 and SaO2 were measured during sleep. Phrenic nerve pacing proved useful in 13 of 14 patients to support breathing either during wakefulness (n = 7) or during sleep (n = 6). We found that adequate ventilation could be achieved at significantly longer interpulse intervals, 95 +/- 25 (mean +/- SD) ms, and shorter Ti, 580 +/- 80 ms, than previously reported. At an average respiratory rate of 21 +/- 8 breaths/min it was thus possible to maintain adequate ventilation despite a marked reduction in the number of phrenic nerve stimuli. Theoretically, these reductions in phrenic nerve stimulation should minimize the chance of pacing-induced diaphragmatic damage. These results suggest that 24 hour per day phrenic nerve pacing may be a realistic goal in selected infants and children.

Lung function in diaphragm pacing.

Electric stimulation of the diaphragm via the phrenic nerve to induce ventilation has recently been used for the long-term management of chronic ventilatory insufficiency. Since 1973 three patients with inadequate alveolar ventilation have been treated with diaphragm pacing at the Toronto Western Hospital. Two, who had quadriplegia due to lesions of the spinal cord in the upper cervical region and a severe restrictive ventilatory defect, were treated with continuous diaphragm pacing. The third patient required assisted nocturnal ventilation because of primary alveolar hypoventilation. All three patients tolerated the diaphragm pacing well, and pulmonary function tests showed satisfactory gas exchange with the patients breathing room air. This form of therapy seems to be a practical clinical method of managing chronic ventilatory failure in patients with lesions of the upper cervical cord or primary alveolar hypoventilation.

Primary alveolar hypoventilation treated with nocturnal electrophrenic respiration.

A case of primary alveolar hypoventilation is described. Despite characteristic clinical findings, the diagnosis was delayed for 4 years. Alleviation of nocturnal hypoxemia and hypercapnia initially by a rocking bed and subsequently by phrenic nerve stimulation was accompanied by reversal of cor pulmonale and polycythemia. Electrophrenic respiration is an effective form of long-term management in primary alveolar hypoventilation.

Central alveolar hypoventilation in a child: an evaluation using a whole body plethysmograph.

A disorder in the central nervous system control of breathing is thought to be responsible for the clinical syndrome of "primary" or central alveolar hypoventilation. Only 2 of the 7 reported cases in children have included any functional evaluation of this control system disorder. We report the case of a 2-year-old girl with central alveolar hypoventilation attributed to an abnormality in be central nervous system of unknown etiology. In evaluating her ventilatory control system, we used a method (whole body pleildren and small animals but has since received little clinical use. The findings included an irregular respiratory rhythm and a diminished ventilatory response to inhaled CO2, which suggested a functional abnormality of brainstem neurons responsible for rhythmic effective breathing and the CO2 response. A relatively normal change in breathing with sleep and exercise as well as qualitively normal peripheral chemoreceptor function suggested that these aspects of the control system were undisturbed. These findings are contrasted to those in other children; it is suggested that the syndrome of central alveolar hypoventilation may reflect a variety of functional abnormalities in the nervous system control of ventilation.