Brainstem Respiratory Centers Research Articles

Brainstem Dysfunction in SARS-COV-2 Infection can be a Potential Cause of Respiratory Distress.

A terrible pandemic, Covid-19, has captivated scientists to investigate if SARS-CoV-2 virus infects the central nervous system (CNS). A crucial question is if acute respiratory distress syndrome (ARDS), the main cause of death in this pandemic, and often refractory to treatments, can be explained by respiratory center dysfunction. To discuss that ARDS can be caused by SARS-CoV-2 infection of the respiratory center in the brainstem. I reviewed literature about SARS-CoV-2 mechanisms to infect the respiratory center in the brainstem. An increasing amount of reports demonstrates that neurotropism is a common feature of coronavirus, which have been found in the brains of patients and experimental models, where the brainstem was severely infested. Recent studies have provided tremendous indication of the incidence of acute respiratory failure due to SARS-CoV-2 infection of the brainstem. SARS-CoV-2 might infect the CNS through the olfactory bulb, spreading from the olfactory nerves to the rhinencephalon, and finally reaching the brainstem. Hence, the virus infection causes respiratory center dysfunctions, leading to ARDS in COVID-19 patients. I conclude that acute ARDS in Covid-19 can be caused by SARS-CoV-2 invasion of brainstem respiratory center, suggesting the needs of more specific and aggressive treatments, with the direct participation of neurologists and neurointensivists.

Apnea Associated with Brainstem Seizures in Cacna1aS218L Mice Is Caused by Medullary Spreading Depolarization.

Seizure-related apnea is common and can be lethal. Its mechanisms however remain unclear and preventive strategies are lacking. We postulate that brainstem spreading depolarization (SD), previously associated with lethal seizures in animal models, initiates apnea upon invasion of brainstem respiratory centers. To study this, we assessed effects of brainstem seizures on brainstem function and respiration in male and female mice carrying a homozygous S218L missense mutation that leads to gain-of-function of voltage-gated CaV2.1 Ca2+ channels and high risk for fatal seizures. Recordings of brainstem DC potential and neuronal activity, cardiorespiratory activity and local tissue oxygen were performed in freely behaving animals. Brainstem SD occurred during all spontaneous fatal seizures and, unexpectedly, during a subset of nonfatal seizures. Seizure-related SDs in the ventrolateral medulla correlated with respiratory suppression. Seizures induced by stimulation of the inferior colliculus could evoke SD that spread in a rostrocaudal direction, preceding local tissue hypoxia and apnea, indicating that invasion of SD into medullary respiratory centers initiated apnea and hypoxia rather than vice versa Fatal outcome was prevented by timely resuscitation. Moreover, NMDA receptor antagonists MK-801 and memantine prevented seizure-related SD and apnea, which supports brainstem SD as a prerequisite for brainstem seizure-related apnea in this animal model and has translational value for developing strategies that prevent fatal ictal apnea.SIGNIFICANCE STATEMENT Apnea during and following seizures is common, but also likely implicated in sudden unexpected death in epilepsy (SUDEP). This underlines the need to understand mechanisms for potentially lethal seizure-related apnea. In the present work we show, in freely behaving SUDEP-prone transgenic mice, that apnea is induced when spontaneous brainstem seizure-related spreading depolarization (SD) reaches respiratory nuclei in the ventrolateral medulla. We show that brainstem seizure-related medullary SD is followed by local hypoxia and recovers during nonfatal seizures, but not during fatal events. NMDA receptor antagonists prevented medullary SD and apnea, which may be of translational value.

DON’T FORGET TO BREATHE: A CASE OF HYPOXEMIA AFTER CAROTID BODY RESECTION

SESSION TITLE: Pulmonary Physiology SESSION TYPE: Fellow Case Report Posters PRESENTED ON: 10/09/2018 01:15 PM - 02:15 PM INTRODUCTION: Carotid body tumors (CBTs) are paragangliomas, slow-growing neuroendocrine tumors that secrete catecholamines. Management involves surgical resection or radiation. Although chronic hypoxia has been identified after resection of these tumors, the effects of altitude on oxygenation in these patients has not been well-described. We present a case of chronic hypoxia in a patient after bilateral CBT resection. CASE PRESENTATION: A 72 year-old male with a personal and family history of bilateral CBTs presented for evaluation of hypoxia. He underwent resection of these tumors one year prior to presentation. Final tissue exam identified benign carotid body paragangliomas. He had a significant history of tobacco use but had quit 5 years prior. Given his new hypoxia, he underwent evaluation for COPD. Review of systems was notable for dyspnea with heavy exertion but he was otherwise without respiratory complaints. He lived at 1200m above sea level without significant dyspnea, but frequently traveled to 2500m above sea level where his dyspnea would worsen. On exam his baseline SpO2 was 90-91%, but increased quickly to 97-98% with frequent deep breaths. Due to concern for COPD, pulmonary function testing (PFT), plethysmography and DLCO were obtained and all normal. 6MWT was significant for desaturations that improved with 2-3L/min of supplemental O2. ABG showed minimal hypoventilation with a PaCO2 42mm Hg at rest. Overnight oximetry showed mild sustained hypoxemia. CT chest, PET and a V/Q scan were obtained and were all unremarkable. The patient was started on 2-3L/min of supplemental O2 with ambulation and sleep. At one year follow-up he reported control of his dyspnea even at high altitudes. DISCUSSION: The effects of ventilatory control in patients after bilateral carotid-body resection has been previously described. It is theorized that the carotid bodies are responsible for the hyperpnea that results from hypoxia; the aortic chemoreceptors to a much lesser extent. Brainstem respiratory centers receive afferent impulses from the carotid bodies during hypoxia and hypercapnia to control ventilation by increasing MV. In those who have undergone bilateral carotid body resection, there is minimal to no change in MV during hypoxia. At altitudes higher than 2000m the atmospheric O2 pressure decreases causing chronic hypoxia. This case demonstrates the effects of this reduced atmospheric O2 pressure in a patient that has undergone a bilateral carotid body resection. CONCLUSIONS: Providers should be aware that in patients who have undergone carotid body resection, regulatory control of ventilation is impaired, resulting in diminished increase in MV response to hypoxia. At higher altitudes, this becomes clinically significant due to the reduced atmospheric O2 pressure inspired. Patients with hypoxia after bilateral carotid body resections should be advised to use supplementary O2, especially at high altitudes. Reference #1: Erickson et al. “Benign Paragangliomas.” J Clin Endocrinol Metab. 2001 Nov; 86 (11): 5210-5216. Reference #2: Lugliani et al. “Effect of bilateral carotid-body resection on ventilatory control at rest and during exercise in man,” The New England Journal of Medicine. 1971; 285 (20):1105–1111. Reference #3: Rodríguez-Cuevas et al. "Carotid body tumors in inhabitants of altitudes higher than 2000 meters above sea level.” Head & Neck. 1998; 20:374-378. DISCLOSURES: No relevant relationships by David Dorsey, source=Web Response No relevant relationships by Brian Foster, source=Web Response

The Consequences of Preterm Birth and Chorioamnionitis on Brainstem Respiratory Centers: Implications for Neurochemical Development and Altered Functions by Inflammation and Prostaglandins.

Preterm birth is a major cause for neonatal morbidity and mortality, and is frequently associated with adverse neurological outcomes. The transition from intrauterine to extrauterine life at birth is particularly challenging for preterm infants. The main physiological driver for extrauterine transition is the establishment of spontaneous breathing. However, preterm infants have difficulty clearing lung liquid, have insufficient surfactant levels, and underdeveloped lungs. Further, preterm infants have an underdeveloped brainstem, resulting in reduced respiratory drive. These factors facilitate the increased requirement for respiratory support. A principal cause of preterm birth is intrauterine infection/inflammation (chorioamnionitis), and infants with chorioamnionitis have an increased risk and severity of neurological damage, but also demonstrate impaired autoresuscitation capacity and prevalent apnoeic episodes. The brainstem contains vital respiratory centers which provide the neural drive for breathing, but the impact of preterm birth and/or chorioamnionitis on this brain region is not well understood. The aim of this review is to provide an overview of the role and function of the brainstem respiratory centers, and to highlight the proposed mechanisms of how preterm birth and chorioamnionitis may affect central respiratory functions.

Recurrent Apnea Following Occipital Encephalocele Surgery in A Child -Responding to Caffeine Citrate

Introduction: Apnea denotes temporary cessation of breathing. It is an ominous symptom in children beyond neonatal period. Central apnea results from a lack of respiratory effort due to either a cessation of output from the brainstem respiratory centers or the inability of the efferent nerves and respiratory muscles to receive or process the signals from the brain. This can be due to the immaturity of the system as seen in premature infants or secondary to different disease processes. Case Presentation: A 13-month-old girl child presented with frequent apneic spells following a major neurosurgical intervention for occipital encephalocele. Marked improvement was seen after the institution of caffeine citrate therapy resulting in complete resolution of apnea along with appreciable growth and development. Conclusions: Recurrent apnea is a potential complication in infants following the repair of occipital encephalocele. Caffeine citrate may be effective in central apnea beyond the neonatal period especially in the treatment of apnea related to neurosurgical procedures.

The Impact of Chronic Sleep Restriction on Neuronal Number and Volumetric Correlates of the Dorsal Respiratory Nuclei in a Rat Model.

Sleep restriction can result in a range of neurophysiological consequences in the brain including some brain stem nuclei. This study aimed to evaluate the effects of chronic sleep restriction (CSR) on quantitative aspects of brain stem respiratory centers using stereological methods. Male rats were randomly assigned into experimental group (CSR through a modified multiple platform apparatus), corresponding apparatus-control group (grid-floor control) and cage controls. In the grid-floor control group, animals were placed on wire-mesh grids positioned upon CSR apparatus and were then allowed to retain the opportunity to sleep. On day 21, all rats were euthanized with their brains removed for stereological assessments. The nuclei which are known to be involved in respiration rhythm including nucleus tractus solitarius (NTS), parabrachial nuclei (PB), and Kölliker-Fuse nucleus (KF) were evaluated. Compared to the control groups, stereological findings in CSR rats revealed a decrease by 5.2 ± 0.01%, 7.1 ± 0.007%, 3.9 ± 0.004%, and 6.3 ± 0.002% (mean ± standard error of the mean [SEM], p < .01 for all) in the volume of NTS, medial PB, lateral PB, and KF nuclei, respectively. Also, the total neuronal number of NTS, medial PB, lateral PB, and KF showed a significant decrease by 10.2 ± 21.4%, 6.3 ± 5.2%, 11.8 ± 8.6%, and 9.3 ± 2.5% (mean ± SEM, p < .05 for all), respectively. CSR may potentially induce neuronal loss and structural changes in the dorsal respiratory nuclei.

Pro- and Antioxidant Systems in the Lower Portion of Rat Brainstem during Hydroxybutyrate-Induced Pathological Periodic Breathing.

Activities of superoxide dismutase and catalase characterizing antioxidant status of the nervous tissue and its resistance to free radical oxidation were measured in the brainstem of rats with hydroxybutyrate-induced pathological periodic breathing. Hydroxybutyrate modified the pro- and antioxidant status in the brainstem respiratory center. It markedly inhibited catalase activity; in rats without the signs of periodic breathing, hydroxybutyrate up-regulated superoxide dismutase activity and to a lesser extent increased the resistance of the membrane structures in the medulla oblongata to induction of free radical oxidation. In rats with periodic breathing pattern, hydroxybutyrate induced more pronounced increase in the sensitivity of membrane structures in the medulla oblongata to induction of free radical oxidation.

Phrenic nerve deficits and neurological immunopathology associated with acute West Nile virus infection in mice and hamsters

Neurological respiratory deficits are serious outcomes of West Nile virus (WNV) disease. WNV patients requiring intubation have a poor prognosis. We previously reported that WNV-infected rodents also appear to have respiratory deficits when assessed by whole-body plethysmography and diaphragmatic electromyography. The purpose of this study was to determine if the nature of the respiratory deficits in WNV-infected rodents is neurological and if deficits are due to a disorder of brainstem respiratory centers, cervical spinal cord (CSC) phrenic motor neuron (PMN) circuitry, or both. We recorded phrenic nerve (PN) activity and found that in WNV-infected mice, PN amplitude is reduced, corroborating a neurological basis for respiratory deficits. These results were associated with a reduction in CSC motor neuron number. We found no dramatic deficits, however, in brainstem-mediated breathing rhythm generation or responses to hypercapnia. PN frequency and pattern parameters were normal, and all PN parameters changed appropriately upon a CO2 challenge. Histological analysis revealed generalized microglia activation, astrocyte reactivity, T cell and neutrophil infiltration, and mild histopathologic lesions in both the brainstem and CSC, but none of these were tightly correlated with PN function. Similar results in PN activity, brainstem function, motor neuron number, and histopathology were seen in WNV-infected hamsters, except that histopathologic lesions were more severe. Taken together, the results suggest that respiratory deficits in acute WNV infection are primarily due to a lower motor neuron disorder affecting PMNs and the PN rather than a brainstem disorder. Future efforts should focus on markers of neuronal dysfunction, axonal degeneration, and myelination.

Developmental neuropathology of brainstem respiratory centers in unexplained stillbirth: What’s the meaning?

Stillbirth is one of the most stressful life events affecting over 3 million pregnancies per year throughout the world. An accurate autopsy of the stillborn fetus, including the placenta and umbilical cord examination, should be performed promptly after delivery. A thorough maternal history also should be taken, including exposures to risk factors. In many cases a death cause, attributable to fetal, maternal, or placental pathology, is clearly identified. However, in 50% or more of cases the cause remains unknown.The purpose of this study is to highlight possible developmental alterations of the autonomic nervous system in unexplained stillbirths to provide an explanation of the pathogenetic mechanism of their death.We conducted a careful neuropathological study of the brainstem, where the main vital centers are located, in 85 unexplained stillbirths and 52 age-matched controls died of known cause. Information on the maternal lifestyle, including the smoking habit, was collected in all cases. Hypodevelopment of neuronal centers involved in breathing control, all connected together in a “respiratory network”, precisely hypoplasia of the facial/parafacial complex, Kölliker-Fuse nucleus, pre-Bötzinger nucleus and intermediolateral nucleus, were frequently observed in unexplained deaths, significantly related to maternal cigarette smoking.We support the hypothesis of a strong action of maternal smoking during pregnancy on the development of brainstem respiratory nuclei and suggest an explanation of the high incidence of the respiratory network alterations in unexplained fetal death, when breathing not represents a vital function.

Synaptogenesis and Myelination in the Nucleus/Tractus Solitarius: Potential Role in Apnea of Prematurity, Congenital Central Hypoventilation, and Sudden Infant Death Syndrome.

Fetuses as early as 15 weeks' gestation exhibit rhythmical respiratory movements shown by real-time ultrasonography. The nucleus/tractus solitarius is the principal brainstem respiratory center; other medullary nuclei also participate. The purpose was to determine temporal maturation of synaptogenesis. Delayed synaptic maturation may explain neurogenic apnea or hypoventilation of prematurity and some cases of sudden infant death syndrome. Sections of medulla oblongata were studied from 30 human fetal and neonatal brains 9 to 41 weeks' gestation. Synaptophysin demonstrated the immunocytochemical sequence of synaptogenesis. Other neuronal markers and myelin stain also were applied. The nucleus/tractus solitarius was similarly studied in fetuses with chromosomopathies, metabolic encephalopathies, and brain malformations. Synapse formation in the nucleus solitarius begins at about 12 weeks' gestation and matures by 15 weeks; myelination initiated at 33 weeks. Synaptogenesis was delayed in 3 fetuses with different conditions, but was not specific for only nucleus solitarius. Delayed synaptogenesis or myelination in the nucleus solitarius may play a role in neonatal hypoventilation, especially in preterm infants and in some sudden infant death syndrome cases.

Cholecalciferol (vitamin D3) improves functional recovery when delivered during the acute phase after a spinal cord trauma

In a previous study, based on a rat model of thoracic spinal cord compression, we demonstrated that cholecalciferol (Vitamin D3), delivered at the dose of 200IU/kg/day, significantly improved ventilatory frequency and spasticity. In order to confirm the restorative potential of vitamin D, we performed a new study, using a rat model of left cervical hemisection (C2). From Day 1 or Day 7, animals received, during three months, a weekly oral bolus of either cholecalciferol, at the dose of 500IU/kg/day, or vehicle, namely triglycerides. Rats were assessed every month, using a ladder test for sensori-locomotor ability and neuromuscular capacity. Three months after injury, H-reflex was recorded from left extensor digitorum muscle in order to measure the reflexivity of the sub-lesional region. Ventilatory frequency was also monitored during an electrically induced muscle fatigue of the hindlimb known to enhance muscle metaboreflex and increase respiratory rate. After recording the phrenic nerve activity, ipsilateral to the lesion, during spontaneous breathing, animals were artificially ventilated while paralyzed with a neuromuscular blocking agent and then the brainstem respiratory centres were provoked to maximal output by temporarily stopping the ventilator. Spinal cords were immunostained with an anti-neurofilament antibody to evaluate axon numbers. We show here that vitamin D-treated animals display i) an enhanced locomotor activity, ii) an improved breathing when hindlimb muscle was electrically stimulated to induce fatigue, iii) an H-reflex depression similar to control animals, iv) a phrenic nerve activity response to a temporary asphyxial stress and v) a non significant decreased number of axons in the proximal stump when compared with the Sham group. This new set of data confirms that vitamin D is a potent molecule that could be tested in clinical trials assessing functional recovery in para-/tetra-plegic patients, shortly after a trauma.

Opioid-induced respiratory depression: reversal by non-opioid drugs.

The human body is critically dependent on the ventilatory control system for adequate uptake of oxygen and removal of carbon dioxide (CO2). Potent opioid analgesics, through their actions on μ-opioid receptor (MOR) expressed on respiratory neurons in the brainstem, depress ventilation. Opioid-induced respiratory depression (OIRD) is potentially life threatening and the cause of substantial morbidity and mortality. One possible way of prevention of OIRD is by adding a respiratory stimulant to the opioid treatment, which through activation of non-opioidergic pathways will excite breathing and consequently will offset OIRD and should not affect analgesia. Various new respiratory stimulants are currently under investigation including (a) potassium channel blockers acting at the carotid bodies, and (b) ampakines and (c) serotonin receptor agonists acting within the brainstem. (a) GAL-021 targets BKCa-channels. Initial animal and human experimental evidence indicates that this potassium channel blocker is a potent respiratory stimulant that reverses OIRD without affecting antinociception. GAL021 is safe and better tolerated than the older K+-channel blocker doxapram and more efficacious in its effect on respiration. (b) Ampakines modulate glutamatergic respiratory neurons in brainstem respiratory centers. Various ampakines have been studied showing their ability to increase respiratory drive during OIRD by increasing respiratory rate. Currently, CX717 is the most promising ampakine for use in humans as it is safe and does not affect opioid analgesia. (c) While animal studies show that serotonin receptor agonists increase respiratory drive via activation of serotonin receptors in brainstem respiratory centers, human studies are without success. Further clinical studies are required to improve our care of patients that are treated with potent opioid analgesics. The use of non-opioid adjuvants may reduce the probability of OIRD but does never relieve us of our duty to continuously monitor these patients, irrespective whether they are treated in-house or in an ambulatory setting.

Lung inflammation induces IL-1β expression in hypoglossal neurons in rat brainstem

Perinatal inflammation is associated with respiratory morbidity. Immune modulation of brainstem respiratory control centers may provide a link for this pathobiology. We exposed 11-day old rats to intratracheal lipopolysaccharide (LPS, 0.5μg/g) to test the hypothesis that intrapulmonary inflammation increases expression of the proinflammatory cytokine IL-1β within respiratory-related brainstem regions. Intratracheal LPS resulted in a 32% increase in IL-1β protein expression in the medulla oblongata. In situ hybridization showed increased intensity of IL-1β mRNA but no change in neuronal numbers. Co-localization experiments showed that hypoglossal neurons express IL-1β mRNA and immunostaining showed a 43% increase in IL-1β protein-expressing cells after LPS exposure. LPS treatment also significantly increased microglial cell numbers though they did not express IL-1β mRNA. LPS-induced brainstem expression of neuronal IL-1β mRNA and protein may have implications for our understanding of the vulnerability of neonatal respiratory control in response to a peripheral proinflammatory stimulus.

Phrenic Nerve Stimulation for Diaphragm Pacing in a Quadriplegic Patient

Chronic hypoventilation due to injury to the brain stem respiratory center or high cervical cord (above the C3 level) can result in dependence to prolonged mechanical ventilation with tracheostomy, frequent nosocomial pneumonia, and prolonged hospitalization. Diaphragm pacing through electrical stimulation of the phrenic nerve is an established treatment for central hypoventilation syndrome. We performed chronic phrenic nerve stimulation for diaphragm pacing with the spinal cord stimulator for pain control in a quadriplegic patient with central apnea due to complete spinal cord injury at the level of C2 from cervical epidural hematoma. After diaphragmatic pacing, the patient who was completely dependent on the mechanical ventilator could ambulate up to three hours every day without aid of mechanical ventilation during the 12 months of follow-up. Diaphragm pacing through unilateral phrenic nerve stimulation with spinal cord stimulator was feasible in an apneic patient with complete quadriplegia who was completely dependent on mechanical ventilation. Diaphragm pacing with the spinal cord stimulator is feasible and effective for the treatment of the central hypoventilation syndrome.

Respiratory and sleep disorders in female children with atypical Rett syndrome caused by mutations in the CDKL5 gene

In female children with drug-resistant seizures and developmental delay from birth, atypical Rett syndrome caused by mutations in the CDKL5 gene should be considered. Several clinical features resemble classic Rett syndrome. Respiratory and sleep abnormalities are frequently present in Rett syndrome, whereas little is known in patients with CDKL5 mutations. In four genetically confirmed female patients with CDKL5 mutations (age range 2-15 y), the presence of breathing and sleep abnormalities was evaluated using the validated Sleep Disturbance Scale for Children and polysomnography (PSG). The Sleep Disturbance Scale for Children indicated disorders of initiating and maintaining sleep, daytime somnolence, and sleep breathing disorders. In one patient, PSG showed central apnoeas during sleep: her total apnoea-hypopnoea index (AHI) was 4.9, of which the central AHI was 3.4/h. When awake, central apnoeas were present in two of the four female children (central AHI 28/h and 41/h respectively), all preceded by hyperventilation. PSG showed low rapid eye movement (REM) sleep (9.7-18.3%), frequent awakenings, and low sleep efficiency (range 59-78%). Episodic hyperventilation followed by central apnoeas was present while awake in two of four patients. This may indicate failure of brainstem respiratory centres. In addition, low REM sleep, frequent arousals (not caused by apnoeas/seizures), and low sleep efficiency were present. Similar to Rett syndrome, in patients with CDKL5 mutations PSG seems warranted to evaluate breathing and sleep disturbances.

Spinal and Pontine Relay Pathways Mediating Respiratory Rhythm Entrainment by Limb Proprioceptive Inputs in the Neonatal Rat

The coordination of locomotion and respiration is widespread among mammals, although the underlying neural mechanisms are still only partially understood. It was previously found in neonatal rat that cyclic electrical stimulation of spinal cervical and lumbar dorsal roots (DRs) can fully entrain (1:1 coupling) spontaneous respiratory activity expressed by the isolated brainstem/spinal cord. Here, we used a variety of preparations to determine the type of spinal sensory inputs responsible for this respiratory rhythm entrainment, and to establish the extent to which limb movement-activated feedback influences the medullary respiratory networks via direct or relayed ascending pathways. During in vivo overground locomotion, respiratory rhythm slowed and became coupled 1:1 with locomotion. In hindlimb-attached semi-isolated preparations, passive flexion-extension movements applied to a single hindlimb led to entrainment of fictive respiratory rhythmicity recorded in phrenic motoneurons, indicating that the recruitment of limb proprioceptive afferents could participate in the locomotor-respiratory coupling. Furthermore, in correspondence with the regionalization of spinal locomotor rhythm-generating circuitry, the stimulation of DRs at different segmental levels in isolated preparations revealed that cervical and lumbosacral proprioceptive inputs are more effective in this entraining influence than thoracic afferent pathways. Finally, blocking spinal synaptic transmission and using a combination of electrophysiology, calcium imaging and specific brainstem lesioning indicated that the ascending entraining signals from the cervical or lumbar limb afferents are transmitted across first-order synapses, probably monosynaptic, in the spinal cord. They are then conveyed to the brainstem respiratory centers via a brainstem pontine relay located in the parabrachial/Kölliker-Fuse nuclear complex.

1. The physiology of the brainstem respiratory centres: Lessons from a concurrent multithreaded computational model of Rett syndrome

1. The physiology of the brainstem respiratory centres: Lessons from a concurrent multithreaded computational model of Rett syndrome

Pathogenesis and Management of Apnea of Prematurity: A Brief Overview

Regular rhythmic breathing requires a patent airway; central respiratory drive originating from respiratory centers in the brainstem modulated by input from peripheral neural and chemical receptors; and coordinated effective functioning of the muscles of respiration. Changes in arterial PCO2, PO2, and pH acts on neural and chemical receptors and inputs from these centers are integrated by the respiratory center in brainstem, which then send signals to the respiratory muscles to maintain airway patency and regulate the level of ventilation. The immature brainstem respiratory centers in preterm infants have an attenuated responses to carbon dioxide and a paradoxical response to hypoxia that results in apnea rather than the hyperventilation observed in term infants and adults [2,5-7]. This immaturity of breathing responses affects central and peripheral

Commentaries on Viewpoint: Initiating inspiration outside the medulla does produce eupneic breathing

Commentaries on Viewpoint: Initiating inspiration outside the medulla does produce eupneic breathing

Initiating inspiration outside the medulla does produce eupneic breathing

ARTERIAL PCO2 IS DICTATED by the ratio between the level of pulmonary gas exchange and alveolar ventilation (VA), not minute ventilation. If so, how could isocapnia be maintained if only the magnitude (tidal volume, VT) and duration (TI and TTOT) of the neural output produced by the central pattern generator of breathing (CPG) can be altered? In other words, what is the strategy used by the respiratory control system to match its output to the level of pulmonary gas exchange to keep arterial blood gas homeostasis if this neural output con- tributes to dead space ventilation? In this Viewpoint, we will show that when the spontaneous breathing is replaced by a cortically triggered breathing pattern at various breathing frequencies (we will name this new rhythm an "ecto-rhythm"), the relationship between TTOT and VT has a positive intercept that averages the pulmonary dead space. As a result, the coupling between ventilation and the pulmonary gas exchange becomes possible (17). We will present the idea that whenever isocapnia is maintained during spontaneous or automatic breathing, the magnitude and dura- tion of breath cycles must display the same relationship as during an ecto-rhythm (15). Conversely, we will discuss the implications of the observation that breathing can display the same essential regulatory properties whether generated outside or within the pontomedullary CPG area (7). Ecto-rhythm, breathing pattern, and gas exchange: the re-