Respiratory Discharge Research Articles

Effects of Hydrogen Sulfide Synthesis Inhibitors on Posthypoxic Ventilatory Behavior in the C57BL/6J Mouse

Background: H₂S synthesis inhibitors (HSSI) have been shown to impact respiratory control. For instance, the HSSI hydroxylamine (HA) decreases the respiratory discharge rate from isolated medullary sections, and HA in addition to other HSSIs propargylglycine and amino-oxyacetic acid (AOAA) have been found to reduce hypoxic responsiveness. Objectives: The aim of this study was to determine if administration of HSSIs could improve respiratory stability in an intact organism prone to recurrent central apneas. Methods: Saline and HSSI compounds were administered to C57BL/6J mice (n = 24), a strain predisposed to recurrent central apneas, prior to measurement of hypoxic and posthypoxic ventilatory behavior. Results: Administration of HA and AOAA resulted in a significantly smaller percentage of animals expressing one or more apneas during reoxygenation compared to saline control, and animals given AOAA demonstrated a smaller coefficient of variation for frequency during reoxygenation, a marker suggesting greater respiratory stability. This occurred despite varying effects of the three HSSI compounds on hypoxic ventilatory response. Conclusions: Instability and pause expression are improved by targeting H₂S synthesis, an effect not predicted by effects on hypoxic responsiveness.

Protective action of endogenously generated H2S on hypoxia-induced respiratory suppression and its relation to antioxidation and down-regulation of c-fos mRNA in medullary slices of neonatal rats

We previously reported that exogenous H(2)S played roles in protection of respiratory centers against hypoxic injury in medullary slices of neonatal rats. The protective action of endogenous H(2)S and its relation to antioxidation and down-regulation of c-fos mRNA were investigated in the present study. Perfusion of the slices with l-cysteine (Cys), substrate of cystathionine β-synthase (CBS, H(2)S synthase), could increase frequency of rhythmic respiratory discharge of the hypoglossal rootlets and prevent respiratory suppression induced by hypoxia, whereas perfusion with hydroxylamine (NH(2)OH, inhibitor of CBS) could postpone recovery of respiration from hypoxic inhibition. NH(2)OH also significantly enhanced hypoxia-induced increase in malondialdehyde (MDA) content of the slices. The hypoxia-induced up-regulation of c-fos mRNA could be markedly antagonized by S-adenosyl-l-methionine (SAM, activator of CBS), but greatly increased by NH(2)OH. Neither NH(2)OH, Cys nor SAM had any effect on expression of bcl-2 mRNA in hypoxic medullary slices. These results indicate that endogenously generated H(2)S was involved in protection of the medullary respiratory centers against hypoxic injury partly via antioxidation and down-regulation of c-fos.

Randomized placebo-controlled trial on azithromycin to reduce the morbidity of bronchiolitis in Indigenous Australian infants: rationale and protocol.

BackgroundAcute lower respiratory infections are the commonest cause of morbidity and potentially preventable mortality in Indigenous infants. Infancy is also a critical time for post-natal lung growth and development. Severe or repeated lower airway injury in very young children likely increases the likelihood of chronic pulmonary disorders later in life. Globally, bronchiolitis is the most common form of acute lower respiratory infections during infancy. Compared with non-Indigenous Australian infants, Indigenous infants have greater bacterial density in their upper airways and more severe bronchiolitis episodes. Our study tests the hypothesis that the anti-microbial and anti-inflammatory properties of azithromycin, improve the clinical outcomes of Indigenous Australian infants hospitalised with bronchiolitis.MethodsWe are conducting a dual centre, randomised, double-blind, placebo-controlled, parallel group trial in northern Australia. Indigenous infants (aged ≤ 24-months, expected number = 200) admitted to one of two regional hospitals (Darwin, Northern Territory and Townsville, Queensland) with a clinical diagnosis of bronchiolitis and fulfilling inclusion criteria are randomised (allocation concealed) to either azithromycin (30 mg/kg/dose) or placebo administered once weekly for three doses. Clinical data are recorded twice daily and nasopharyngeal swab are collected at enrolment and at the time of discharge from hospital. Primary outcomes are 'length of oxygen requirement' and 'duration of stay,' the latter based upon being judged as 'ready for respiratory discharge'. The main secondary outcome is readmission for a respiratory illness within 6-months of leaving hospital. Descriptive virological and bacteriological (including development of antibiotic resistance) data from nasopharyngeal samples will also be reported.DiscussionTwo published studies, both involving different patient populations and settings, as well as different macrolide antibiotics and treatment duration, have produced conflicting results. Our randomised, placebo-controlled trial of azithromycin in Indigenous infants hospitalised with bronchiolitis is designed to determine whether it can reduce short-term (and potentially long-term) morbidity from respiratory illness in Australian Indigenous infants who are at high risk of developing chronic respiratory illness. If azithromycin is efficacious in reducing the morbidly of Indigenous infants hospitalised with bronchiolitis, the intervention would lead to improved short term (and possibly long term) health benefits.Trial registrationAustralia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12610000326099

Water deprivation increases respiratory rhythmic sympathetic discharge through a mechanism that depends on neuronal activity in the hypothalamic paraventricular nucleus (PVN)

As in specific neurogenic cardiovascular diseases, activation of the hypothalamic PVN during water deprivation likely plays a key role in supporting sympathetic nerve activity (SNA) and arterial blood pressure (ABP). To determine if PVN support of SNA in water deprived (WD) rats involves increasing specific rhythmic bursting patterns, vagal intact euhydrated (control) and 48 h WD male rats were instrumented to record ABP, ECG, expired CO2, and splanchnic SNA (SSNA) or renal SNA (RSNA). Autospectral analysis (0.2 Hz resolution) revealed that respiratory power (1.3 - 1.7 Hz) of SSNA and RSNA was greater in WD rats (n=3/4) than controls (n=3). Bilateral inhibition of PVN with the GABA-AR agonist muscimol (100pmol in 100nl/side) reduced mean ABP (P<0.001), SSNA and RSNA (P<0.05/0.005) in WD rats but not controls. Muscimol also tended to reduce respiratory power of SSNA only in WD rats (P<0.09) such that respiratory power : total power (0.2 – 15 Hz) ratios were no longer different between groups. PVN muscimol did not affect respiratory power of RSNA in either group. These data indicate that PVN neuronal activity in WD rats supports respiratory rhythmic bursting of SSNA, but not RSNA. Ongoing studies seek to determine if reduced respiratory rhythmic SSNA by PVN muscimol in WD rats is a direct effect of suppressed PVN output to respiratory/sympathetic networks or an indirect effect of reduced mean ABP. Support: HL102310 (GMT)

Validity and underrecording of diagnosis of COPD in the Danish National Patient Registry

We examined the positive predictive value of diagnoses of acute exacerbation of chronic obstructive pulmonary disease (COPD) in the Danish National Patient Registry. We also examined the negative predictive value of acute pneumonia or respiratory failure discharge diagnoses for absence of underlying COPD. We identified all patients aged 30 years or older with acute hospital admission in Denmark from January 1st to December 31st 2008. Physicians at 34 Danish hospitals retrieved and reviewed medical records for 1581 patients with a discharge diagnosis of COPD, and for 1546 patients with a discharge diagnosis of either pneumonia or respiratory failure but no COPD diagnosis. Presence of COPD was assessed based on medical history, clinical symptoms and findings, and spirometry results. The overall positive predictive value for COPD was 92% (95% confidence interval [CI] = 91-93%). Among patients coded with pneumonia or respiratory failure but not COPD, 19% (95% CI = 17-21%) had COPD, corresponding to a negative predictive value for COPD of 81% (95% CI = 79-83%). The positive predictive value of acute COPD discharge diagnoses in the Danish National Patient Registry is high. At the same time, there is a substantial underrecording of COPD during hospitalizations with other acute respiratory disorders like pneumonia and respiratory failure.

Hypoxic and hypercapnic challenges unveil respiratory vulnerability of Surf1 knockout mice, an animal model of Leigh syndrome

Surf1 gene mutations were detected as a main cause for Leigh syndrome (LS), also known as infantile subacute necrotizing encephalomyelopathy. This syndrome which is commonly associated with systemic cytochrome c oxidase (COX) deficiency manifests in early childhood and has an invariable poor prognosis. Progressive disturbances of the respiratory function, for which both the metabolic condition and necrotizing brainstem lesions contribute, belong to the major symptoms of LS.A constitutive knockout (KO) mouse for Surf1 enables invasive investigations of distinct aspects of LS. In the present study the respiratory function was analyzed applying an arterially perfused brainstem preparation. Compared to wild type (WT) preparations Surf1 KO preparations had a higher baseline respiratory frequency and abnormal responses to hypoxia and hypercapnia that involved both respiratory frequency and motor nerve discharge pattern. These data suggest that COX deficiency impairs peripheral and/or central chemoreceptor function.

Two types of independent bursting mechanisms in inspiratory neurons: an integrative model

The network of coupled neurons in the pre-Bötzinger complex (pBC) of the medulla generates a bursting rhythm, which underlies the inspiratory phase of respiration. In some of these neurons, bursting persists even when synaptic coupling in the network is blocked and respiratory rhythmic discharge stops. Bursting in inspiratory neurons has been extensively studied, and two classes of bursting neurons have been identified, with bursting mechanism depends on either persistent sodium current or changes in intracellular Ca(2+), respectively. Motivated by experimental evidence from these intrinsically bursting neurons, we present a two-compartment mathematical model of an isolated pBC neuron with two independent bursting mechanisms. Bursting in the somatic compartment is modeled via inactivation of a persistent sodium current, whereas bursting in the dendritic compartment relies on Ca(2+) oscillations, which are determined by the neuromodulatory tone. The model explains a number of conflicting experimental results and is able to generate a robust bursting rhythm, over a large range of parameters, with a frequency adjusted by neuromodulators.

Patterns of expiratory and inspiratory activation for thoracic motoneurones in the anaesthetized and the decerebrate rat

The nervous control of expiratory muscles is less well understood than that of the inspiratory muscles, particularly in the rat. The patterns of respiratory discharges in adult rats were therefore investigated for the muscles of the caudal intercostal spaces, with hypercapnia and under either anaesthesia or decerebration. With neuromuscular blockade and artificial ventilation, efferent discharges were present for both inspiration and expiration in both external and internal intercostal nerves. This was also the case for proximal internal intercostal nerve branches that innervate only internal intercostal and subcostalis muscles. If active, this region of muscle in other species is always expiratory. Here, inspiratory bursts were almost always present. The expiratory activity appeared only gradually and intermittently, when the anaesthesia was allowed to lighten or as the pre-decerebration anaesthesia wore off. The intermittent appearance is interpreted as the coupling of a slow medullary expiratory oscillator with a faster inspiratory one. The patterns of nerve discharges, in particular the inspiratory or biphasic activation of the internal and subcostalis layers, were confirmed by observations of equivalent patterns of EMG discharges in spontaneously breathing preparations, using denervation procedures to identify which muscles generated the signals. Some motor units were recruited in both inspiratory and expiratory bursts. These patterns of activity have not previously been described and have implications both for the functional role of multiple respiratory oscillators in the adult and for the mechanical actions of the muscles of the caudal intercostal spaces, including subcostalis, which is a partly bisegmental muscle.

Pre‐inspiratory and inspiratory hypoglossal motor output during hypoxia induced plasticity in the rat

Respiratory discharge in the hypoglossal (XII) nerve is composed of pre‐inspiratory (pre‐I) and inspiratory (I) activity. Our first purpose was to test the hypothesis that hypoxia‐induced plasticity in XII motor output is differentially expressed in pre‐I vs. I XII bursting. Short‐term potentiation (STP) of XII motor output was induced in vagotomized and ventilated rats by isocapnic hypoxia. Both pre‐I and I XII discharge abruptly increased at beginning of hypoxia, and the relative increase in amplitude was much greater for pre‐I vs. I bursting. In addition, STP was expressed in I but not pre‐I bursting following hypoxia. Specifically, I activity remained elevated following hypoxia but pre‐I bursting abruptly returned to pre‐hypoxia levels. Our second purpose was to test the hypothesis that STP of I XII activity results from recruitment of silent XII motoneurons (MNs) vs. rate coding of active MNs. Single fiber recordings were used to classify XII MNs as I, expiratory‐inspiratory (E‐I), or silent based on baseline discharge patterns. STP of I XII activity following hypoxia was associated with increased discharge frequency in active I and silent MNs, but not E‐I MNs. We conclude that the expression of respiratory plasticity is differentially regulated between pre‐I and I XII activity. Moreover, both recruitment of silent MNs and rate coding of active I MNs contribute to STP of XII motor output following hypoxia.

Respiratory and Mayer wave-related discharge patterns of raphé and pontine neurons change with vagotomy

Previous models have attributed changes in respiratory modulation of pontine neurons after vagotomy to a loss of pulmonary stretch receptor "gating" of an efference copy of inspiratory drive. Recently, our group confirmed that pontine neurons change firing patterns and become more respiratory modulated after vagotomy, although average peak and mean firing rates of the sample did not increase (Dick et al., J Physiol 586: 4265-4282, 2008). Because raphé neurons are also elements of the brain stem respiratory network, we tested the hypotheses that after vagotomy raphé neurons have increased respiratory modulation and that alterations in their firing patterns are similar to those seen for pontine neurons during withheld lung inflation. Raphé and pontine neurons were recorded simultaneously before and after vagotomy in decerebrated cats. Before vagotomy, 14% of 95 raphé neurons had increased activity during single respiratory cycles prolonged by withholding lung inflation; 13% exhibited decreased activity. After vagotomy, the average index of respiratory modulation (eta(2)) increased (0.05 +/- 0.10 to 0.12 +/- 0.18 SD; Student's paired t-test, P < 0.01). Time series and frequency domain analyses identified pontine and raphé neuron firing rate modulations with a 0.1-Hz rhythm coherent with blood pressure Mayer waves. These "Mayer wave-related oscillations" (MWROs) were coupled with central respiratory drive and became synchronized with the central respiratory rhythm after vagotomy (7 of 10 animals). Cross-correlation analysis identified functional connectivity in 52 of 360 pairs of neurons with MWROs. Collectively, the results suggest that a distributed network participates in the generation of MWROs and in the coordination of respiratory and vasomotor rhythms.

Glial cells are involved in the exciting effects of doxapram on brainstem slices in vitro.

This study tested whether the glial cells are involved in the exciting effects of doxapram on brainstem slice in vitro. Experiments were performed in brainstem slice preparations from neonatal rats. The medial area of nucleus retrofacialis (mNRF) and the hypoglossal nerve (XII nerve) were contained in the preparations. The slices were perfused with modified Kreb's solution (MKS), and the rhythmical respiratory discharge activity (RRDA) was simultaneously recorded from the XII nerve by using suction electrodes, including the discharge time course of inspiratory (Ti), expiratory (Te), respiratory cycle (RC), and integrity amplitude of inspiratory discharge (IA). After applying of doxapram (5 microM) to the MKS for 10 min, Ti and IA increased significantly (85.0 +/- 25.0%, 13.2 +/- 2.5%, respectively, P < 0.05), the Te and the RC decreased significantly (19.0 +/- 1.4%, 12.8 +/- 1.4%, respectively, P < 0.05) when compared with control group. When the methionine sulfoximine (MS, 10 microM), a blockage of glutamine synthetase, was applied, all the exciting effects of doxapram on RRDA were reversed. After the glutamine (20 microM) was applied to the MKS for 10 min, the exciting effects were revealed again. Our results suggest that the normal metabolism of glial cells takes a key role in the modification of the RRDA in the slices. In conclusion, glial cells are involved in the exciting effects of doxapram on brainstem slice in vitro.

Activity patterns of the diaphragm during voluntary movements in awake cats

The diaphragm is an important inspiratory muscle, and is also known to participate in the postural function. However, the activity of the diaphragm during voluntary movements has not been fully investigated in awake animals. In order to investigate the diaphragmatic activity during voluntary movements such as extending or rotating their body, we analyzed the electromyogram (EMG) of the diaphragm and trunk muscles in the cat using a technique for simultaneous recordings of EMG signals and video images. Periodic respiratory discharges occurred in the left and right costal diaphragm when the cat kept still. However, once the cat moved, their periodicity and/or synchrony were sometimes buried by non-respiratory activity. Such non-periodic diaphragmatic activities during voluntary movements are considered as the combination of respiratory activity and non-respiratory activity. Most of the diaphragmatic activities started shortly after the initiation of standing-up movements and occurred after the onset of trunk muscle activities. Those activities were more active compared to the normal respiratory activity. During rotation movements, left and right diaphragmatic activities showed asymmetrical discharge patterns and higher discharges than those during the resting situation. This asymmetrical activity may be caused by taking different lengths of each side of the diaphragm and trunk muscles. During reaching movements, the diaphragmatic activity occurred prior to or with the onset of trunk muscle activities. It is likely that diaphragmatic activities during reaching movements and standing-up movements may have been controlled by some different control mechanisms of the central nervous system. This study will suggest that the diaphragmatic activity is regulated not only by the respiratory center but also by inputs from the center for voluntary movements and/or sensory reflex pathways under the awake condition.

Characterization of fast oscillatory rhythms in multiple respiratory‐related motor outputs during eupnea in decerebrate adult rat in vivo

Respiratory motor discharges exhibit both slow and fast oscillatory rhythms. The slow rhythms correspond to inspiratory (I), expiratory (E), or phase‐spanning behaviors while the fast rhythms appear to be exclusive to motor outputs exhibiting inspiratory‐related discharges. To further evaluate these respiratory‐related rhythms, we examined basal phrenic (PHR), hypoglossal (XII), and recurrent laryngeal (RLN) nerve bursts recorded simultaneously from decerebrate (unanesthetized) paralyzed mechanically‐ventilated adult rats in vivo. PHR discharge served as an index of I activity, and burst duration (TI) and the duration between bursts (TE) were determined from PHR traces. XII activity exhibited pre‐I and I phase discharge and RLN activity exhibited pre‐I, I, and E phase discharge. In each respiratory‐related motor output, high frequency oscillations (HFO) were identified but they were restricted to the I phase of each burst (i.e., no significant HFO activity was seen during pre‐I or E phases). PHR and RLN HFO peaks were located between 100‐150 Hz, and XII activity exhibited several distinct peaks with a broadband power distribution. HFO onset occurred at ~50% TI for PHR activity and somewhat earlier for XII and RLN activities; RLN HFO activity spanned most of the TI period. These data suggest that fast oscillatory rhythms in respiratory‐related motor discharges underlie only the I phase. Supported by NS049310.

Role of Glutamate in the Mechanisms of Adaptation of the System of Respiratory Control in Rats to Intermittent Hypoxia

In experiments on Wistar rats, we studied the role of changes in the state of glutamatergic transmission in the course of adaptation of the system of respiratory control to intermittent hypoxia. The volume/temporal parameters of respiration were estimated according to characteristics of EMG activity (amplitude, integral intensity of EMG discharges) recorded from the diaphragmatic muscle. Changes in EMG activity of the diaphragm induced by acute hypoxia (breathing a 12% О2-containing gas mixture) were estimated before and after of a 14-day-long course of intermittent hypoxia trainings and before and after inductions of a blocker of NMDA receptors, МK-801. The results prove that the glutamatergic transmitter system is significantly involved in the reaction of the respiratory system to presentation of a hypoxic stimulus within all stages of formation of the ventilatory response, both before and after the action of intermittent hypoxia. Blocking of NMDA receptors under conditions of adaptation to intermittent hypoxia exerted a more intense influence on the amplitude of respiratory EMG discharges of the diaphragm than on their frequency.

PARACLINCAL INVESTIGATION CONCERNING CALVES WITH RESPIRATORY DISEASES TREATED WITH NATURIST PRODUCTS (CETARIA ISLANDICA, PLANTAGO LANCEOLATA, GLYCYRRHIZA GLABRA, VALERIANA OFFICINALIS)

We are taken into study three-four months old calves, males and females, that had respiratory symptoms such nasal discharge, tahypnea, epyphora, normothermia, even subfebrility. The ill calves were separated in three experimental groups of eight calves each. The naturist products were administrated as following: group 1 - Cetraria islandica; group 2 - Plantago lanceolata, Glycyrrhiza glabra, Valeriana officinalis; group 3 - Certaria islandica, Plantago lanceolata, Glycyrrhiza glabra and Valeriana officinalis. The plants extract were administrated per os twice daily for ten days. On day three and day ten of treatment period, blood was taken from the calves and were determined the following parameters: leukocytes formula with hematologic analyzer MS9, enzymatic, proteic and mineral profile with Vet-Screen analyzer. The lymphocytes number increases gradually on all groups. On group 3, at the end of treatment a 7,8 % increase was observed in comparison with the reference values. The eosinophilic percentage is placed between physiological limits (3 ± 0,17 %) excepting group 2 where we have registered a slightly increase (4 ± 0,12 %). The monocytes and basophiles on all groups had values between physiological limits. Individual medium values of ALAT and ASAT are between normal limits on all groups (30 - 35 U/I for ALAT and 21 – 25 U/I for ASAT). Uric acid, creatinin, protein and albumin levels during the period treatment are also between physiological limits. The mineral profile represented by calcium and phosphorus levels revealed in both cases a significant increase at the end of treatment (12,0 ± 1,1 mg/dl for Ca and 9,8 ± 0,5 mg/dl for P). In conclusion we can say that the general status of health improved after treatment even on the calves with reserved prognosis. The medicines based on plant extracts does not contain residues and do not remains in blood, tissues and organs. These extracts do not influence significantly enzymatic, proteic and mineral parameters and can be successfully used on calves in ecological farms.

Early laparoscopic fundoplication and gastrostomy in infants with spinal muscular atrophy type I

Background/Purpose Spinal muscular atrophy (SMA) in children leads to progressive muscle weakness, dysphagia, aspiration, and death. We hypothesized that early laparoscopic fundoplication and gastrostomy in infants with SMA type I could be performed safely perhaps leading to fewer aspiration events and improved nutritional status. Methods Children diagnosed with SMA type I from 2002 through 2005 were included (n = 12). All children underwent laparoscopic Nissen fundoplication with gastrostomy shortly after diagnosis. Postoperative respiratory management and discharge criteria were standardized. Results All patients were extubated immediately postoperatively. There were no significant complications. Average time to full feeding and inpatient length of stay were 42 ± 4.9 hours (range, 30-48 hours) and 78 ± 22.5 hours (range, 44-120 hours), respectively. Mean weight-for-length percentile was doubled at 1 year postoperatively ( P = .03). The number of respiratory-related hospitalizations in the cohort decreased by almost 50% in the ensuing 12 months after surgery, although this did not reach statistical significance in this small cohort ( P = .34). Conclusions Early laparoscopic fundoplication and gastrostomy is safe and is associated with improved nutritional status. A trend toward fewer significant long-term aspiration-related events was seen after fundoplication. To better assess the long-term benefits of performing an antireflux procedure in these high-risk patients, a larger prospective trial comparing current nutritional support practices is needed.

Calcium‐activated potassium currents differentially modulate respiratory rhythm generation

The pre-Bötzinger complex (PBC) generates eupnea and sighs in normoxia and gasping during hypoxia through particular mixtures of intrinsic and synaptic properties. Among intrinsic properties, little is known about the role of Ca(2+)-activated potassium channels in respiratory rhythms generation. To examine this role, we tested the effects of openers and blockers of the large-conductance (BK) and small-conductance (SK) Ca(2+)-activated potassium channels on the respiratory rhythms recorded both in vitro and in vivo, as well as on the discharge pattern of respiratory neurons in the PBC. Activation of SK channels with 1-ethyl-2-benzimidazolinone (1-EBIO) abolished sigh-like activity and inhibited eupneic-like activity, whereas blockade of SK channels with apamine (APA) increased frequency in both rhythms. In hypoxia, APA did not affect the transition to gasping-like activity. At the cellular level, activation of SK channels abolished pacemaker activity and decreased non-pacemaker neurons discharge; opposite effects were observed with SK blockade. In contrast to SK channel modulation, either activation or blockade of BK channels with NS 1619 or iberiotoxin and paxilline, respectively, produced mild effects on eupneic-like and sigh-like bursts during normoxia in vitro. However, BK blockers prevented the changes associated with the transition to gasping-like activity in vitro and perturbed gasping generation and autoresuscitation in vivo. At the cellular level BK channel modulation did not affect respiratory neurons discharge. We conclude that K(Ca) participate in rhythm generation in a state-dependent manner; SK channels are preferentially involved in rhythm generation in normoxia whereas BK channels participate in the transition to gasping generation in hypoxia.

An innovative maintenance follow-up program after a first inpatient pulmonary rehabilitation

Although the benefits of pulmonary rehabilitation (PR) have been demonstrated in patients with COPD, most studies suggest that short-term programs are insufficient to maintain the benefits beyond a post-discharge period of 6 months to 1 year. We were interested to evaluate the effects of an innovative maintenance intervention compared with a usual after-care. Forty moderate to severe COPD patients, who had just completed their first inpatient PR, were consecutively included in either a maintenance group (MG) or a standard after-care group. The maintenance program was coordinated within a health-care network including self-help associations, and offered weekly activities. We measured the 6-min walk distance (6MWD), the quality of life using the St George Respiratory Questionnaire (SGRQ), the dyspnea, the maximal workload and the health-care utilization. Data were collected at respiratory clinic admission and discharge, and at 6- and 12-month visits after the PR. After 12 months, we found statistically and clinically significant differences in favor of the MG in 6MWD (74 m; p < or = 0.01) and in the three domains of SGRQ: symptom (19%; p < or = 0.01), activity (27%; p < or = 0.01) and impact (32%; p < or = 0.01). The results showed no difference between groups in dyspnea and maximal workload. We also found that the number of days spent in hospital for respiratory disorders was significantly lower in the MG after 12 months (p < or = 0.03). The multidisciplinary management of COPD patients in the post-rehabilitation period within a health-care network including self-help associations seems to be an effective strategy for maintaining, and even improving, the benefits of a first initial structured program.

Pathophysiology of Dyspnea in Chronic Obstructive Pulmonary Disease: A Roundtable

Effective management of dyspnea in chronic obstructive pulmonary disease (COPD) requires a clearer understanding of its underlying mechanisms. This roundtable reviews what is currently known about the neurophysiology of dyspnea with the aim of applying this knowledge to the clinical setting. Dyspnea is not a single sensation, having multiple qualitative descriptors. Primary sources of dyspnea include: (1) inputs from multiple somatic proprioceptive and bronchopulmonary afferents, and (2) centrally generated signals related to inspiratory motor command output or effort. Respiratory disruption that causes a mismatch between medullary respiratory motor discharge and peripheral mechanosensor afferent feedback gives rise to a distressing urge to breathe which is independent of muscular effort. Recent brain imaging studies have shown increased limbic system activation in response to various dyspneogenic stimuli and emphasize the affective dimension of this symptom. All of these mechanisms are likely instrumental in exertional dyspnea causation in COPD. Increased central motor drive (and effort) is required to increase ventilation during activity because the inspiratory muscles become acutely overloaded and functionally weakened. Abnormal dynamic ventilatory mechanics and excessive chemostimulation during exercise also result in a widening disparity between escalating central neural drive and restricted thoracic volume displacement. This neuromechanical uncoupling may form the basis for the distressing sensation of unsatisfied inspiration. Interventions that alleviate dyspnea in COPD do so by improving ventilatory mechanics, reducing central neural drive, or both-thereby partially restoring neuromechanical coupling of the respiratory system. Self-management strategies address the affective aspect of dyspnea and are essential to successful treatment.

Respiratory activity in brainstem of fetal mice lacking glutamate decarboxylase 65/67 and vesicular GABA transporter

The respiratory neural network in the mammalian medulla oblongata shows rhythmic activity before birth. GABA and glycine are considered to be involved in control of respiratory rhythm. Recently we have demonstrated respiratory failure in glutamic acid decarboxylase (GAD) 67-deficient mice [Tsunekawa N, Arata A, Obata K (2005) Development of spontaneous mouth/tongue movement and related neural activity, and their repression in mouse fetus lacking glutamate decarboxylase 67. Eur J Neurosci 21:173–178]. To further evaluate the involvement of GABA and glycine in fetal respiratory function, we studied neural activities in brainstem–spinal cord blocks prepared from GAD65−/−:67−/− and vesicular GABA transporter (VGAT) −/− mice on embryonic day 14 (E14)–E15 and E18. In these knockout mice, the synthesis of GABA and the vesicular release of GABA and glycine are completely absent, respectively. Spontaneous respiratory discharges were observed in the ventral roots at the cervical cord (C) 4 level from wild-type mice but not from the knockout mice on E18. Administration of substance P induced C4 discharges in GAD65−/−:67−/− preparations but not in VGAT−/− preparations. C4 discharges were observed in the knockout mice on E14–E15, although the frequency was lower than that in the wild-type. Neuronal activities in the respiratory network of the E18 brainstem were recorded using a “blind” patch-clamp technique. Expiratory and inspiratory neurons with their characteristic firing patterns were observed in the wild-type fetuses. Strychnine reversed inspiratory-phase hyperpolarization to large depolarization in expiratory neurons. On the other hand, neurons in the same area of the knockout mice fired spontaneously without any rhythm. Substance P induced hyperpolarizing potentials in medullary neurons of GAD65−/−:67−/− mice. Further administration of strychnine induced large depolarizing potentials. Rhythmic activities were not observed in VGAT−/− mice even in the presence of substance P and strychnine. These results indicate that the lack of GABA and glycine impairs the function of the respiratory network in mouse fetuses and the impairment progresses with fetal age.