Endogenous hydrogen sulfide in the rostral ventrolateral medulla/Bötzinger complex downregulates ventilatory responses to hypoxia.

Hydrogen sulfide (H2S) is now recognized as a new gaseous transmitter involved in several brain-mediated responses. The rostral ventrolateral medulla (RVLM)/Bötzinger complex is a region in the brainstem that is involved in cardiovascular and respiratory functions. Recently, it has been shown that exogenous H2S in the RVLM modulates autonomic function and thus blood pressure. In the present study, we investigated whether H2S, endogenously produced in the RVLM/Bötzinger complex, plays a role in the control of hypoxia-induced hyperventilation. Ventilation (VE) was measured before and after bilateral microinjection of Na2S (H2S donor, 0.04, 1 and 2 pmol/100 nl) or aminooxyacetate (AOA, 0.2, 1 and 2 pmol/100 nl, a cystathionine ß-synthase, CBS, inhibitor) into the RVLM/Bötzinger complex followed by a 60-min period of hypoxia (7% inspired O2) or normoxia exposure. Control rats received microinjection of vehicle. Microinjection of vehicle, AOA or Na2S did not change VE in normoxic conditions. Exposure to hypoxia evoked a typical increase in VE. Microinjection of Na2S (2 pmol) followed by hypoxia exposure attenuated the hyperventilation. Conversely, microinjection of AOA (2 pmol) into the RVLM/Bötzinger complex caused an increase in the hypoxia-induced hyperventilation. Thus, endogenous H2S in the RVLM/Bötzinger complex seems to play no role in the maintenance of basal pulmonary ventilation during normoxia whereas during hypoxia H2S has a downmodulatory function. Homogenates of RVLM/Bötzinger complex of animals previously exposed to hypoxia for 60 min exhibited a decreased rate of H2S production. Our data are consistent with the notion that the gaseous messenger H2S synthesis is downregulated in the RVLM/Bötzinger complex during hypoxia favoring hyperventilation.

[Device diagnosis and combined treatment of hyperventilation syndrome].

Hyperventilation syndrome is a separate disease and a symptom of other psychosomatic diseases. A variant of device diagnosis of the disease is proposed--integral rheoplethysmography by M. I. Tischenko and cardiointervalography by R. M. Baevsky. Hyper- and asthenic courses of the disease are described, the pathological psychoemotional pattern is recognized. The proposed treatment combines physiohemotherapy (laser treatment) and pharmacotherapy.

Dynamic hyperinflation after metronome-paced hyperventilation in COPD--a 2 year follow-up.

UNLABELLED: In contrast to the decline in FEV(1), the behavior of dynamic hyperinflation (DH) over time is unknown in patients with COPD. Metronome-paced hyperventilation (MPH) is a simple applicable surrogate for exercise to detect DH. OBJECTIVE: To evaluate changes in MPH-induced DH during two years follow-up in mild-to-severe COPD patients. Additionally, influence of smoking status on DH and the relation between DH and other lung function parameters were assessed. METHODS: Patients were recruited from a randomized controlled trial conducted in general practice. Measurements of lung function and DH were performed at baseline and after 12 and 24 months. DH was assessed by MPH with breathing frequency set at twice the baseline rate. Change in inspiratory capacity after MPH was used to reflect change in end-expiratory lung volume and therefore DH, presuming constant total lung capacity. RESULTS: During follow-up, 68 patients completed all measurements. DH increased by 0.23±0.06L (p≤0.001). No significant changes in FEV(1) %pred were seen. Smokers had lower FEV(1) and a more rapid decline than non-smokers. DH in smokers increased more over time compared to non-smokers. The amount of DH correlated positively with resting inspiratory capacity. CONCLUSION: After two years, a significant increase in MPH-induced DH in COPD patients was demonstrated, which was not accompanied by a decline in FEV(1). It might be that DH is a sensitive measure to track consequences of changes in airflow obstruction.

Respiratory manifestations of panic disorder: causes, consequences and therapeutic implications: [revision] / Manifestações respiratórias do transtorno de pânico: causas, consequências e implicações terapêuticas: [revisão]

Multiple respiratory abnormalities can be found in anxiety disorders, especially in panic disorder (PD). Individuals with PD experience unexpected panic attacks, characterized by anxiety and fear, resulting in a number of autonomic and respiratory symptoms. Respiratory stimulation is a common event during panic attacks. The respiratory abnormality most often reported in PD patients is increased CO2 sensitivity, which has given rise to the hypothesis of fundamental abnormalities in the physiological mechanisms that control breathing in PD. There is evidence that PD patients with dominant respiratory symptoms are more sensitive to respiratory tests than are those who do not manifest such symptoms, and that the former group constitutes a distinct subtype. Patients with PD tend to hyperventilate and to panic in response to respiratory stimulants such as CO2, triggering the activation of a hypersensitive fear network. Although respiratory physiology seems to remain normal in these subjects, recent evidence supports the idea that they present subclinical abnormalities in respiration and in other functions related to body homeostasis. The fear network, composed of the hippocampus, the medial prefrontal cortex, the amygdala and its brain stem projections, might be oversensitive in PD patients. This theory might explain why medication and cognitive-behavioral therapy are both clearly effective. Our aim was to review the relationship between respiration and PD, addressing the respiratory subtype of PD and the hyperventilation syndrome, with a focus on respiratory challenge tests, as well as on the current mechanistic concepts and the pharmacological implications of this relationship.

Múltiplas anormalidades respiratórias podem ser encontradas em pacientes com transtornos de ansiedade, particularmente no transtorno de pânico (TP). Indivíduos com TP experimentam ataques de pânico inesperados, caracterizados por ansiedade, medo e diversos sintomas autonômicos e respiratórios. A estimulação respiratória é um fenômeno comum durante os ataques de pânico. A anormalidade respiratória mais citada em pacientes com TP é a sensibilidade aumentada para o CO2, que originou a hipótese de uma disfunção fundamental nos mecanismos fisiológicos de controle da respiração no TP. Há evidências de que pacientes com TP com sintomas respiratórios predominantes são mais sensíveis a testes respiratórios do que aqueles sem a manifestação de tais sintomas, representando um subtipo distinto. Pacientes com TP tendem a hiperventilar e a reagir com pânico como resposta a estimulantes respiratórios como o CO2, gerando uma ativação de um circuito de medo hipersensível. Apesar de a fisiologia respiratória desses pacientes permanecer normal, algumas evidências recentes apontam a presença de disfunções subclínicas na respiração e em outras funções relacionadas à homeostase corporal. O circuito do medo, composto pelo hipocampo, córtex pré-frontal medial, amígdala e projeções do tronco cerebral, pode estar hipersensível em pacientes com TP. Essa teoria pode explicar porque os medicamentos e a terapia cognitivocomportamental são claramente eficazes. Nosso objetivo foi revisar a relação entre respiração e TP, especialmente o subtipo respiratório de TP e a síndrome da hiperventilação, focalizando os testes respiratórios, bem como as hipóteses mecanísticas e as implicações farmacológicas dessa relação.

Central neurogenic hyperventilation treated with intravenous fentanyl followed by transdermal application.

Central neurogenic hyperventilation (CNH) is a rare clinical condition that is sometimes difficult to treat. We report a 51-year-old female patient who was successfully treated with intravenous fentanyl followed by transdermal fentanyl. She had a transient epileptic episode with a temporary loss of consciousness. Immediately before her admission to the intensive care unit (ICU), her Pa(CO2) and pH were 6.7 mmHg and 7.64, respectively. Rebreathing from a paper bag and the intravenous administration of diazepam failed to improve the decreased Pa(CO2). Therefore, we administered intravenous fentanyl, at the rate of 50 microg x h(-1). Two days after her admission to the ICU, the Pa(CO2) had increased gradually to 22.9 mmHg, and the pH to 7.50. Although infiltration of recurrent lymphoma to the brain became apparent, she remained active, without epilepsy or loss of consciousness, in a general ward for 1 month with transdermal fentanyl, treatment until she again became drowsy; she died on hospital day 58. Transdermal fentanyl seems to be a good palliative measure to treat CNH in patients who have advanced neoplasms.

Effects of progesterone on apneic events during behaviorally defined sleep in male rats.

Drug therapy with progesterone has been applied to the patients with sleep apnea syndrome, but its clinical efficacy is equivocal. In the present study, we examined the effects of progesterone (1 and 30 mg/kg, i.p.) on the apneic events during behaviorally defined sleep in male rats at 4, 14 and 26 weeks of age by using a whole body plethysmographic measurement. The number of events of spontaneous apnea (SA) and post-sigh apnea (PSA) increased with aging. The duration of SA or PSA was also prolonged in old rats. A low dose (1 mg/kg) of progesterone significantly decreased the number of both SA and PSA, and this effect increased in an age-dependent manner. However, progesterone had no effect on the duration of SA and PSA. Neither the basal respiratory rate nor the total sleep time was changed. On the other hand, a higher dose (30 mg/kg) of progesterone had no effect on the number of SA and PSA, while it prolonged the duration of PSA. It also prolonged the total sleep time without affecting the basal respiratory rate. Pretreatment with mifepristone (5 mg /kg, i.p.), an antagonist of progesterone receptors, inhibited the effects of the low dose of progesterone, but did not show any antagonistic effect on the high dose-induced changes. These results suggest that the progesterone-mediated mechanisms are involved, at least partly, in respiratory function during sleep and the progesterone therapy is possibly effective within an appropriate dose range for the sleep apnea syndrome.

Eicosanoid and muscarinic receptor blockade abolishes hyperventilation-induced bronchoconstriction.

This study was designed to test the hypothesis that hyperventilation-induced bronchoconstriction (HIB) results from the combined effects of prostanoid and leukotriene metabolism. A bronchoscope was used in anesthetized dogs to record peripheral airway resistance and HIB before and after combined treatment with inhibitors of cyclooxygenase (indomethacin) and 5-lipoxygenase (MK-0591). Bronchoalveolar lavage fluid (BALF) cells and mediators from hyperventilated and control airways were also measured. Pretreatment with MK-0591 and indomethacin significantly attenuated, but did not abolish, HIB. However, addition of atropine nearly eliminated the residual response. Blockade of eicosanoid metabolism markedly reduced the concentrations of eicosanoids recovered in BALF after hyperventilation. Positive correlations between posthyperventilation BALF prostanoid and epithelial cell concentrations are suggestive of mucosal injury-induced mediator production and release. We conclude that HIB is prevented in the presence of eicosanoid and muscarinic-receptor blockade and that both classes of eicosanoids contribute similarly to the development of HIB.

Central neurogenic hyperventilation: pharmacologic intervention with morphine sulfate and correlative analysis of respiratory, sleep, and ocular motor dysfunction.

Central neurogenic hyperventilation (CNH), for which there is no effective therapy, can eventually result in respiratory fatigue and death. This report describes a patient with CNH due to a brainstem anaplastic astrocytoma who also exhibited disturbances of sleep and ocular motor function. The CNH responded clinically to morphine sulfate and methadone. Analysis of ventilatory response to CO2 before and after morphine demonstrated a depression of ventilatory response (49 to 53% of baseline) and occlusion pressure response (35 to 50% of baseline) to CO2, with a requirement for high doses of naloxone (10 mg IV) to reverse the effect. Polysomnography revealed sustained hyperventilation, elevated O2 saturation, and low end-tidal CO2 throughout all stages of non-rapid eye movement (NREM) sleep, and absence of rapid eye movement (REM) sleep. Ocular motor evaluation disclosed absence of horizontal and reflexive saccades with compensatory head thrusts. Correlation of the clinical and physiologic data with the MRI abnormalities suggested that the lesion responsible for CNH in this patient might reside in the medial tegmental parapontine reticular formation. Since recurrent episodes of hyperventilation responded in a sustained fashion to IV and oral opiates, this treatment may warrant consideration in other patients with CNH.

Central neurogenic hyperventilation in an awake patient with brainstem astrocytoma.

A patient had the rare combination of central neurogenic hyperventilation (PaCO2 of 9 torr) and a normal level of consciousness for eight days. Morphine attenuated but never corrected the hyperventilation. Experimental effects of hypocapnia, which decreases both cerebral blood flow and metabolism in humans, are at odds with the normal mentation initially seen in this patient despite her marked and persistent hypocapnia. Death occurred after progressive brainstem dysfunction. Pathological study showed a well-differentiated astrocytoma involving primarily the medulla and pons, with scattered tumor foci throughout the entire neuraxis. Possible mechanisms for central neurogenic hyperventilation are discussed briefly in relation to the pathological findings and the observed response to morphine.