The Use of Ethamivan in the Treatment of Barbiturate Poisoning

Ethamivan was used as a respiratory analeptic in the treatment of nine cases of severe barbiturate poisoning. Initial intravenous injections of 100 to 150 mg. of ethamivan increased the depth of respirations within a minute. Prolonged respiratory stimulation was achieved by a continuous intravenous infusion of 500 to 3000 mg. of ethamivan per litre of fluid. If hypotension occurred, an intravenous drip of noradrenaline was used; fluid overloading was avoided by adjusting the concentrations of drugs given, so that no more than a total of 125 c.c. of fluid per hour was administered. The chief side effect of overdosage of ethamivan was muscular twitching. This did not prove to be a problem and was of some value in determining the amount of drug given. The nine patients survived. It was concluded that ethamivan is a useful agent in the treatment of barbiturate poisoning.     

Effects of Ethamivan in Patients with Chronic Respiratory Disease

Nineteen patients suffering from chronic respiratory disease were evaluated before, during and after ethamivan administration by serial measurement of arterial pH, pCO₂, plasma ethamivan levels and alveolar ventilation. Ethamivan was administered intravenously as a single injection of 50 mg. in five patients; as an injection of 25 mg./kg. in five patients; as an intravenous injection of (a) 50 mg. over 15 minutes and (b) 150 mg. over 15 minutes in five patients; and finally as an oral dose of 300 to 500 mg. in five patients.Plasma levels of ethamivan became unmeasurable within 15 minutes of receiving the largest dose. Alveolar ventilation increased only in patients receiving the highest intravenous dose, and no significant changes in blood gases were elicited in any patient.     

Inflation reflex in the rat.

The Breuer-Hering inflation reflex [BHIR] was elicited in conscious and anaesthetized rats by inflating the lungs with constant pressures of 5--20 cm H2O. The reflex was elicited well in conscious animals, but even with the maximum stimulus [inflation of 20 cm H2O, corresponding to about 4.5-fold the tidal volume] the duration of apnoea did not exceed 4 control respiration cycles. In anaesthetized animals, the same stimulus let to apnoea lasting 180--400 control respiration cycles on the average, according to the type and depth of general anaesthesia. The duration of apnoea in occlusion of the air passages in the expiratory position increased with the depth of anaesthesia, while in occlusion of the air passages at the peak of inspiration it was shortened. Stimulation of chemoreceptors [inhalation of a mixture 4% CO2 in O2 or of 8% O2 in N2] did not influence the elicitability or duration of the BHIR, nor did cooling the rats to 28 degrees C or heating them to 38 degrees C. The mean respiration frequency was 98 c/min in unanaesthetized rats, 96 c/min in urethane anaesthesis and 79--48 c/min in halothane anaesthesia, according to the depth of anaesthesia. Bilateral cervical vagotomy reduced mean respiration frequency to 35.6 c/min in conscious rats and to 31 c/min in urethane-anaesthetized animals. The results indicate the existence of species-related differences between basic regulatory mechanisms in the rat and certain other mammals.     

Central sleep apnoea syndrome in chronic heart failure: an underestimated and treatable comorbidity

Chronic heart failure is a clinical syndrome with a high mortality and morbidity. Despite optimal therapy, five-year survival is still only 50%. Central sleep apnoea syndrome is seen in approximately 40% of patients with congestive heart failure. Sleep apnoea syndrome can be divided into two forms in these patients: obstructive sleep apnoea syndrome (OSAS) and central sleep apnoea syndrome (CSAS, Cheyne-Stokes respiration), of which CSAS is the most common. CSAS is a form of sleep apnoea in congestive heart failure which is driven by changes in pCO₂. As a consequence of apnoea-hypopnoea an imbalance in myocardial oxygen delivery/consumption ratio will develop, sympathetic and other neurohormonal systems will be activated and right and left ventricular afterload will be increased. Sleep apnoea is associated with an increased mortality in patients with systolic heart failure. Treatment of sleep apnoea increases left ventricular ejection fraction and transplant-free survival. Because of its high prevalence, poor quality of life, poor outcome, and the beneficial effects of treatment, physicians treating patients with heart failure should be aware of central sleep apnoea. There are different treatment options, but the exact effects and indications of each option have not yet been fully determined. Further studies should be done to further investigate its prevalence, and to establish the most adequate therapy for the individual patient. (Neth Heart J 2010;18:260-3.)     

Persistence of eupnea and gasping following blockade of both serotonin type 1 and 2 receptors in the in situ juvenile rat preparation.

In severe hypoxia or ischemia, normal eupneic breathing is replaced by gasping, which can serve as a powerful mechanism for "autoresuscitation." We have proposed that gasping is generated by medullary neurons having intrinsic pacemaker bursting properties dependent on a persistent sodium current. A number of neuromodulators, including serotonin, influence persistent sodium currents. Thus we hypothesized that endogenous serotonin is essential for gasping to be generated. To assess such a critical role for serotonin, a preparation of the perfused, juvenile in situ rat was used. Activities of the phrenic, hypoglossal, and vagal nerves were recorded. We added blockers of type 1 and/or type 2 classes of serotonergic receptors to the perfusate delivered to the preparation. Eupnea continued following additions of any of the blockers. Changes were limited to an increase in the frequency of phrenic bursts and a decline in peak heights of all neural activities. In ischemia, gasping was induced following any of the blockers. Few statistically significant changes in parameters of gasping were found. We thus did not find a differential suppression of gasping, compared with eupnea, following blockers of serotonin receptors. Such a differential suppression had been proposed based on findings using an in vitro preparation. We hypothesize that multiple neurotransmitters/neuromodulators influence medullary mechanisms underlying the neurogenesis of gasping. In greatly reduced in vitro preparations, the importance of any individual neuromodulator, such as serotonin, may be exaggerated compared with its role in more intact preparations.     

Phrenic and external intercostal motoneuron activity during progressive asphyxia

Phrenic and external intercostal motoneuron activities were compared during progressive asphyxia induced by the interruption of artificial ventilation in the pentobarbital-urethan-anesthetized, gallamine-paralysed rabbit. The relative augmentation of inspiratory activity of the T1-T4 external intercostal nerves was significantly greater than that of the phrenic nerve during asphyxic hyperpnea. This was associated with a greater recruitment of intercostal than of phrenic motoneurons, particularly late in the hyperpneic phase immediately before the period of asphyxic apnea. However, peak and average discharge frequencies developed by intercostal motoneurons (n = 20) were only approximately 60% of those of the phrenic motoneurons (n = 28). Gasping respiration terminated the apneic period and was associated with a further intense recruitment of intercostal though not of phrenic motoneurons, but discharge frequencies developed by the intercostal motoneurons remained approximately 60% of those of the phrenic motoneurons. The instantaneous frequency profiles generated by the motoneurons often exhibited progressive changes during the terminal stages of hyperpnea (reduction in inspiratory duration and duty cycle and increases in inspiratory slope and discharge frequencies) such that much of the character of gasping respiration became evident before the apnea. Such smooth transitional sequences do not obviate the existence of an "independent gasping center" but do require that such a proposed center at least possess the capacity for interaction with those sites responsible for the generation of eupneic and hyperpneic respiration.     

Control of hypoxia using apneic oxygenation with extrapulmonary membrane elimination of CO2

The peculiarities and conditions of optimal gas exchange for arresting hypoxia during prolonged (3 hours) apnoea or bradypnoea were experimentally studied in 34 dogs, using the method of apnoea oxygenation and extrapulmonary membrane removal of CO2 on "Sever" membrane gas-exchanger. It was shown that successful arrest of severe ventilation disorders of respiration by this method depends on precise registration and skillful use of the factors influencing oxygenation and CO2 removal in membrane gas-exchanger connected with peripheral arteriovenous or venovenous shunts.     

Phasic pulmonary stretch receptor feedback modulates both eupnea and gasping in an in situ rat preparation

The perfused in situ juvenile rat preparation produces patterns of phrenic discharge comparable to eupnea and gasping in vivo. These ventilatory patterns differ in multiple aspects, including most prominently the rate of rise of inspiratory activity. Although we have recently demonstrated that both eupnea and gasping are similarly modulated by a Hering-Breuer expiratory-promoting reflex to tonic pulmonary stretch, it has generally been assumed that gasping was unresponsive to afferent stimuli from pulmonary stretch receptors. In the present study, we recorded eupneic and gasplike efferent activity of the phrenic nerve in the in situ juvenile rat perfused brain stem preparation, with and without phrenic-triggered phasic pulmonary inflation. We tested the hypothesis that phasic pulmonary inflation produces reflex responses in situ akin to those in vivo and that both eupnea and gasping are similarly modulated by phasic pulmonary stretch. In eupnea, we found that phasic pulmonary inflation decreases inspiratory burst duration and the period of expiration, thus increasing burst frequency of the phrenic neurogram. Phasic pulmonary inflation also decreases the duration of expiration and increases the burst frequency during gasping. Bilateral vagotomy eliminated these changes. We conclude that the neural substrate mediating the Hering-Breuer reflex is retained in the in situ preparation and that the brain stem circuitry generating the respiratory patterns respond to phasic activation of pulmonary stretch receptors in both eupnea and gasping. These findings support the homology of eupneic phrenic discharge patterns in the reduced in situ preparation and eupnea in vivo and disprove the common supposition that gasping is insensitive to vagal afferent feedback from pulmonary stretch receptor mechanisms.     

Analeptic and antianaleptic effects of naloxone and naltrexone in rabbits.

Naloxone (5 mg/kg), but not naltrexone, shortened the duration of anaesthesia in rabbits pretreated with pentobarbital. This analeptic effect was blocked by atropine, but not by methylatropine; it thus appears that a central cholinergic mechanism is involved. In contrast, smaller doses of both naloxone and naltrexone attenuated the arousal property of thyrotropin releasing hormone (TRH). Naloxone, but not naltrexone, also antagonized the analeptic property of d-amphetamine. In conscious animals naloxone potentiated, whereas naltrexone attenuated, the excitatory effects of TRH and d-amphetamine.     

Tonic pulmonary stretch receptor feedback modulates both eupnea and gasping in an in situ rat preparation

The perfused in situ juvenile rat preparation produces phrenic discharge patterns comparable to eupnea and gasping in vivo. These ventilatory patterns of eupnea and gasping differ in multiple aspects, including most prominently the rate of rise of inspiratory activity. Because gasping, but not eupnea, appeared similar after vagotomy in spontaneous breathing preparations, it has been assumed that gasping was unresponsive to afferent stimuli from pulmonary stretch receptors. In the present study, efferent activity of the phrenic nerve was recorded during eupnea and gasping in the in situ juvenile rat preparation. Gasping was induced in hypoxic-hypercapnia or ischemia. An increase in the pressure of tonic lung inflation from 1 to 10 cmH2O caused a prolongation of the duration between phrenic bursts in both eupnea or gasping. Bilateral vagotomy eliminated these changes. We conclude that the neural substrate mediating the Hering-Breuer reflex is retained in the in situ preparation and that the brain stem circuitry generating the respiratory patterns responds to tonic activation of pulmonary stretch receptors in a similar manner in eupnea and gasping. These findings support the homology of eupnea-like phrenic discharge patterns in the reduced in situ preparation and eupnea in vivo and disprove the common supposition that gasping is insensitive to vagal afferent feedback from pulmonary stretch receptor mechanisms.     

Time-frequency coherence analysis of phrenic and hypoglossal activity in the decerebrate rat during eupnea, hyperpnea, and gasping

Fast respiratory rhythms include medium- (MFO) and high-frequency oscillations (HFO), which are much faster than the fundamental breathing rhythm. According to previous studies, HFO is characterized by high coherence (Coh) in phrenic (Ph) nerve activity, thereby providing a means of distinguishing between these two types of oscillations. Changes in Coh between the Ph and hypoglossal (XII) nerves during the transition from normal eupnic breathing to gasping have not been characterized. Experiments were performed on nine unanesthetized, chemo- and barodenervated, decerebrate adult rats, in which sustained asphyxia elicited hyperpnea and gasping. A gated time-frequency Coh analysis was developed and applied to whole Ph and medial XII nerve recordings. The results showed dynamic Ph-Ph Coh during eupnea, including MFO and HFO. XII-XII Coh during eupnea was broadband and included four distinct peaks, with low-frequency Coh dominating the epochs preceding the onset of Ph activity. During gasping, only MFO-peaks were present in Ph-Ph Coh. Bilateral XII activity showed a significant reduction in Coh and a shift toward lower frequencies during gasping. In contrast, contralateral Ph-XII Coh progressively increased during state changes from eupnea to gasping, a tendency mirrored in the startup part of the Ph activity. These data suggest significant hypoxia/hypercapnia-induced alterations in synchronization between respiratory outputs during the transition from eupnea to gasping, reflecting a reconfiguration of the respiratory network and/or alterations in the circuitry associated with the motor pools, including dynamic coupling between outputs.     

High-frequency oscillations of phrenic activity in eupnea and gasping of in situ rat: influence of temperature

We hypothesized that the in situ perfused preparation of the juvenile rat exhibits patterns of ventilatory activity comparable to eupnea and gasping in vivo. To evaluate this hypothesis, we examined high-frequency oscillations of activity of the phrenic nerve at 27-34 degrees C. The peak frequency of these high-frequency oscillations was defined from power spectral analysis. In situ, recordings were obtained in hyperoxic normocapnia, during ventilatory cycles in which the peak of integrated phrenic activity was achieved late in the burst, as in eupnea in vivo. Recordings were also obtained in hypoxic hypercapnia, when the peak of integrated phrenic activity occurred in the first half of the burst, as in gasping in vivo. In situ, peak frequencies in the power spectra were significantly higher in gasping than during eupnea. Frequencies during eupnea and gasping were progressively elevated as the temperature of the in situ preparation was increased. The shift in peak frequencies between eupnea and gasping and the temperature sensitivity of frequencies in situ were the same as in vivo. Results provide additional support for the conclusion that the in situ preparation demonstrates distinctly different patterns of automatic ventilatory activity, comparable to eupnea and gasping in vivo.     

Differing activities of medullary respiratory neurons in eupnea and gasping

Our purpose was to compare further eupneic ventilatory activity with that of gasping. Decerebrate, paralyzed, and ventilated cats were used; the vagi were sectioned within the thorax caudal to the laryngeal branches. Activities of the phrenic nerve and medullary respiratory neurons were recorded. Antidromic invasion was used to define bulbospinal, laryngeal, or not antidromically activated units. The ventilatory pattern was reversibly altered to gasping by exposure to 1% carbon monoxide in air. In eupnea, activities of inspiratory neurons commenced at various times during inspiration, and for most the discharge frequency gradually increased. In gasping, the peak discharge frequency of inspiratory neurons was unaltered. However, all commenced activities at the start of the phrenic burst and reached peak discharge almost immediately. The discharge frequencies of all groups of expiratory neurons fell in gasping, with many neurons ceasing activity entirely. These data are consistent with the hypothesis that brain stem mechanisms controlling eupnea and gasping differ fundamentally.     

Identification of medullary loci critical for neurogenesis of gasping

We hypothesized that a discrete medullary locus, critical for gasping neurogenesis, could be identified. In decerebrate, cerebellectomized, vagotomized, paralyzed, and ventilated cats, activities of phrenic, hypoglossal, and recurrent laryngeal nerves were monitored. Gasping was induced by freezing the brain stem, via a fork thermode, at the pontomedullary junction. By reversible cooling of the medulla, chemical lesions with kainic acid, and radio-frequency lesions, a critical area for gasping neurogenesis was localized bilaterally 2-3 mm rostral to obex, 2.0-2.5 mm lateral to midline, and 3-4 mm ventral to medullary surface. Electrical stimulation in this area elicited premature gasps, whereas unilateral lesions or lidocaine injections eliminated gasping activities in all nerves. These procedures did not cause similar changes during eupnea. In apneusis, however, lidocaine injections markedly altered the pattern or caused apnea. We conclude that discharge of neurons in a discrete portion of the lateral tegmental field of medulla is required for gasping neurogenesis. Our results are consistent with these neurons comprising the central pattern generator for gasping.     

Effects of thyrotropin-releasing hormone (TRH) microinjected into various brain areas of conscious and pentobarbital-pretreated rabbits

Thyrotropin releasing hormone (TRH) was administered intracerebrally into various brain regions of conscious and pentobarbitalnarcotized rabbits. In conscious animals tachypnea was observed after TRH administration into all brain regions investigated. Behavioral excitation was most pronounced after TRH administration into the cerebral cortex, caudate nucleus and hypothalamus. Hyperthermia was produced only after hypothalamic injections of TRH. In pentobarbital-narcotized rabbits TRH exerted analeptic activity (shortening of narcosis) regardless of the brain area injected, although some quantitative differences were observed. These results indicate that the analeptic effect of TRH may be initiated from various areas of the brain.     

Ricerche Sulle Infrastrutture Cellulari Dello Spadice Di Arum

Abstract

Electronmicroscope studies on fine structure of the ARUM spadix. — Three main stages of spadix development have been recognized. In the first stage — during wigh the growth would be embrional and by cell division, while respiration would sharply increase — new mitochondria are continously generated, mainly by the activity of long organules (chondriochontha). The morphology of these mitochondria is quite peculiar, showing bended cristae, often ring — or arc-shaped, and closed. In the second stage — during wich the growth would be by cell enlargment and respiration would further increase — the production of new mitochondria is decreasing, but thed are still numerous in each cell, and show a larger number of cristae (or tubules) than mitochondria observed in the first stage. A generalized vesicle production by the endoplasmic reticulum and the cristae of mitochondria is apparent at the beginning of the third stage — during wich the spadix gradually involves and respiration would fall down. Later, presumably in concurrence with the loss of cell vitality, the membranes of mitochopdria are disrupted, and all the cell structuree less evident. A great interest is presented by the vesicle production; indeed visicle production by the endoplasmic reticulum, and often also by mitochondria, can be observed in the senescent cells, already present and scattered in the tissues of the very young spadices. This ultimate process is howerer often preceded by the re-absorption of the outer membranes of these organules, in connection of the cristae, wich therefore become opened and in communication with the cell cavity.     

Centrally administered vasopressin antagonizes pentobarbital-induced narcosis and depression of hippocampal cholinergic activity

Intracerebroventricular (ICV) microinjection of arginine vasopressin (AVP) to pentobarbital-anesthetized rats produced shortening of the duration of narcosis. This analeptic effect was blocked by atropine, indicating the central cholinergic nature of the response. AVP also increased hippocampal sodium-dependent high affinity choline uptake activity that had been depressed by the barbiturate. The AVP analeptic effect was blocked by pretreatment with a V-1 (vasopressor), but not a V-2 (antidiuretic), vasopressin receptor antagonist. These results suggest that ICV AVP produces its analeptic effect by interacting with central V-1 receptors to activate a hippocampal cholinergic arousal system. The cholinergic arousal effect may be a factor in the memory enhancing property of AVP.     

Effect of lung inflation on the respiratory frequency and heart rate of premature neonates

Changes in the respiratory frequency and heart rate in response to 10 seconds' inflation of the lungs with oxygen by the CPAP method were studied in 32 premature neonates. Elevation of the pressure in the airways and lungs of 0.25, 0.49, 0.73 and 0.98 kPa led to a slower respiration rate or to apnoea. The incidence of apnoea rose in proportion to the pressure. When inflation was started, forced inspiratory efforts (a gasp reflex) occurred. The incidence of the efforts was higher at higher inflation pressures, but their intensity was not correlated to the size of the pressure. They were manifested in a drop in oesophageal pressure to a mean -2.0 +/- 0.2 kPa and their mean duration was 169 +/- 8 ms. The administration of oxygen without an increase in pressure produced neither apnoea nor forced inspiratory reactions. Neither an increase in the pressure in the airways and lungs to the above values, nor the plain administration of oxygen, produced any significant changes in the instantaneous heart rate.     

Effect of aminophylline on the respiratory depressant action of intravenous adenosine in neonatal rabbits

We administered intravenous adenosine to 11 neonatal rabbits. Adenosine depressed respiration in 10 of 11 rabbits. For the group as a whole the adenosine-induced respiratory depression was highly significant (p less than 0.001). After aminophylline administration to the same animals the respiratory effect of intravenous adenosine was abolished in 3 animals. In 7 animals the effect of adenosine was reversed and respiratory stimulation was observed. After aminophylline adenosine produced a significant (p less than 0.001) increase in respiration in the group studied. The alteration of responses to intravenous adenosine by aminophylline in neonatal rabbits is similar to the effect of aminophylline on respiratory responses to hypoxia in neonates. Such an effect of aminophylline and other methylxanthines on adenosine actions, possibly central in site may explain their beneficial effect in the treatment of apnoea in the human neonate.     

Comparison of phrenic motoneuron activity during eupnea and gasping

Single-fiber phrenic nerve action potentials were recorded together with activity of contralateral whole phrenic nerve rootlets during eupnea and gasping in decerebrate, cerebellectomized, vagotomized, paralyzed, and ventilated cats. Gasping was reversibly produced by cooling a fork thermode positioned through the pontomedullary junction. In eupnea, phrenic motoneurons were distributed into "early" and "late" populations relative to their onset of activity during inspiration. During gasping, however, both fiber types typically commenced activity at the beginning of the phrenic nerve burst. Moreover, late fibers, but not early units, exhibited an augmentation of discharge frequency with the onset of gasping. The concentration of activity of all phrenic motoneurons at the beginning of inspiration and the increase in late-unit discharge frequency account for the faster rise of the gasp as compared with the eupneic breath. It is concluded that the pattern of phrenic nerve activation during gasping differs fundamentally from that during eupnea. These results support the concept that mechanisms underlying the neurogenesis of gasping and eupnea may not be identical.