Zoltan Tomori

Beneficial effects of severe sleep apnea therapy on nocturnal glucose control in persons with type 2 diabetes mellitus

Given the consequences of sleep apnea and coexisting diabetes, satisfactory treatment of both diseases is required. Our results of continuous glucose monitoring in severe sleep apnea diabetic patients before and during continuous positive airway pressure/CPAP therapy showed significant reduction of nocturnal glucose variability and improved overnight glucose control on CPAP.

Brainstem circuitry of tracheal-bronchial cough: c-fos study in anesthetized cats.

The c-fos gene expression method was used to localize brainstem neurons functionally related to the tracheal-bronchial cough on 13 spontaneously breathing, pentobarbitone anesthetized cats. The level of Fos-like immunoreactivity (FLI) in 6 animals with repetitive coughs (170+/-12) induced by mechanical stimulation of the tracheobronchial mucosa was compared to FLI in 7 control non-stimulated cats. Thirty-four nuclei were compared for the number of labeled cells. Enhanced cough FLI was found bilaterally at following brainstem structures, as compared to controls: In the medulla, FLI was increased in the medial, interstitial and ventrolateral subnuclei of the solitary tract (p < 0.02), in the retroambigual nucleus of the caudal medulla (p < 0.05), in the ambigual, paraambigual and retrofacial nuclei of the rostral medulla along with the lateral reticular nuclei, the ventrolateral reticular tegmental field (p < 0.05), and the raphe nuclei (p < 0.05). In pons, increased FLI was detected in the lateral parabrachial and Kölliker-Fuse nuclei (p < 0.01), in the posteroventral cochlear nuclei (p < 0.01), and the raphe midline (p < 0.05). Within the mesencephalon cough-related FLI was enhanced at the rostral midline area (p < 0.05), but a decrease was found at its caudal part in the periaqueductal gray (p < 0.02). Results of this study suggest a large medullary - pontine - mesencephalic neuronal circuit involved in the control of the tracheal-bronchial cough in cats.

Do Differences in Sleep Architecture Exist between Persons with Type 2 Diabetes and Nondiabetic Controls

Background: It has been shown previously that the suppression of slow-wave sleep (SWS) markedly reduced insulin sensitivity and led to an impairment of glucose tolerance. We hypothesized that a decreased amount of SWS is a feature peculiar to subjects with type 2 diabetes. Method: A retrospective case-control study analyzed polysomnographic recordings and covariate data of 22 type 2 diabetic and 22 nondiabetic subjects [n = 44; 8 women, 36 men, aged 57.5 ± 5.5 years, body mass index (BMI) 33.8 ± 5.9 kg/m2, apnea-hypopnea index (AHI) 29.6 ± 22.2 episodes/hr] matched individually for sex, race, age, BMI, and severity of sleep-related breathing disorders (SRBD). We assessed differences in sleep architecture between the study group and the control group. Primary end points included the percentage of total sleep time spent in each sleep stage. Results: Despite similar age and severity of SRBD, subjects with type 2 diabetes demonstrated a significantly decreased amount of SWS (3.9 ± 5.95% vs 8.4 ± 4.57%; p = 0.012), increased percentage time in rapid eye movement sleep (24.1 ± 12.14% vs 13.8 ± 6.96%; p = 0.005), and higher arousal index (44.3 ± 19.53/hr vs 35.7 ± 12.67/hr; p = 0.037) compared to nondiabetic controls. After adjustment for sex, BMI, AHI, and smoking, age and presence of type 2 diabetes were independent predictors of the decreased SWS percentage (p = 0.001). Variables in this model accounted for 34% of the variance in the SWS percentage in our cohort. Conclusions: Results demonstrated distinct differences in sleep architecture in our cohort with decreased amounts of SWS in type 2 diabetes. These findings suggest that polysomnographic recognition of altered sleep architecture may be partially implicated in the early detection of persons with type 2 diabetes.

Sleep apnoea inducing hypoxemia is associated with early signs of carotid atherosclerosis in males

The intima-media thickness (IMT) of carotid arteries as a marker of preclinical atherosclerosis was measured by ultrasonography in 49 subjects to determine, how strongly the obstructive sleep apnoea (OSA) syndrome is associated with atherosclerosis. Maximal IMT was higher in patients with cardiovascular diseases and with or without risk factors of atherosclerosis, presenting also OSA (apnoea-hypopnoea index=26.1+/-15.6/h) compared to controls without OSA (0.91+/-0.21 mm versus 0.77+/-0.18 mm, p<0.05). The prevalence of IMT > or = 0.85 mm was also higher in patients with cardiovascular pathology presenting OSA than without it (p<0.05). IMT(max) was increased in subjects with mild to moderate OSA alone (AHI=20.4+/-8.7/h) versus healthy controls (0.83+/-0.14 mm versus 0.63+/-0.08 mm, p<0.01). Regression analysis revealed a correlation of IMT(max) with the frequency, intensity and duration of intermittent hypoxemia reflected by AHI (p<0.01), minimal oxygen saturation (p<0.01) and time spent with Sa(O2) < 90% (p<0.05) in patients presenting OSA. The results indicate clear association between early signs of carotid atherosclerosis and moderate OSA in males with and without concomitant cardiovascular pathology.

Power spectral analysis of respiratory responses to pharyngeal stimulation in cats: comparisons with eupnoea and gasping.

1. Based on similarities between properties of gasping and the aspiration reflex, we hypothesized that this reflex activates the central pattern generator for gasping. To evaluate this hypothesis, we have analysed high‐frequency oscillations in phrenic and hypoglossal neural activities. These oscillations, analysed by power and coherence spectra, are considered as signatures of the central pattern generators for automatic ventilatory activity. 2. In decerebrate, vagotomized, paralysed and ventilated cats, the aspiration reflex was elicited in eupnoea and gasping by mechanical stimulation of the pharynx and electrical stimulation of the glossopharyngeal nerve. 3. Compared with eupnoeic values, the peaks in the power spectra occurred at higher frequencies in spontaneous gasping. Peaks in the coherence spectra showed identical changes. 4. Power and coherence spectra of inspiratory neural activities during the aspiration reflex differed markedly from those of eupnoea, but were similar to those in gasping. 5. We conclude that mechanical stimulation of the pharynx or electrical stimulation of the glossopharyngeal nerve activates a reflex by which the central pattern generator for eupnoea is depressed, and that for gasping is activated. Our results also support the concept that separate brainstem mechanisms generate ventilatory activity in eupnoea and gasping.

The sniff-like aspiration reflex evoked by electrical stimulation of the nasopharynx

Forced inspiratory efforts resembling the sniff-like aspiration reflex (AR) were evoked by single-shocks or trains of electrical impulses to the dorsal pharyngeal and nasal mucosal surfaces in 12 anaesthetized spontaneously breathing cats. The strongest ARs determined by diaphragmatic (DIA) EMG and peak-inspiratory flows were elicited from the dorsolateral nasopharyngeal wall close to the torus tubalis. Highly responsive sites were also detected in the posterolateral nasal cavity and in the rostrolateral oropharynx. Repetitive stimulation at threshold strength evoked ARs exclusively in the late inspiration and early expiration. Suprathreshold responses abolished and replaced the tidal respiration. ARs exhibited a two-phase response in DIA EMG: a short latency (25.2 +/- 2.4 msec, M +/- SD) powerful excitation (69.7 +/- 10.7 msec) followed by an voltage-dependent inhibition (63.9 +/- 11.3 msec). Irrespective of voltage repetitive ARs were attenuated at rates above 7-9 Hz. In conclusion, electrical stimulation within the large receptive area of the nasal-pharyngeal airway evokes sniff-like efforts with biphasic inspiratory pattern and marked phase-dependent properties.

Reflex recruitment of medullary gasping mechanisms in eupnoea by pharyngeal stimulation in cats.

1. Mechanical stimulation of the naso‐ and oropharynx causes the replacement of the eupnoeic ventilatory pattern by a brief, but large, burst of activity of the phrenic nerve. Our purpose was to define whether these changes in phrenic activity represent a switch to gasping. 2. In decerebrate, vagotomized, paralysed and ventilated cats, mechanical stimulation of the pharynx was performed during eupnoea, apneusis and gasping. The latter two ventilatory patterns were produced by ventilating the experimental animal with 1.0% carbon monoxide in air or with 100% nitrogen. Eupnoea could be re‐established by a recommencement of ventilation with oxygen. 3. The rate of rise of phrenic activity and its peak height were much greater following mechanical stimulation of the pharynx than the phrenic bursts of eupnoea or apneusis. The durations of phrenic burst and the period between these were much less following pharyngeal stimulation. In contrast, these variables of phrenic activity were the same during pharyngeal stimulation and in gasping. 4. Previous studies had established that activity within a region of the lateral tegmental field of medulla is critical for the manifestation of gasping. Hence, electrical stimulation of this region during gasping elicits premature gasps whereas its ablation irreversibly eliminates gasping. 5. We positioned a multibarrelled pipette in the critical medullary region for gasping. Its location was verified, once gasping was established in hypoxia or anoxia, by the elicitation of premature gasps following electrical stimulation. Neurons in this region were destroyed by microinjections of the neurotoxin kainic acid; in a few experiments the region was destroyed by electrolytic lesions. 6. Following destruction of the region of the lateral tegmental field, gasping could no longer be provoked in anoxia. In contrast, the eupnoeic pattern of phrenic activity continued. However, mechanical stimulation of the pharynx no longer caused any changes in the on‐going pattern of phrenic activity. 7. We conclude that mechanical stimulation of the pharynx elicits a powerful reflex by which eupnoea is suppressed and gasping is elicited. Stated differently, the changes in phrenic activity during this pharyngeal stimulation in fact represent gasps. 8. Gasps are dependent upon activity within a region of the lateral tegmental field of the medulla. This region plays no role in the neurogenesis of eupnoea. Hence, our results provide additional support for the concept that there are multiple sites for ventilatory neurogenesis in the mammalian brainstem.

Reflex reversal of apnoeic episodes by electrical stimulation of upper airway in cats

Respiratory effects of electrical stimulation of the upper airways (UAW) before and during apnoeic episodes induced by nitrogen inhalation were studied in 9 anaesthetized cats. In eupnoeic animals these electrically-evoked reflexes comprise rapid and powerful inspiratory efforts characterized by strong maximal airway occlusion pressures (Pmax = 635 +/- 39 mm H2O) and rapid peak inspiratory flow rates (PIF = 536 +/- 36 ml.sec-1) similar to the sniff-like aspiration reflex elicited mechanically. Electrical stimulation of the UAW mucosa can elicit reflex inspirations and sniff-like aspiration reflexes even during reversible hypoxic apnoea but their intensity and reproducibility are transiently reduced. When repeated adequately, the electrically-induced reflexes can increase the reactivity of respiratory centre and interrupt or terminate apnoeic episodes as do other types of UAW stimulation. Reflex mechanisms and respiratory centre activations seem to be involved in these effects. The results suggest that electrical stimulation of UAW could be useful for testing the respiratory centre reactivity as well as for reflex reversal of apnoeic episodes and restoration of normal breathing in animal experiments and clinico-physiological studies. Such investigation of the role of UAW reflexes in the pathogenesis and therapy of apnoeic syndromes might also be possible by using a cardiostimulator adapted as respiratory pacemaker.

Sniff-like aspiration reflex evoked by pressure pulses from the upper airways in cats.

Respiratory effects of single positive and negative pressure pulses (PPP, NPP) applied to the functionally isolated upper airways (UA) were studied in 11 anaesthetized cats breathing spontaneously through a tracheal tube. The UA pressure and the changes of tracheal airflow were recorded and the blood pressure and electrocardiogram were occasionally monitored. Sniff-like aspiration reflexes comprising powerful spasmodic inspirations could be elicited by PPP or NPP of 20 to 110 cm H2O or -14 to -140 cm H2O. The responses to NPP but also to PPP characterized by high peak inspiratory flow, mean inspiratory flow and tidal volume (PIF = 312.5 +/- 64.3 and 231.1 +/- 21.7 ml.sec-1; VTI = 178.3 +/- 46.7 and 110.1 +/- 14.4 ml.sec-1; VT = 40.9 +/- 8.3 and 22.5 +/- 1.7 ml) resembled closely the aspiration reflex elicited by mechanical stimulation of the pharyngeal wall. Occasionally, sneezing, minor modifications of breathing pattern and solitary forced inspirations could be induced by lower pressures. The results indicate that sudden pressure stimulation of the UA evokes vigorous respiratory responses including the aspiration reflex. These reflexes and their alterations may contribute to development or release of both UA obstruction and apnoea, at least in cats.

Resuscitation and auto resuscitation by airway reflexes in animals.

Various diseases often result in decompensation requiring resuscitation. In infantsmoderate hypoxia evokes a compensatory augmented breath – sigh and more severehypoxia results in a solitary gasp. Progressive asphyxia provokes gasping respirationsaving the healthy infant – autoresuscitation by gasping. A neonate with suddeninfant death syndrome, however, usually will not survive. Our systematic research inanimals indicated that airway reflexes have similar resuscitation potential asgasping respiration. Nasopharyngeal stimulation in cats and most mammals evokes theaspiration reflex, characterized by spasmodic inspiration followed by passiveexpiration. On the contrary, expiration reflex from the larynx, or cough reflex fromthe pharynx and lower airways manifest by a forced expiration, which in cough ispreceded by deep inspiration. These reflexes of distinct character activate thebrainstem rhythm generators for inspiration and expiration strongly, but differently.They secondarily modulate the control mechanisms of various vital functions of theorganism. During severe asphyxia the progressive respiratory insufficiency may inducea life-threatening cardio-respiratory failure. The sniff- and gasp-like aspirationreflex and similar spasmodic inspirations, accompanied by strong sympatho-adrenergicactivation, can interrupt a severe asphyxia and reverse the developing dangerouscardiovascular and vasomotor dysfunctions, threatening with imminent loss ofconsciousness and death. During progressive asphyxia the reversal of graduallydeveloping bradycardia and excessive hypotension by airway reflexes starts withreflex tachycardia and vasoconstriction, resulting in prompt hypertensive reaction,followed by renewal of cortical activity and gradual normalization of breathing. Acombination of the aspiration reflex supporting venous return and the expiration orcough reflex increasing the cerebral perfusion by strong expirations, provides apowerful resuscitation and autoresuscitation potential, proved in animal experiments.They represent a simple but unique model tested in animal experiments.