The role of computed tomography pulmonary angiography in COVID-19 patients with suspected pulmonary embolism.

OBJECTIVES: This study is aimed to determine the location and distribution of pulmonary embolism (PE) and presence of signs potentially indicative of right heart overload on computed tomography pulmonary angiography (CTPA) in COVID-19 and non-COVID-19 patients. We also evaluated the extent and severity of COVID-19-associated lung changes in relation to PE. METHODS: The total number of 1,698 patients with CTPA included in the study were divided into 2 groups according to their COVID-19 status and each group was divided into 2 subgroups based on their PE status. These groups and subgroups were compared in terms of location of PE, diameter of pulmonary artery, right heart strain, ground-glass opacities (GGO), consolidations and other imaging features. RESULTS: In COVID-19 patients, there was a significant predominance of PE in peripheral branches of pulmonary artery (p < 0.001). There was an increased right-to-left ratio of ventricular diameters in cases with PE (p = 0.032 in patients with COVID-19 and p < 0.001 in non-COVID-19 patients). There was no association between the extent and severity of the disease and distribution of PE. CONCLUSION: COVID-19 is associated with a higher incidence of peripheral location of PE and presence of GGO. There were signs indicative of right heart overload in cases with PE regardless of COVID-19 (Tab. 3, Fig. 1, Ref. 29) Keywords: COVID-19, computed tomography, CTPA, pneumonia, pulmonary embolism.

PIXE analysis of iron in rabbit cerebellum after exposure to radiofrequency electromagnetic fields.

PURPOSE: We investigated iron accumulation and the possible mechanisms in the rabbit cerebellum after the exposure to the real GSM and generated radiofrequency electromagnetic fields (RF EMF) using inductively coupled plasma mass spectrometry (ICP MS) and particles induced X-ray emission (PIXE). MATERIALS AND METHODS: Four groups of rabbits were exposed to the real EMF, generated EMF, combination of both the real and generated signals and the control group with no exposition. For determination of iron concentration in the four groups of cerebellum samples ICP MS was used. Iron accumulation in samples by PIXE analysis using the 3 MeV proton beam was carried out. RESULTS: Iron concentration measured by ICP MS revealed no significant differences for all the groups. PIXE results showed a focal accumulation of iron with the size up to 3 mm. Highest concentration of iron after exposure to real signal was observed. CONCLUSION: We suggest that the iron accumulation after the exposure to RF ELF is not the result of higher permeability of blood-brain barrier and leaking out of iron from the bloodstream into the brain cells and tissues. It could be the result of an iron actuation and its redistribution in the tissue (Fig. 2, Ref. 86).

Volume feedback during cough in anesthetized cats, effects of occlusions and modulation summary.

The study investigates the effects of 6 occlusion conditions on the mechanically induced cough reflex in 15 anesthetized (pentobarbital) spontaneously breathing cats (14♂, 1♀). Esophageal pressure and integrated EMG activities of inspiratory (I) diaphragm and expiratory (E) abdominal muscles were recorded and analyzed. Occlusions: inspiratory (Io), continual I (cIo), during I and active E (I+Eo) cough phase, during I and then E phase with short releasing of airflow before each phase (I-Eo), and E occlusion (Eo) had little influence on cough number. Only continual E occlusion (cEo) reduced the number of coughs by 19 % (to 81 %, p < 0.05). Cough I esophageal pressure reached higher amplitudes under all conditions, but only Eo caused increased I diaphragm motor drive (p < 0.05). Cough E efforts (abdominal motor drive and E amplitudes of esophageal pressure) increased during Eo, decreased during I+Eo (p < 0.05), and did not change significantly under other conditions (p > 0.05). All I blocks resulted in prolonged I cough characteristics (p < 0.05) mainly cough I phase (incrementing part of the diaphragm activity). Shorter I phase occurred with cEo (p < 0.05). Cough cycle time and active E phase (from the I maximum to the end of cough E motor drive) prolonged (p < 0.05) during all occlusions (E phase duration statistically non-significantly for I+Eo). Airflow block during cough (occlusions) results in secondary changes in the cough response due to markedly altered function of cough central pattern generator and cough motor pattern produced. Cough compensatory effects during airflow resistances are more favorable compared to occlusions. Volume feedback represents significant factor of cough modulation under various pathological obstruction and/or restriction conditions of the respiratory system.

The motor pattern of tracheobronchial cough is affected by inspiratory resistance and expiratory occlusion - The evidence for volume feedback during cough expiration.

The role of pulmonary stretch receptor discharge and volume feedback in modulation of tracheobronchial cough is not fully understood. The current study investigates the effect of expiratory occlusion with or without preceding inspiratory resistance (delivery of tidal or cough volume by the ventilator lasting over the active cough expiratory period) on the cough motor pattern. Experiments on 9 male cats under pentobarbital sodium anesthesia have shown that inspiratory resistance followed by expiratory occlusion increased cough inspiratory and expiratory efforts and prolonged several time intervals (phases) related to muscle activation during cough. Expiratory occlusion (at regular cough volume) decreased number of coughs, increased amplitudes of abdominal electromyographic activity, inspiratory and expiratory esophageal pressure during cough and significantly prolonged cough temporal features. Correlation analysis supported major changes in cough expiratory effort and timing due to the occlusion. Our results support a high importance of volume feedback, including that during cough expulsion, for generation and modulation of cough motor pattern with obstruction or expiratory airway resistances, the conditions present during various pulmonary diseases.

Heart rate variability affected by radiofrequency electromagnetic field in adolescent students.

This study examines the possible effect of radiofrequency (RF) electromagnetic fields (EMF) on the autonomic nervous system (ANS). The effect of RF EMF on ANS activity was studied by measuring heart rate variability (HRV) during ortho-clinostatic test (i.e., transition from lying to standing and back) in 46 healthy grammar school students. A 1788 MHz pulsed wave with intensity of 54 ± 1.6 V/m was applied intermittently for 18 min in each trial. Maximum specific absorption rate (SAR10 ) value was determined to 0.405 W/kg. We also measured the respiration rate and estimated a subjective perception of EMF exposure. RF exposure decreased heart rate of subjects in a lying position, while no such change was seen in standing students. After exposure while lying, a rise in high frequency band of HRV and root Mean Square of the Successive Differences was observed, which indicated an increase in parasympathetic nerve activity. Tympanic temperature and skin temperature were measured showing no heating under RF exposure. No RF effect on respiration rate was observed. None of the tested subjects were able to distinguish real exposure from sham exposure when queried at the end of the trial. In conclusion, short-term RF EMF exposure of students in a lying position during the ortho-clinostatic test affected ANS with significant increase in parasympathetic nerve activity compared to sham exposed group. Bioelectromagnetics. 39:277-288, 2018. © 2018 Wiley Periodicals, Inc.

Role of the dorsomedial medulla in suppression of cough by codeine in cats.

The modulation of cough by microinjections of codeine in 3 medullary regions, the solitary tract nucleus rostral to the obex (rNTS), caudal to the obex (cNTS) and the lateral tegmental field (FTL) was studied. Experiments were performed on 27 anesthetized spontaneously breathing cats. Electromyograms (EMG) were recorded from the sternal diaphragm and expiratory muscles (transversus abdominis and/or obliquus externus; ABD). Repetitive coughing was elicited by mechanical stimulation of the intrathoracic airways. Bilateral microinjections of codeine (3.3 or 33mM, 54±16nl per injection) in the cNTS had no effect on cough, while those in the rNTS and in the FTL reduced coughing. Bilateral microinjections into the rNTS (3.3mM codeine, 34±1 nl per injection) reduced the number of cough responses by 24% (P<0.05), amplitudes of diaphragm EMG by 19% (P<0.01), of ABD EMG by 49% (P<0.001) and of expiratory esophageal pressure by 56% (P<0.001). Bilateral microinjections into the FTL (33mM codeine, 33±3 nl per injection) induced reductions in cough expiratory as well as inspiratory EMG amplitudes (ABD by 60% and diaphragm by 34%; P<0.01) and esophageal pressure amplitudes (expiratory by 55% and inspiratory by 26%; P<0.001 and 0.01, respectively). Microinjections of vehicle did not significantly alter coughing. Breathing was not affected by microinjections of codeine. These results suggest that: 1) codeine acts within the rNTS and the FTL to reduce cough in the cat, 2) the neuronal circuits in these target areas have unequal sensitivity to codeine and/or they have differential effects on spatiotemporal control of cough, 3) the cNTS has a limited role in the cough suppression induced by codeine in cats.

Changes in vagal afferent drive alter tracheobronchial coughing in anesthetized cats.

Unilateral cooling of the vagus nerve (<5°C, blocking mainly conductivity of myelinated fibers) and unilateral vagotomy were employed to reduce cough afferent drive in order to evaluate the effects of these interventions on the temporal features of the cough reflex. Twenty pentobarbitone anesthetized, spontaneously breathing cats were used. Cough was induced by mechanical stimulation of the tracheobronchial airways. The number of coughs during vagal cooling was significantly decreased (p<0.001). Inspiratory cough efforts were reduced by approximately 30% (p<0.001) and expiratory motor drive by more than 80% (p<0.001). Temporal analysis showed prolonged inspiratory and expiratory phases, the total cycle duration, its active portion, and the interval between maxima of the diaphragm and the abdominal activity during coughing (p<0.001). There was no significant difference in the average effects on the cough reflex between cooling of the left or the right vagus nerve. Compared to control, vagal cooling produced no significant difference in heart rate and mean arterial blood pressure (p>0.05), however, cold block of vagal conduction reduced respiratory rate (p<0.001). Unilateral vagotomy significantly reduced cough number, cough-related diaphragmatic activity, and relative values of maximum expiratory esophageal pressure (all p<0.05). Our results indicate that reduced cough afferent drive (lower responsiveness) markedly attenuates the motor drive to respiratory pump muscles during coughing and alters cough temporal features. Differences in the effects of unilateral vagal cooling and vagotomy on coughing support an inhibitory role of sensory afferents that are relatively unaffected by cooling of the vagus nerve to 5°C on mechanically induced cough.

The course of lung inflation alters the central pattern of tracheobronchial cough in cat-The evidence for volume feedback during cough.

The effect of volume-related feedback and output airflow resistance on the cough motor pattern was studied in 17 pentobarbital anesthetized spontaneously-breathing cats. Lung inflation during tracheobronchial cough was ventilator controlled and triggered by the diaphragm electromyographic (EMG) signal. Altered lung inflations during cough resulted in modified cough motor drive and temporal features of coughing. When tidal volume was delivered (via the ventilator) there was a significant increase in the inspiratory and expiratory cough drive (esophageal pressures and EMG amplitudes), inspiratory phase duration (CTI), total cough cycle duration, and the duration of all cough related EMGs (Tactive). When the cough volume was delivered (via the ventilator) during the first half of inspiratory period (at CTI/2-early over inflation), there was a significant reduction in the inspiratory and expiratory EMG amplitude, peak inspiratory esophageal pressure, CTI, and the overlap between inspiratory and expiratory EMG activity. Additionally, there was significant increase in the interval between the maximum inspiratory and expiratory EMG activity and the active portion of the expiratory phase (CTE1). Control inflations coughs and control coughs with additional expiratory resistance had increased maximum expiratory esophageal pressure and prolonged CTE1, the duration of cough abdominal activity, and Tactive. There was no significant difference in control coughing and/or control coughing when sham ventilation was employed. In conclusion, modified lung inflations during coughing and/or additional expiratory airflow resistance altered the spatio-temporal features of cough motor pattern via the volume related feedback mechanism similar to that in breathing.

Interactions of mechanically induced coughing and sneezing in cat.

Mutual interactions of cough and sneeze were studied in 12 spontaneously breathing pentobarbitone anesthetized cats. Reflexes were induced by mechanical stimulation of the tracheobronchial and nasal airways, respectively. The amplitude of the styloglossus muscle EMG moving average during the sneeze expulsion was 16-fold higher than that during cough (p<0.01). Larger inspiratory efforts occurred during coughing (p<0.01) vs. those in sneeze. The number of reflexes during simultaneous mechanical stimulation of the nasal and tracheal airways was not altered significantly compared to controls (p>0.05) and there was no modulation in temporal characteristics of the behaviors. When both reflexes occurred during simultaneous stimuli the responses were classified as either sneeze or cough (no hybrid responses occurred). During simultaneous stimulation of both airway sites, peak diaphragm EMG and inspiratory esophageal pressures during sneezes were significantly increased. The expiratory maxima of esophageal pressure and amplitudes of abdominal EMGs were increased in coughs and sneezes during simultaneous mechanical stimulation trials compared to control reflexes.

Control of coughing by medullary raphé.

The medullary raphé nuclei participate in the regulation of breathing and airway defensive reflexes. Our focus was to analyze the effects of codeine and kainic acid within the medullary raphé on coughing, sneezing, solitary expulsions, and concomitant breathing changes using models of anesthetized cats (n=12) and rabbits (n=15) and microinjection techniques. Our findings are consistent with (1) involvement of neurons within the medullary raphé in the generation of the cough motor pattern by a codeine-sensitive and -insensitive mechanisms, (2) a contribution of raphé nuclei to the control of expiratory efforts, (3) limited contribution of the medullary raphé to the cough-gating mechanism, (4) minor contribution of respiration/coughing neuronal network, including the portion within raphé nuclei and the respiratory/cough central pattern generator, to the production of the sneeze reflex motor pattern.

Resuscitation and auto resuscitation by airway reflexes in animals.

Various diseases often result in decompensation requiring resuscitation. In infants moderate hypoxia evokes a compensatory augmented breath - sigh and more severe hypoxia results in a solitary gasp. Progressive asphyxia provokes gasping respiration saving the healthy infant - autoresuscitation by gasping. A neonate with sudden infant death syndrome, however, usually will not survive. Our systematic research in animals indicated that airway reflexes have similar resuscitation potential as gasping respiration. Nasopharyngeal stimulation in cats and most mammals evokes the aspiration reflex, characterized by spasmodic inspiration followed by passive expiration. On the contrary, expiration reflex from the larynx, or cough reflex from the pharynx and lower airways manifest by a forced expiration, which in cough is preceded by deep inspiration. These reflexes of distinct character activate the brainstem rhythm generators for inspiration and expiration strongly, but differently. They secondarily modulate the control mechanisms of various vital functions of the organism. During severe asphyxia the progressive respiratory insufficiency may induce a life-threatening cardio-respiratory failure. The sniff- and gasp-like aspiration reflex and similar spasmodic inspirations, accompanied by strong sympatho-adrenergic activation, can interrupt a severe asphyxia and reverse the developing dangerous cardiovascular and vasomotor dysfunctions, threatening with imminent loss of consciousness and death. During progressive asphyxia the reversal of gradually developing bradycardia and excessive hypotension by airway reflexes starts with reflex tachycardia and vasoconstriction, resulting in prompt hypertensive reaction, followed by renewal of cortical activity and gradual normalization of breathing. A combination of the aspiration reflex supporting venous return and the expiration or cough reflex increasing the cerebral perfusion by strong expirations, provides a powerful resuscitation and autoresuscitation potential, proved in animal experiments. They represent a simple but unique model tested in animal experiments.

Reversal of functional disorders by aspiration, expiration, and cough reflexes and their voluntary counterparts.

Agonal gasping provoked by asphyxia can save ~15% of mammals even from untreated ventricular fibrillation (VF), but it fails to revive infants with sudden infant death syndrome (SIDS). Our systematic study of airway reflexes in cats and other animals indicated that in addition to cough, there are two distinct airway reflexes that may contribute to auto-resuscitation. Gasp- and sniff-like spasmodic inspirations (SIs) can be elicited by nasopharyngeal stimulation, strongly activating the brainstem generator for inspiration, which is also involved in the control of gasping. This "aspiration reflex" (AspR) is characterized by SI without subsequent active expiration and can be elicited during agonal gasping, caused by brainstem trans-sections in cats. Stimulation of the larynx can activate the generator for expiration to evoke the expiration reflex (ExpR), manifesting with prompt expiration without preceding inspiration. Stimulation of the oropharynx and lower airways provokes the cough reflex (CR) which results from activating of both generators. The powerful potential of the AspR resembling auto-resuscitation by gasping can influence the control mechanisms of vital functions, mediating reversal of various functional disorders. The AspR in cats interrupted hypoxic apnea, laryngo- and bronchospasm, apneusis and even transient asphyxic coma, and can normalize various hypo- and hyper-functional disorders. Introduction of a nasogastric catheter evoked similar SIs in premature infants and interrupted hiccough attacks in adults. Coughing on demand can prevent anaphylactic shock and resuscitate the pertinent subject. Sniff representing nasal inspiratory pressure and maximal inspiratory and expiratory pressures (MIP and MEP) are voluntary counterparts of airway reflexes, and are useful for diagnosis and therapy of various cardio-respiratory and neuromuscular disorders.

Contribution of medullary raphé to control of coughing--codeine trials in cat.

In order to determine if a codeine-sensitive control system for cough exists in the medullary raphé four microinjections of codeine (3.3 and 16.5 mM; 36.6±0.7 nl 1.5 and 3 mm rostral to the obex at the depths 1.5 and 3 mm; the total dose 1.12±0.3 nmol, 9 animals) were performed on pentobarbitone anesthetized spontaneously breathing cats. Amplitudes of abdominal muscle EMG moving averages during mechanically induced tracheobronchial cough decreased by 18% compared to control coughs (p<0.05). The duration between maxima of cough diaphragm and abdominal muscle EMG discharge, cough expiratory phase duration and period of relative motor quiescence between coughs were increased (all p<0.05). Cough number, other cough parameters, and cardiorespiratory characteristics were not altered significantly. Control microinjections of artificial cerebro-spinal fluid had no effect on coughing. Codeine sensitive neurons involved in the generation or modulation of motor pattern of tracheobronchial cough are located in the medullary midline raphé nuclei; however, their contribution to codeine induced cough suppression is limited.

Short reflex expirations (expiration reflexes) induced by mechanical stimulation of the trachea in anesthetized cats.

Fifty spontaneously breathing pentobarbital-anesthetized cats were used to determine the incidence rate and parameters of short reflex expirations induced by mechanical stimulation of the tracheal mucosa (ERt). The mechanical stimuli evoked coughs; in addition, 67.6% of the stimulation trials began with ERt. The expiration reflex mechanically induced from the glottis (ERg) was also analyzed (99.5% incidence, p < 0.001 compared to the incidence of ERt). We found that the amplitudes of abdominal, laryngeal abductor posterior cricoarytenoid, and laryngeal adductor thyroarytenoid electromyograms (EMG) were significantly enhanced in ERg relative to ERt. Peak intrathoracic pressure (esophageal or intra-pleural pressure) was higher during ERg than ERt. The interval between the peak in EMG activity of the posterior cricoarytenoid muscle and that of the EMG of abdominal muscles was lower in ERt compared to ERg. The duration of thyroarytenoid EMG activity associated with ERt was shorter than that in ERg. All other temporal features of the pattern of abdominal, posterior cricoarytenoid, and thyroarytenoid muscles EMGs were equivalent in ERt and ERg.In an additional 8 cats, the effect of codeine administered via the vertebral artery was tested. Codeine, in a dose (0.03 mg/kg) that markedly suppressed cough did not significantly alter either the incidence rate or magnitudes of ERt.In the anesthetized cat the ERt induced by mechanical stimulation of the trachea was similar to the ERg from the glottis. These two reflex responses differ substantially only in the frequency of occurrence in response to mechanical stimulus and in the intensity of motor output.

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.

Brainstem regions involved in the expiration reflex. A c-fos study in anesthetized cats.

Expression of the immediate-early gene c-fos, a marker of neuronal activation, was employed to localize brainstem neuronal populations functionally related to the expiration reflex (ER). Twelve spontaneously breathing, non-decerebrate, pentobarbital anesthetized cats were used. The level of Fos-like immunoreactivity (FLI) in 6 animals with repetitive ERs mechanically induced from the glottis (296+/-9 ERs) was compared to FLI in 6 control non-stimulated cats. Respiratory rate, arterial blood pressure, and end tidal CO(2) concentration remained stable during the experiment. In the medulla, increased FLI was found in the region of nucleus tractus solitarii (p<0.001), in the ventrolateral medulla along with the lateral tegmental field (p<0.01), and in the vestibular nuclei (p<0.01). In the pons, increased FLI was detected in the caudal extensions of the lateral parabrachial and Kölliker-Fuse nuclei (p<0.05). Within the rostral mesencephalon, FLI was enhanced in the midline area (p<0.05). A lower level of ER-related FLI compared to control animals was detected in the pontine raphe region (p<0.05) and the lateral division of mesencephalic periaqueductal gray (p<0.05). The results suggest that the ER is coordinated by a complex long loop of medullary-pontine-mesencephalic neuronal circuits, some of which may differ from those of other respiratory reflexes. The FLI related to the expulsive behavior ER differs from that induced by laryngeal stimulation and laryngeal adductor responses, particularly in ventrolateral medulla and mesencephalon.

Neurogenesis of cough, other airway defensive behaviors and breathing: A holarchical system?

Cough and breathing are generated by a common muscular system. However, these two behaviors differ significantly in their mechanical features and regulation. The current conceptualization of the neurogenic mechanism for these behaviors holds that the multifunctional respiratory pattern generator undergoes reconfiguration to produce cough. Our previous results indicate the presence of a functional cough gate mechanism that controls the excitability of this airway defensive behavior, but is not involved in the regulation of breathing. We propose that the neurogenesis of cough, breathing, and other nonbreathing behaviors is controlled by a larger network, of which the respiratory pattern generator is part. This network we term a holarchical system. This system is governed by functional control elements known as holons, which confer unique regulatory features to each behavior. The cough gate is an example of such a holon. Neurons that participate in a cough holon may include behavior selective elements. That is, neurons that are either specifically recruited during cough and/or tonically-active neurons with little or no modulation during breathing but with significant alterations in discharge during coughing. We also propose that the holarchical system is responsible for the orderly expression of different airway defensive behaviors such that each motor task is executed in a temporally and mechanically discrete manner. We further propose that a holon controlling one airway defensive behavior can regulate the excitability of, and cooperate with, holons unique to other behaviors. As such, co-expression of multiple rhythmic behaviors such as cough and swallow can occur without compromising airway defense.