Helmet CPAP to Treat Acute Hypoxemic Respiratory Failure in Patients with COVID-19 : a Management Strategy Proposal

Since the beginning of March 2020, the coronavirus disease 2019 (COVID-19) pandemic has caused more than 13,000 deaths in Europe, almost 54% of which has occurred in Italy. The Italian healthcare system is experiencing a stressful burden, especially in terms of intensive care assistance. In fact, the main clinical manifestation of COVID-19 patients is represented by an acute hypoxic respiratory failure secondary to bilateral pulmonary infiltrates, that in many cases, results in an acute respiratory distress syndrome and requires an invasive ventilator support. A precocious respiratory support with non-invasive ventilation or high flow oxygen should be avoided to limit the droplets' air-dispersion and the healthcare workers' contamination. The application of a continuous positive airway pressure (CPAP) by means of a helmet can represent an effective alternative to recruit diseased alveolar units and improve hypoxemia. It can also limit the room contamination, improve comfort for the patients, and allow for better clinical assistance with long-term tolerability. However, the initiation of a CPAP is not free from pitfalls. It requires a careful titration and monitoring to avoid a delayed intubation. Here, we discuss the rationale and some important considerations about timing, criteria, and monitoring requirements for patients with COVID-19 respiratory failure requiring a CPAP treatment

The Effect of Hypoxia on Airway Smooth Muscle Function

Resistance to airflow in the respiratory tract is largely determined by the degree of tone in the smooth muscle layer surrounding the airways. The tone of the airway smooth muscle in vivo is regulated by neural control mechanisms, locally released mediators as well as humoral factors. Environmental factors, such as hypoxia, may also influence the tone of the airway smooth muscle and in addition, alter its responsiveness to various pharmacological agonists. Since hypoxia can be a feature of respiratory disorders, such as asthma and chronic obstructive pulmonary disease, it may be of importance to determine if airway smooth muscle function is altered under hypoxic conditions. Using various techniques, I assessed: (i) The effect of acute changes in oxygen tension on responses to contractile agents and relaxatory agents in bovine isolated bronchi. (ii) The effect of chronic hypoxia on contractile responses in rat isolated airways. (iii) The effect of chronic hypoxia on endothelin receptor-mediated responses in rat isolated airways. (iv) The effect of hypoxia on the proliferation of cultured human airway smooth muscle cells. (v) The effect of changes in inspired oxygen tension on salbutamol-mediated bronchodilation and methacholine- and histamine-mediated bronchoconstriction in asthmatic patients in vivo. In rings of bovine bronchi (3rd-5th order, 3-5mm internal diameter), isometric contractions were significantly potentiated when the oxygen tension in the Krebs- Henseleit solution was lowered from 524mm Hg (hyperoxia) to either 147 mm Hg (normoxia) or 26mm Hg (hypoxia). The ability of the dilator agents salbutamol, atrial natriuretic peptide (ANP), sodium nitroprusside (SNP) and isosorbide dinitrate (ISDN) to reverse methacholine-induced tone was also altered by changing the oxygen tension, although the pattern of response differed between the various agents: The ability of salbutamol to reverse the induced tone was attenuated in hypoxia, whereas ANP was more effective in hypoxia than either hyperoxia or normoxia. ISDN and SNP were similar in that they were both more effective in either hypoxia or normoxia than in hyperoxia. In addition, the ability of these four dilators to confer protection against subsequent challenge with methacholine was compared under hyperoxic, normoxic and hypoxic conditions. Salbutamol attenuated responses to methacholine, but only under hyperoxic conditions, in normoxia and hypoxia it was ineffective. In hyperoxia, ANP protected against methacholine challenge, but in hypoxia, ANP actually potentiated the methacholine-induced contractions. The ability of both SNP and ISDN to protect against methacholine challenge was enhanced when the oxygen tension was reduced from hyperoxia to either normoxia or hypoxia. Tracheal rings (internal diameter ~2mm) isolated from rats exposed to 14 days of chronic hypobaric hypoxia (500-550mBar) produced contractions to methacholine, endothelin-1 (ET-1) and potassium chloride which were significantly less than responses in control rats. In both control and hypoxic rats, responses to methacholine and ET-1 were not altered by indomethacin (a cyclooxygenase inhibitor) but were potentiated by either L-NAME (a nitric oxide synthase inhibitor) or by removal of the epithelium. Responses to the nitric oxide donor, SNP, but not the beta adrenoceptor agonist salbutamol were enhanced in chronically hypoxic rats. Taken together, these results indicate that nitric oxide or a nitric oxide-like substance is released from the epithelium of both control and chronically hypoxic rats and that this subsequently attenuates the contractile responses to methacholine and ET-1. In chronically hypoxic rats, however, the airway smooth muscle appears to be more sensitive to nitric oxide than control rats, which may explain why contractile responses are significantly smaller in the chronically hypoxic rats. ET-1 acts via at least two G protein-coupled receptor subtypes, termed ETA and ETB- Contractile responses to ET-1 were attenuated in chronically hypoxic rats, whereas responses to sarafotoxin S6c (an ETB receptor agonist) were not altered. The ETA receptor antagonist, FR 139317 at a concentration of 10-8M potentiated contractile responses to ET-1 in trachea from control but not chronically hypoxic rats. The ETB receptor antagonist, BQ 788, potentiated responses to ET-1 in both control and chronically hypoxic rat trachea. It was found that ET-1 responses were only blocked by simultaneous blockade of both ETA and ETB receptors, either by using the non-selective ET receptor antagonist, SB 209670, or by combining BQ 788 and FR 139317. The proliferative response of cultured human airway smooth muscle cells was examined under different environmental oxygen tensions

Pathophysiology of Spinal Cord Injury (SCI)

Spinal cord injury (SCI) leads to paralysis, sensory, and autonomic nervous system dysfunctions. However, the pathophysiology of SCI is complex, and not limited to the nervous system. Indeed, several other organs and tissue are also affected by the injury, directly or not, acutely or chronically, which induces numerous health complications. Although a lot of research has been performed to repair motor and sensory functions, SCI-induced health issues are less studied, although they represent a major concern among patients. There is a gap of knowledge in pre-clinical models studying these SCI-induced health complications that limits translational applications in humans. This reprint describes several aspects of the pathophysiology of spinal cord injuries. This includes, but is not limited to, the impact of SCI on cardiovascular and respiratory functions, bladder and bowel function, autonomic dysreflexia, liver pathology, metabolic syndrome, bones and muscles loss, and cognitive functions

Utilisation du préconditionnement ischémique pour optimiser la performance aérobie chez l'athlète

L'optimisation de la performance sportive et sa fascinante complexité suscitent l'intérêt et la passion des scientifiques qui tentent depuis des décennies de percer les mystères de la machine humaine. Cette curiosité entourant les multiples facteurs pouvant permettre l'atteinte de niveaux d'excellence a donné lieu à l'émergence de recherches s'intéressant à des thématiques diversifiées comme l'optimisation des méthodes d'entraînement et de récupération ainsi que l'impact potentiel des aides ergogéniques. Dans les dernières années, une nouvelle stratégie vint s'ajouter à cette liste et sollicita l'attention de la communauté sportive, le préconditionnement ischémique (ischemic preconditioning, en anglais, IPC). Cette technique consiste à induire des épisodes d'ischémie et de reperfusion via la compression de brassards positionnés sur les membres inférieurs et/ou supérieurs. Cette méthode, initialement testée pour ses effets protecteurs sur le myocarde, rendrait différents tissus du corps, incluant le muscle squelettique, plus résistants aux effets d'une réduction indésirable d'oxygénation telle que retrouvée durant l'exercice maximal ou dans des environnements hypoxiques. En fait, l'IPC agit par l'entremise d'une diversité de mécanismes et de réponses physiologiques vasculaires, métaboliques et neurales. Ceci suggère que l'IPC pourrait non seulement être considéré comme une aide ergogénique, mais pourrait également s'intégrer à différents contextes, encore peu examinés, permettant une optimisation globale de la performance sportive. Ainsi, le présent travail de thèse s'inscrit dans une logique d'optimisation générale de la performance aérobie en évaluant l'intérêt d'utiliser l'IPC à différents moments clés du calendrier annuel des sports d'endurance. Le projet #1 de cette thèse a évalué l'efficacité ergogénique de l'IPC en situation de compétition en altitude. Un devis randomisé contrôlé a permis de démontrer que l'IPC améliore la performance chronométrique et la puissance mécanique développée lors de contre-la-montre (CLM) de 5 km effectués à des altitudes simulées faible (~1200 m) et modérée (~2400 m), comparativement à une manœuvre placébo. L'effet était plus marqué en altitude modérée avec une amélioration concomitante de la perception de l'effort, de la saturation pulsée en O2 (SpO2) et de la désaturation musculaire, suggérant une optimisation de la réponse oxydative avec l'amplification de l'hypoxémie artérielle après l'IPC. Au cours du projet #2, nous nous sommes intéressés à la récupération des capacités physiologiques et de la performance aérobie maximale aérobie chez l'athlète. À l'aide d'un devis randomisé contrôlé, nous avons démontré que l'IPC s'avère tout aussi efficace que l'électrostimulation neuromusculaire ou la récupération active pour maintenir la performance aérobie maximale lors de deux CLM de 5 km répétés à moins d'une ii heure d'intervalle. Les trois modalités de récupération ont par ailleurs induit des effets similaires sur la perfusion musculaire, l'élimination des déchets métaboliques et les réponses physiologiques pendant l'effort. Suite à ces deux premiers projets sur l'impact aigu de l'IPC, il devenait nécessaire d'examiner davantage les effets chroniques sur la performance en endurance. Le projet #3 a utilisé un devis avant-après avec groupe témoin pour démontrer que l'ajout de l'IPC avant des entraînements de sprints par intervalles (SIT), effectués pendant 4 semaines, optimise les adaptations à l'entraînement. En effet, seul le groupe combinant l'IPC et le SIT avait une amélioration de l'indice de fatigue au test de Wingate, de la performance au CLM de 5 km, du volume sanguin musculaire et de l'extraction d‟O2 musculaire. L'évaluation des marqueurs sanguins n'a pas mis en évidence d'effet de l'IPC sur l'angiogenèse, la réponse hypoxique ou la fonction immunitaire chez ces athlètes entraînés. En somme, ces projets de recherche ont mis en évidence le potentiel aigu et chronique de l'IPC pour améliorer la performance aérobie. Cette technique non invasive semble particulièrement efficace avant un effort en altitude modérée et lors d'une application chronique combinée à l'entraînement de haute intensité. L‟IPC représenterait également une option supplémentaire pour les athlètes d'endurance en période de récupération. Les données physiologiques des trois études indiquent que l'amélioration de la performance aérobie est corrélée à des changements de la perfusion sanguine et d'extraction musculaire d‟O2, suggérant que l'IPC agit essentiellement sur les réponses et les adaptations périphériques.The fascinating complexity of athletic performance has aroused the interest and passion of the scientific community which has tried to unravel the mysteries surrounding human performance for decades. This curiosity and the multiple factors associated with this quest resulted in a diversity of research themes including the optimization of training and recovery methods, as well the identification and potential impact of ergogenic aids. Recently, a new strategy has gained the attention of the sports community, ischemic preconditioning (IPC). This technique alternates episodes of muscle ischemia and reperfusion by the compression of cuffs around the lower and/or upper limbs. Originally studied for its clinical relevance in myocardial infarction, this technique may render different tissues within the body, including the skeletal muscle, more resistant to subsequent ischemic-hypoxic insults such as those found during maximal effort or hypoxic environment exposure. Indeed, IPC operates via various mechanisms and vascular, metabolic and neural physiological responses. The complexity of this phenomenon underlies the potential of IPC integration in a diversity of contexts, still poorly investigated, to improve sports performance. Thus, this thesis is focused on the global optimization of aerobic performance through the utilization of IPC during key moments of endurance athletes‟ training and competition schedule. Project #1 evaluated the ergogenic potential of IPC for competition at altitude. A randomized crossover study demonstrated that IPC enhances time to complete 5-km cycling time trials (TT) and power output at simulated low (~1200 m) and moderate (~2400 m) altitudes compared to a SHAM procedure. IPC has a more convincing impact at 2400 m than at 1200 m, and was associated with a lower perception of effort and an increase in pulse O2 saturation (SpO2) and peripheral O2 extraction at this altitude suggesting an optimization of the oxidative response with the increase of arterial hypoxemia. During project #2, we focused on the post-exercise recovery of physiological abilities and maximal aerobic performance in athletes. A randomized controlled design demonstrated that IPC is as effective as neuromuscular electrical stimulation or active recovery to maintain performance during two 5-km TT interspaced by less than 1 hour of recovery. The three recovery modalities induced similar effects on muscle perfusion, metabolic by-products clearance, and physiological responses during exercise. After the previous studies investigating the acute responses to IPC, there was a scope to examine the potential chronic effects of this technique. Project #3 used a randomized controlled trial to investigate if the addition of IPC before sprint-interval training (SIT), performed for 4 weeks, induced greater training adaptations. Indeed, IPC combined to SIT was the only condition shown to increase fatigue resistance during v a Wingate test, completion time during a 5-km TT, muscle blood volume and O2 extraction. Blood markers analyse did not reveal any effect of IPC on angiogenesis, hypoxic signaling and immune function in endurance athletes. In summary, these projects highlight some of the acute and chronic effects of IPC on aerobic performance. This non-invasive technique was particularly relevant for maximal exercise at moderate altitude and after its combination with chronic high-intensity interval training. IPC also represents an alternative for endurance athletes to promote recovery. The physiological data from these studies indicate an association between performance enhancement and perfusion and muscle O2 extraction changes, suggesting that IPC essentially influenced peripheral responses and adaptations