Discontinuous gas exchange in Madagascan hissing cockroaches is not a consequence of hysteresis around a fixed PCO2 threshold

It has been hypothesised that insects display discontinuous gas-exchange cycles (DGCs) due to hysteresis in their ventilatory control, where CO2-sensitive respiratory chemoreceptors respond to changes in hemolymph PCO2 only after some delay. If correct, DGCs would be a manifestation of an unstable feedback loop between chemoreceptors and ventilation causing PCO2 to oscillate around some fixed threshold value: PCO2 above this ventilatory threshold would stimulate excessive hyperventilation, driving PCO2 below the threshold and causing a subsequent apnoea. This hypothesis was tested by implanting micro-optodes into the hemocoel of Madagascar hissing cockroaches and measuring hemolymph PO2 and PCO2 simultaneously during continuous and discontinuous gas exchange. The mean hemolymph PCO2 of 1.9 kPa measured during continuous gas exchange was assumed to represent the threshold level stimulating ventilation, and this was compared with PCO2 levels recorded during DGCs elicited by decapitation. Cockroaches were also exposed to hypoxic (PO2 10 kPa) and hypercapnic (PCO2 2 kPa) gas mixtures to manipulate hemolymph PO2 and PCO2. Decapitated cockroaches maintained DGCs even when their hemolymph PCO2 was forced above or below the putative ∼2 kPa ventilation threshold, demonstrating that the characteristic oscillation between apnoea and gas exchange is not driven by a lag between changing hemolymph PCO2 and a PCO2 chemoreceptor with a fixed ventilatory threshold. However, it was observed that the gas exchange periods within the DGC were altered to enhance O2 uptake and CO2 release during hypoxia and hypercapnia exposure. This indicates that while respiratory chemoreceptors do modulate ventilatory activity in response to hemolymph gas levels, their role in initiating or terminating the gas exchange periods within the DGC remains unclear.

Breath-holding as a novel approach to risk stratification in COVID-19

Background Despite considerable progress, it remains unclear why some patients admitted for COVID-19 develop adverse outcomes while others recover spontaneously. Clues may lie with the predisposition to hypoxemia or unexpected absence of dyspnea (‘silent hypoxemia’) in some patients who later develop respiratory failure. Using a recently-validated breath-holding technique, we sought to test the hypothesis that gas exchange and ventilatory control deficits observed at admission are associated with subsequent adverse COVID-19 outcomes (composite primary outcome: non-invasive ventilatory support, intensive care admission, or death). Methods Patients with COVID-19 (N = 50) performed breath-holds to obtain measurements reflecting the predisposition to oxygen desaturation (mean desaturation after 20-s) and reduced chemosensitivity to hypoxic-hypercapnia (including maximal breath-hold duration). Associations with the primary composite outcome were modeled adjusting for baseline oxygen saturation, obesity, sex, age, and prior cardiovascular disease. Healthy controls (N = 23) provided a normative comparison. Results The adverse composite outcome (observed in N = 11/50) was associated with breath-holding measures at admission (likelihood ratio test, p = 0.020); specifically, greater mean desaturation (12-fold greater odds of adverse composite outcome with 4% compared with 2% desaturation, p = 0.002) and greater maximal breath-holding duration (2.7-fold greater odds per 10-s increase, p = 0.036). COVID-19 patients who did not develop the adverse composite outcome had similar mean desaturation to healthy controls. Conclusions Breath-holding offers a novel method to identify patients with high risk of respiratory failure in COVID-19. Greater breath-hold induced desaturation (gas exchange deficit) and greater breath-holding tolerance (ventilatory control deficit) may be independent harbingers of progression to severe disease.

Physiologic and neurochemical adaptations following abrupt termination of chronic hypercapnia in goats

Chronic hypercapnia (CH) is a hallmark of respiratory diseases such as chronic obstructive pulmonary disease. In such patients, mechanical ventilation is often used to restore normal blood-gas homeostasis. However, little is known regarding physiologic changes and neuroplasticity within physiological control networks after termination of CH. Utilizing our goat model of increased inspired CO2-induced CH, we determined whether termination of CH elicits time-dependent physiologic and neurochemical changes within brainstem sites of physiologic control. Thirty days (d) of CH increased PaCO2 (+15mmHg) and steady-state ventilation (SS V̇I) (283% of control). Within 24 hours (h) after terminating CH, SS V̇I, blood gases, arterial [H+] and most physiologic measurements returned to control. However, the acute ventilatory chemoreflex (ΔV̇I/Δ[H+]) was greater than control, and measured SS V̇I exceeded ventilation predicted by arterial [H+] and ΔV̇I/Δ[H+]. Potentially contributing to these differences were increased excitatory neuromodulators serotonin and norepinephrine in the nucleus tractus solitarius, which contrasts to minimal changes observed at 24h and 30d of hypercapnia. Similarly, there were minimal changes found in markers of neuroinflammation and glutamate receptor-dependent neuroplasticity upon termination of CH, which were previously increased following 24h of hypercapnia. Thus, following termination of CH: 1) ventilatory, renal, and other physiologic functions rapidly return to control 2) neuroplasticity within the ventilatory control network may contribute to the difference between measured vs. predicted ventilation, and the elevation in the acute ventilatory [H+] chemoreflex, and 3) neuroplasticity is fundamentally distinct from acclimatization to CH.

Hyperventilation: A Possible Explanation for Long-Lasting Exercise Intolerance in Mild COVID-19 Survivors?

Since the outbreak of the coronavirus (COVID-19) pandemic, most attention has focused on containing transmission and addressing the surge of critically ill patients in acute care settings. As we enter the second phase of the pandemic, emphasis must evolve to post-acute care of COVID-19 survivors. Persisting cardiorespiratory symptoms have been reported at several months after the onset of the infection. Information is lacking on the pathophysiology of exercise intolerance after COVID-19. Previous outbreaks of coronaviruses have been associated with persistent dyspnea, muscle weakness, fatigue and reduced quality of life. The extent of Covid-19 sequelae remains to be evaluated, but persisting cardiorespiratory symptoms in COVID-19 survivors can be described as two distinct entities. The first type of post-Covid symptoms are directly related to organ injury in the acute phase, or the complications of treatment. The second type of persisting symptoms can affect patients even with mild initial disease presentation without evidence of organ damage. The mechanisms are still poorly qualified to date. There is a lack of correlation between initial symptom severity and residual symptoms at exertion. We report exercise hyperventilation as a major limiting factor in COVID-19 survivors. The origin of this hyperventilation may be related to an abnormality of ventilatory control, by either hyperactivity of activator systems (automatic and cortical ventilatory control, peripheral afferents, and sensory cortex) or failure of inhibitory systems (endorphins) in the aftermath of pulmonary infection. Hyperventilation-induced hypocapnia can cause a multitude of extremely disabling symptoms such as dyspnea, tachycardia, chest pain, fatigue, dizziness and syncope at exertion.

RELATIONSHIP AND IMPACTS OF CENTRAL SLEEP APNEA SYNDROME IN PEOPLE WITH HEART FAILURE: A BIBLIOGRAPHIC REVIEW

Central sleep apnea (CSA) is a disorder of the central ventilatory control of the nervous system characterized by prolonged episodes of apnea during the individual’s sleep period. One of the etiologies described by several scientific studies for this condition is congestive heart failure (CHF), a disease of big prevalence and relevance for contemporary medicine. This article, in addition to describing the significant aspects of sleep physiology to the current study, seeks to correlate the sleep process with the mechanisms involved in the pathophysiology of CSA in patients with CHF, as well as the impacts on the quality of life of these people.

Title: Prematurity, the Diagnosis of Bronchopulmonary Dysplasia, and Maturation of Ventilatory Control Abbreviated Title: Control of Breathing and the Diagnosis of BPD

Infants born before 32 weeks post-menstrual age (PMA) and receiving respiratory support at 36 weeks PMA are diagnosed with bronchopulmonary dysplasia. This label suggests that their need for supplemental oxygen is primarily due to acquired dysplasia of airways and airspaces, and that the supplemental oxygen (O2) is treating residual parenchymal lung disease. However, current approaches to ventilatory support in the first days of life, including artificial surfactant use and lower ventilating pressures have changed the pathology of chronic lung disease, and emerging evidence suggests that immature ventilatory control may also contribute to the need for supplemental oxygen at 36 weeks PMA. In all newborns, maturation of ventilatory control continues ex utero and is a plastic process. Supplemental O2 mitigates the hypoxemic effects of delayed maturation of ventilatory control, as well as reduces the duration and frequency of periodic breathing events. Prematurity is associated with altered and occasionally aberrant maturation of ventilatory control. Infants born prematurely, with or without a diagnosis of BPD, are more prone to long-lasting effects of dysfunctional ventilatory control. Awareness of the interaction between parenchymal lung disease and delayed maturation of ventilatory control is essential to understanding why a given premature infant requires and is benefitting from supplemental O2 at 36 weeks PMA.

Is the healthy respiratory system built just right, overbuilt, or underbuilt to meet the demands imposed by exercise?

In the healthy, untrained young adult, a case is made for a respiratory system (airways, pulmonary vasculature, lung parenchyma, respiratory muscles, and neural ventilatory control system) that is near ideally designed to ensure a highly efficient, homeostatic response to exercise of varying intensities and durations. Our aim was then to consider circumstances in which the intra/extrathoracic airways, pulmonary vasculature, respiratory muscles, and/or blood-gas distribution are underbuilt or inadequately regulated relative to the demands imposed by the cardiovascular system. In these instances, the respiratory system presents a significant limitation to O2 transport and contributes to the occurrence of locomotor muscle fatigue, inhibition of central locomotor output, and exercise performance. Most prominent in these examples of an “underbuilt” respiratory system are highly trained endurance athletes, with additional influences of sex, aging, hypoxic environments, and the highly inbred equine. We summarize by evaluating the relative influences of these respiratory system limitations on exercise performance and their impact on pathophysiology and provide recommendations for future investigation.