How do the respiratory centres of patients with chronic obstructive pulmonary disease (COPD) and hypercapnia respond to acute increases in inspiratory load? A depressed respiratory motor output has long been postulated, but studies on this issue have yielded inconsistent results, partly due to limitations of investigative techniques. Many of these limitations can be overcome by the twitch interpolation technique, which is capable of accurately quantifying the degree of diaphragmatic activation, termed the voluntary drive to breathe. The hypothesis that patients with COPD and hypercapnia compensate for an acute increase in mechanical load on the inspiratory muscles with a lower voluntary drive to breathe than is the case with normocapnic patients was tested.Measurements were obtained in 15 patients with COPD, six of whom displayed hypercapnia and nine normocapnia. The maximum degree of diaphragmatic activation, expressed as a voluntary activation index (mean±sem), was higher in hypercapnic than in normocapnic patients (98.7±0.7versus94.5±0.9% (p=0.006)), as was the mean value (94.5±0.7versus88.5±1.9% (p=0.01)). Within-patient values of the index were also less variable in the hypercapnic patients (coefficients of variation, 3.4±0.3versus6.1±0.9%, p=0.01). Multiple regression analysis revealed the ratio of dynamic elastance to maximum transdiaphragmatic pressure, an index of inspiratory muscle loading, and pH as the only variables that correlated with maximum voluntary activation index (r2=0.69, p=0.02 for each variable).Contrary to the hypothesis, it was concluded that voluntary activation of the diaphragm was greater and less variable in hypercapnic patients than normocapnic patients with severe chronic obstructive pulmonary disease during an acute increase in inspiratory mechanical load. Whether greater diaphragmatic recruitment during episodes of a severe exacerbation of chronic obstructive pulmonary disease provides a survival advantage for hypercapnic patients with chronic obstructive pulmonary disease remains to be determined.

Respiratory chemoreceptor activity encoding arterial Pco2 and Po2 is a critical determinant of ventilation. Currently, the relative importance of several putative chemoreceptor mechanisms for maintaining eupneic breathing and respiratory homeostasis is debated. Transcriptomic and anatomic evidence suggests that bombesin-related peptide Neuromedin-B (Nmb) expression identifies chemoreceptor neurons in the retrotrapezoid nucleus (RTN) that mediate the hypercapnic ventilatory response, but functional support is missing. In this study, we generated a transgenic Nmb-Cre mouse and used Cre-dependent cell ablation and optogenetics to test the hypothesis that RTNNmb neurons are necessary for the CO2-dependent drive to breathe in adult male and female mice. Selective ablation of ∼95% of RTNNmb neurons causes compensated respiratory acidosis because of alveolar hypoventilation, as well as profound breathing instability and respiratory-related sleep disruption. Following RTNNmb lesion, mice were hypoxemic at rest and were prone to severe apneas during hyperoxia, suggesting that oxygen-sensitive mechanisms, presumably the peripheral chemoreceptors, compensate for the loss of RTNNmb neurons. Interestingly, ventilation following RTNNmb-lesion was unresponsive to hypercapnia, but behavioral responses to CO2 (freezing and avoidance) and the hypoxia ventilatory response were preserved. Neuroanatomical mapping shows that RTNNmb neurons are highly collateralized and innervate the respiratory-related centers in the pons and medulla with a strong ipsilateral preference. Together, this evidence suggests that RTNNmb neurons are dedicated to the respiratory effects of arterial Pco2/pH and maintain respiratory homeostasis in intact conditions and suggest that malfunction of these neurons could underlie the etiology of certain forms of sleep-disordered breathing in humans. SIGNIFICANCE STATEMENT Respiratory chemoreceptors stimulate neural respiratory motor output to regulate arterial Pco2 and Po2, thereby maintaining optimal gas exchange. Neurons in the retrotrapezoid nucleus (RTN) that express the bombesin-related peptide Neuromedin-B are proposed to be important in this process, but functional evidence has not been established. Here, we developed a transgenic mouse model and demonstrated that RTN neurons are fundamental for respiratory homeostasis and mediate the stimulatory effects of CO2 on breathing. Our functional and anatomic data indicate that Nmb-expressing RTN neurons are an integral component of the neural mechanisms that mediate CO2-dependent drive to breathe and maintain alveolar ventilation. This work highlights the importance of the interdependent and dynamic integration of CO2- and O2-sensing mechanisms in respiratory homeostasis of mammals.

Besides the typical cognitive decline, patients with Alzheimer’s disease (AD) develop disorders of the respiratory system, such as sleep apnea, shortness of breath, and arrhythmias. These symptoms are aggravated with the progression of the disease. However, the cause and nature of these disturbances are not well understood. Here, we treated animals with intracerebroventricular streptozotocin (STZ, 2 mg/kg), a drug that has been described to cause Alzheimer-like behavioral and histopathological impairments. We measured ventilation ( V ̇ E ), electroencephalography, and electromyography during normocapnia, hypercapnia, and hypoxia in Wistar rats. In addition, we performed western blot analyses for phosphorylated tau, total tau, and amyloid-β (Aβ) peptide in the locus coeruleus (LC), retrotrapezoid nucleus, medullary raphe, pre-Bötzinger/Bötzinger complex, and hippocampus, and evaluated memory and learning acquisition using the Barnes maze. STZ treatment promoted memory and learning deficits and increased the percentage of total wakefulness during normocapnia and hypercapnia due to a reduction in the length of episodes of wakefulness. CO2-drive to breathe during wakefulness was increased by 26% in STZ-treated rats due to an enhanced tidal volume, but no changes in V ̇ E were observed in room air or hypoxic conditions. The STZ group also showed a 70% increase of Aβ in the LC and no change in tau protein phosphorylation. In addition, no alteration in body temperature was observed. Our findings suggest that AD animals present an increased sensitivity to CO2 during wakefulness, enhanced Aβ in the LC, and sleep disruption.

begins with the primary urge to breathe, triggered by rising carbon dioxide (CO2) levels in the bloodstream. Carbon dioxide builds up in the bloodstream Freediving blackout, breath-hold blackout, or apnea blackout is a class of hypoxic blackout, a loss of consciousness caused by cerebral hypoxia towards the end of a breath-hold (freedive or dynamic apnea) dive, when the swimmer does not necessarily experience an urgent need to breathe and has no other obvious medical condition that might have caused it. It can be provoked by hyperventilating just Otherwise unexplained underwater blackouts have been associated with the practice of hyperventilation. Survivors of shallow water blackouts often report using hyperventilation as a technique to increase the time they can spend underwater. Hyperventilation, or over-breathing, involves breathing faster and/or deeper than the body naturally demands, and is often used by divers in the mistaken belief that this will increase oxygen saturation. Although this appears to be intuitively true, the breathing rate dictated by the body alone under normal circumstances already leads to 98–99% oxygen saturation of the arterial blood, and the effect of over-breathing on the oxygen intake is minor. What instead happens is that divers are extending their dive by postponing the body's natural breathing mechanism, not by increasing oxygen load. This mechanism begins with the primary urge to breathe, triggered by rising carbon dioxide (CO2) levels in the bloodstream. Carbon dioxide builds up in the bloodstream when oxygen is metabolized and it needs to be expelled as a waste product. The body detects carbon dioxide levels very accurately and relies on this as the primary trigger to control breathing. Hyperventilation artificially depletes the resting concentration of carbon dioxide, causing a low blood carbon dioxide condition called hypocapnia. Hypocapnia reduces the reflexive respiratory drive, allowing the delay of breathing and leaving the diver susceptible to loss of consciousness from hypoxia. For most healthy people, the first sign of low oxygen levels is a greyout or unconsciousness: there is no bodily sensation that warns a diver of an impending blackout. Significantly, victims often drown quietly underwater, without alerting anyone to the fact that there is a problem, and are typically found on the bottom as shown in the staged image above. Survivors of shallow water blackout are typically puzzled as to why they blacked out. Pool life guards are trained to scan the bottom for the situation shown.

to swimming or diving. The primary urge to breathe is triggered by rising carbon dioxide (CO2) levels in the bloodstream. The body detects CO2 levels Drowning is a type of suffocation induced by the submersion of the mouth and nose in a liquid. Submersion injury refers to both drowning and near-miss incidents. Most instances of fatal drowning occur alone or in situations where others present are either unaware of the victim's situation or unable to offer assistance. After successful resuscitation, drowning victims may experience breathing probl Ascent blackout, also called deep water blackout, is caused by hypoxia during ascent from depth. The partial pressure of oxygen in the lungs under pressure at the bottom of a deep…

When questioned afterwards all subjects said the sensation could be described by the terms 'air hunger', 'urge to breathe', and 'shortness of breath', and that is was like breath holding. They reported no fundamental difference in the sensation before and after paralysis. We conclude that respiratory muscle contraction is not important in the genesis of air hunger evoked by hypercapnia. Published in Respiration physiology (1990)

In red blood cells, carbonic anhydrase forces the dissociation of the acid, rendering the blood less acidic. Because of this acid dissociation, CO2 is exhaled (see equations above). The level of bicarbonate in the blood is controlled through the renal system, where bicarbonate ions in the renal filtrate are conserved and passed back into the blood. However, the bicarbonate buffer is the primary buffering system of the IF surrounding the cells in tissues throughout the body. The respiratory system contributes to the balance of acids and bases in the body by regulating the blood levels of carbonic acid (Figure 26.16). CO2 in the blood readily reacts with water to form carbonic acid, and the levels of CO2 and carbonic acid in the blood are in equilibrium. When the CO2 level in the blood rises (as it does when you hold your breath), the excess CO2 reacts with water to form additional carbonic acid, lowering blood pH. Increasing the rate and/or depth of respiration (which you might feel the “urge” to do after holding your breath) allows you to exhale more CO2. The loss of CO2 from the body reduces blood levels of carbonic acid and thereby adjusts the pH upward, toward normal levels.