Acute respiratory failure (ARF) often leads to ICU admission, ventilatory support, illness, and death. The usual classification into hypoxemic and hypercapnic types does not capture its full complexity. Precision medicine uses the concept of "treatable traits" to guide care based on traits that are clinically relevant, identifiable, measurable, and possibly changeable. Arterial carbon dioxide pressure (PaCO2) reflects factors like alveolar ventilation, dead space, respiratory mechanics, and how patients respond to ventilatory support. This makes it clinically relevant in selected situations. We carried out a scoping review using PRISMA-ScR and JBI guidelines to summarize evidence on hypocapnia and hypercapnia as prognostic, stratification, or clinically relevant variables during respiratory support. We searched PubMed/MEDLINE, ScienceDirect, and Web of Science (1994-2025), and checked references by hand. Thirty-four studies met our criteria and were grouped into four areas: pre-intubation or early acute presentation, non-invasive support (NIV/HFNC), invasive mechanical ventilation (IMV), and weaning or post-extubation. In summary, hypocapnia was linked to worse outcomes or failure of support in hypoxemic or cardiogenic cases. Hypercapnia helped identify patients who benefited from NIV, such as those with chronic obstructive pulmonary disease or obesity hypoventilation. For IMV, the effects depended on the presence and severity of acidosis and on its duration. Overall, PaCO2 showed context-dependent clinical relevance, acting mainly as a prognostic or stratification marker and, in narrower settings, as a variable that may inform monitoring or support decisions. This review provides a pragmatic framework for interpreting PaCO2 across respiratory support contexts and highlights the need for safe and clinically meaningful targets.

Acute chest syndrome (ACS) is a common pulmonary complication in children with sickle cell disease, defined by a new pulmonary infiltrate on imaging accompanied by fever and/or respiratory symptoms. ACS pathophysiology is multifactorial and incompletely understood, involving vaso-occlusion, pulmonary infarction, inflammation, hypoventilation, and infection-the latter being a frequent trigger in children. While most pediatric cases are mild, ACS can be life-threatening and requires prompt diagnosis and management to prevent progression into respiratory failure. Mild cases are managed with pain control, IV hydration, empiric antibiotics, incentive spirometry, and supplemental oxygen when needed. More severe cases may require simple or exchange transfusion to reduce hemoglobin S levels and limit further vaso-occlusion. ACS is associated with neurologic events and long-term pulmonary complications, making prevention a clinical priority. Disease-modifying therapies include hydroxyurea and chronic transfusion. This review summarizes current evidence on the pathophysiology, risk factors, clinical presentation, diagnosis, acute management, and preventative therapies for ACS in children.

Essential hypertension remains a major global health problem with poorly defined mechanisms. Increased vascular sympathetic activity and sleep-disordered breathing are common features in hypertensive patients and adult spontaneously hypertensive rats (SHRs), an experimental model of essential hypertension. We hypothesized that SHRs exhibit inherent respiratory dysfunctions during postnatal development, leading to irregular breathing and hypoxaemia that contribute to later sympathetic hyperactivity. We assessed pulmonary ventilation, oxygen consumption, systemic and tissue oxygen levels and cardiovascular parameters in male and female normotensive (Wistar-Kyoto and Sprague-Dawley, NT) rats and SHRs from birth to adulthood. Newborn SHRs (0-2 days old) exhibited hypoventilation, fluctuating respiratory frequency and increased episodes of apnoea and breath-hold, resulting in hypoxaemia and reduced brain oxygen levels in comparison to NT pups. These irregularities and hypoxaemia persisted until postnatal day 12. During hypoxic challenges, SHR pups from 0 to 12 days of life displayed an impaired ventilatory response, contrasting with the developmental increase in hypoxic ventilatory response seen in NT animals. In adult animals, the higher mean arterial pressure levels in SHRs were correlated with postnatal hypoventilation, suggesting a developmental link between postnatal respiratory dysfunction and hypertension. Chronic exposure to hyperoxia (50% O2) during the first 2 weeks of life attenuated respiratory irregularities in neonatal SHRs and reduced sympathetic vasoconstrictor tone in adult SHRs. Our results show that SHRs show early-life respiratory deficits that lead to breathing irregularities and hypoxaemia during postnatal development, which might contribute to the development of sympathetic hyperactivity in essential hypertension. KEY POINTS: Arterial hypertension is a common cardiovascular disease globally; however, its underlying mechanisms are still not fully understood. In spontaneously hypertensive rats (SHRs), a widely used experimental model of arterial hypertension, we identified inherent respiratory dysfunctions that cause breathing irregularities during the postnatal period. Neonatal SHR pups exhibit hypoventilation, fluctuating respiratory frequency and increased episodes of apnoea and breath-hold, leading to hypoxaemia and reduced oxygen levels in the brain. Exposure to high oxygen levels during postnatal life attenuates the respiratory irregularities in neonatal SHRs and reduces sympathetic vasoconstrictor tone in adult SHRs. Our study shows that early-life respiratory irregularities and hypoxaemia are present in SHRs from birth and might contribute to the development of sympathetic hyperactivity in arterial hypertension.

Long dismissed as a passive marker of ventilatory failure, elevated carbon dioxide (PaCO2 > 45 mmHg) is now recognized as a potent signaling molecule that orchestrates complex cellular responses. This review synthesizes recent advances revealing how hypercapnia modulates fundamental processes, immune regulation, tissue repair, and metabolism, through direct molecular mechanisms. We detail how CO2 triggers noncanonical NF-κB signaling, alters Wnt ligand secretion to impair alveolar regeneration, and exacerbates TLR4-primed NLRP3 inflammasome activation; this pro-inflammatory effect is most prominent in specific cell types like microglia and under conditions of sustained high CO2 levels. Furthermore, hypercapnia drives profound metabolic reprogramming and induces lasting epigenetic changes, such as TET1-downregulation-mediated CDH1 hypermethylation, which reinforces immunosuppression in chronic lung disease. Critically, we evaluate emerging tools like CarboSen probes that enable more precise separation of CO2-specific effects from associated acidosis in buffered experimental systems. Therapeutically, these insights argue for precision strategies: macrophage-specific Akt1 inhibition to restore antiviral immunity, localized Wnt agonists to promote repair, or targeting the leptin/STAT3/SOCS3 axis to improve ventilatory drive. However, translation requires navigating significant species differences and unresolved questions regarding epigenetic reversibility. By framing hypercapnia not as a uniform stressor but as a complex modulator whose effects are dictated by concentration, duration, and the specific tissue type involved, this review charts a course toward targeting CO2-driven signaling for therapeutic benefit in conditions ranging from ARDS and COPD to obesity hypoventilation syndrome.

The ability to sense and regulate breathing in response to changes in carbon dioxide (CO2) levels is vital for maintaining respiratory and systemic homeostasis. Impaired CO2 chemosensitivity is a common feature of several debilitating conditions, including chronic obstructive pulmonary disease (COPD), central hypoventilation syndromes, and cervical spinal cord injury (cSCI) and contributes to significant respiratory complications such as reduced ventilatory drive, poor gas exchange, and diminished adaptability to metabolic demands. Chronic cSCI disrupts descending respiratory pathways, leading to impaired ventilatory function and, consequently disrupted CO2 regulation leading to reliance on mechanical ventilation. Currently there are few effective treatments for spinal cord injury induced respiratory dysfunction, particularly in the chronic phase of injury where additional recovery is difficult to elicit. In this study, we investigated whether stimulation of excitatory spinal interneurons (eINs) could enhance respiratory responses to hypercapnia in health and during chronic cSCI. Mid-cervical eINs located in the intermediate lamina were chemogenetically activated via Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), and breathing was assessed during CO2 challenges in awake, unrestrained animals using whole-body plethysmography. Acute stimulation of cervical eINs increased breathing in response to acute respiratory challenges in animals at 8-and 12-weeks post-traumatic cSCI and in uninjured animals. Importantly, this respiratory enhancement occurred without observable affects in non-respiratory motor functions, such as forelimb grip strength, suggesting that the effects of eIN activation were specific to respiratory circuits. Together these findings identify cervical eINs as a promising neuromodulatory target and a promising therapeutic avenue for improving ventilatory function in chronic SCI. More broadly, this approach may offer therapeutic potential for other respiratory conditions characterized by diminished chemosensitivity and ventilatory control, providing a foundation for future translational strategies in respiratory neurorehabilitation.