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Purpose: Patients receiving venoarterial extracorporeal membrane oxygenation (VA-ECMO) frequently develop arterial hyperoxaemia, which may be harmful. However, lower oxygen saturation targets may also lead to harmful episodes of hypoxaemia. Methods: In this registry-embedded, multicentre trial, we randomly assigned adult patients receiving VA-ECMO in an intensive care unit (ICU) to either a conservative (target SaO2 92–96%) or to a liberal oxygen strategy (target SaO2 97–100%) through controlled oxygen administration via the ventilator and ECMO gas blender. The primary outcome was the number of ICU-free days to day 28. Secondary outcomes included ICU-free days to day 60, mortality, ECMO and ventilation duration, ICU and hospital lengths of stay, and functional outcomes at 6 months. Results: From September 2019 through June 2023, 934 patients who received VA-ECMO were reported to the EXCEL registry, of whom 300 (192 cardiogenic shock, 108 refractory cardiac arrest) were recruited. We randomised 149 to a conservative and 151 to a liberal oxygen strategy. The median number of ICU-free days to day 28 was similar in both groups (conservative: 0 days [interquartile range (IQR) 0–13.7] versus liberal: 0 days [IQR 0–13.7], median treatment effect: 0 days [95% confidence interval (CI) – 3.1 to 3.1]). Mortality at day 28 (59/159 [39.6%] vs 59/151 [39.1%]) and at day 60 (64/149 [43%] vs 62/151 [41.1%] were similar in conservative and liberal groups, as were all other secondary outcomes and adverse events. The conservative group experienced 44 (29.5%) major protocol deviations compared to 2 (1.3%) in the liberal oxygen group (P < 0.001). Conclusions: In adults receiving VA-ECMO in ICU, a conservative compared to a liberal oxygen strategy, did not affect the number of ICU-free days to day 28. [ABSTRACT FROM AUTHOR]

Hyperoxia has been suggested as a mechanism for secondary injury following adult traumatic brain injury (TBI), but its effects have not been well described in pediatric patients. Pediatric (≤18yo) TBI patients were identified in a prospective institutional registry from October 2008 to April 2022. The first, highest, and the Area Under the Curve (AUC) PaO2 in the first 24 hours were collected and calculated for each patient from arterial blood gas reports after admission to the ICU. Neurological outcome after 6 months was measured using dichotomized modified Rankin Scale (mRS) and Glasgow Outcome Scale – Extended (GOS-E). Multivariable logistic regression models were used to determine if the three measurements for hyperoxia predicted an unfavorable outcome after controlling for well-established clinical and imaging predictors of outcome. We identified 98 pediatric patients with severe accidental TBI during the study period. Hyperoxia (PaO2 > 300 mmHg) occurred in 33% of the patients. The presence of elevated PaO2 values, determined by all three evaluations of hyperoxia, was not associated with unfavorable outcome after 6 months. Utilizing multiple methods to assess exposure, hyperoxia was present in a substantial number of patients with severe TBI but was not associated with an unfavorable outcome. [ABSTRACT FROM AUTHOR]

BACKGROUND: When treating acute respiratory failure, both hypoxemia and hyperoxemia should be avoided. ... should be monitored closely and O2 flows adjusted accordingly. Achieving this goal might be easier with automated O2 titration compared with manual titration of fixed-flow O2. We evaluated the feasibility of using an automated O2 titration device in subjects treated for acute hypoxemic respiratory failure in a tertiary care hospital. METHODS: Health-care workers received education and training about oxygen therapy, and were familiarized with an automated O2 titration device (FreeO2,). A coordinator was available from 8:00 AM to 5:00 PM during weekdays to provide technical assistance. The ability of the device to maintain ... within the prescribed therapeutic window was recorded. Basic clinical information was recorded. RESULTS: Subjects were enrolled from November 2020 to August 2022. We trained 508 health-care workers on the use of automated O2 titration, which was finally used on 872 occasions in 763 subjects, distributed on the respiratory, COVID-19, and thoracic surgery wards, and in the emergency department. Clinical information could be retrieved for 609 subjects (80%) who were on the system for a median (interquartile range) of 3 (2-6) d, which represented 2,567 subject-days of clinical experience with the device. In the 82 subjects (14%) for whom this information was available, the system maintained ... within the prescribed targets 89% of the time. Ninety-six subjects experienced clinical deterioration as defined by the need to be transferred to the ICU and/or requirement of high flow nasal oxygen but none of these events were judged to be related to the O2 device. CONCLUSIONS: Automated O2 titration could be successfully implemented in hospitalized subjects with hypoxemic respiratory failure from various causes. This experience should foster further improvement of the device and recommendations for an optimized utilization. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Biomarker responses to intensive decompression indicate systemic proinflammatory responses and possible neurological stress. To further investigate responses, 12 additional brain and lung biomarkers were assayed. METHODS: A total of 15 healthy men (20 to 50 yr) undertook consecutive same-day ascents to 25,000 ft (7620 m), following denitrogenation, breathing 100% oxygen. Venous blood was sampled at baseline (T0), after the second ascent (T8), and next morning (T24). Soluble protein markers of brain and lung insult were analyzed by enzyme-linked immunosorbent assay with plasma microparticles quantified using flow cytometry. RESULTS: Levels of monocyte chemoattractant protein-1 and high mobility group box protein 1 were elevated at T8, by 36% and 16%, respectively, before returning to baseline. Levels of soluble receptor for advanced glycation end products fell by 8%, recovering by T24. Brain-derived neurotrophic factor rose by 80% over baseline at T24. Monocyte microparticle levels rose by factors of 3.7 at T8 and 2.7 at T24 due to early and late responses in different subjects. Other biomarkers were unaffected or not detected consistently. DISCUSSION: The elevated biomarkers at T8 suggest a neuroinflammatory response, with later elevation of brain-derived neurotrophic factor at T24 indicating an ongoing neurotrophic response and incomplete recovery. A substantial increase at T8 in the ratio of high mobility group box protein 1 to soluble receptor for advanced glycation end products suggests this axis may mediate the systemic inflammatory response to decompression. The mechanism of neuroinflammation is unclear but elevation of monocyte microparticles and monocyte chemoattractant protein-1 imply a key role for activated monocytes and/or macrophages. [ABSTRACT FROM AUTHOR]

Key points Preclinical work supports a role for the peripheral chemoreceptors in the progression of cardiovascular and metabolic pathologies. In the present study, we examined peripheral chemosensitivity in adults with type 2 diabetes (T2D) and the contribution of the peripheral chemoreceptors to resting cardiovascular and metabolic control. We hypothesized that: (1) adults with T2D exhibit exaggerated peripheral chemoreflex sensitivity; (2) the peripheral chemoreceptors contribute to cardiovascular dysfunction in T2D; and (3) attenuation of peripheral chemoreceptor activity improves glucose tolerance in T2D. Seventeen adults with diagnosed T2D [six males/11 females; aged 54 ± 11 years; glycated haemoglobin (HbA1c) 7.6 ± 1.5%] and 20 controls without T2D (9 males/11 females; aged 49 ± 13 years, HbA1c 5.2 ± 0.4%) participated in the study. The hypoxic ventilatory response (HVR) was assessed as an index of peripheral chemosensitivity. Resting heart rate, blood pressure and minute ventilation were measured when breathing normoxic followed by hyperoxic air (1.0FIO2${{F}_{{\mathrm{I}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$) to acutely attenuate peripheral chemoreceptor activity. A subset of participants (n = 9 per group) completed two additional visits [normoxia (0.21FIO2${{F}_{{\mathrm{I}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$), hyperoxia (1.0FIO2${{F}_{{\mathrm{I}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$)] where glucose and insulin were measured for 2 h following an oral glucose challenge. HVR was augmented in adults with T2D (–0.84 ± 0.49 L min–1/%) vs. control (–0.48 ± 0.40 L min–1/%, P = 0.021). Attenuation of peripheral chemoreceptor activity decreased heart rate (P < 0.001), mean blood pressure (P = 0.009) and minute ventilation (P = 0.002); any effect of hyperoxia did not differ between groups. There was no effect of hyperoxia on the glucose (control, P = 0.864; T2D, P = 0.982), nor insulin (control, P = 0.763; T2D, P = 0.189) response to the oral glucose challenge. Peripheral chemoreflex sensitivity is elevated in adults with T2D; however, acute attenuation of peripheral chemoreflex activity with hyperoxia does not restore cardiometabolic function. Preclinical work supports a role for the peripheral chemoreceptors in the progression of cardiovascular and metabolic pathologies. In the present study, we examined peripheral chemosensitivity in adults with type 2 diabetes and the contribution of the peripheral chemoreceptors to resting cardiovascular control and glucose tolerance. We observed elevated peripheral chemoreflex sensitivity in adults with diabetes which was associated with glycaemic control (i.e. glycated haemoglobin). Notably, acute attenuation of peripheral chemoreflex activity with hyperoxia did not restore cardiometabolic function in the individuals studied. [ABSTRACT FROM AUTHOR]

Background: Retinopathy of prematurity (ROP) is a leading cause of avoidable blindness in children, particularly in Latin America, where hyperoxia is a significant risk factor. This study evaluated resource availability and use for administering and monitoring supplemental oxygen in Mexico. Methods: In 2011, an observational study in which 32 government neonatal intensive care units (NICUs) across Mexico were visited. Data collected included occupancy, staffing levels, and equipment to deliver and monitor supplemental oxygen. Preterm infants receiving oxygen were observed. In 2023, 13 NICUs were revisited, and similar data collected. Staffing levels were benchmarked against Argentinian and US recommendations. Results: In 2011, only 38% of NICUs had adequate medical and staffing levels to meet recommended cot-to-staff ratios for all shifts. Staffing ratios were worse during weekends and at night than during weekdays. Only 25.5% of cots had blenders, and 80.1% had saturation monitors. 153 infants were observed 87% of whom were being monitored. Upper and lower oxygen saturations were ≥ 96% in 53%, and ≤ 89% in 8%, respectively. Alarm settings were inadequate, as 38% and 32% of upper and lower alarms were switched off and 16% and 53% were incorrectly set, respectively. In the 13 NICUs with data from 2011 and 2023, cot-to-staff ratios deteriorated over time, and in 2023 no unit had recommended ratios for all shifts. Equipment provision did not change, with similar proportions of babies in oxygen being monitored (79% 2011; 75% 2023). Rates of hyperoxia decreased slightly from 54% in 2011 to 49% in 2023. More upper alarms were set (46% 2011; 75% 2023), but a higher proportion were incorrectly set (52% 2011; 68% 2023). Conclusions: Between 2011 and 2023, cot-to-staff ratios worsened, and equipment for safe oxygen delivery and monitoring remained insufficient. Despite available monitoring equipment, oxygen saturations often exceeded recommended levels, and alarms were frequently not set or incorrectly configured. Urgent improvements are needed in healthcare workforce numbers and practices, along with ensuring adequate equipment for safe oxygen delivery. [ABSTRACT FROM AUTHOR]

Background: Circulatory shock, defined as decreased tissue perfusion, leading to inadequate oxygen delivery to meet cellular metabolic demands, remains a common condition with high morbidity and mortality. Rapid restitution and restoration of adequate tissue perfusion are the main treatment goals. To achieve this, current hemodynamic strategies focus on adjusting global physiological variables such as cardiac output (CO), hemoglobin (Hb) concentration, and arterial hemoglobin oxygen saturation (SaO2). However, it remains a challenge to identify optimal targets for these global variables that best support microcirculatory function. Weighting up the risks and benefits is especially difficult for choosing the amount of oxygen supplementation in critically ill patients. This review assesses the physiological basis for oxygen delivery to the tissue and provides an overview of the relevant literature to emphasize the importance of considering risks and benefits and support decision making at the bedside. Physiological premises: Oxygen must reach the tissue to enable oxidative phosphorylation. The human body timely detects hypoxia via different mechanisms aiming to maintain adequate tissue oxygenation. In contrast to the pulmonary circulation, where the main response to hypoxia is arteriolar vasoconstriction, the regulatory mechanisms of the systemic circulation aim to optimize oxygen availability in the tissues. This is achieved by increasing the capillary density in the microcirculation and the capillary hematocrit thereby increasing the capacity of oxygen diffusion from the red blood cells to the tissue. Hyperoxia, on the other hand, is associated with oxygen radical production, promoting cell death. Current state of research: Clinical trials in critically ill patients have primarily focused on comparing macrocirculatory endpoints and outcomes based on stroke volume and oxygenation targets. Some earlier studies have indicated potential benefits of conservative oxygenation. Recent trials show contradictory results regarding mortality, organ dysfunction, and ventilatory-free days. Empirical studies comparing various targets for SaO2, or partial pressure of oxygen indicate a U-shaped curve balancing positive and negative effects of oxygen supplementation. Conclusion and future directions: To optimize risk–benefit ratio of resuscitation measures in critically ill patients with circulatory shock in addition to individual targets for CO and Hb concentration, a primary aim should be to restore tissue perfusion and avoid hyperoxia. In the future, an individualized approach with microcirculatory targets will become increasingly relevant. Further studies are needed to define optimal targets. [ABSTRACT FROM AUTHOR]

Introduction: Intrapulmonary arteriovenous anastomoses (IPAVAs) are defined as relatively large, dynamic shunt vessels that connect the pulmonary arterial and venous systems, thereby bypassing the pulmonary capillary system. IPAVAs lower elevated pulmonary arterial pressure; however, the presence of the shunt can result in impaired pulmonary gas exchange and paradoxical embolism. Furthermore, the prevalence and effects of IPAVAs in raccoon dogs remain unknown. This study aimed to determine the prevalence of IPAVA among rescued Korean raccoon dogs and evaluate the changes in IPAVA following oxygen supplementation. Methods: Nineteen raccoon dogs rescued by the Jeonbuk Wildlife Centre between August 2022 and December 2023 were subjected to echocardiography. Sixteen healthy and three abnormal raccoon dogs were subjected to transthoracic agitated saline contrast echocardiography (bubble study) based on the echocardiography results. IPAVA was considered to be present if the left heart contrast was visualised after four cardiac cycles following the visualisation of the first right heart contrast. Bubble scores (BS0-5) were assigned based on the maximum number of microbubbles observed in the left ventricular lumen per frame of the ultrasound image. BS was assigned before and after supplementation with 100% oxygen for 5 min. Results: IPAVA was detected in 12 of the 16 healthy raccoon dogs at rest (75%). The BS of the 15 IPAVA-positive raccoon dogs ranged from 1 to 4 points (BS1, 1; BS2, 4; BS3, 8; and BS4, 2). Blood flow through the IPAVA (QIPAVA) was reduced or absent in the 15 IPAVA-positive raccoon dogs after supplementation with 100% oxygen (BS0, 11; BS2, 4). Moreover, BS of the IPAVA showed a significant correlation with the cardiac output per body weight (BW). Conclusion: The prevalence of IPAVA in healthy raccoon dogs at rest was 75%. Adequate oxygen supplementation was found to be effective in reducing QIPAVA, which may help prevent potential negative factors such as pulmonary gas exchange impairments and paradoxical embolismthat can occur with IPAVA. [ABSTRACT FROM AUTHOR]

miR-146b-5p has been studied to be highly expressed in bronchopulmonary dysplasia (BPD), but whether it is involved in regulating the process of BPD in premature infants remains unclear. This study was to explore miR-146b-5p in premature BPD and reveal its molecular mechanism. BPD mouse model and high-oxygen MLE-12 cell model were established. HE staining, TUNEL staining, and IF staining were conducted to evaluate the pathological injury and protein expression in mouse lung tissue. LDH assay, MMT assay, and flow cytometry were achieved to evaluate cytotoxicity, cell viability, and apoptosis. ELISA and immunoblotting were performed to evaluate inflammatory cytokines and Wnt pathway proteins in lung tissues and cells. Dual-luciferase reporter assay and RIP assay were needed to examine the targeting relationship between miR-146b-5p and KDM6B. miR-146b-5p was abundantly expressed in BPD and KDM6B was lowly expressed. miR-146b-5p knockdown improved hyperoxia-induced lung epithelial cell inflammation and apoptosis in both models. miR-146b-6p upregulation or KDM6B downregulation aggravated hyperoxia-induced inflammation and apoptosis of lung epithelial cells. This effect of overexpressing miR-146b-5p was rescued by forcing KDM6B. MiR-146b-5p activated Wnt signaling by regulating KDM6B. miR-146b-5p activates the Wnt pathway through targeted regulation of KDM6B, thereby aggravating hyperoxia-induced inflammation and apoptosis of lung epithelial cells. [ABSTRACT FROM AUTHOR]

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The presence of hypoxics, bacterial infection, and the creation of bacterial biofilms are significant obstacles that hinder the healing of diabetic wounds. Calcium peroxide (CaO2) can be hydrolyzed to produce oxygen (O2) and hydrogen peroxide (H2O2), resulting in the simultaneous creation of oxygen and an antimicrobial effect. However, oxygen delivery is limited by the skin and bacterial biofilm barrier. Herein, we proposed a microneedles patch loading CaO2 nanoparticles (abbreviated as CaO2 NPs@MN). The microneedles can puncture the skin and destroy the biofilm barrier. Meanwhile, upon contact with the biological fluid, the microneedles would be dissolved, and CaO2 NPs would be released into the wound site, further being hydrolyzed to O2 and H2O2 to achieve antibacterial effect and local deep oxygen delivery. Notably, in order to encapsulate CaO2 powders evenly into the microneedle tips and avoid their hydrolysis during the preparation process, we fabricated the nanoscaled CaO2 particles and encapsulated them in microneedles in an ethanol system for the first time. The in vitro experiments demonstrated that CaO2 NPs@MN possessed the desired oxygen delivery and antibacterial effect. Furthermore, the elimination of bacteria, reduction in inflammation, promotion of collagen formation, stimulation of blood vessel growth, and subsequent acceleration of wound healing were observed in in vivo experiments. In conclusion, we provided a simple process for the application of CaO2 in wound healing and also a promising strategy for infected diabetic ulcer treatment. [ABSTRACT FROM AUTHOR]

Nuclear factor‐erythroid‐2‐related factor‐2 (NRF‐2) is a cellular resistance protein to oxidants. We investigated the effect of exogenous all‐trans retinoic acid (ATRA) on the antioxidant system and NRF‐2 in mice kidneys under hyperoxia‐induced oxidative stress. Mice were divided into four groups. Daily, two groups were given either peanut‐oil/dimethyl sulfoxide (PoDMSO) mixture or 50 mg/kg ATRA. Oxidative stress was induced by hyperoxia in the remaining groups. They were treated with PoDMSO or ATRA as described above, following hyperoxia (100% oxygen) for 72 h. NRF‐2 and active‐caspase‐3 levels, lipid peroxidation (LPO), activities of antioxidant enzymes, xanthine oxidase (XO), paraoxonase1 (PON1), lactate dehydrogenase (LDH), tissue factor (TF), and prolidase were assayed in kidneys. Hyperoxia causes kidney damage induced by oxidative stress and apoptosis. Increased LPO, LDH, TF, and XO activities and decreased PON1 and prolidase activities contributed to kidney damage in hyperoxic mice. After hyperoxia, increases in the activities of antioxidant enzymes and NRF‐2 level could not prevent this damage. ATRA attenuated damage via its oxidative stress‐lowering effect. The decreased LDH and TF activities increased PON1 and prolidase activities, and normalized antioxidant statuses are indicators of the positive effects of ATRA. We recommend that ATRA can be used as a renoprotective agent against oxidative stress induced‐kidney damage. Significance Statement: This study investigates the protective effects of all‐trans retinoic acid (ATRA) against oxidative stress and oxidative stress‐induced tissue damage in mouse kidneys. Exposure to high oxygen levels significantly damages kidney tissues by increasing lipid peroxidation and enzyme activities, leading to cellular dysfunction. However, treatment with ATRA demonstrated a remarkable ability to attenuate these effects, increase the activity of antioxidant defenses, and stabilize essential renal enzymes. These findings suggest that ATRA may be a potent renoprotector and offer a promising approach to managing oxidative stress‐induced renal damage. [ABSTRACT FROM AUTHOR]

High oxygen (hyperoxia) concentration may damage multiple organs and systems in newborns, such as the lung, brain and intestines. Metabolic abnormalities are important early events in the pathogenesis of neonatal hyperoxia related pulmonary diseases. This article reviews the increased glucose and lipid metabolism as well as dys-regulation of amino acid metabolism after hyperoxia related bronchopulmonary dysplasia in newborns. The potential mechanism may be that the high oxygen concentration increases formation of mitochondrial reactive oxygen species (mtROS), and also change the mitochondrial dynamics of neonatal bronchopulmonary dysplasia, leading to reduction of mitochondrial fusion, enhances fission and autophagy. This study also finds that many metabolism-related enzymes and metabolites are changed during hyperoxia related diseases. However, clinical research has not yet been conducted. Future research should focus on combining metabolic profiles with multi omies data, including transcriptome sequencing, genomics and proteomics to identify potential biomarkers and therapeutic targets for hyperoxia related neonatal lung injury in order to develop new strategies for the treatment of metabolic abnormalities resulted from neonatal hyperoxia related pulmonary diseases. [ABSTRACT FROM AUTHOR]

Supplemental O2 (hyperoxia) is a critical intervention for premature infants (<34 weeks) but consequently is associated with development of bronchial airway hyperreactivity (AHR) and asthma. Clinical practice shifted toward the use of moderate hyperoxia (<60% O2), but risk for subsequent airway disease remains. In mouse models of moderate hyperoxia, neonatal mice have increased AHR with effects on airway smooth muscle (ASM), a cell type involved in airway tone, bronchodilation, and remodeling. Understanding mechanisms by which moderate O2 during the perinatal period initiates sustained airway changes is critical to drive therapeutic advancements toward treating airway diseases. We propose that cellular clock factor BMAL1 is functionally important in developing mouse airways. In adult mice, cellular clocks target pathways highly relevant to asthma pathophysiology and Bmal1 deletion increases inflammatory response, worsens lung function, and impacts survival outcomes. Our understanding of BMAL1 in the developing lung is limited, but our previous findings show functional relevance of clocks in human fetal ASM exposed to O2. Here, we characterize Bmal1 in our established mouse neonatal hyperoxia model. Our data show that Bmal1 KO deleteriously impacts the developing lung in the context of O2 and these data highlight the importance of neonatal sex in understanding airway disease. [ABSTRACT FROM AUTHOR]

With recent advances in neonatal intensive care, preterm infants are surviving into adulthood. Nonetheless, epidemiological data on the health status of these preterm infants have begun to reveal a worrying theme; prematurity and the supplemental oxygen therapy these infants receive after birth appear to be risk factors for kidney disease in adulthood, affecting their quality of life. As the incidence of chronic kidney disease and the survival time of preterm infants both increase, the management of the hyperoxia-induced renal disease is becoming increasingly relevant to neonatologists. The mechanism of this increased risk is currently unknown, but prematurity itself and hyperoxia exposure after birth may predispose to disease by altering the normal trajectory of kidney maturation. This article reviews altered renal reactivity due to hyperoxia, the possible mechanisms of renal injury due to hyperoxia, and the role of resveratrol in renal injury. Key Points Premature infants commonly receive supplementary oxygen. Hyperoxia can cause kidney damage via signal pathways. We should reduce the occurrence of late sequelae. [ABSTRACT FROM AUTHOR]

Organogenesis occurs in the uterus under low oxygen levels (4%). Preterm birth exposes immature newborns to a hyperoxic environment, which can induce a massive production of reactive oxygen species and potentially affect organ development, leading to diseases such as necrotizing enterocolitis. The β3-adrenoreceptor (β3-AR) has an oxygen-dependent regulatory mechanism, and its activation exerts an antioxidant effect. To test the hypothesis that β3-AR could protect postnatal ileal development from the negative impact of high oxygen levels, Sprague–Dawley rat pups were raised under normoxia (21%) or hyperoxia (85%) for the first 2 weeks after birth and treated or not with BRL37344, a selective β3-AR agonist, at 1, 3, or 6 mg/kg. Hyperoxia alters ileal mucosal morphology, leading to increased cell lipid oxidation byproducts, reduced presence of β3-AR-positive resident cells, decreased junctional protein expression, disrupted brush border, mucin over-production, and impaired vascularization. Treatment with 3 mg/kg of BRL37344 prevented these alterations, although not completely, while the lower 1 mg/kg dose was ineffective, and the higher 6 mg/kg dose was toxic. Our findings indicate the potential of β3-AR agonism as a new therapeutic approach to counteract the hyperoxia-induced ileal alterations and, more generally, the disorders of prematurity related to supra-physiologic oxygen exposure. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the effect of inhaled oxygen level on dynamic glucose enhanced (DGE) MRI in mouse brain tissue and CSF at 3 T. Methods: DGE data of brain tissue and CSF from mice under normoxia or hyperoxia were acquired in independent and interleaved experiments using on‐resonance variable delay multi‐pulse (onVDMP) MRI. A bolus of 0.15 mL filtered 50% D‐glucose was injected through the tail vein over 1 min during DGE acquisition. MRS was acquired before and after DGE experiments to confirm the presence of D‐glucose. Results: A significantly higher DGE effect under normoxia than under hyperoxia was observed in brain tissue (p = 0.0001 and p = 0.0002 for independent and interleaved experiments, respectively), but not in CSF (p > 0.3). This difference is attributed to the increased baseline MR tissue signal under hyperoxia induced by a shortened T1 and an increased BOLD effect. When switching from hyperoxia to normoxia without glucose injection, a signal change of ˜3.0% was found in brain tissue and a signal change of ˜1.5% was found in CSF. Conclusions: DGE signal was significantly lower under hyperoxia than that under normoxia in brain tissue, but not in CSF. The reason is that DGE effect size of brain tissue is affected by the baseline signal, which could be influenced by T1 change and BOLD effect. Therefore, DGE experiments in which the oxygenation level is changed from baseline need to be interpreted carefully. [ABSTRACT FROM AUTHOR]

High oxygen(hyperoxia) concentration may damage multiple organs and systems in newborns, such as the lung, brain and intestines. Metabolic abnormalities are important early events in the pathogenesis of neonatal hyperoxia related pulmonary diseases. This article reviews the increased glucose and lipid metabolism as well as dys-regulation of amino acid metabolism after hyperoxia related bronchopulmonary dysplasia in newborns. The potential mechanism may be that the high oxygen concentration increases formation of mitochondrial reactive oxygen species (mtROS), and also change the mitochondrial dynamics of neonatal bronchopulmonary dysplasia, leading to reduction of mitochondrial fusion, enhances fission and autophagy. This study also finds that many metabolism-related enzymes and metabolites are changed during hyperoxia related diseases. However, clinical research has not yet been conducted. Future research should focus on combining metabolic profiles with multi omics data, including transcriptome sequencing, genomics and proteomics to identify potential biomarkers and therapeutic targets for hyperoxia related neonatal lung injury in order to develop new strategies for the treatment of metabolic abnormalities resulted from neonatal hyperoxia related pulmonary diseases.

Prolonged exposure to hyperbaric hyperoxia can lead to pulmonary oxygen toxicity (PO2tox). PO2tox is a mission limiting factor for special operations forces divers using closed-circuit rebreathing apparatus and a potential side effect for patients undergoing hyperbaric oxygen (HBO) treatment. In this study, we aim to determine if there is a specific breath profile of compounds in exhaled breath condensate (EBC) that is indicative of the early stages of pulmonary hyperoxic stress/PO2tox. Using a double-blind, randomized 'sham' controlled, cross-over design 14 U.S. Navy trained diver volunteers breathed two different gas mixtures at an ambient pressure of 2 ATA (33 fsw, 10 msw) for 6.5 h. One test gas consisted of 100% O2(HBO) and the other was a gas mixture containing 30.6% O2with the balance N2(Nitrox). The high O2stress dive (HBO) and low O2stress dive (Nitrox) were separated by at least seven days and were conducted dry and at rest inside a hyperbaric chamber. EBC samples were taken immediately before and after each dive and subsequently underwent a targeted and untargeted metabolomics analysis using liquid chromatography coupled to mass spectrometry (LC-MS). Following the HBO dive, 10 out of 14 subjects reported symptoms of the early stages of PO2tox and one subject terminated the dive early due to severe symptoms of PO2tox. No symptoms of PO2tox were reported following the nitrox dive. A partial least-squares discriminant analysis of the normalized (relative to pre-dive) untargeted data gave good classification abilities between the HBO and nitrox EBC with an AUC of 0.99 (±2%) and sensitivity and specificity of 0.93 (±10%) and 0.94 (±10%), respectively. The resulting classifications identified specific biomarkers that included human metabolites and lipids and their derivatives from different metabolic pathways that may explain metabolomic changes resulting from prolonged HBO exposure.

Supplemental oxygen (hyperoxia) improves physical performance during hypoxic exercise. Based on the analysis of metabolome and iron homeostasis from human athlete blood samples, we show that hyperoxia during recovery periods interferes with metabolic alterations following hypoxic exercise. This may impair beneficial adaptations to exercise and/or hypoxia and highlights risks of oxygen supplementation in hypoxia. [Display omitted] • Hyperoxic recovery does not improve training efficiency of hypoxic exercise in healthy men. • Hyperoxic recovery prevents inter-session improvements of hypoxic exercise. • Hyperoxic recovery abolishes the metabolic fingerprint of hypoxic exercise after one week. • Hyperoxic recovery during hypoxic exercise may reduce hypoxia acclimatization, potentially increasing the risks of hypoxia. [ABSTRACT FROM AUTHOR]

Abstract Introduction Administration of oxygen therapy is common, yet there is a lack of knowledge on its ability to prevent cellular hypoxia as well as on its potential toxicity. Consequently, the optimal oxygenation targets in clinical practice remain unresolved. The novel PpIX technique measures the mitochondrial oxygen tension in the skin (mitoPO2) which allows for non-invasive investigation on the effect of hypoxemia and hyperoxemia on cellular oxygen availability. Results During hypoxemia, SpO2 was 80 (77–83)% and PaO2 45(38–50) mmHg for 15 min. MitoPO2 decreased from 42(35–51) at baseline to 6(4.3–9)mmHg (p 200 mmHg were both associated with a reduction in mitoPO2. Conclusions Hypoxemia decreases mitoPO2 profoundly, despite complete compensation of global oxygen delivery. In addition, hyperoxemia also decreases mitoPO2, accompanied by a reduction in microcirculatory perfusion. These results suggest that mitoPO2 can be used to titrate oxygen support.

Abstract Backgound Hyperoxemia is common and associated with poor outcome during veno-arterial extracorporeal membrane oxygenation (VA ECMO) support for cardiogenic shock. However, little is known about practical daily management of oxygenation. Then, we aim to describe sweep gas oxygen fraction (FSO2), postoxygenator oxygen partial pressure (PPOSTO2), inspired oxygen fraction (FIO2), and right radial arterial oxygen partial pressure (PaO2) between day 1 and day 7 of peripheral VA ECMO support. We also aim to evaluate the association between oxygenation parameters and outcome. In this retrospective multicentric study, each participating center had to report data on the last 10 eligible patients for whom the ICU stay was terminated. Patients with extracorporeal cardiopulmonary resuscitation were excluded. Primary endpoint was individual mean FSO2 during the seven first days of ECMO support (FSO2 mean (day 1−7) ). Results Between August 2019 and March 2022, 139 patients were enrolled in 14 ECMO centers in France, and one in Switzerland. Among them, the median value for FSO2 mean (day 1−7) was 70 [57; 79] % but varied according to center case volume. Compared to high volume centers, centers with less than 30 VA-ECMO runs per year were more likely to maintain FSO2 ≥ 70% (OR 5.04, CI 95% [1.39; 20.4], p = 0.017). Median value for right radial PaO2 mean (day 1−7) was 114 [92; 145] mmHg, and decreased from 125 [86; 207] mmHg at day 1, to 97 [81; 133] mmHg at day 3 (p

Abstract Background Several studies have identified graded oxygen saturation targets to prevent retinopathy of prematurity (ROP), a serious complication in preterm infants. We aimed to analyze the critical period of oxygen supplementation and/or invasive ventilation associated with severe ROP. Methods This retrospective case-control study included neonates with a gestational age (GA)

Hyperoxia has been shown to expand the aerobic capacity of some fishes, although there have been very few studies examining the underlying mechanisms and how they vary across different exposure durations. Here, we investigated the cardiorespiratory function of yellowtail kingfish (Seriola lalandi) acutely (~20 h) and chronically (3–5 weeks) acclimated to hyperoxia (~200% air saturation). Our results show that the aerobic performance of kingfish is limited in normoxia and increases with environmental hyperoxia. The aerobic scope was elevated in both hyperoxia treatments driven by a ~33% increase in maximum O2 uptake (MO2max), although the mechanisms differed across treatments. Fish acutely transferred to hyperoxia primarily elevated tissue O2 extraction, while increased stroke volume-mediated maximum cardiac output was the main driving factor in chronically acclimated fish. Still, an improved O2 delivery to the heart in chronic hyperoxia was not the only explanatory factor as such. Here, maximum cardiac output only increased in chronic hyperoxia compared with normoxia when plastic ventricular growth occurred, as increased stroke volume was partly enabled by an ~8%–12% larger relative ventricular mass. Our findings suggest that hyperoxia may be used long term to boost cardiorespiratory function potentially rendering fish more resilient to metabolically challenging events and stages in their life cycle. [ABSTRACT FROM AUTHOR]

Objective: Preterm neonates encounter hyperoxia relatively early, and are more exposed to hyperoxic stress due to their insufficient antioxidant defense mechanisms. This study was planned around the hypothesis that this hyperoxic effect may cause a disposition to future acute seizures. Methods: This study was composed of two main groups Hyperoxy and Control (Room air with normal O2 levels) Groups. Group 1 – hyperoxia (Study): The experimental group consisted of premature newborn rats exposed to hyperoxia with their dams from birth to postnatal day 5. Group 2 – room air (Control): The group was not exposed to hyperoxia and housed the same room air and temperature as their dams. Female, Acute Epilepsy Female, Male, Acute Epilepsy Male, and a total of eight subgroups were formed in both the control and hyperoxia groups. When the rats were two months old, intracranial electrodes were attached to obtain electrocorticography (ECoG) recordings. Pre-model recordings were taken, after which an acute pentylenetetrazole (PTZ) model of absence seizure was induced by the intraperitoneal administration of PTZ at 50 mg/kg. ECoG records were examined using the PowerLab system for 180 min. Spike wave number and duration, Spike wave frequency and amplitude data were evaluated.Results: Seven female and three male rats were exposed to hyperoxia, and a control group of five female and three male rats were included in the study. The median interquartile range for spike wave latency in the hyperoxia and control groups were 1112 (644–1545) and 654 (408–1152), frequency 4476 (3120–7421) and 3934 (2264–4704), and amplitude data 0.68 (0.59–0.79) and 0.52 (0.37–0.67), respectively. Although a difference was observed in median values capable of constituting susceptibility to epilepsy, the difference was not statistically significant (p > 0.05). In terms of gender, spike-wave counts were significantly higher in female rats (p < 0.05). Females exposed to hyperoxia were more susceptible to epilepsy than both males and females in the control group (p < 0.05).Conclusion: Exposure to hyperoxia in the first days of life of premature neonates due to their susceptibility to oxidative stress and insufficient antioxidant mechanisms, can cause a disposition to acute seizures. As a result, females exposed to hyperoxia during the neonatal period may be prone to epilepsy in maturity. [ABSTRACT FROM AUTHOR]

Numerous studies have shown that oxidative stress plays an important role in peripheral artery disease (PAD). Prior reports suggested autonomic dysfunction in PAD. We hypothesized that responses of the autonomic nervous system and coronary tone would be impaired in patients with PAD during exposure to acute hyperoxia, an oxidative stressor. In 20 patients with PAD and 16 healthy, sex- and age-matched controls, beat-by-beat heart rate (HR, from ECG) and blood pressure (BP, with Finometer) were recorded for 10 min during room air breathing and 5 min of hyperoxia. Cardiovagal baroreflex sensitivity and HR variability (HRV) were evaluated as measures of autonomic function. Transthoracic coronary echocardiography was used to assess peak coronary blood flow velocity (CBV) in the left anterior descending coronary artery. Cardiovagal baroreflex sensitivity at rest was lower in PAD than in healthy controls. Hyperoxia raised BP solely in the patients with PAD, with no change observed in healthy controls. Hyperoxia induced an increase in cardiac parasympathetic activity assessed by the high-frequency component of HRV in healthy controls but not in PAD. Indices of parasympathetic activity were lower in PAD than in healthy controls throughout the trial as well as during hyperoxia. Hyperoxia induced coronary vasoconstriction in both groups, while the coronary perfusion time fraction was lower in PAD than in healthy controls. These results suggest that the response in parasympathetic activity to hyperoxia (i.e., oxidative stress) is blunted and the coronary perfusion time is shorter in patients with PAD. NEW & NOTEWORTHY: Patients with peripheral artery disease (PAD) showed consistently lower parasympathetic activity and blunted cardiovagal baroreflex sensitivity compared with healthy individuals. Notably, hyperoxia, which normally boosts parasympathetic activity in healthy individuals, failed to induce this response in patients with PAD. These data suggest altered autonomic responses during hyperoxia in PAD. [ABSTRACT FROM AUTHOR]

Objectives Our previous study showed that resveratrol (Res) attenuates apoptosis and mitochondrial dysfunction in alveolar epithelial cell injury induced by hyperoxia by activating the SIRT1/PGC-1α signaling pathway. In the present study, we investigated whether Res protects against hyperoxia-induced lung injury in neonatal rats by activating SIRT1/PGC-1α signaling pathway. Methods Naturally delivered neonatal rats were randomly divided into six groups: normoxia + normal saline, normoxia + dimethyl sulfoxide (DMSO), normoxia + Res, hyperoxia + normal saline, hyperoxia + DMSO, and hyperoxia + Res. Lung tissue samples were collected on postnatal days 1, 7, and 14. Hematoxylin and eosin staining was used to evaluate lung development. Dual-immunofluorescence staining, real-time polymerase chain reaction, and western blotting were used to evaluate the levels of silencing information regulator 2-related enzyme 1 (SIRT1), peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α), nuclear respiratory factor 1 (Nrf1), Nrf2, transcription factor A (TFAM) and citrate synthase, the number of mitochondrial DNA (mtDNA) and mitochondria, the integrity of mtDNA, and the expression of TFAM in mitochondria. Results We found that hyperoxia insulted lung development, whereas Res attenuated the hyperoxia lung injury. Res significantly upregulated the levels of SIRT1, PGC-1α, Nrf1, Nrf2, TFAM, and citrate synthase; promoted TFAM expression in the mitochondria; and increased the copy number of ND1 and the ratio of ND4/ND1. Conclusion Our data suggest that Res attenuates hyperoxia-induced lung injury in neonatal rats, and this was achieved, in part, by activating the SIRT1/PGC-1α signaling pathway to promote mitochondrial biogenesis. Key Points Hyperoxia insulted lung development in neonatal rats. Resveratrol promoted mitochondrial biogenesis to attenuate hyperoxia lung injury in neonatal rats. Resveratrol, at least in part, promoted mitochondrial biogenesis by activating the SIRT1/PGC-1α signaling pathway. [ABSTRACT FROM AUTHOR]

Rationale: Adult and pediatric studies provide conflicting data regarding whether post–cardiac arrest hypoxemia, hyperoxemia, hypercapnia, and/or hypocapnia are associated with worse outcomes. Objectives: We sought to determine whether postarrest hypoxemia or postarrest hyperoxemia is associated with lower rates of survival to hospital discharge, compared with postarrest normoxemia, and whether postarrest hypocapnia or hypercapnia is associated with lower rates of survival, compared with postarrest normocapnia. Methods: An embedded prospective observational study during a multicenter interventional cardiopulmonary resuscitation trial was conducted from 2016 to 2021. Patients ⩽18 years old and with a corrected gestational age of ≥37 weeks who received chest compressions for cardiac arrest in one of the 18 intensive care units were included. Exposures during the first 24 hours postarrest were hypoxemia, hyperoxemia, or normoxemia—defined as lowest arterial oxygen tension/pressure (PaO2) <60 mm Hg, highest PaO2 ⩾200 mm Hg, or every PaO2 60–199 mm Hg, respectively—and hypocapnia, hypercapnia, or normocapnia, defined as lowest arterial carbon dioxide tension/pressure (PaCO2) <30 mm Hg, highest PaCO2 ⩾50 mm Hg, or every PaCO2 30–49 mm Hg, respectively. Associations of oxygenation and carbon dioxide group with survival to hospital discharge were assessed using Poisson regression with robust error estimates. Results: The hypoxemia group was less likely to survive to hospital discharge, compared with the normoxemia group (adjusted relative risk [aRR] = 0.71; 95% confidence interval [CI] =  0.58–0.87), whereas survival in the hyperoxemia group did not differ from that in the normoxemia group (aRR = 1.0; 95% CI = 0.87–1.15). The hypercapnia group was less likely to survive to hospital discharge, compared with the normocapnia group (aRR = 0.74; 95% CI = 0.64–0.84), whereas survival in the hypocapnia group did not differ from that in the normocapnia group (aRR = 0.91; 95% CI = 0.74–1.12). Conclusions: Postarrest hypoxemia and hypercapnia were each associated with lower rates of survival to hospital discharge. [ABSTRACT FROM AUTHOR]

Background: Although several trials were conducted to optimize the oxygenation range in intensive care unit (ICU) patients, no studies have yet reached a universal recommendation on the optimal a partial pressure of oxygen in arterial blood (PaO2) range in patients with sepsis. Our aim was to evaluate whether a relatively high arterial oxygen tension is associated with longer survival in sepsis patients compared with conservative arterial oxygen tension. Methods: From the Korean Sepsis Alliance nationwide registry, patients treated with liberal PaO2 (PaO2 ≥ 80 mm Hg) were 1:1 matched with those treated with conservative PaO2 (PaO2 < 80 mm Hg) over the first three days after ICU admission according to the propensity score. The primary outcome was 28-day mortality. Results: The median values of PaO2 over the first three ICU days in 1211 liberal and 1211 conservative PaO2 groups were, respectively, 107.2 (92.0–134.0) and 84.4 (71.2–112.0) in day 1110.0 (93.4–132.0) and 80.0 (71.0–100.0) in day 2, and 106.0 (91.9–127.4) and 78.0 (69.0–94.5) in day 3 (all p-values < 0.001). The liberal PaO2 group showed a lower likelihood of death at day 28 (14.9%; hazard ratio [HR], 0.79; 95% confidence interval [CI] 0.65–0.96; p-value = 0.017). ICU (HR, 0.80; 95% CI 0.67–0.96; p-value = 0.019) and hospital mortalities (HR, 0.84; 95% CI 0.73–0.97; p-value = 0.020) were lower in the liberal PaO2 group. On ICU days 2 (p-value = 0.007) and 3 (p-value < 0.001), but not ICU day 1, hyperoxia was associated with better prognosis compared with conservative oxygenation., with the lowest 28-day mortality, especially at PaO2 of around 100 mm Hg. Conclusions: In critically ill patients with sepsis, higher PaO2 (≥ 80 mm Hg) during the first three ICU days was associated with a lower 28-day mortality compared with conservative PaO2. [ABSTRACT FROM AUTHOR]

The mechanisms governing brain vascularization during development remain poorly understood. A key regulator of developmental vascularization is delta like 4 (DLL4), a Notch ligand prominently expressed in endothelial cells (EC). Exposure to hyperoxia in premature infants can disrupt the development and functions of cerebral blood vessels and lead to long‐term cognitive impairment. However, its role in cerebral vascular development and the impact of postnatal hyperoxia on DLL4 expression in mouse brain EC have not been explored. We determined the DLL4 expression pattern and its downstream signalling gene expression in brain EC using Dll4+/+ and Dll4+/LacZ mice. We also performed in vitro studies using human brain microvascular endothelial cells. Finally, we determined Dll4 and Cldn5 expression in mouse brain EC exposed to postnatal hyperoxia. DLL4 is expressed in various cell types, with EC being the predominant one in immature brains. Moreover, DLL4 deficiency leads to persistent abnormalities in brain microvasculature and increased vascular permeability both in vivo and in vitro. We have identified that DLL4 insufficiency compromises endothelial integrity through the NOTCH‐NICD‐RBPJ‐CLDN5 pathway, resulting in the downregulation of the tight junction protein claudin 5 (CLDN5). Finally, exposure to neonatal hyperoxia reduces DLL4 and CLDN5 expression in developing mouse brain EC. We reveal that DLL4 is indispensable for brain vascular development and maintaining the blood–brain barrier's function and is repressed by neonatal hyperoxia. We speculate that reduced DLL4 signalling in brain EC may contribute to the impaired brain development observed in neonates exposed to hyperoxia. Key points: The role of delta like 4 (DLL4), a Notch ligand in vascular endothelial cells, in brain vascular development and functions remains unknown.We demonstrate that DLL4 is expressed at a high level during postnatal brain development in immature brains and DLL4 insufficiency leads to abnormal cerebral vasculature and increases vascular permeability both in vivo and in vitro.We identify that DLL4 regulates endothelial integrity through NOTCH‐NICD‐RBPJ‐CLDN5 signalling.Dll4 and Cldn5 expression are decreased in mouse brain endothelial cells exposed to postnatal hyperoxia. [ABSTRACT FROM AUTHOR]

Newborn infants face a rapid surge of oxygen and a more protracted rise of unconjugated bilirubin after birth. Bilirubin has a strong antioxidant capacity by scavenging free radicals, but it also exerts direct toxicity. This study investigates whether cultured rat alveolar epithelial cells type II (AEC II) react differently to bilirubin under different oxygen concentrations. The toxic threshold concentration of bilirubin was narrowed down by means of a cell viability test. Subsequent analyses of bilirubin effects under 5% oxygen and 80% oxygen compared to 21% oxygen, as well as pretreatment with bilirubin after 4 h and 24 h of incubation, were performed to determine the induction of apoptosis and the gene expression of associated transcripts of cell death, proliferation, and redox-sensitive transcription factors. Oxidative stress led to an increased rate of cell death and induced transcripts of redox-sensitive signaling pathways. At a non-cytotoxic concentration of 400 nm, bilirubin attenuated oxidative stress-induced responses and possibly mediated cellular antioxidant defense by influencing Nrf2/Hif1α- and NFκB-mediated signaling pathways. In conclusion, the study demonstrates that rat AEC II cells are protected from oxidative stress-induced impairment by low-dose bilirubin. [ABSTRACT FROM AUTHOR]

Hyperbaric Oxygen Therapy (HBOT) utilizes 100% oxygen at high atmospheric pressure for clinical applications. HBOT has proven to be an effective supplementary treatment for a variety of clinical and pathological disorders. HBOT's therapeutic results are based on the physiological effects of increased tissue oxygenation, or improved oxygen bioavailability. HBOT's current indications in illnesses like as wound healing, thermal or radiation burns, and tissue necrosis point to its function in facilitating the regeneration process. Various research has revealed that HBOT plays a function in vascularization, angiogenesis, and collagen production augmentation. Individual regeneration capacity is influenced by both environmental and genetic factors. Furthermore, the regenerating ability of different types of tissues varies, and this ability declines with age. HBOT affects physiological processes at the genetic level by altering gene expression, delaying cell senescence, and assisting in telomere length enhancement. The positive results in a variety of indications, ranging from tissue regeneration to better cognitive function, indicate that it has enormous potential in regenerative and anti-aging therapy. [ABSTRACT FROM AUTHOR]