PEG300 Protects Mitochondrial Function By Upregulating PGC-1α to Delay Central Nervous System Oxygen Toxicity in Mice.

Central nervous system oxygen toxicity (CNS-OT) is a complication of hyperbaric oxygen (HBO) treatment, with limited prevention and treatment options available. In this study, we aimed to explore the effect of polyethylene glycol 300 (PEG300) on CNS-OT and underlying mechanisms. Motor and cognitive functions of mice in normobaric conditions were evaluated by Morris water maze, passive active avoidance, and rotarod tests. HBO was applied at 6 atmospheres absolute (ATA) for 30 min after drug administration. The latency period of convulsion in mice was recorded, and hippocampal tissues were extracted for biochemical experiments. Our experimental results showed that PEG300 extended the convulsion latencies in CNS-OT mice, reduced oxidative stress and inflammation levels in hippocampal tissues. Furthermore, PEG300 preserved mitochondrial integrity and maintained mitochondrial membrane potential in hippocampal tissue by upregulating Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha (PGC-1α). This protective effect was enhanced following the administration of ZLN005, an agonist of PGC-1a. Hence, our study suggests that PEG300 might exert protective effects by upregulating PGC-1α expression and preserving mitochondrial health, offering promising prospects for CNS-OT treatment.

Hyperoxemia among Pediatric Intensive Care Unit Patients Receiving Oxygen Therapy.

Supratherapeutic oxygen levels consistently cause oxygen toxicity in the lungs and other organs. The prevalence and severity of hyperoxemia among pediatric intensive care unit (PICU) patients remain unknown. This was the first study to examine the prevalence and duration of hyperoxemia in PICU patients receiving oxygen therapy. This is a retrospective chart review. This was performed in a setting of 36-bed PICU in a quaternary-care children's hospital. All the patients were children aged <18 years, admitted to the PICU for ≥24 hours, receiving oxygen therapy for ≥12 hours who had at least one arterial blood gas during this time. There was no intervention. Of 5,251 patients admitted to the PICU, 614 were included in the study. On average, these patients received oxygen therapy for 91% of their time in the PICU and remained hyperoxemic, as measured by pulse oximetry, for 65% of their time on oxygen therapy. Patients on oxygen therapy remained hyperoxemic for a median of 38 hours per patient and only 1.1% of patients did not experience any hyperoxemia. Most of the time (87.5%) patients received oxygen therapy through a fraction of inspired oxygen (FiO 2 )-adjustable device. Mean FiO 2 on noninvasive support was 0.56 and on invasive support was 0.37. Mean partial pressure of oxygen (PaO 2 ) on oxygen therapy was 108.7 torr and 3,037 (42.1%) of PaO 2 measurements were >100 torr. Despite relatively low FiO 2 , PICU patients receiving oxygen therapy are commonly exposed to prolonged hyperoxemia, which may contribute to ongoing organ injury.

Timing of intubation of pediatric hematopoietic cell transplant patients: an international survey.

Introduction: Retrospective data suggest that pediatric hematopoietic cell transplant (HCT) patients placed on non-invasive ventilation (NIV) prior to intubation have increased risk of mortality compared to patients who are intubated earlier in their course. The HCT-CI subgroup of the PALISI Network set out to gain a better understanding of factors that influence clinician's decisions surrounding timing of intubation of pediatric HCT patients. Methods: We validated and distributed a brief survey exploring potential factors that may influence clinician's decisions around timing of intubation of pediatric HCT patients with acute lung injury (ALI). Results: One hundred and four of the 869 PALISI Network's members responded to the survey; 97 of these respondents acknowledged caring for HCT patients and were offered the remainder of the survey. The majority of respondents were PICU physicians (96%), with a small number of Advanced Practice Providers and HCT physicians. As expected, poor prognosis categories were perceived as a factors that delay timing to intubation whereas need for invasive procedures was perceived as a factor shortening timing to intubation. Concerns for oxygen toxicity or NIV-associated lung injury were not believed to influence timing of intubation. Discussion: Our survey indicates increased risk of ALI from prolonged NIV and oxygen toxicity in HCT patients are not a concern for most clinicians. Further education of pediatric ICU clinicians around these risk factors could lead to improvement in outcomes and demands further study. Additionally, clinicians identified concerns for the patient's poor prognosis as a common reason for delayed intubation.

Volatile Organic Compounds in Cellular Headspace after Hyperbaric Oxygen Exposure: An In Vitro Pilot Study.

Volatile organic compounds (VOCs) might be associated with pulmonary oxygen toxicity (POT). This pilot study aims to identify VOCs linked to oxidative stress employing an in vitro model of alveolar basal epithelial cells exposed to hyperbaric and hyperoxic conditions. In addition, the feasibility of this in vitro model for POT biomarker research was evaluated. The hyperbaric exposure protocol, similar to the U.S. Navy Treatment Table 6, was conducted on human alveolar basal epithelial cells, and the headspace VOCs were analyzed using gas chromatography-mass spectrometry. Three compounds (nonane [p = 0.005], octanal [p = 0.009], and decane [p = 0.018]), of which nonane and decane were also identified in a previous in vivo study with similar hyperbaric exposure, varied significantly between the intervention group which was exposed to 100% oxygen and the control group which was exposed to compressed air. VOC signal intensities were lower in the intervention group, but cellular stress markers (IL8 and LDH) confirmed increased stress and injury in the intervention group. Despite the observed reductions in compound expression, the model holds promise for POT biomarker exploration, emphasizing the need for further investigation into the complex relationship between VOCs and oxidative stress.

Exposure to hyperbaric O2 levels leads to blood-brain barrier breakdown in rodents.

INTRODUCTION: Hyperbaric oxygen has been used as a medical treatment tool in hyperbaric chambers and is an integral part of professional and combat divers' activity. In extreme cases, exposure to hyperbaric oxygen can develop central nervous system oxygen toxicity (CNS-OT), which leads to seizures and eventually death. CNS-OT is caused by neuronal hyperactivity due to high oxygen levels, potentially damaging brain cells including the blood-brain barrier (BBB). However, the effect of hyperbaric oxygen levels on the healthy BBB has not been characterized directly yet. METHODS: Six or three different groups of ~ eight rats or mice, respectively, were exposed to increasing levels of partial pressure of oxygen (0.21 to 5 ATA) in a hyperbaric chamber, followed by MRI scanning with gadolinium. Statistical significance (adjusted p-value ≤ 0.05) was assessed using linear regression and ordinary one-way (rats) or two-way (mice) ANOVA with correction of multiple comparison tests. In rats, the effect of 100% oxygen at 5 ATA was independently validated using FITC-Dextran (5 kDa). Statistical significance (p-value ≤ 0.05) was assessed using Welch's t-test and effect size was calculated by Cohen's D. RESULTS: In rats, analyzed MRI scans showed a significant trend of increase in the % gadolinium in brain tissues as a result of hyperbaric oxygen pressures (p-value = 0.0079). The most significant increase was measured at 4 ATA compared to air (adjusted p-value = 0.0461). Significant increased FITC-Dextran levels were measured in the rats' brains under 100% oxygen at 5 ATA versus air (p-value = 0.0327; Effect size = 2.0). In mice, a significant increase in gadolinium penetration into the hippocampus and frontal cortex was measured over time (adjusted p-value < 0.05) under 100% oxygen at 3 and 5 ATA versus air, and between the treatments (adjusted p-value < 0.0001). CONCLUSIONS: The BBB is increasingly disrupted due to higher levels of hyperbaric oxygen in rodents, indicating a direct relation between hyperbaric oxygen and BBB dysregulation for the first time. We suggest considering this risk in different diving activities, and protocols using a hyperbaric chamber. On the other hand, this study highlights the potential therapeutic usage of hyperbaric oxygen for controlled drug delivery through the BBB into brain tissues in different brain-related diseases.

Acute and chronic central nervous system oxidative stress/toxicity during hyperbaric oxygen treatment of subacute and chronic neurological conditions.

Introduction: Oxygen toxicity has been defined as acute central nervous system (CNS), acute pulmonary, and chronic pulmonary oxygen toxicity. This study identifies acute and chronic CNS oxygen toxicity under 2.0 atmospheres absolute (ATA) pressure of oxygen. Methods: The authors' medical records from September 29, 1989 to January 20, 2023 and correspondence to the authors (9/1994 to 1/20.2023) from patients with signs and/or symptoms historically identified as acute CNS oxygen toxicity and those with neurological deterioration receiving hyperbaric oxygen for neurological conditions were reviewed. Acute cases were those occurring with ≤5 HBOTs and chronic cases >5 HBOTs. Chronic cases were separated into those at 1.5 ATA, > 1.5 ATA, or < 1.5 ATA oxygen. Cumulative dose of oxygen in atmosphere-hours (AHs) was calculated at symptom onset. Results: Seven acute cases, average 4.0 ± 2.7 AHs, and 52 chronic cases were identified: 31 at 1.5 ATA (average 116 ± 106 AHs), 12 at >1.5 ATA (103 ± 74 AHs), and 9 at <1.5 ATA (114 ± 116 AHs). Second episodes occurred at 81 ± 55, 67 ± 49, and 22 ± 17 AHs, and three or more episodes at 25 ± 18, 83 ± 7.5, and 5.4 ± 6.0 AHs, respectively. Most cases were reversible. There was no difference between adults and children (p = 0.72). Acute intervention in cases (<3 months) was more sensitive than delayed intervention (21.1 ± 8.8 vs. 123 ± 102 AHs, p = 0.035). Outside sources reported one acute and two chronic exposure deaths and one patient institutionalized due to chronic oxygen toxicity. A withdrawal syndrome was also identified. Conclusion: Hyperbaric oxygen therapy-generated acute and chronic cases of CNS oxygen toxicity in chronic neurological conditions were identified at <2.0 ATA. Chronic CNS oxygen toxicity is idiosyncratic, unpredictable, and occurred at an average threshold of 103-116 AHs with wide variability. There was no difference between adults and children, but subacute cases were more sensitive than chronic intervention cases. When identified early it was reversible and an important aid in proper dosing of HBOT. If ignored permanent morbidity and mortality resulted with continued HBOT.

The electron transport chain of Shewanella oneidensis MR-1 can operate bidirectionally to enable microbial electrosynthesis.

Extracellular electron transfer is a process by which bacterial cells can exchange electrons with a redox-active material located outside of the cell. In Shewanella oneidensis, this process is natively used to facilitate respiration using extracellular electron acceptors such as Fe(III) or an anode. Previously, it was demonstrated that this process can be used to drive the microbial electrosynthesis (MES) of 2,3-butanediol (2,3-BDO) in S. oneidensis exogenously expressing butanediol dehydrogenase (BDH). Electrons taken into the cell from a cathode are used to generate NADH, which in turn is used to reduce acetoin to 2,3-BDO via BDH. However, generating NADH via electron uptake from a cathode is energetically unfavorable, so NADH dehydrogenases couple the reaction to proton motive force. We therefore need to maintain the proton gradient across the membrane to sustain NADH production. This work explores accomplishing this task by bidirectional electron transfer, where electrons provided by the cathode go to both NADH formation and oxygen (O2) reduction by oxidases. We show that oxidases use trace dissolved oxygen in a microaerobic bioelectrical chemical system (BES), and the translocation of protons across the membrane during O2 reduction supports 2,3-BDO generation. Interestingly, this process is inhibited by high levels of dissolved oxygen in this system. In an aerated BES, O2 molecules react with the strong reductant (cathode) to form reactive oxygen species, resulting in cell death.IMPORTANCEMicrobial electrosynthesis (MES) is increasingly employed for the generation of specialty chemicals, such as biofuels, bioplastics, and cancer therapeutics. For these systems to be viable for industrial scale-up, it is important to understand the energetic requirements of the bacteria to mitigate unnecessary costs. This work demonstrates sustained production of an industrially relevant chemical driven by a cathode. Additionally, it optimizes a previously published system by removing any requirement for phototrophic energy, thereby removing the additional cost of providing a light source. We also demonstrate the severe impact of oxygen intrusion into bioelectrochemical systems, offering insight to future researchers aiming to work in an anaerobic environment. These studies provide insight into both the thermodynamics of electrosynthesis and the importance of the bioelectrochemical systems' design.

Better off breathing: an explanation for the seemingly detrimental impact of aerobic respiration on Zymomonas mobilis.

The bacterium Zymomonas mobilis is best known for fermentatively producing more ethanol than yeast. However, Z. mobilis has also puzzled researchers for decades with the counterintuitive observation that disrupting aerobic respiration benefits aerobic growth, implying that fermentation remains favorable. Retention of detrimental respiration genes seemed to defy natural selection. New findings by Felczak et al. help clarify the importance of respiration for Z. mobilis and the factors that led to the confusing prior results (M. M. Felczak, M. P. Bernard, and M. A. TerAvest, 2023, mBio 14:e02043-23, https://doi.org/10.1128/mbio.02043-23). The team overcame redundancy from multiple genome copies to delete what turned out to be a key terminal oxidase. Unlike previous studies, wherein mutants exhibited low respiration rates and had improved aerobic growth, this mutant was incapable of respiration and had poor aerobic growth. Thus, respiration is important but surprisingly exceeds what is optimal under lab conditions. Respiration likely protects against toxic effects of oxygen, ensuring retention of respiration genes in the Z. mobilis genome.

Plasma Proteomics-Based Discovery of Mechanistic Biomarkers of Hyperbaric Stress and Pulmonary Oxygen Toxicity.

Our aim was to identify proteins that reflect an acute systemic response to prolonged hyperbaric stress and discover potential biomarker pathways for pulmonary O2 toxicity. The study was a double-blind, randomized, crossover design in trained male Navy diver subjects. Each subject completed two dry resting hyperbaric chamber dives separated by a minimum of one week. One dive exposed the subject to 6.5 h of 100% oxygen (O2) at 2ATA. The alternate dive exposed the subjects to an enhanced air nitrox mixture (EAN) containing 30.6% O2 at the same depth for the same duration. Venous blood samples collected before (PRE) and after (POST) each dive were prepared and submitted to LC-MS/MS analysis (2 h runs). A total of 346 total proteins were detected and analyzed. A total of 12 proteins were significantly increased at EANPOST (vs. EANPRE), including proteins in hemostasis and immune signaling and activation. Significantly increased proteins at O2PRE (vs. O2POST) included neural cell adhesion molecule 1, glycoprotein Ib, catalase, hemoglobin subunit beta, fibulin-like proteins, and complement proteins. EANPOST and O2POST differed in biomarkers related to coagulation, immune signaling and activation, and metabolism. Of particular interest is (EANPOST vs. O2POST), which is protective against oxidative stress.

Exhaled Nitric Oxide and Pulmonary Oxygen Toxicity Susceptibility.

Individual susceptibility to pulmonary oxygen toxicity (PO2tox) is highly variable and currently lacks a reliable biomarker for predicting pulmonary hyperoxic stress. As nitric oxide (NO) is involved in many respiratory system processes and functions, we aimed to determine if expired nitric oxide (FENO) levels can provide an indication of PO2tox susceptibility in humans. Eight U.S. Navy-trained divers volunteered as subjects. The hyperoxic exposures consisted of six- and eight-hour hyperbaric chamber dives conducted on consecutive days in which subjects breathed 100% oxygen at 202.65 kPa. Subjects' individual variability in pulmonary function and FENO was measured twice daily over five days and compared with their post-dive values to assess susceptibility to PO2tox. Only subjects who showed no decrements in pulmonary function following the six-hour exposure conducted the eight-hour dive. FENO decreased by 55% immediately following the six-hour oxygen exposure (n = 8, p < 0.0001) and by 63% following the eight-hour exposure (n = 4, p < 0.0001). Four subjects showed significant decreases in pulmonary function immediately following the six-hour exposure. These subjects had the lowest baseline FENO, had the lowest post-dive FENO, and had clinical symptoms of PO2tox. Individuals with low FENO were the first to develop PO2tox symptoms and deficits in pulmonary function from the hyperoxic exposures. These data suggest that endogenous levels of NO in the lungs may protect against the development of PO2tox.

CNS-oxygen toxicity and blood glucose levels in MnSOD enzyme knockdown mice.

Many studies have been conducted in the search for the mechanism underlying CNS-oxygen toxicity (OT), which may be fatal when diving with a closed-circuit apparatus. We investigated the influence of hyperbaric oxygen (HBO) on blood glucose level (BGL) in Mn-superoxide dismutase (SOD2) knockdown mice regarding CNS-OT in particular under stress conditions such as hypoglycemia or hyperglycemia. Two groups of mice were used: SOD2 knockdown (Heterozygous, HET) mice and their WT family littermates. Animals were exposed to HBO from 2 up to 5 atmosphere absolute (ATA). Blood samples were drawn before and after each exposure for measurement of BGL. The mice were sacrificed following the final exposure, which was at 5 ATA. We used RT-PCR and Western blot to measure levels of glucose transporter 1 (GLUT1) and hypoxia inducible factor (HIF)1a in the cortex and hippocampus. In the hypoglycemic condition, the HET mice were more sensitive to oxidative stress than the WT. In addition, following exposure to sub-toxic HBO, which does not induce CNS-OT, BGL were higher in the HET mice compared with the WT. The expression of mRNA of GLUT1 and HIF-1a decreased in the hippocampus in the HET mice, while the protein level decreased in the HET and WT following HBO exposure. The results suggest that the higher BGL following HBO exposure especially at SOD2 HET mice is in part due to reduction in GLUT1 as a consequence of lower HIF-1a expression. This may add part to the puzzle of the understanding the mechanism leading to CNS-OT.

COVID-19-Induced Acute Respiratory Distress Syndrome Treated with Hyperbaric Oxygen: Interim Safety Report from a Randomized Clinical Trial (COVID-19-HBO).

BACKGROUND: A few prospective trials and case series have suggested that hyperbaric oxygen therapy (HBOT) may be efficacious for the treatment of severe COVID-19, but safety is a concern for critically ill patients. We present an interim analysis of the safety of HBOT via a randomized controlled trial (COVID-19-HBO). METHODS: A randomized controlled, open-label, clinical trial was conducted in compliance with good clinical practice to explore the safety and efficacy of HBOT for severe COVID-19 in critically ill patients with moderate acute respiratory distress syndrome (ARDS). Between 3 June 2020, and 17 May 2021, 31 patients with severe COVID-19 and moderate-to-severe ARDS, a ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) < 26.7 kPa (200 mmHg), and at least two defined risk factors for intensive care unit (ICU) admission and/or mortality were enrolled in the trial and randomized 1:1 to best practice, or HBOT in addition to best practice. The subjects allocated to HBOT received a maximum of five treatments at 2.4 atmospheres absolute (ATA) for 80 min over seven days. The subjects were followed up for 30 days. The safety endpoints were analyzed. RESULTS: Adverse events (AEs) were common. Hypoxia was the most common adverse event reported. There was no statistically significant difference between the groups. Numerically, serious adverse events (SAEs) and barotrauma were more frequent in the control group, and the differences between groups were in favor of the HBOT in PaO2/FiO2 (PFI) and the national early warning score (NEWS); statistically, however, the differences were not significant at day 7, and no difference was observed for the total oxygen burden and cumulative pulmonary oxygen toxicity dose (CPTD). CONCLUSION: HBOT appears to be safe as an intervention for critically ill patients with moderate-to-severe ARDS induced by COVID-19. CLINICAL TRIAL REGISTRATION: NCT04327505 (31 March 2020) and EudraCT 2020-001349-37 (24 April 2020).

Exhaled breath condensate profiles of U.S. Navy divers following prolonged hyperbaric oxygen (HBO) and nitrogen-oxygen (Nitrox) chamber exposures.

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.

Prenatal vitamin D supplementation mitigates inflammation-related alveolar remodeling in neonatal mice.

The development of chronic lung disease in the neonate, also known as bronchopulmonary dysplasia (BPD), is the most common long-term complication in prematurely born infants. In BPD, the disease-characteristic inflammatory response culminates in nonreversible remodeling of the developing gas exchange area, provoked by the impact of postnatal treatments such as mechanical ventilation (MV) and oxygen treatment. To evaluate the potential of prenatal treatment regimens to modulate this inflammatory response and thereby impact the vulnerability of the lung toward postnatal injury, we designed a multilayered preclinical mouse model. After administration of either prenatal vitamin D-enriched (VitD+; 1,500 IU/g food) or -deprived (VitD-; <10 IU/kg) food during gestation in C57B6 mice (the onset of mating until birth), neonatal mice were exposed to hyperoxia (FiO2 = 0.4) with or without MV for 8 h at days 5-7 of life, whereas controls spontaneously breathed room air. Prenatal vitamin D supplementation resulted in a decreased number of monocytes/macrophages in the neonatal lung undergoing postnatal injury together with reduced TGF-ß pathway activation. In consequence, neonatal mice that received a VitD+ diet during gestation demonstrated less extracellular matrix (ECM) remodeling upon lung injury, reflected by the reduction of pulmonary α-smooth muscle actin-positive fibroblasts, decreased collagen and elastin deposition, and lower amounts of interstitial tissue in the lung periphery. In conclusion, our findings support strategies that attempt to prevent vitamin D insufficiency during pregnancy as they could impact lung health in the offspring by mitigating inflammatory changes in neonatal lung injury and ameliorating subsequent remodeling of the developing gas exchange area.NEW & NOTEWORTHY Vitamin D-enriched diet during gestation resulted in reduced lung inflammation and matrix remodeling in neonatal mice exposed to clinically relevant, postnatal injury. The results underscore the need to monitor the subclinical effects of vitamin D insufficiency that impact health in the offspring when other risk factors come into play.

Hyperoxia for accidental hypothermia and increased mortality: a post-hoc analysis of a multicenter prospective observational study.

BACKGROUND: Supraphysiologic oxygen administration causes unfavorable clinical outcomes in various diseases, including traumatic brain injury, post-cardiac arrest syndrome, and acute lung injury. Accidental hypothermia is a critical illness that reduces oxygen demands, and excessive oxygen is likely to emerge. This study aimed to determine whether hyperoxia would be associated with increased mortality in patients with accidental hypothermia. METHODS: A post-hoc analysis of a nationwide multicenter prospective observational study (ICE-CRASH study) on patients with accidental hypothermia admitted in 2019-2022 was conducted. Adult patients without cardiac arrest whose core body temperature was < 32 °C and whose arterial partial pressure of oxygen (PaO2) was measured at the emergency department were included. Hyperoxia was defined as a PaO2 level of 300 mmHg or higher, and 28-day mortality was compared between patients with and without hyperoxia before rewarming. Inverse probability weighting (IPW) analyses with propensity scores were performed to adjust patient demographics, comorbidities, etiology and severity of hypothermia, hemodynamic status and laboratories on arrival, and institution characteristics. Subgroup analyses were conducted according to age, chronic cardiopulmonary diseases, hemodynamic instability, and severity of hypothermia. RESULTS: Of the 338 patients who were eligible for the study, 65 had hyperoxia before rewarming. Patients with hyperoxia had a higher 28-day mortality rate than those without (25 (39.1%) vs. 51 (19.5%); odds ratio (OR) 2.65 (95% confidence interval 1.47-4.78); p < 0.001). IPW analyses with propensity scores revealed similar results (adjusted OR 1.65 (1.14-2.38); p = 0.008). Subgroup analyses showed that hyperoxia was harmful in the elderly and those with cardiopulmonary diseases and severe hypothermia below 28 °C, whereas hyperoxia exposure had no effect on mortality in patients with hemodynamic instability on hospital arrival. CONCLUSIONS: Hyperoxia with PaO2 levels of 300 mmHg or higher before initiating rewarming was associated with increased 28-day mortality in patients with accidental hypothermia. The amount of oxygen to administer to patients with accidental hypothermia should be carefully determined. TRIAL REGISTRATION: The ICE-CRASH study was registered at the University Hospital Medical Information Network Clinical Trial Registry on April 1, 2019 (UMIN-CTR ID, UMIN000036132).

Effect of low-to-moderate hyperoxia on lung injury in preclinical animal models: a systematic review and meta-analysis.

BACKGROUND: Extensive animal investigation informed clinical practice regarding the harmful effects of high fractional inspired oxygen concentrations (FiO2s > 0.60). Since questions persist whether lower but still supraphysiologic FiO2 ≤ 0.60 and > 0.21 (FiO2 ≤ 0.60/ > 0.21) are also harmful with inflammatory lung injury in patients, we performed a systematic review examining this question in animal models. METHODS: Studies retrieved from systematic literature searches of three databases, that compared the effects of exposure to FiO2 ≤ 0.60/ > 0.21 vs. FiO2 = 0.21 for ≥ 24 h in adult in vivo animal models including an inflammatory challenge or not were analyzed. Survival, body weight and/or lung injury measures were included in meta-analysis if reported in ≥ 3 studies. RESULTS: More than 600 retrieved reports investigated only FiO2s > 0.60 and were not analyzed. Ten studies with an inflammatory challenge (6 infectious and 4 noninfectious) and 14 studies without, investigated FiO2s ≤ 0.60/ > 0.21 and were analyzed separately. In seven studies with an inflammatory challenge, compared to FiO2 = 0.21, FiO2 ≤ 0.60/ > 0.21 had consistent effects across animal types on the overall odds ratio of survival (95%CI) that was on the side of harm but not significant [0.68 (0.38,1.23), p = 0.21; I2 = 0%, p = 0.57]. However, oxygen exposure times were only 1d in 4 studies and 2-4d in another. In a trend approaching significance, FiO2 ≤ 0.60/ > 0.21 with an inflammatory challenge consistently increased the standardized mean difference (95%CI) (SMD) in lung weights [0.47 (- 0.07,1.00), p = 0.09; I2 = 0%, p = 0.50; n = 4 studies] but had inconsistent effects on lung lavage protein concentrations (n = 3), lung pathology scores (n = 4) and/or arterial oxygenation (n = 4) (I2 ≥ 43%, p ≤ 0.17). Studies without an inflammatory challenge had consistent effects on lung lavage protein concentration (n = 3) SMDs on the side of being increased that was not significant [0.43 (- 0.23,1.09), p = 0.20; I2 = 0%, p = 0.40] but had inconsistent effects on body and lung weights (n = 6 and 8 studies, respectively) (I2 ≥ 71%, p < 0.01). Quality of evidence for studies was weak. INTERPRETATION: Limited animal studies have investigated FiO2 ≤ 0.60/ > 0.21 with clinically relevant models and endpoints but suggest even these lower FiO2s may be injurious. Given the influence animal studies examining FiO2 > 0.60 have had on clinical practice, additional ones investigating FiO2 ≤ 0.60/ > 0.21 appear warranted, particularly in pneumonia models.

Analysis of Volatile Organic Compounds in Exhaled Breath Following a COMEX-30 Treatment Table.

The COMEX-30 hyperbaric treatment table is used to manage decompression sickness in divers but may result in pulmonary oxygen toxicity (POT). Volatile organic compounds (VOCs) in exhaled breath are early markers of hyperoxic stress that may be linked to POT. The present study assessed whether VOCs following COMEX-30 treatment are early markers of hyperoxic stress and/or POT in ten healthy, nonsmoking volunteers. Because more oxygen is inhaled during COMEX-30 treatment than with other treatment tables, this study hypothesized that VOCs exhaled following COMEX-30 treatment are indicators of POT. Breath samples were collected before and 0.5, 2, and 4 h after COMEX-30 treatment. All subjects were followed-up for signs of POT or other symptoms. Nine compounds were identified, with four (nonanal, decanal, ethyl acetate, and tridecane) increasing 33-500% in intensity from before to after COMEX-30 treatment. Seven subjects reported pulmonary symptoms, five reported out-of-proportion tiredness and transient ear fullness, and four had signs of mild dehydration. All VOCs identified following COMEX-30 treatment have been associated with inflammatory responses or pulmonary diseases, such as asthma or lung cancer. Because most subjects reported transient pulmonary symptoms reflecting early-stage POT, the identified VOCs are likely markers of POT, not just hyperbaric hyperoxic exposure.

The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1.

Superoxide dismutase-1 is a ubiquitously expressed antioxidant enzyme. Mutations in SOD1 can cause amyotrophic lateral sclerosis, probably via a toxic gain-of-function involving protein aggregation and prion-like mechanisms. Recently, homozygosity for loss-of-function mutations in SOD1 has been reported in patients presenting with infantile-onset motor neuron disease. We explored the bodily effects of superoxide dismutase-1 enzymatic deficiency in eight children homozygous for the p.C112Wfs*11 truncating mutation. In addition to physical and imaging examinations, we collected blood, urine and skin fibroblast samples. We used a comprehensive panel of clinically established analyses to assess organ function and analysed oxidative stress markers, antioxidant compounds, and the characteristics of the mutant Superoxide dismutase-1. From around 8 months of age, all patients exhibited progressive signs of both upper and lower motor neuron dysfunction, cerebellar, brain stem, and frontal lobe atrophy and elevated plasma neurofilament concentration indicating ongoing axonal damage. The disease progression seemed to slow down over the following years. The p.C112Wfs*11 gene product is unstable, rapidly degraded and no aggregates were found in fibroblast. Most laboratory tests indicated normal organ integrity and only a few modest deviations were found. The patients displayed anaemia with shortened survival of erythrocytes containing decreased levels of reduced glutathione. A variety of other antioxidants and oxidant damage markers were within normal range. In conclusion, non-neuronal organs in humans show a remarkable tolerance to absence of Superoxide dismutase-1 enzymatic activity. The study highlights the enigmatic specific vulnerability of the motor system to both gain-of-function mutations in SOD1 and loss of the enzyme as in the here depicted infantile superoxide dismutase-1 deficiency syndrome.

Oxygen toxicity: cellular mechanisms in normobaric hyperoxia.

In clinical settings, oxygen therapy is administered to preterm neonates and to adults with acute and chronic conditions such as COVID-19, pulmonary fibrosis, sepsis, cardiac arrest, carbon monoxide poisoning, and acute heart failure. In non-clinical settings, divers and astronauts may also receive supplemental oxygen. In addition, under current standard cell culture practices, cells are maintained in atmospheric oxygen, which is several times higher than what most cells experience in vivo. In all the above scenarios, the elevated oxygen levels (hyperoxia) can lead to increased production of reactive oxygen species from mitochondria, NADPH oxidases, and other sources. This can cause cell dysfunction or death. Acute hyperoxia injury impairs various cellular functions, manifesting ultimately as physiological deficits. Chronic hyperoxia, particularly in the neonate, can disrupt development, leading to permanent deficiencies. In this review, we discuss the cellular activities and pathways affected by hyperoxia, as well as strategies that have been developed to ameliorate injury. • Hyperoxia promotes overproduction of reactive oxygen species (ROS). • Hyperoxia dysregulates a variety of signaling pathways, such as the Nrf2, NF-κB and MAPK pathways. • Hyperoxia causes cell death by multiple pathways. • Antioxidants, particularly, mitochondria-targeted antioxidants, have shown promising results as therapeutic agents against oxygen toxicity in animal models.

Practice of oxygen use in anesthesiology - a survey of the European Society of Anaesthesiology and Intensive Care.

BACKGROUND: Oxygen is one of the most commonly used drugs by anesthesiologists. The World Health Organization (WHO) gave recommendations regarding perioperative oxygen administration, but the practice of oxygen use in anesthesia, critical emergency, and intensive care medicine remains unclear. METHODS: We conducted an online survey among members of the European Society of Anaesthesiology and Intensive Care (ESAIC). The questionnaire consisted of 46 queries appraising the perioperative period, emergency medicine and in the intensive care, knowledge about current recommendations by the WHO, oxygen toxicity, and devices for supplemental oxygen therapy. RESULTS: Seven hundred ninety-eight ESAIC members (2.1% of all ESAIC members) completed the survey. Most respondents were board-certified and worked in hospitals with > 500 beds. The majority affirmed that they do not use specific protocols for oxygen administration. WHO recommendations are unknown to 42% of respondents, known but not followed by 14%, and known and followed by 24% of them. Respondents prefer inspiratory oxygen fraction (FiO2) ≥80% during induction and emergence from anesthesia, but intraoperatively < 60% for maintenance, and higher FiO2 in patients with diseased than non-diseased lungs. Postoperative oxygen therapy is prescribed more commonly according to peripheral oxygen saturation (SpO2), but shortage of devices still limits monitoring. When monitoring is used, SpO2 ≤ 95% is often targeted. In critical emergency medicine, oxygen is used frequently in patients aged ≥80 years, or presenting with respiratory distress, chronic obstructive pulmonary disease, myocardial infarction, and stroke. In the intensive care unit, oxygen is mostly targeted at 96%, especially in patients with pulmonary diseases. CONCLUSIONS: The current practice of perioperative oxygen therapy among respondents does not follow WHO recommendations or current evidence, and access to postoperative monitoring devices impairs the individualization of oxygen therapy. Further research and additional teaching about use of oxygen are necessary.