Mild Hyperoxia Research Articles

Short-term hyperoxia-induced functional and morphological changes in rat hippocampus.

Excess oxygen (O2) levels may have a stimulating effect, but in the long term, and at high concentrations of O2, it is harmful to the nervous system. The hippocampus is very sensitive to pathophysiological changes and altered O2 concentrations can interfere with hippocampus-dependent learning and memory functions. In this study, we investigated the hyperoxia-induced changes in the rat hippocampus to evaluate the short-term effect of mild and severe hyperoxia. Wistar male rats were randomly divided into control (21% O2), mild hyperoxia (30% O2), and severe hyperoxia groups (100% O2). The O2 exposure lasted for 60 min. Multi-channel silicon probes were used to study network oscillations and firing properties of hippocampal putative inhibitory and excitatory neurons. Neural damage was assessed using the Gallyas silver impregnation method. Mild hyperoxia (30% O2) led to the formation of moderate numbers of silver-impregnated "dark" neurons in the hippocampus. On the other hand, exposure to 100% O2 was associated with a significant increase in the number of "dark" neurons located mostly in the hilus. The peak frequency of the delta oscillation decreased significantly in both mild and severe hyperoxia in urethane anesthetized rats. Compared to normoxia, the firing activity of pyramidal neurons under hyperoxia increased while it was more heterogeneous in putative interneurons in the cornu ammonis area 1 (CA1) and area 3 (CA3). These results indicate that short-term hyperoxia can change the firing properties of hippocampal neurons and network oscillations and damage neurons. Therefore, the use of elevated O2 concentration inhalation in hospitals (i.e., COVID treatment and surgery) and in various non-medical scenarios (i.e., airplane emergency O2 masks, fire-fighters, and high altitude trekkers) must be used with extreme caution.

Testing the Resilience, Physiological Plasticity and Mechanisms Underlying Upper Temperature Limits of Antarctic Marine Ectotherms.

Antarctic marine ectotherms live in the constant cold and are characterised by limited resilience to elevated temperature. Here we tested three of the central paradigms underlying this resilience. Firstly, we assessed the ability of eight species, from seven classes representing a range of functional groups, to survive, for 100 to 303 days, at temperatures 0 to 4 °C above previously calculated long-term temperature limits. Survivors were then tested for acclimation responses to acute warming and acclimatisation, in the field, was tested in the seastar Odontaster validus collected in different years, seasons and locations within Antarctica. Finally, we tested the importance of oxygen limitation in controlling upper thermal limits. We found that four of 11 species studied were able to survive for more than 245 days (245-303 days) at higher than previously recorded temperatures, between 6 and 10 °C. Only survivors of the anemone Urticinopsis antarctica did not acclimate CTmax and there was no evidence of acclimatisation in O. validus. We found species-specific effects of mild hyperoxia (30% oxygen) on survival duration, which was extended (two species), not changed (four species) or reduced (one species), re-enforcing that oxygen limitation is not universal in dictating thermal survival thresholds. Thermal sensitivity is clearly the product of multiple ecological and physiological capacities, and this diversity of response needs further investigation and interpretation to improve our ability to predict future patterns of biodiversity.

Pulsed Hyperoxia Acts on Plasmatic Advanced Glycation End Products and Advanced Oxidation Protein Products and Modulates Mitochondrial Biogenesis in Human Peripheral Blood Mononuclear Cells: A Pilot Study on the "Normobaric Oxygen Paradox".

The "normobaric oxygen paradox" (NOP) describes the response to the return to normoxia after a hyperoxic event, sensed by tissues as an oxygen shortage, up-regulating redox-sensitive transcription factors. We have previously characterized the time trend of oxygen-sensitive transcription factors in human PBMCs, in which the return to normoxia after 30% oxygen is sensed as a hypoxic trigger, characterized by hypoxia-induced factor (HIF-1) activation. On the contrary, 100% and 140% oxygen induce a shift toward an oxidative stress response, characterized by NRF2 and NF-kB activation in the first 24 h post exposure. Herein, we investigate whether this paradigm triggers Advanced Glycation End products (AGEs) and Advanced Oxidation Protein Products (AOPPs) as circulating biomarkers of oxidative stress. Secondly, we studied if mitochondrial biogenesis was involved to link the cellular response to oxidative stress in human PBMCs. Our results show that AGEs and AOPPs increase in a different manner according to oxygen dose. Mitochondrial levels of peroxiredoxin (PRX3) supported the cellular response to oxidative stress and increased at 24 h after mild hyperoxia, MH (30% O2), and high hyperoxia, HH (100% O2), while during very high hyperoxia, VHH (140% O2), the activation was significantly high only at 3 h after oxygen exposure. Mitochondrial biogenesis was activated through nuclear translocation of PGC-1α in all the experimental conditions. However, the consequent release of nuclear Mitochondrial Transcription Factor A (TFAM) was observed only after MH exposure. Conversely, HH and VHH are associated with a progressive loss of NOP response in the ability to induce TFAM expression despite a nuclear translocation of PGC-1α also occurring in these conditions. This study confirms that pulsed high oxygen treatment elicits specific cellular responses, according to its partial pressure and time of administration, and further emphasizes the importance of targeting the use of oxygen to activate specific effects on the whole organism.

Determining the effects of elevated partial pressure of oxygen on hypercapnia-induced cerebrovascular reactivity

Evaluation of cerebrovascular reactivity (CVR) to hypo- and hypercapnia is a valuable test for the assessment of vasodilatory reserve. While hypercapnia-induced CVR testing is usually performed at normoxia, mild hyperoxia may increase tolerability of hypercapnia by reducing the ventilatory distress. However, the effects of mild hyperoxia on CVR was unknown. We therefore recruited 21 patients with a range of steno-occlusive diseases and 12 healthy participants who underwent a standardized 13-minute step plus ramp CVR test with a carbon dioxide gas challenge at the subject’s resting end-tidal partial pressure of oxygen or at mild hyperoxia (PetO2 = 150 mmHg) depending on to which group they were assigned. In 11 patients, the second CVR test was at normoxia to examine test-retest differences. CVR was defined as % Δ Signal/ΔPetCO2. We found that there was no significant difference between CVR test results conducted at normoxia and at mild hyperoxia for participants in Groups 1 and 2 for the step and ramp portion. We also found no difference between test and retest CVR at normoxia for patients with cerebrovascular pathology (Group 3) for step and ramp portion. We concluded normoxic CVR is repeatable, and that mild hyperoxia does not affect CVR.

Exposure to Arterial Hyperoxia During Extracorporeal Membrane Oxygenator Support and Mortality in Patients With Cardiogenic Shock.

Exposure to hyperoxia, a high arterial partial pressure of oxygen (PaO2), may be associated with worse outcomes in patients receiving extracorporeal membrane oxygenator (ECMO) support. We examined hyperoxia in the Extracorporeal Life Support Organization Registry among patients receiving venoarterial ECMO for cardiogenic shock. We included Extracorporeal Life Support Organization Registry patients from 2010 to 2020 who received venoarterial ECMO for cardiogenic shock, excluding extracorporeal CPR. Patients were grouped based on PaO2 after 24 hours of ECMO: normoxia (PaO2 60-150 mmHg), mild hyperoxia (PaO2 151-300 mmHg), and severe hyperoxia (PaO2 >300 mmHg). In-hospital mortality was evaluated using multivariable logistic regression. Among 9959 patients, 3005 (30.2%) patients had mild hyperoxia and 1972 (19.8%) had severe hyperoxia. In-hospital mortality increased across groups: normoxia, 47.8%; mild hyperoxia, 55.6% (adjusted odds ratio, 1.37 [95% CI, 1.23-1.53]; P<0.001); severe hyperoxia, 65.4% (adjusted odds ratio, 2.20 [95% CI, 1.92-2.52]; P<0.001). A higher PaO2 was incrementally associated with increased in-hospital mortality (adjusted odds ratio, 1.14 per 50 mmHg higher [95% CI, 1.12-1.16]; P<0.001). Patients with a higher PaO2 had increased in-hospital mortality in each subgroup and when stratified by ventilator settings, airway pressures, acid-base status, and other clinical variables. In the random forest model, PaO2 was the second strongest predictor of in-hospital mortality, after older age. Exposure to hyperoxia during venoarterial ECMO support for cardiogenic shock is strongly associated with increased in-hospital mortality, independent from hemodynamic and ventilatory status. Until clinical trial data are available, we suggest targeting a normal PaO2 and avoiding hyperoxia in CS patients receiving venoarterial ECMO.

Differential regional cerebrovascular reactivity to end-tidal gas combinations commonly seen during anaesthesia: A blood oxygenation level-dependent MRI observational study in awake adult subjects.

Regional cerebrovascular reactivity (rCVR) is highly variable in the human brain as measured by blood oxygenation level-dependent (BOLD) MRI to changes in both end-tidal CO 2 and O 2 . We examined awake participants under carefully controlled end-tidal gas concentrations to assess how regional CVR changes may present with end-tidal gas changes seen commonly with anaesthesia. Observational study. Tertiary care centre, Winnipeg, Canada. The imaging for the study occurred in 2019. Twelve healthy adult subjects. Cerebral BOLD response was studied under two end-tidal gas paradigms. First end-tidal oxygen (ETO 2 ) maintained stable whereas ETCO 2 increased incrementally from hypocapnia to hypercapnia (CO 2 ramp); second ETCO 2 maintained stable whereas ETO 2 increased from normoxia to hyperoxia (O 2 ramp). BOLD images were modeled with end-tidal gas sequences split into two equal segments to examine regional CVR. The voxel distribution comparing hypocapnia to mild hypercapnia and mild hyperoxia (mean F I O 2 = 0.3) to marked hyperoxia (mean F I O 2 = 0.7) were compared in a paired fashion ( P < 0.005 to reach threshold for voxel display). Additionally, type analysis was conducted on CO 2 ramp data. This stratifies the BOLD response to the CO 2 ramp into four categories of CVR slope based on segmentation (type A; +/+slope: normal response, type B +/-, type C -/-: intracranial steal, type D -/+.) Types B to D represent altered responses to the CO 2 stimulus. Differential regional responsiveness was seen for both end-tidal gases. Hypocapnic regional CVR was more marked than hypercapnic CVR in 0.3% of voxels examined ( P < 0.005, paired comparison); the converse occurred in 2.3% of voxels. For O 2 , mild hyperoxia had more marked CVR in 0.2% of voxels compared with greater hyperoxia; the converse occurred in 0.5% of voxels. All subjects had altered regional CO 2 response based on Type Analysis ranging from 4 ± 2 to 7 ± 3% of voxels. In awake subjects, regional differences and abnormalities in CVR were observed with changes in end-tidal gases common during the conduct of anaesthesia. On the basis of these findings, consideration could be given to minimising regional CVR fluctuations in patients-at-risk of neurological complications by tighter control of end-tidal gases near the individual's resting values.

Intraoperative mild hyperoxia may be associated with improved survival after off-pump coronary artery bypass grafting: a retrospective observational study

BackgroundThe effect of hyperoxia due to supplemental oxygen administration on postoperative outcomes in patients undergoing cardiac surgery remains unclear. This retrospective study aimed to evaluate the relationship between intraoperative oxygen tension and mortality after off-pump coronary artery bypass grafting (OPCAB).MethodsThe study included adult patients who underwent isolated OPCAB between July 2010 and June 2020. Patients were categorised into three groups based on their intraoperative time-weighted average arterial oxygen partial pressure (PaO2): normoxia/near-normoxia (< 150 mmHg), mild hyperoxia (150–250 mmHg), and severe hyperoxia (> 250 mmHg). The risk of in-hospital mortality was compared using weighted logistic regression analysis. Restricted cubic spline analysis was performed to analyse intraoperative PaO2 as a continuous variable. The risk of cumulative all-cause mortality was compared using Cox regression analysis.ResultsThe normoxia/near-normoxia, mild hyperoxia, and severe hyperoxia groups included 229, 991, and 173 patients (n = 1393), respectively. The mild hyperoxia group had a significantly lower risk of in-hospital mortality than the normoxia/near-normoxia (odds ratio [OR], 0.12; 95% confidence interval [CI], 0.06–0.22) and severe hyperoxia groups (OR, 0.06; 95% CI, 0.03–0.14). Intraoperative PaO2 exhibited a U-shaped relationship with in-hospital mortality in the non-hypoxic range. The risk of cumulative all-cause mortality was significantly lower in the mild hyperoxia group (hazard ratio, 0.72; 95% CI, 0.52–0.99) than in the normoxia/near-normoxia group.ConclusionsMaintaining intraoperative PaO2 at 150–250 mmHg was associated with a lower risk of mortality after OPCAB than PaO2 at < 150 mmHg and at > 250 mmHg. Future randomised trials are required to confirm if mildly increasing arterial oxygen tension during OPCAB to 150–250 mmHg improves postoperative outcomes.

IV ASCORBATE REDUCTION OF ARDS MORTALITY IS CONTINGENT AND DOSE-DEPENDENT WITH THE DEGREE OF HYPEROXIC SUPPORT

TYPE: Late Breaking Abstract TOPIC: Critical Care PURPOSE: Several randomized trials have failed to demonstrate a mortality benefit of high-dose intravenous ascorbate (vitamin C) in patients with sepsis. Recent ex-vivo human lung experiments have revealed that ascorbate acts directly on lung endothelium in hyperoxic conditions. We hypothesized that similar effects may have occurred in CITRIS-ALI trial patients, a double-blind randomized controlled trial of high-dose intravenous vitamin C in patients with ARDS. METHODS: CITRIS-ALI patients were classified, post-hoc, into three groups: Low, moderate, and severe hyperoxia based upon FiO2 < 50%, 50-80%, and ≥ 80% respectively. Logistic regression analysis was applied to evaluate the statistical interactions between hyperoxic groups and 28-day mortality and marginal analysis was performed. RESULTS: Severe hyperoxia support significantly interacted with vitamin C administration instead of placebo (p<0.001). Patients with mild hyperoxia had mortality 30% (95% CI 13.6–46.4%) and 42.4% (95% CI 25.6–59.3) for placebo and vitamin C arms respectively, p=0.3. Moderate hyperoxia groups exhibited mortality of 41.4% (95% CI 23.5 – 59.3%) and 26.7% (95% CI10.8–42.5) for placebo and vitamin C arms, p=0.2. The highest degree of hyperoxia group had mortality 74% (95% CI 56–92%) and 14.3% (95% CI 0–29.3%) for placebo and vitamin C arms, p<0.001. CONCLUSIONS: These findings suggest that high-dose intravenous vitamin C reduction of ARDS mortality is significantly linked to the degree of hyperoxia required for support, being most significant in patients who require the highest levels of hyperoxia. CLINICAL IMPLICATIONS: These findings explain the heterogeneity of outcomes in vitamin C sepsis trials in contrast to CITRIS-ALI and could guide the design of future clinical trials. DISCLOSURE: Nothing to declare. KEYWORD: Hyperoxia

Hyperoxia Is Not Associated With 30-day Survival in Out-of-Hospital Cardiac Arrest Patients Who Undergo Extracorporeal Cardiopulmonary Resuscitation.

IntroductionThe appropriate arterial partial pressure of oxygen (PaO2) in patients undergoing extracorporeal cardiopulmonary resuscitation (ECPR) for out-of-hospital cardiac arrest (OHCA) remains unclear. The present study aimed to investigate the relationship between hyperoxia and 30-day survival in patients who underwent ECPR.Materials and MethodsThis single-center retrospective cohort study was conducted between January 2010 and December 2018. OHCA patients who underwent ECPR were included in the study. Exclusion criteria were (1) age <18 years, (2) death within 24 h after admission, (3) return of spontaneous circulation at hospital arrival, and (4) hypoxia (PaO2 < 60 mmHg) 24 h after admission. Based on PaO2 at 24 h after admission, patients were classified into normoxia (60 mmHg ≤ PaO2 ≤ 100 mmHg), mild hyperoxia (100 mmHg < PaO2 ≤ 200 mmHg), and severe hyperoxia (PaO2 > 200 mmHg) groups. The primary outcome was 30-day survival after cardiac arrest, while the secondary outcome was 30-day favorable neurological outcome. Multivariate logistic regression analysis for 30-day survival or 30-day favorable neurological outcome was performed using multiple propensity scores as explanatory variables. To estimate the multiple propensity score, we fitted a multinomial logistic regression model using the patients' demographic, pre-hospital, and in-hospital characteristics.ResultsOf the patients who underwent ECPR in the study center, 110 were eligible for the study. The normoxia group included 29 cases, mild hyperoxia group included 46 cases, and severe hyperoxia group included 35 cases. Mild hyperoxia was not significantly associated with survival, compared with normoxia as the reference (adjusted odds ratio, 1.06; 95% confidence interval: 0.30–3.68; p = 0.93). Severe hyperoxia was also not significantly associated with survival compared to normoxia (adjusted odds ratio, 1.05; 95% confidence interval: 0.27–4.12; p = 0.94). Furthermore, no association was observed between oxygenation and 30-day favorable neurological outcomes.ConclusionsThere was no significant association between hyperoxia at 24 h after admission and 30-day survival in OHCA patients who underwent ECPR.

Effects of chronic mild hyperoxia on retinal and choroidal blood flow and retinal function in the DBA/2J mouse model of glaucoma.

PurposeTo test the hypothesis that mild chronic hyperoxia treatment would improve retinal function despite a progressive decline in ocular blood flow in the DBA/2J mouse model of glaucoma.Materials and methodsDBA/2J mice were treated with chronic mild hyperoxia (30% O2) beginning at 4.5 months of age or were untreated by giving normal room air. Retinal and choroidal blood flow (RBF and ChBF, respectively) were measured at 4, 6, and 9 months of age by MRI. Blood flow was additionally measured under hypercapnia challenge (5% CO2 inhalation) to assess vascular reactivity. Intraocular pressure (IOP) was measured using a rebound tonometer at the same time points. Scotopic flash electroretinograms (ERGs) were recorded at 9 months of age.ResultsBoth ChBF and RBF were reduced and significantly affected by age (p < 0.01), but neither were significantly affected by O2-treatment (p > 0.05). ChBF significantly increased in response to hypercapnia (p < 0.01), which was also unaffected by O2-treatment. Significant effects of age (p < 0.001) and of the interaction of age with treatment (p = 0.028) were found on IOP. IOP significantly decreased in O2-treated mice at 6 months compared to 4 months of age (p < 0.001), while IOP trended to increase with age in untreated mice. The amplitude of the b-wave from ERG was significantly increased in O2-treated DBA/2J compared to the untreated mice (p = 0.012), while the a-wave and oscillatory potentials were not significantly affected (p > 0.05).ConclusionThis study investigated the effects of chronic mild hyperoxia on retinal function and on retinal and choroidal blood flow in a mouse model of glaucoma. Retinal function was improved in the O2-treated mice at late stage, despite a progressive decline of RBF and ChBF with age that was comparable to untreated mice.

Incidence of hyperoxia in trauma patients receiving pre-hospital emergency anaesthesia: results of a 5-year retrospective analysis

BackgroundPrevious studies have demonstrated an association between hyperoxia and increased mortality in various patient groups. Critically unwell and injured patients are routinely given high concentration oxygen in the pre-hospital phase of care. We aim to investigate the incidence of hyperoxia in major trauma patients receiving pre-hospital emergency anesthesia (PHEA) in the pre-hospital setting and determine factors that may help guide clinicians with pre-hospital oxygen administration in these patients.MethodsA retrospective cohort study was performed of all patients who received PHEA by a single helicopter emergency medical service (HEMS) between 1 October 2014 and 1 May 2019 and who were subsequently transferred to one major trauma centre (MTC). Patient and treatment factors were collected from the electronic patient records of the HEMS service and the MTC. Hyperoxia was defined as a PaO2 > 16 kPA on the first arterial blood gas analysis upon arrival in the MTC.ResultsOn arrival in the MTC, the majority of the patients (90/147, 61.2%) had severe hyperoxia, whereas 30 patients (20.4%) had mild hyperoxia and 26 patients (19.7%) had normoxia. Only 1 patient (0.7%) had hypoxia. The median PaO2 on the first arterial blood gas analysis (ABGA) after HEMS handover was 36.7 [IQR 18.5–52.2] kPa, with a range of 7.0–86.0 kPa. SpO2 pulse oximetry readings before handover were independently associated with the presence of hyperoxia. An SpO2 ≥ 97% was associated with a significantly increased odds of hyperoxia (OR 3.99 [1.58–10.08]), and had a sensitivity of 86.7% [79.1–92.4], a specificity of 37.9% [20.7–57.8], a positive predictive value of 84.5% [70.2–87.9] and a negative predictive value of 42.3% [27.4–58.7] for the presence of hyperoxemia.ConclusionTrauma patients who have undergone PHEA often have profound hyperoxemia upon arrival at hospital. In the pre-hospital setting, where arterial blood gas analysis is not readily available a titrated approach to oxygen therapy should be considered to reduce the incidence of potentially harmful tissue hyperoxia.

Association Between Oxygen Partial Pressure Trajectories and Short-Term Outcomes in Patients With Hemorrhagic Brain Injury.

Objectives: Arterial hyperoxia is reportedly a risk factor for poor outcomes in patients with hemorrhagic brain injury (HBI). However, most previous studies have only evaluated the effects of hyperoxia using static oxygen partial pressure (PaO2) values. This study aimed to investigate the association between overall dynamic oxygenation status and HBI outcomes, using longitudinal PaO2 data.Methods: Data were extracted from the Medical Information Mart for Intensive Care III database. Longitudinal PaO2 data obtained within 72 h of admission to an intensive care unit were analyzed, using a group-based trajectory approach. In-hospital mortality was used as the primary outcomes. Multivariable logistic models were used to explore the association between PaO2 trajectory and outcomes.Results: Data of 2,028 patients with HBI were analyzed. Three PaO2 trajectory types were identified: Traj-1 (mild hyperoxia), Traj-2 (transient severe hyperoxia), and Traj-3 (persistent severe hyperoxia). The initial and maximum PaO2 of patients with Traj-2 and Traj-3 were similar and significantly higher than those of patients with Traj-1. However, PaO2 in patients with Traj-2 decreased more rapidly than in patients with Traj-3. The crude in-hospital mortality was the lowest for patients with Traj-1 and highest for patients with Traj-3 (365/1,303, 209/640, and 43/85 for Traj-1, Traj-2, and Traj-3, respectively; p < 0.001), and the mean Glasgow Coma Scale score at discharge (GCSdis) was highest for patients with Traj-1 and lowest in patients with Traj-3 (13 [7–15], 11 [6–15], and 7 [3–14] for Traj-1, Traj-2, and Traj-3, respectively; p < 0.001). The multivariable model revealed that the risk of death was higher in patients with Traj-3 than in patients with Traj-1 (odds ratio [OR]: 3.3, 95% confidence interval [CI]: 1.9–5.8) but similar for patients with Traj-1 and Traj-2. Similarly, the logistic analysis indicated the worst neurological outcomes in patients with Traj-3 (OR: 3.6, 95% CI: 2.0–6.4, relative to Traj-1), but similar neurological outcomes for patients in Traj-1 and Traj-2.Conclusion: Persistent, but not transient severe arterial hyperoxia, was associated with poor outcome in patients with HBI.

Duration of Hyperoxia and Neurologic Outcomes in Patients Undergoing Extracorporeal Membrane Oxygenation.

To evaluate the impact of duration of hyperoxia on neurologic outcome and mortality in patients undergoing venoarterial extracorporeal membrane oxygenation. A retrospective analysis of venoarterial extracorporeal membrane oxygenation patients admitted to the Johns Hopkins Hospital. The primary outcome was neurologic function at discharge defined by modified Rankin Scale, with a score of 0-3 defined as a good neurologic outcome, and a score of 4-6 defined as a poor neurologic outcome. Multivariable logistic regression analysis was performed to evaluate the association between hyperoxia and neurologic outcomes. The Johns Hopkins Hospital Cardiovascular ICU and Cardiac Critical Care Unit. None. We measured first and maximum Pao2 values, area under the curve per minute over the first 24 hours, and duration of mild, moderate, and severe hyperoxia. Of 132 patients on venoarterial extracorporeal membrane oxygenation, 127 (96.5%) were exposed to mild hyperoxia in the first 24 hours. Poor neurologic outcomes were observed in 105 patients (79.6%) (102 with vs 3 without hyperoxia; p = 0.14). Patients with poor neurologic outcomes had longer exposure to mild (19.1 vs 15.2 hr; p = 0.01), moderate (14.6 vs 9.2 hr; p = 0.003), and severe hyperoxia (9.1 vs 4.0 hr; p = 0.003). In a multivariable analysis, patients with worse neurologic outcome experienced longer durations of mild (adjusted odds ratio, 1.10; 95% CI, 1.01-1.19; p = 0.02), moderate (adjusted odds ratio, 1.12; 95% CI, 1.04-1.22; p = 0.002), and severe (adjusted odds ratio, 1.19; 95% CI, 1.06-1.35; p = 0.003) hyperoxia. Additionally, duration of severe hyperoxia was independently associated with inhospital mortality (adjusted odds ratio, 1.18; 95% CI, 1.08-1.29; p < 0.001). In patients undergoing venoarterial extracorporeal membrane oxygenation, duration and severity of early hyperoxia were independently associated with poor neurologic outcomes at discharge and mortality.

Gestational intermittent hyperoxia rescues murine genetic congenital heart disease in part

Cardiac development is a dynamic process, temporally and spatially. When disturbed, it leads to congenital cardiac anomalies that affect approximately 1% of live births. Genetic variants in several loci lead to anomalies, with the transcription factor NKX2-5 being one of the largest. However, there are also non-genetic factors that influence cardiac malformations. We examined the hypothesis that hyperoxia may be beneficial and can rescue genetic cardiac anomalies induced by an Nkx2-5 mutation. Intermittent mild hyperoxia (40% PO2) was applied for 10 h per day to normal wild-type female mice mated with heterozygous Nkx2-5 mutant males from gestational day 8.5 to birth. Hyperoxia therapy reduced excessive trabeculation in Nkx2-5 mutant mice compared to normoxic conditions (ratio of trabecular layer relative to compact layer area, normoxia 1.84 ± 0.07 vs. hyperoxia 1.51 ± 0.04) and frequency of muscular ventricular septal defects per heart (1.53 ± 0.32 vs. 0.68 ± 0.15); however, the incidence of membranous ventricular septal defects in Nkx2-5 mutant hearts was not changed. Nkx2-5 mutant embryonic hearts showed defective coronary vessel organization, which was improved by intermittent mild hyperoxia. The results of our study showed that mild gestational hyperoxia therapy rescued genetic cardiac malformation induced by Nkx2-5 mutation in part.

Oxygen therapy in emergency and intensive care medicine

Oxygen treatment is being widely used in intensive care and emergency medicine and is required to maintain aerobic metabolism. It may be administered by nasal cannula, face mask, high-flow therapy, and by ventilation. Under clinical circumstances, blood oxygen concentration is not relevantly increased above a partial pressure of 80 mmHg. Although oxygen therapy is often life-saving, it has recently been shown that its indiscriminate administration may increase morbidity and mortality, presumably due to a formation of reactive-oxygen species.For ventilated critically ill patients the optimal targets need to be further defined but harm has been shown for mild hyperoxia. For patients with acute exacerbation of chronic obstructive lung disease hyperoxia may lead to an increase of hypercarbia. Hyperoxia may increase myocardial necrosis in myocardial infarction. For patients with stroke, data do not show any benefit or harm from oxygen administration.On the other hand, hyperoxia shall be used for treatment in patients with cardiac arrest until return of spontaneous circulation and in patients with carbon monoxide poisoning.For other conditions, no benefit has been shown for hyperoxia, but undoubtedly, hypoxemia must be avoided, as well. Therefore, a normoxic oxygenation strategy should be employed. The optimal oxygenation targets for distinct conditions need to be further defined.

The effect of hyperoxia on inflammation and platelet responses in an ex vivo extracorporeal membrane oxygenation circuit.

Use of extracorporeal membrane oxygenation (ECMO) is expanding, however, it is still associated with significant morbidity and mortality. Activation of inflammatory and innate immune responses and hemostatic alterations contribute to complications. Hyperoxia may play a role in exacerbating these responses. Nine ex vivo ECMO circuits were tested using fresh healthy human whole blood, with two oxygen levels: 21% inspired fraction of oxygen (FiO2 ; mild hyperoxia; n=5) and 100% FiO2 (severe hyperoxia; n=4). Serial blood samples were taken for analysis of platelet aggregometry, leukocyte activation, inflammatory, and oxidative stress markers. ECMO resulted in reduced adenosine diphosphate- (P<.05) and thrombin receptor activating peptide-induced (P<.05) platelet aggregation, as well as increasing levels of the neutrophil activation marker, neutrophil elastase (P=.013). Additionally, levels of the inflammatory chemokine interleukin-8 were elevated (P<.05) and the activity of superoxide dismutase, a marker of oxidative stress, was increased (P=.002). Hyperoxia did not augment these responses, with no significant differences detected between mild and severe hyperoxia. Our ex vivo model of ECMO revealed that the circuit itself triggers a pro-inflammatory and oxidative stress response, however, exposure to supra-physiologic oxygen does not amplify that response. Extended-duration studies and inclusion of an endothelial component could be beneficial in characterizing longer term changes.

The Oxygen Mirror‐J‐Curve: Mild Hyperoxia and Mild Hypoxia Induce Beneficial Adaptations

BackgroundMirror‐J‐response, named based on the shape of dose response curve, claims that physiological agents of living organism (including humans) when they deviate mildly from the reference range produce beneficial effects (e.g. glucose, calcium and osmolality, etc). A higher degree of deviations of those same agents produces harmful effects.HypothesisBoth mild hyperoxia and mild hypoxia may induce a positive adaptive response. Could the mirror‐J be substantiated for oxygen?MethodsObjective of this study was to search for a support of hypothesis in the published data.ResultsBeneficial effects of mild hypoxia have been shown both on cells and whole organisms. Cellular response to hypoxia consists of gene transcription modification and metabolic adaptations. These effects translate to adaptations of whole organisms. Animal studies show improved outcomes in both healthy subjects and disease models when challenged with hypoxia. Studies on healthy human subjects were mainly focused on physical activity performance, but have also shown decrease in inflammatory cytokines and glucose resistance. Studies on patients mostly focused on cardiovascular and neurologic diseases and show improvement in cardiorespiratory fitness similar to physical exercise.Mild hyperoxia animal studies demonstrated that ischemia improved tolerance following hyperoxia in myocardium, brain and kidney. Human studies focus primarily on exercise performance in healthy subjects and cardiovascular and neurological pathology, same as hypoxia research. Mild hyperoxia during exercise promoted fat oxidation, reduced sugar oxidation, and delayed time to exhaustion. Hyperoxia preconditioning reduced risk of heart surgery. Also, following traumatic brain injury, periods of hyperoxia can normalize oxidative metabolism markers in brain long after return to normoxia.Conclusion/DiscussionHypoxia and hyperoxia are in antithesis, but their effects are surprisingly similar. Both were shown to precondition various tissues to ischemia and to improve cardiorespiratory fitness. These similarities invoke a usage of a similar mechanism of action, as suggested for disarrangements in calcium, glucose and osmolality. Indeed, it was shown that both, mild hypoxia and mild hyperoxia induce production of reactive oxygen species which induce cellular adaptive response. Furthermore, studies have shown that both hypoxia and hyperoxia activate hypoxia inducible factor and promote erythropoietin production. Taken together, this data supports single unified cellular response to tipping oxygen balance. Those responses follow the mirror‐J nonlinearity. These adaptive responses appear to function on cellular level and level of organism as a whole and may improve functioning in normoxia.

TURNING THE OXYGEN DIAL AS A THERAPY: HYPOXIA TREATMENT FOR MITOCHONDRIAL DYSFUNCTION

Mitochondrial disease affects 1 in 4800 live births, with little in the way of therapies. We found that chronic hypoxia extends the life of a Complex 1 disease model by 5-fold. Starting hypoxia therapy at a late-stage of disease can even reverse the MRI-detectable lesions. At the other extreme, mild hyperoxia greatly exacerbates disease and leads to death within several days. These findings have now led to a phase 1 clinical trial in healthy volunteers, with the ultimate goal of human translation. We believe we have identified a new mode of treatment that will be broadly applicable to different forms of mitochondrial dysfunction, ranging from rare inborn errors of metabolism to more common, age-associated pathologies. We believe that “turning the oxygen dial” to low or high oxygen will serve as a novel therapeutic for a range of conditions in the coming years.

Mild Hyperoxia Stimulation Increases Regional Tissue Oxygen Pressure in Rat Hippocampus via Oxygen Radical

Aims: The purpose of this study is to examine a rise of the local tissue oxygen pressure in hippocampus (Hip-pO2) which means neuronal activation by mild hyperoxia through oxygen radical.&#x0D; Study Design: Study was an animal experiment with rat.&#x0D; Place and Duration of Study: Department of Department of Life Science and Applied Chemistry, Nagaya Institute of Technology, between January 2014 and January 2018.&#x0D; Methodology: Rats were exposed to air or mild oxygen gas. At the same time, Local tissue oxygen pressure in hippocampus (Hip-pO2) were measured for 20 min with or without treatment of two type of radical scavengers.&#x0D; Results: The Hip-pO2 levels were significantly increased by mild hyperoxia exposure (50-60% above resting level). The mild hyperoxia-induced enhancement of the Hip-pO2 levels were inhibited by MnTMPyP (radical scavenger), but not by NADPH oxidase (NOX) inhibitor Apocynin.&#x0D; Conclusion: These findings suggested that mild hyperoxia could activate hippocampus through generation of oxygen radicals.

Early Hyperoxia in The Intensive Care Unit is Significantly Associated With Unfavorable Neurological Outcomes in Patients With Mild-to-Moderate Aneurysmal Subarachnoid Hemorrhage.

Although oxygen administration is fundamental in the management of aneurysmal subarachnoid hemorrhage (SAH) patients in the acute stage, hyperoxia has harmful effects. The effects of hyperoxia on neurological outcomes in SAH patients are unclear. We aimed to examine the association of hyperoxia during the first 24 h in the intensive care unit (ICU) with unfavorable neurological outcomes in SAH patients. We retrospectively selected consecutive adult patients admitted to ICU for SAH between January 2009 and April 2018. We defined normoxia during the first 24 h in ICU as PaO2 of 60 mm Hg to 120 mm Hg, mild hyperoxia as PaO2 of 121 mm Hg to 200 mm Hg, moderate hyperoxia as PaO2 of 201 mm Hg to 300 mm Hg, and severe hyperoxia as PaO2 of >300 mm Hg. Univariate and multivariate analyses were performed to examine the association between hyperoxia during the first 24 h in ICU and unfavorable neurological outcomes (i.e., modified Rankin scale score of 3-6 at hospital discharge). Among 196 SAH patients, 90 had unfavorable neurological outcomes. Hyperoxia was observed in 93.4% of patients. No significant association was observed between unfavorable neurological outcomes and hyperoxia in overall patients. However, we found that early hyperoxia in ICU was significantly associated with unfavorable neurological outcomes in SAH patients with Hunt and Kosnik (H&K) grades I to III (Relative risk, 1.84; 95% confidence interval, 1.10-2.94; P = 0.02). Early hyperoxia was not associated with unfavorable neurological outcomes in overall SAH patients, but it was associated with unfavorable neurological outcomes in those with H&K grades I to III.