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Hyperoxia and Antioxidants for Myocardial Injury in Noncardiac Surgery: A 2 × 2 Factorial, Blinded, Randomized Clinical Trial.
Holse, C, Aasvang, EK, Vester-Andersen, M, Rasmussen, LS, Wetterslev, J, Christensen, R, Jorgensen, LN, Pedersen, SS, Loft, FC, Troensegaard, H, et al
Anesthesiology. 2022;(3):408-419
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Abstract
BACKGROUND Hyperoxia and oxidative stress may be associated with increased risk of myocardial injury. The authors hypothesized that a perioperative inspiratory oxygen fraction of 0.80 versus 0.30 would increase the degree of myocardial injury within the first 3 days of surgery, and that an antioxidant intervention would reduce degree of myocardial injury versus placebo. METHODS A 2 × 2 factorial, randomized, blinded, multicenter trial enrolled patients older than 45 yr who had cardiovascular risk factors undergoing major noncardiac surgery. Factorial randomization allocated patients to one of two oxygen interventions from intubation and at 2 h after surgery, as well as antioxidant intervention or matching placebo. Antioxidants were 3 g IV vitamin C and 100 mg/kg N-acetylcysteine. The primary outcome was the degree of myocardial injury assessed by the area under the curve for high-sensitive troponin within the first 3 postoperative days. RESULTS The authors randomized 600 participants from April 2018 to January 2020 and analyzed 576 patients for the primary outcome. Baseline and intraoperative characteristics did not differ between groups. The primary outcome was 35 ng · day/l (19 to 58) in the 80% oxygen group; 35 ng · day/l (17 to 56) in the 30% oxygen group; 35 ng · day/l (19 to 54) in the antioxidants group; and 33 ng · day/l (18 to 57) in the placebo group. The median difference between oxygen groups was 1.5 ng · day/l (95% CI, -2.5 to 5.3; P = 0.202) and -0.5 ng · day/l (95% CI, -4.5 to 3.0; P = 0.228) between antioxidant groups. Mortality at 30 days occurred in 9 of 576 patients (1.6%; odds ratio, 2.01 [95% CI, 0.50 to 8.1]; P = 0.329 for the 80% vs. 30% oxygen groups; and odds ratio, 0.79 [95% CI, 0.214 to 2.99]; P = 0.732 for the antioxidants vs. placebo groups). CONCLUSIONS Perioperative interventions with high inspiratory oxygen fraction and antioxidants did not change the degree of myocardial injury within the first 3 days of surgery. This implies safety with 80% oxygen and no cardiovascular benefits of vitamin C and N-acetylcysteine in major noncardiac surgery.
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Hypoxia in Obesity and Diabetes: Potential Therapeutic Effects of Hyperoxia and Nitrate.
Norouzirad, R, González-Muniesa, P, Ghasemi, A
Oxidative medicine and cellular longevity. 2017;:5350267
Abstract
The prevalence of obesity and diabetes is increasing worldwide. Obesity and diabetes are associated with oxidative stress, inflammation, endothelial dysfunction, insulin resistance, and glucose intolerance. Obesity, a chronic hypoxic state that is associated with decreased nitric oxide (NO) bioavailability, is one of the main causes of type 2 diabetes. The hypoxia-inducible factor-1α (HIF-1α) is involved in the regulation of several genes of the metabolic pathways including proinflammatory adipokines, endothelial NO synthase (eNOS), and insulin signaling components. It seems that adipose tissue hypoxia and NO-dependent vascular and cellular dysfunctions are responsible for other consequences linked to obesity-related disorders. Although hyperoxia could reverse hypoxic-related disorders, it increases the production of reactive oxygen species (ROS) and decreases the production of NO. Nitrate can restore NO depletion and has antioxidant properties, and recent data support the beneficial effects of nitrate therapy in obesity and diabetes. Although it seems reasonable to combine hyperoxia and nitrate treatments for managing obesity/diabetes, the combined effects have not been investigated yet. This review discusses some aspects of tissue oxygenation and the potential effects of hyperoxia and nitrate interventions on obesity/diabetes management. It can be proposed that concomitant use of hyperoxia and nitrate is justified for managing obesity and diabetes.
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[Resveratrol increases sirtuin 1 expression in peripheral blood mononuclear cells of premature infants and inhibits the oxidative stress induced by hyperoxia in vivo].
Yang, X, Dong, WB, Li, QP, Kang, L, Lei, XP, Zhang, LY, Lu, YY, Zhai, XS
Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics. 2016;(1):72-7
Abstract
OBJECTIVE To explore the effect of resveratrol on the levels of sirtuin 1 (SIRT1) and reactive oxygen species (ROS) in peripheral blood mononuclear cells (PBMCs) of premature infants exposed to hyperoxia. METHODS Peripheral blood and isolated PBMCs from premature infants (gestational age<32 weeks) without oxygen supplement were collected and were randomly assigned into four groups: control, air+resveratrol, hyperoxia, and hyperoxia+resveratrol. The PBMCs were cultured in vitro for 48 hours, then the ROS content in PBMCs was measured by laser scanning confocal microscopy. Malondialdehyde (MDA) content in the medium was measured by the whole spectrum spectrophotometer. SIRT1 positioning was assessed by immunofluorescence. SIRT1 expression levels in PBMCs were measured by Western bolt. RESULTS Compared with the control group, the level of SIRT1 in the air+resveratrol group increased significantly (P<0.05). The levels of ROS and MDA and the SIRT1 transposition rate in the hyperoxia group increased significantly, while the expression level of SIRT1 decreased significantly compared with the control group (P<0.05). The levels of ROS and MDA and the SIRT1 transposition rate decreased significantly (P<0.05), and the expression level of SIRT1 increased significantly in the hyperoxia+resveratrol group (P<0.05). CONCLUSIONS Resveratrol can increase SIRT1 expression in PBMCs and inhibit SIRT1 shuttle from nucleus to cytoplasm in order to increase the ability of antioxidative stress in premature infants exposed to hyperoxia, thereby reducing the oxidative stress injury in premature infants.
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Oxygen Saturation Targets for Extremely Preterm Infants after the NeOProM Trials.
Stenson, BJ
Neonatology. 2016;(4):352-8
Abstract
Five randomized controlled trials comparing lower (85-89%) versus higher (91-95%) pulse oximeter saturation (SpO2) targets for extremely preterm infants have now been reported from the United States of America, Canada, the United Kingdom, Australia and New Zealand. These trials included more than 4,800 infants, and they provide robust evidence to permit comparison of these target ranges and consider the next steps for clinicians and researchers. The lower SpO2 range was associated with a significant increase in the risk of death. There was no significant difference between the two target ranges in the rate of disability at 18-24 months, including blindness. A significant difference between groups in the risk of the composite primary outcome of death or disability in favour of the higher SpO2 range was mainly attributable to the difference between groups in the risk of death. The lower target range did not reduce bronchopulmonary dysplasia or severe visual impairment, but it did increase the risk of necrotizing enterocolitis requiring surgery or causing death. The trials provide no reason to prefer SpO2 targets below 90% and indicate the importance of more trials to see if a further survival advantage can be identified. The safety of targets above 95% has not been evaluated. The five trials were designed to be similar to facilitate an individual patient data meta-analysis, and this Neonatal Oxygen Prospective Meta-Analysis (NeOProM) may provide further insights.
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Effects of modest hyperoxia and oral vitamin C on exercise hyperaemia and reactive hyperaemia in healthy young men.
Caruana, H, Marshall, JM
European journal of applied physiology. 2015;(9):1995-2006
Abstract
PURPOSE We have argued that breathing 40 % O2 attenuates exercise hyperaemia by decreasing production of O2-dependent vasodilators. However, breathing 100 % O2 attenuated endothelium-dependent vasodilatation evoked by acetylcholine and this effect was prevented by vitamin C, implicating reactive oxygen species (ROS). We have therefore used vitamin C to test the hypothesis that 40 % O2 modulates exercise hyperaemia and reactive hyperaemia independently of ROS. METHOD In a cross-over study on 10 male subjects (21.1 ± 0.84 years), we measured forearm blood flow (venous occlusion plethysmography) and calculated forearm vascular conductance (FVC) at rest and following static handgrip at 60 % maximum voluntary contraction for 2 min and following arterial occlusion for 2 min, after placebo or oral vitamin C (2000 mg), and when breathing air or 40 % O2. RESULT During air breathing, vitamin C augmented the peak increase in FVC following static contraction, or release of arterial occlusion, by ~50 or 60 %, respectively (P < 0.05). Breathing 40 % O2 in the presence of placebo attenuated post-contraction hyperaemia by ~25 % (P < 0.05), but had no effect on reactive hyperaemia. By contrast, in the presence of vitamin C, 40 % O2 attenuated the peak increase in FVC following static contraction, or release of arterial occlusion by ~25 and 50 %, respectively (P < 0.05). CONCLUSION These results indicate that in young men, exercise hyperaemia following strenuous muscle contraction and reactive hyperaemia are blunted by ROS. However, they are also consistent with the view that modest hyperoxia induced by breathing 40 % O2 acts independently of ROS to attenuate not only post-contraction hyperaemia, but also reactive hyperaemia, by decreasing release of O2-dependent vasodilators.
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Oxygen saturation limits and evidence supporting the targets.
Newnam, KM
Advances in neonatal care : official journal of the National Association of Neonatal Nurses. 2014;(6):403-9
Abstract
Supplemental oxygen use in the preterm infant is required for survival. Evidence supports a narrow therapeutic window between the helpful and harmful effects of supplemental oxygen in this vulnerable population. The clinical question was-what are the recommended oxygen saturation targets for the preterm infant and the preterm infant corrected to term? Multiple databases were searched for published research in English from 2008 to 2014 using key search terms. A total of 18 articles met inclusion criteria. Early neonatal research linked high levels of supplemental oxygen with retinopathy of prematurity and blindness. Years later, correlations between high arterial oxygen levels and oxidative stress leading to pulmonary and/or neurologic insults were established. Three large multicentered, international studies have recently been published (BOOST II, COT, and SUPPORT), which support oxygen saturation target ranges of 87% to 94% until vascular maturation of the retina is achieved. Two of the 3 studies reported a significant correlation between low saturation limits (85%-89%) and death in the extremely preterm population. Identified best care strategies to prevent states of hypoxia and/or hyperoxia include establishing clear target saturation limits according to recommendations, which are supported by the multidisciplinary team, adequate nurse to patient ratio, improve knowledge deficits, improve bedside compliance, and finally visual cues to remind caregivers of target saturation ranges.
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Automated adjustments of inspired fraction of oxygen to avoid hypoxemia and hyperoxemia in neonates - a systematic review on clinical studies.
Hummler, H, Fuchs, H, Schmid, M
Klinische Padiatrie. 2014;(4):204-10
Abstract
Supplemental oxygen is commonly provided during transition of neonates immediately after birth. Whereas an initial FiO2 of 0.21 is now recommended to stabilize full-term infants in the delivery room, the best FiO2 to start resuscitation of the very low birth weight infant (VLBWI) immediately after delivery is currently not known. Recent recommendations include the use of pulse oximetry to titrate the use of supplemental oxygen. As reference values for pulse oximetry during the first minutes of life have become available, automated FiO2-adjustments are feasible and may be very useful for delivery room care to limit oxygen exposure. Beyond neonatal transition, preterm infants in the neonatal intensive care unit (NICU) commonly require supplemental oxygen to avoid hypoxemia, especially VLBWI receiving respiratory support because of poor respiratory drive and/or lung disease. For respiratory care of newborn infants in the NICU automated FiO2-adjustment systems have been developed and have been studied in preterm infants for limited time frames using short-term physiological outcomes. These studies could demonstrate short-term benefits such as more stable arterial oxygen saturation. Recent clinical trials have shown that oxygen targeting may significantly affect mortality and morbidity. Therefore, randomized controlled trials are needed to study the effects of automated FiO2-adjustment on long-term outcomes to prove possible benefits on survival, the rate of retino-pathy of prematurity and on neuro-development-al outcome.
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Effects of antioxidants (AREDS medication) on ocular blood flow and endothelial function in an endotoxin-induced model of oxidative stress in humans.
Pemp, B, Polska, E, Karl, K, Lasta, M, Minichmayr, A, Garhofer, G, Wolzt, M, Schmetterer, L
Investigative ophthalmology & visual science. 2010;(1):2-6
Abstract
PURPOSE The Age-Related Eye Disease Study (AREDS) has shown that supplementation of antioxidants slows the progression of age-related macular degeneration (AMD). The mechanism underlying this therapeutic effect may be related to a reduction of reactive oxygen species (ROS). The authors have recently introduced a model showing that the response of retinal blood flow (RBF) to hyperoxia is diminished by administration of lipopolysaccharide (LPS). In the present study, the hypothesis was that this response can be restored by the AREDS medication. METHODS Twenty-one healthy volunteers were included in this randomized, double-masked, placebo-controlled, parallel group study. On each study day, RBF and the reactivity of RBF to hyperoxia were investigated before and after infusion of 2 ng/kg LPS. Between the two study days, subjects took either the AREDS medication or placebo for 14 days. RESULTS After administration of LPS reduced retinal arterial vasoconstriction during hyperoxia (AREDS group: 12.5% +/- 4.8% pre-LPS vs. 9.4% +/- 4.6% post-LPS; placebo group: 9.2% +/- 3.3% pre-LPS vs. 7.1% +/- 3.5% post-LPS) and a reduced reactivity of RBF during hyperoxia (AREDS 50.4% +/- 8.9% vs. 44.9% +/- 11.6%, placebo: 54.2% +/- 8.6% vs. 46.0% +/- 6.9%) was found. The reduced responses were normalized after 2 weeks of AREDS antioxidants but not after placebo (vasoconstriction: 13.1% +/- 4.5% vs. 13.1% +/- 5.0% AREDS, 11.2% +/- 4.2 vs. 7.4% +/- 4.2% placebo; RBF: 52.8% +/- 10.5% vs. 52.4% +/- 10.5% AREDS, 52.4% +/- 9.3% vs. 44.2% +/- 6.3% placebo). CONCLUSIONS The sustained retinal vascular reaction to hyperoxia after LPS in the AREDS group indicates that antioxidants reduce oxidative stress-induced endothelial dysfunction, possibly by eliminating ROS. The model may be an attractive approach to studying the antioxidative capacity of dietary supplements for the treatment of AMD (ClinicalTrials.gov number, NCT00431691).
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Influence of hyperoxia on muscle metabolic responses and the power-duration relationship during severe-intensity exercise in humans: a 31P magnetic resonance spectroscopy study.
Vanhatalo, A, Fulford, J, DiMenna, FJ, Jones, AM
Experimental physiology. 2010;(4):528-40
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Abstract
Severe-intensity constant-work-rate exercise results in the attainment of maximal oxygen uptake, but the muscle metabolic milieu at the limit of tolerance (T(lim)) for such exercise remains to be elucidated. We hypothesized that T(lim) during severe-intensity exercise would be associated with the attainment of consistently low values of intramuscular phosphocreatine ([PCr]) and pH, as determined using (31)P magnetic resonance spectroscopy, irrespective of the work rate and the inspired O(2) fraction. We also hypothesized that hyperoxia would increase the asymptote of the hyperbolic power-duration relationship (the critical power, CP) without altering the curvature constant (W). Seven subjects (mean +/- s.d., age 30 +/- 9 years) completed four constant-work-rate knee-extension exercise bouts to the limit of tolerance (range, 3-10 min) both in normoxia (N) and in hyperoxia (H; 70% O(2)) inside the bore of 1.5 T superconducting magnet. The [PCr] (approximately 5-10% of resting baseline) and pH (approximately 6.65) at the limit of tolerance during each of the four trials was not significantly different either in normoxia or in hyperoxia. At the same fixed work rate, the overall rate at which [PCr] fell with time was attenuated in hyperoxia (mean response time: N, 59 +/- 20 versus H, 116 +/- 46 s; P < 0.05). The CP was higher (N, 16.1 +/- 2.6 versus H, 18.0 +/- 2.3 W; P < 0.05) and the W was lower (N, 1.92 +/- 0.70 versus H, 1.48 +/- 0.31 kJ; P < 0.05) in hyperoxia compared with normoxia. These data indicate that T(lim) during severe-intensity exercise is associated with the attainment of consistently low values of muscle [PCr] and pH. The CP and W parameters of the power-duration relationship were both sensitive to the inspiration of hyperoxic gas.
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The effects of training in hyperoxia vs. normoxia on skeletal muscle enzyme activities and exercise performance.
Perry, CG, Talanian, JL, Heigenhauser, GJ, Spriet, LL
Journal of applied physiology (Bethesda, Md. : 1985). 2007;(3):1022-7
Abstract
Inspiring a hyperoxic (H) gas permits subjects to exercise at higher power outputs while training, but there is controversy as to whether this improves skeletal muscle oxidative capacity, maximal O(2) consumption (Vo(2 max)), and endurance performance to a greater extent than training in normoxia (N). To determine whether the higher power output during H training leads to a greater increase in these parameters, nine recreationally active subjects were randomly assigned in a single-blind fashion to train in H (60% O(2)) or N for 6 wk (3 sessions/wk of 10 x 4 min at 90% Vo(2 max)). Training heart rate (HR) was maintained during the study by increasing power output. After at least 6 wk of detraining, a second 6-wk training protocol was completed with the other breathing condition. Vo(2 max) and cycle time to exhaustion at 90% of pretraining Vo(2 max) were tested in room air pre- and posttraining. Muscle biopsies were sampled pre- and posttraining for citrate synthase (CS), beta-hydroxyacyl-coenzyme A dehydrogenase (beta-HAD), and mitochondrial aspartate aminotransferase (m-AsAT) activity measurements. Training power outputs were 8% higher (17 W) in H vs. N. However, both conditions produced similar improvements in Vo(2 max) (11-12%); time to exhaustion (approximately 100%); and CS (H, 30%; N, 32%), beta-HAD (H, 23%; N, 21%), and m-AsAT (H, 21%; N, 26%) activities. We conclude that the additional training stimulus provided by training in H was not sufficient to produce greater increases in the aerobic capacity of skeletal muscle and whole body Vo(2 max) and exercise performance compared with training in N.