NORMOBARIC OXYGEN (95-100%)

Continuing Home Application Combined With Intensive Hyperbaric Oxygen Therapy

Int J Mol Med. 2019 Mar;43(3):1193-1202. doi: 10.3892/ijmm.2018.4037. Epub 2018 Dec 20.

Normobaric oxygen inhibits AQP4 and NHE1 expression in experimental focal ischemic stroke.

Yang D1, Ma L2, Wang P1, Yang D2, Zhang Y3, Zhao X3, Lv J3, Zhang J3, Zhang Z1, Gao F3.

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Abstract

The aim of the present study was to determine the effect of 60% normobaric oxygen (NBO) on neurological function, brain edema and the expression of hypoxia‑inducible factor‑1α (HIF‑1α), aquaporin 4 (AQP4) and Na+/H+ exchanger 1 (NHE1) in a rat model of cerebral ischemia‑reperfusion injury.

Male Sprague‑Dawley rats underwent transient focal cerebral ischemia via right middle cerebral artery occlusion (MCAO) for 120 min followed by 48 h of reperfusion. The rats were exposed to NBO at 60 and 100% or no treatment during reperfusion for 48 h. Neurological impairment score (NIS) was evaluated prior to the sacrifice of all rats. Hematoxylin‑eosin staining was performed after 48 h of reperfusion with NBO treatment. The infarct volume and brain water content (BWC) were determined to assess brain ischemic injury at 24 and 48 h. The levels of HIF‑1α, AQP4 and NHE1 expression in brain tissue samples were determined by western blotting and reverse transcription‑quantitative polymerase chain reaction analysis. During reperfusion, the protein and mRNA expression of HIF‑1α, AQP4 and NHE1 increased over time (up to 48 h).

 * Exposure to 60 and 100% NBO during reperfusion following MCAO improved NIS, and alleviated BWC and infarct volume after 24 and 48 h, with further improvements in the 100% NBO group, compared with 60%.

 ** Additionally, the molecular mechanisms involved in the effects of NBO may be associated with reduced AQP4 and NHE1 expression and increased HIF‑1α expression.

 

However, 60% NBO therapy during reperfusion following an acute ischemic stroke did not achieve the same effects as 100% NBO. Further experimental studies should be performed to elucidate the mechanism and beneficial effects of 60% NBO, as it is more cost‑effective to use, compared with 100% NBO.

Front Cardiovasc Med. 2018 Aug 28;5:114. doi: 10.3389/fcvm.2018.00114. eCollection 2018.

Supplemental Oxygen Protects Heart Against Acute Myocardial Infarction.

Prabhat AM1, Kuppusamy ML1,2, Naidu SK2, Meduru S2, Reddy PT2, Dominic A2, Khan M2,3, Rivera BK2, Kuppusamy P1,2.

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Abstract

Myocardial infarction (MI), which occurs often due to acute ischemia followed by reflow, is associated with irreversible loss (death) of cardiomyocytes. If left untreated, MI will lead to progressive loss of viable cardiomyocytes, deterioration of cardiac function, and congestive heart failure. While supplemental oxygen therapy has long been in practice to treat acute MI, there has not been a clear scientific basis for the observed beneficial effects. Further, there is no rationale for the amount or duration of administration of supplemental oxygenation for effective therapy. The goal of the present study was to determine an optimum oxygenation protocol that can be clinically applicable for treating acute MI. Using EPR oximetry, we studied the effect of exposure to supplemental oxygen cycling (OxCy) administered by inhalation of 21-100% oxygen for brief periods (15-90 min), daily for 5 days, using a rat model of acute MI.

 * Myocardial oxygen tension (pO2), cardiac function and pro-survival/apoptotic signaling molecules were used as markers of treatment outcome. OxCy resulted in a significant reduction of infarct size and improvement of cardiac function.

 ** An optimal condition of 30-min OxCy with 95% oxygen + 5% CO2 under normobaric conditions was found to be effective for cardioprotection.

Diving Hyperb Med. 2012 Jun;42(2):67-71.

The 'normobaric oxygen paradox': does it increase haemoglobin?

De Bels D1, Theunissen SDevriendt JGermonpré PLafere PValsamis JSnoeck TMeeus PBalestra C.

Daily versus alternate days 100% O2, breathed for 30 minutes, on haemoglobin concentrations during a 12-day period. Nine subjects underwent the two protocols six weeks apart. We observed a significant increase in haemoglobin (as a percentage of baseline) in the alternate-days group compared to the daily group and to baseline after four days (105.5 ∓ 5.7 % vs. 99.6 ∓ 3.3 % difference from baseline; P < 0.01).

At the end of the experimental period haemoglobin values increased significantly compared to baseline in both groups. There was a significant percentage rise in reticulocyte count  (new red blood cells) in the alternate-days group compared to the daily group (182 ∓ 94 % vs. 93 ∓ 34 %; P < 0.001).

CONCLUSION: The normobaric oxygen paradox seems effective in increasing haemoglobin in non-anaemic, healthy volunteers, providing sufficient time is allowed between O2 applications.

 * Intermittent normobaric hyperoxia combined with chemotherapy reduced the tumor number by 59% and the load by 72% compared with the control

Korean J Intern Med. 2018 May;33(3):541-551. doi: 10.3904/kjim.2016.334. Epub 2017 Dec 15.

Combination of carboplatin and intermittent normobaric hyperoxia synergistically suppresses benzo[a]pyrene-induced lung cancer.

We explored the effects of intermittent normobaric hyperoxia alone or combined with chemotherapy on the growth, general morphology, oxidative stress, and apoptosis of benzo[a]pyrene (B[a]P)-induced lung tumors in mice.

METHODS:

Female A/J mice were given a single dose of B[a]P and randomized into four groups: control, carboplatin (50 mg/kg intraperitoneally), hyperoxia (95% fraction of inspired oxygen), and carboplatin and hyperoxia. Normobaric hyperoxia (95%) was applied for 3 hours each day from weeks 21 to 28. Tumor load was determined as the average total tumor numbers and volumes. Several markers of oxidative stress and apoptosis were evaluated.

RESULTS:

Intermittent normobaric hyperoxia combined with chemotherapy reduced the tumor number by 59% and the load by 72% compared with the control B[a]P group. Intermittent normobaric hyperoxia, either alone or combined with chemotherapy, decreased the levels of superoxide dismutase and glutathione and increased the levels of catalase and 8-hydroxydeoxyguanosine. The Bax/Bcl-2 mRNA ratio, caspase 3 level, and number of transferase-mediated dUTP nick end-labeling positive cells increased following treatment with hyperoxia with or without chemotherapy.

CONCLUSIONS:

Intermittent normobaric hyperoxia was found to be tumoricidal and thus may serve as an adjuvant therapy for lung cancer. Oxidative stress and its effects on DNA are increased following exposure to hyperoxia and even more with chemotherapy, and this may lead to apoptosis of lung tumors.

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Korean J Intern Med. 2018 May;33(3):541-551. doi: 10.3904/kjim.2016.334. Epub 2017 Dec 15.

Combination of carboplatin and intermittent normobaric hyperoxia synergistically suppresses benzo[a]pyrene-induced lung cancer.

BACKGROUND/AIMS:

We explored the effects of intermittent normobaric hyperoxia alone or combined with chemotherapy on the growth, general morphology, oxidative stress, and apoptosis of benzo[a]pyrene (B[a]P)-induced lung tumors in mice.

METHODS:

Female A/J mice were given a single dose of B[a]P and randomized into four groups: control, carboplatin (50 mg/kg intraperitoneally), hyperoxia (95% fraction of inspired oxygen), and carboplatin and hyperoxia. Normobaric hyperoxia (95%) was applied for 3 hours each day from weeks 21 to 28. Tumor load was determined as the average total tumor numbers and volumes. Several markers of oxidative stress and apoptosis were evaluated.

RESULTS:

Intermittent normobaric hyperoxia combined with chemotherapy reduced the tumor number by 59% and the load by 72% compared with the control B[a]P group. Intermittent normobaric hyperoxia, either alone or combined with chemotherapy, decreased the levels of superoxide dismutase and glutathione and increased the levels of catalase and 8-hydroxydeoxyguanosine. The Bax/Bcl-2 mRNA ratio, caspase 3 level, and number of transferase-mediated dUTP nick end-labeling positive cells increased following treatment with hyperoxia with or without chemotherapy.

CONCLUSIONS:

Intermittent normobaric hyperoxia was found to be tumoricidal and thus may serve as an adjuvant therapy for lung cancer. Oxidative stress and its effects on DNA are increased following exposure to hyperoxia and even more with chemotherapy, and this may lead to apoptosis of lung tumors.

 

Niger J Clin Pract. 2018 Apr;21(4):401-416. doi: 10.4103/njcp.njcp_315_16.

The neuroprotection effect of oxygen therapy: A systematic review and meta-analysis.

This study reviews the oxygen therapy (normobaric oxygen [NBO] and hyperbaric oxygen [HBO]) in both stroke and traumatic brain injury (TBI) patients and meta-analyzes the efficacy of two oxygen therapies in different kinds of injuries. In stroke patients, NBO showed significant improvement in reperfusion rate while there is no favorable outcome effect of HBO treatment. In patients with TBI, HBO showed significant improvement of Glasgow outcome scale score and reduction of overall mortality while NBO may play a favorable role in improving brain metabolism.

Exp Biol Med (Maywood). 2018 May;243(9):739-748. doi: 10.1177/1535370218774737.

Normobaric hyperoxia inhibits the progression of lung cancer by inducing apoptosis.

Hypoxia is a critical characteristic of solid tumors with respect to cancer cell survival, angiogenesis, and metastasis. Hyperoxic treatment has been attempted to reverse hypoxia by enhancing the amount of dissolved oxygen in the plasma. In this study, we evaluated the effects of normobaric hyperoxia on the progression of lung cancer to determine whether oxygen toxicity can be used in cancer therapy. Following a tail vein injection of the Lewis lung carcinoma cells, C57BL/6J mice were exposed to a 24-h normobaric hyperoxia/normoxia cycle for two weeks. In addition, A549 lung cancer cells were incubated in a normobaric hyperoxia chamber for a 24-h period. As a result, the size and number of tumors in the lung decreased significantly with exposure to normobaric hyperoxia in the mouse model. Cell viability, colony-forming ability, migration, and invasion all decreased significantly in A549 cells exposed to normobaric hyperoxia and the normal control group exposed to normobaric hyperoxia showed no significant damage. Oxidative stress was more prominent with exposure to normobaric hyperoxia in cancer cells. A549 cells exposed to normobaric hyperoxia showed a significantly higher cell apoptosis ratio compared with A549 cells without normobaric hyperoxia exposure and normal human lung cells (BEAS-2B cells). The Bax/Bcl-2 mRNA expression ratio also increased significantly. Changes in the key regulators of apoptosis were similar between in vivo and in vitro conditions. The p-ERK level decreased, while the p-JNK level increased, after normobaric hyperoxia exposure in A549 cells. This study demonstrated the role of normobaric hyperoxia in inhibiting lung cancer. Normal tissue and cells showed no significant hyperoxic damage in our experimental setting. The anti-tumor effect of normobaric hyperoxia may due to the increased reactive oxygen species activity and apoptosis, which is related to the mitogen-activated protein kinase pathway. Impact statement Normobaric hyperoxia (NBO) is a feasible therapy for cancer with a low complication rate. Although NBO may be beneficial in cancer treatment, very few studies have been conducted; thus, the evidence is thin. This is the first study to clearly demonstrate morphological changes in lung cancer with NBO exposure and to investigate the underlying mechanisms both in vivo and in vitro. This study will arouse interest in NBO treatment and promote further research.

Physiol Behav. 2018 Aug 29;196:95-103. doi: 10.1016/j.physbeh.2018.08.016. [Epub ahead of print]

Melatonin and sleep responses to normobaric hypoxia and aerobic physical exercise: A randomized controlled trial.

This work evaluated the effects of moderate physical exercise performed under hypoxic conditions on melatonin and sleep. Forty healthy men were randomized into four groups: Normoxia (N) (n = 10); Hypoxia (H) (n = 10); Exercise under Normoxia (EN) (n = 10); and Exercise under Hypoxia (EH) (n = 10). The observation period for all groups was approximately 36 h, beginning with a first night devoid of any intervention. Aerobic exercise was performed by the EN and EH groups on a treadmill at 50% of the ventilatory threshold intensity for 60 min. Sleep evaluation was performed on the 1st and 2nd nights. Venous blood samples for the melatonin measurement were obtained on the 1st and 2nd days at 7:30 AM as well as on the 1st and 2nd nights at 10:30 PM. On the 2nd night, melatonin was higher in the H group than in the N group, but both were lower than values of the EH group. The nocturnal increase in melatonin was inversely correlated with the oxygen saturation of hemoglobin (SaO2%) on the 2nd night in the H group and on the 2nd day in the EH group. Diurnal remission of nocturnal melatonin appeared to be postponed in the H group and even more so in the EH group. Thus, normobaric hypoxia, which is equivalent to oxygen availability at an altitude of 4500 m, acutely increases melatonin. Moreover, diurnal remission of the nocturnal increase in melatonin seems to be delayed by hypoxia alone but even more so when acting together with exercise.

BMC Anesthesiol. 2017 Mar 23;17(1):49. doi: 10.1186/s12871-017-0342-2.

Effects of short-term hyperoxia on erythropoietin levels and microcirculation in critically Ill patients: a prospective observational pilot study.

Donati A1, Damiani E2, Zuccari S2, Domizi R2, Scorcella C2, Girardis M3, Giulietti A4, Vignini A4, Adrario E2, Romano R2, Mazzanti L4, Pelaia P2, Singer M5.

The normobaric oxygen paradox states that a short exposure to normobaric hyperoxia followed by rapid return to normoxia creates a condition of 'relative hypoxia' which stimulates erythropoietin (EPO) production. Alterations in glutathione and reactive oxygen species (ROS) may be involved in this process. We tested the effects of short-term hyperoxia on EPO levels and the microcirculation in critically ill patients.

METHODS:

In this prospective, observational study, 20 hemodynamically stable, mechanically ventilated patients with inspired oxygen concentration (FiO2) ≤0.5 and PaO2/FiO2 ≥ 200 mmHg underwent a 2-hour exposure to hyperoxia (FiO2 1.0). A further 20 patients acted as controls. Serum EPO was measured at baseline, 24 h and 48 h. Serum glutathione (antioxidant) and ROS levels were assessed at baseline (t0), after 2 h of hyperoxia (t1) and 2 h after returning to their baseline FiO2 (t2). The microvascular response to hyperoxia was assessed using sublingual sidestream dark field videomicroscopy and thenar near-infrared spectroscopy with a vascular occlusion test.

RESULTS:

EPO increased within 48 h in patients exposed to hyperoxia from 16.1 [7.4-20.2] to 22.9 [14.1-37.2] IU/L (p = 0.022). Serum ROS transiently increased at t1, and glutathione increased at t2. Early reductions in microvascular density and perfusion were seen during hyperoxia (perfused small vessel density: 85% [95% confidence interval 79-90] of baseline). The response after 2 h of hyperoxia exposure was heterogeneous. Microvascular perfusion/density normalized upon returning to baseline FiO2.

CONCLUSIONS:

A two-hour exposure to hyperoxia in critically ill patients was associated with a slight increase in EPO levels within 48 h. Adequately controlled studies are needed to confirm the effect of short-term hyperoxia on erythropoiesis.

J Neurotrauma. 2017 Apr 26. doi: 10.1089/neu.2017.4992. [Epub ahead of print]

Does Normobaric Hyperoxia Cause Oxidative Stress in the Injured Brain? A Microdialysis Study Using 8-Iso-Prostaglandin F2α as a Biomarker.

Vidal-Jorge M1, Sánchez-Guerrero A1, Mur-Bonet G1, Castro L1, Rădoi A1, Riveiro M2, Fernández-Prado N2, Baena J2, Poca MA1,3, Sahuquillo J1,3.

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Abstract

Significant controversy exists regarding the potential clinical benefit of normobaric hyperoxia (NBO) in patients with traumatic brain injury (TBI). This study consisted of two aims: 1) to assess whether NBO improves brain oxygenation and metabolism and 2) to determine whether this therapy may increase the risk of oxidative stress (OxS), using 8-iso-Prostaglandin F2α (PGF2α) as a biomarker. Thirty-one patients with a median admission Glasgow Coma Scale score of 4 (min: 3, max: 12) were monitored with cerebral microdialysis and brain tissue oxygensensors and treated with fraction of inspired oxygen (FiO2) of 1.0 for 4 h. Patients were divided into two groups according to the area monitored by the probes: normal injured brain and traumatic penumbra/traumatic core. NBO maintained for 4 h did not induce OxS in patients without preOxS at baseline, except in one case. However, for patients in whom OxS was detected at baseline, NBO induced a significant increase in 8-iso-PGF2α. The results of our study showed that NBO did not change energy metabolism in the whole group of patients. In the five patients with brain lactate concentration ([Lac]brain) > 3.5 mmol/L at baseline, NBO induced a marked reduction in both [Lac]brain and lactate-to-pyruvate ratio. Although these differences were not statistically significant, together with the results of our previous study, they suggest that TBI patients would benefit from receiving NBO when they show indications of disturbed brain metabolism. These findings, in combination with increasing evidence that TBI metabolic crises are common without brain ischemia, open new possibilities for the use of this accessible therapeutic strategy in TBI patients.

Eur J Appl Physiol. 2017 May;117(5):901-912. doi: 10.1007/s00421-017-3574-4. Epub 2017 Mar 9.

Determinants of curvature constant (W') of the power duration relationship under normoxia and hypoxia: the effect of pre-exercise alkalosis.

Deb SK1, Gough LA1, Sparks SA1, McNaughton LR2.

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Abstract

PURPOSE:

This study investigated the effect of induced alkalosis on the curvature constant (W') of the power-duration relationship under normoxic and hypoxic conditions.

METHODS:

Eleven trained cyclists (mean ± SD) Age: 32 ± 7.2 years; body mass (bm): 77.0 ± 9.2 kg; VO2peak: 59.2 ± 6.8 ml·kg-1·min-1completed seven laboratory visits which involved the determination of individual time to peak alkalosis following sodium bicarbonate (NaHCO3) ingestion, an environment specific ramp test (e.g. normoxia and hypoxia) and four x 3 min critical power (CP) tests under different experimental conditions. Participants completed four trials: alkalosis normoxia (ALN); placebo normoxia (PLN); alkalosis hypoxia (ALH); and placebo hypoxia (PLH). Pre-exercise administration of 0.3 g.kg-1 BM of NaHCO3 was used to induce alkalosis. Environmental conditions were set at either normobaric hypoxia (FiO2: 14.5%) or normoxia (FiO2: 20.93%).

RESULTS:

An increase in W' was observed with pre-exercise alkalosis under both normoxic (PLN: 15.1 ± 6.2 kJ vs. ALN: 17.4 ± 5.1 kJ; P = 0.006) and hypoxic conditions (ALN: 15.2 ± 4.9 kJ vs. ALN: 17.9 ± 5.2 kJ; P < 0.001). Pre-exercise alkalosis resulted in a larger reduction in bicarbonate ion (HCO3-) concentrations during exercise in both environmental conditions (p < 0.001) and a greater blood lactate accumulation under hypoxia (P = 0.012).

CONCLUSION:

Pre-exercise alkalosis substantially increased W' and, therefore, may determine tolerance to exercise above CP under normoxic and hypoxic conditions. This may be due to NaHCO3 increasing HCO3- buffering capacity to delay exercise-induced acidosis, which may, therefore, enhance anaerobic energy contribution.

Mol Cell Biochem. 2017 Apr 21. doi: 10.1007/s11010-017-3037-6. [Epub ahead of print]

Proteomic analysis of mitochondrial proteins in the guinea pig heart following long-term normobaric hyperoxia.

Lichardusova L1, Tatarkova Z1, Calkovska A2,3, Mokra D2,3, Engler I4, Racay P1,3, Lehotsky J1,3, Kaplan P5,6.

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Abstract

Normobaric hyperoxia is applied for the treatment of a wide variety of diseases and clinical conditions related to ischemia or hypoxia, but it can increase the risk of tissue damage and its efficiency is controversial. In the present study, we analyzed cardiac mitochondrial proteome derived from guinea pigs after 60 h exposure to 100% molecular oxygen (NBO) or O2 enriched with oxygen cation (NBO+). Two-dimensional gel electrophoresis followed by MALDI-TOF/TOF mass spectrometry identified twenty-two different proteins (among them ten nonmitochondrial) that were overexpressed in NBO and/or NBO+ group. Identified proteins were mainly involved in cellular energy metabolism (tricarboxylic acid cycle, oxidative phosphorylation, glycolysis), cardioprotection against stress, control of mitochondrial function, muscle contraction, and oxygen transport. These findings support the viewpoint that hyperoxia is associated with cellular stress and suggest complex adaptive responses which probably contribute to maintain or improve intracellular ATP levels and contractile function of cardiomyocytes. In addition, the results suggest that hyperoxia-induced cellular stress may be partially attenuated by utilization of NBO+ treatment.

 

Brain Behav. 2016 May 4;6(7):e00478. doi: 10.1002/brb3.478. eCollection 2016 Jul.

Methylene blue and normobaric hyperoxia combination therapy in experimental ischemic stroke.

Rodriguez P1, Zhao J2, Milman B3, Tiwari YV4, Duong TQ3.

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Abstract

INTRODUCTION:

Ischemic stroke is a global burden that contributes to the disability and mortality of millions of patients. This study aimed to evaluate the efficacy of combined MB (methylene blue) and NBO (normobaric hyperoxia) therapy in experimental ischemic stroke.

METHODS:

Rats with transient (60 min) MCAO (middle cerebral artery occlusion) were treated with: (1) air + vehicle (N = 8), (2) air + MB (N = 8), (3) NBO + vehicle (N = 7), and (4) NBO + MB (N = 9). MB (1 mg/kg) was administered at 30 min, again on days 2, 7, and 14 after stroke. NBO was given during MRI (30-150 min) on day 0, and again 1 h each during MRI on subsequent days. Serial diffusion, perfusion and T2 MRI were performed to evaluate lesion volumes. Foot-fault and cylinder tests were performed to evaluate sensorimotor function.

RESULTS:

The major findings were: (1) NBO + MB therapy showed a greater decrease in infarct volume compared to NBO alone, but similar infarct volume compared to MB alone, (2) NBO + MB therapy accelerated sensorimotor functional recovery compared to NBO or MB alone, (3) Infarct volumes on day 2 did not change significantly from those on day 28 for all four groups, but behavioral function continued to show improved recovery in the NBO + MB group.

CONCLUSIONS:

These findings support the hypothesis that combined NBO + MB further improves functional outcome and reduces infarct volume compared to either treatment alone and these improvements extended up to 28 days.

 

Diving Hyperb Med. 2012 Jun;42(2):67-71.

The 'normobaric oxygen paradox': does it increase haemoglobin?

De Bels D1, Theunissen SDevriendt JGermonpré PLafere PValsamis JSnoeck TMeeus PBalestra C.

A novel approach to increasing erythropoietin (EPO) using oxygen (O2) (the 'normobaric oxygen paradox') has been reported in healthy volunteers. We investigated whether the EPO increase is sufficient to induce erythropoiesis by comparing two protocols of O2 administration.

METHODS:

We compared the effect of daily versus alternate days 100% O2, breathed for 30 minutes, on haemoglobin concentrations during a 12-day period. Nine subjects underwent the two protocols six weeks apart.

RESULTS:

We observed a significant increase in haemoglobin (as a percentage of baseline) in the alternate-days group compared to the daily group and to baseline after four days (105.5 ∓ 5.7 % vs. 99.6 ∓ 3.3 % difference from baseline; P < 0.01). At the end of the experimental period, haemoglobin values increased significantly compared to baseline in both groups. There was a significant percentage rise in reticulocyte count  (new red blood cells) in the alternate-days group compared to the daily group (182 ∓ 94 % vs. 93 ∓ 34 %; P < 0.001).

CONCLUSION:

The normobaric oxygen paradox seems effective in increasing haemoglobin in non-anaemic, healthy volunteers, providing sufficient time is allowed between O2 applications. The exact time interval is not clearly defined by this study but should probably be at least or greater than two days. Further studies are needed to define more precisely clinical applications in the use of O2 as a pharmaceutical agent.

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