Hyperglycemia and Hypoglycemia Contributions to Acute Respiratory Distress Syndrome

Purpose of Study Non-diabetic COVID-19 patients with elevated admission fasting blood glucose levels ('hyperglycemia') inexplicably have an increased 28 day mortality and higher inhospital complications including the Acute Respiratory Distress Syndrome (ARDS) but potentially contributing blood glucose changes during ARDS development were not reported (Wang S et al: Diabetologia 2020). Our goal was to determine blood glucose alterations before and during acute lung injury development in a rat model used to study ARDS. Methods Used We sequentially evaluated blood glucose levels for 24 hours and lung lavage protein levels (lung permeability) and lung lavage neutrophil numbers (lung inflammation) at 24 hours to assess acute lung injury ('ARDS') in young (~3 month) and old (~12 month) control and a novel strain of hyperoxia surviving 'resistant' rats before and after administering high and low insulin doses and before and after interleukin- 1/lipopolysaccharide (IL-1/LPS) insufflation. Summary of Results Glucose levels increase rapidly and sequentially in young control, but not young resistant, rats peaking ~2 hours after insufflation. Glucose levels also increase in old control and old resistant rats after insufflation compared to young control and young resistant rats after insufflation. The pattern of glucose levels at 2 hours after insufflation resembles lung lavage proteins and neutrophils at 24 h after insufflation (table 1). Administering high insulin (High In) doses decreases glucose levels ('hypoglycemia') and worsens ARDS while administering low insulin (Low In) doses correct glucose levels and improve ARDS. Conclusions Hyperglycemia develops in both young and old rats developing ARDS and high or low glucose levels parallel worse acute lung inflammation and acute lung injury ('ARDS'). Controlling glucose judiciously with insulin may be beneficial in combatting ARDS caused by SARS-CoV-2 infection and other insults.

Impacts Of A Fraction Of Inspired Oxygen Adjustment Protocol In Covid-19 Patients Under Mechanical Ventilation: A Prospective Cohort Study.

OBJECTIVE: We examined weather a protocol for fraction of inspired oxygen (FiO2) adjustment can reduce hyperoxemia and excess oxygen use in COVID-19 patients mechanically ventilated. DESIGN: Prospective cohort study. SETTING: Two intensive care units (ICUs) dedicated to COVID-19 patients in Brazil. PATIENTS: Consecutive patients with COVID-19 mechanically ventilated. INTERVENTIONS: One ICU followed a FiO2 adjustment protocol based on SpO2 (conservative-oxygen ICU) and the other, which did not follow the protocol, constituted the control ICU. MAIN VARIABLES OF INTEREST: Pprevalence of hyperoxemia (PaO2>100 mmHg) on day 1, sustained hyperoxemia (present on days 1 and 2), and excess oxygen use (FiO2>0.6 in patients with hyperoxemia) were compared between the two ICUs. RESULTS: 82 patients from the conservative-oxygen ICU and 145 from the control ICU were included. The conservative-oxygen ICU presented lower prevalence of hyperoxemia on day 1 (40.2% vs. 75.9%, p<0.001) and of sustained hyperoxemia (12.2% vs. 49.6%, p<0.001). Excess oxygen use was less frequent in the conservative-oxygen ICU on day 1 (18.3% vs. 52.4%, p<0.001). Being admitted in the control ICU was independently associated with hyperoxemia and excess oxygen use. Multivariable analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FiO2 use and adverse clinical outcomes. CONCLUSIONS: Following FiO2 protocol was associated with lower hyperoxemia and less excess oxygen use. Although those results were not associated with better clinical outcomes, adopting FiO2 protocol may be useful in a scenario of depleted oxygen resources, as was seen during the COVID-19 pandemic.

Impacts of a fraction of inspired oxygen adjustment protocol in COVID-19 patients under mechanical ventilation: A prospective cohort study.

OBJECTIVE: We examined weather a protocol for fraction of inspired oxygen (FiO2) adjustment can reduce hyperoxemia and excess oxygen use in COVID-19 patients mechanically ventilated. DESIGN: Prospective cohort study. SETTING: Two intensive care units (ICUs) dedicated to COVID-19 patients in Brazil. PATIENTS: Consecutive patients with COVID-19 mechanically ventilated. INTERVENTIONS: One ICU followed a FiO2 adjustment protocol based on SpO2 (conservative-oxygen ICU) and the other, which did not follow the protocol, constituted the control ICU. MAIN VARIABLES OF INTEREST: Prevalence of hyperoxemia (PaO2>100mmHg) on day 1, sustained hyperoxemia (present on days 1 and 2), and excess oxygen use (FiO2>0.6 in patients with hyperoxemia) were compared between the two ICUs. RESULTS: Eighty two patients from the conservative-oxygen ICU and 145 from the control ICU were included. The conservative-oxygen ICU presented lower prevalence of hyperoxemia on day 1 (40.2% vs. 75.9%, p<0.001) and of sustained hyperoxemia (12.2% vs. 49.6%, p<0.001). Excess oxygen use was less frequent in the conservative-oxygen ICU on day 1 (18.3% vs. 52.4%, p<0.001). Being admitted in the control ICU was independently associated with hyperoxemia and excess oxygen use. Multivariable analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FiO2 use and adverse clinical outcomes. CONCLUSIONS: Following FiO2 protocol was associated with lower hyperoxemia and less excess oxygen use. Although those results were not associated with better clinical outcomes, adopting FiO2 protocol may be useful in a scenario of depleted oxygen resources, as was seen during the COVID-19 pandemic.

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.

Too much tolerance for hyperoxemia in mechanically ventilated patients with SARS-CoV-2 pneumonia? Report from an Italian intensive care unit.

Background: In COVID-19 patients requiring mechanical ventilation, the administration of high oxygen (O2) doses for prolonged time periods may be necessary. Although life-saving in most cases, O2 may exert deleterious effects if administered in excessive concentrations. We aimed to describe the prevalence of hyperoxemia and excessive O2 administration in mechanically ventilated patients with SARS-CoV-2 pneumonia and determine whether hyperoxemia is associated with mortality in the Intensive Care Unit (ICU) or the onset of ventilator-associated pneumonia (VAP). Materials and methods: Retrospective single-center study on adult patients with SARS-CoV-2 pneumonia requiring invasive mechanical ventilation for ≥48 h. Patients undergoing extracorporeal respiratory support were excluded. We calculated the excess O2 administered based on the ideal arterial O2 tension (PaO2) target of 55-80 mmHg. We defined hyperoxemia as PaO2 > 100 mmHg and hyperoxia + hyperoxemia as an inspired O2 fraction (FiO2) > 60% + PaO2 > 100 mmHg. Risk factors for ICU-mortality and VAP were assessed through multivariate analyses. Results: One hundred thirty-four patients were included. For each day of mechanical ventilation, each patient received a median excess O2 of 1,121 [829-1,449] L. Hyperoxemia was found in 38 [27-55]% of arterial blood gases, hyperoxia + hyperoxemia in 11 [5-18]% of cases. The FiO2 was not reduced in 69 [62-76]% of cases of hyperoxemia. Adjustments were made more frequently with higher PaO2 or initial FiO2 levels. ICU-mortality was 32%. VAP was diagnosed in 48.5% of patients. Hyperoxemia (OR 1.300 95% CI [1.097-1.542]), time of exposure to hyperoxemia (OR 2.758 [1.406-5.411]), hyperoxia + hyperoxemia (OR 1.144 [1.008-1.298]), and daily excess O2 (OR 1.003 [1.001-1.005]) were associated with higher risk for ICU-mortality, independently of age, Sequential Organ failure Assessment score at ICU-admission and mean PaO2/FiO2. Hyperoxemia (OR 1.033 [1.006-1.061]), time of exposure to hyperoxemia (OR 1.108 [1.018-1.206]), hyperoxia + hyperoxemia (OR 1.038 [1.003-1.075]), and daily excess O2 (OR 1.001 [1.000-1.001]) were identified as risk factors for VAP, independently of body mass index, blood transfusions, days of neuromuscular blocking agents (before VAP), prolonged prone positioning and mean PaO2/FiO2 before VAP. Conclusion: Excess O2 administration and hyperoxemia were common in mechanically ventilated patients with SARS-CoV-2 pneumonia. The exposure to hyperoxemia may be associated with ICU-mortality and greater risk for VAP.

Effect of invasive mechanical ventilation on the diversity of the pulmonary microbiota.

Pulmonary microbial diversity may be influenced by biotic or abiotic conditions (e.g., disease, smoking, invasive mechanical ventilation (MV), etc.). Specially, invasive MV may trigger structural and physiological changes in both tissue and microbiota of lung, due to gastric and oral microaspiration, altered body posture, high O2 inhalation-induced O2 toxicity in hypoxemic patients, impaired airway clearance and ventilator-induced lung injury (VILI), which in turn reduce the diversity of the pulmonary microbiota and may ultimately lead to poor prognosis. Furthermore, changes in (local) O2 concentration can reduce the diversity of the pulmonary microbiota by affecting the local immune microenvironment of lung. In conclusion, systematic literature studies have found that invasive MV reduces pulmonary microbiota diversity, and future rational regulation of pulmonary microbiota diversity by existing or novel clinical tools (e.g., lung probiotics, drugs) may improve the prognosis of invasive MV treatment and lead to more effective treatment of lung diseases with precision.

TREK-1 Potassium Channel Activation Protects Against Influenza-A Induced Lung Injury

Introduction and Rationale: No targeted therapies exist that improve the outcomes of patients with Acute Respiratory Distress Syndrome (ARDS), in part to the multifactorial etiology of this devastating disease. Infectious agents remain the most common initiating insults, and besides SARS-CoV-2, Influenza-A virus (IAV) is responsible for more ARDS cases and deaths than any other agent. In fact, IAV increases the risk of mortality in ARDS patients three-fold, and accounts for almost half of all ARDS deaths. We recently identified TREK-1 potassium channels on epithelial cells as important regulators of alveolar inflammation and barrier function, two hallmarks of ARDS, and found that pharmacological activation of TREK-1 protects against hyperoxia-induced lung injury. However, whether TREK-1 channels convey similar protection in a clinically more relevant IAVinduced lung injury model, remains unknown. Methods: We infected adult C57BL/6 wildtype mice intra-tracheally (i.t.) with IAV (PR8 strain;TCID50 400), followed by once-daily i.t. injections (days 5, 6 and 7 post-IAV) with the novel TREK-1 activating compounds ML335 (60mcg/kg), BL1249 (100mcg/kg), or a vehicle control, to create a clinically-relevant treatment model. To evaluate the role of epithelial cells in this model, we infected primary human alveolar epithelial cells (HAEC) with IAV (0.01 pfu) for 24 hours. Endpoint analysis consistent in quantification of quasi-static lung compliance;BAL fluid total protein, cell counts, and ROS concentrations;cytokine levels in BAL fluid and cell supernatants;and HAEC viability (XTT assay). In addition, we measured alterations in epithelial potassium currents (fluorometric FLIPR assays) and in IAV-induced signaling cascades (real-time PCR) following IAV infection and treatment with our TREK-1 activators. Results: Oncedaily treatment of mice with the TREK-1 activating compounds ML335 or BL1249 following IAV infection improved lung compliance, and BAL fluid total protein levels, cell counts, IL-6, CXCL-10, MIP-1alpha, and TNF-alpha concentrations, but not ROS, CCL-2 or IL-10 levels. In HAEC, TREK-1 activation improved IAV-induced IL-6, CXCL-10, and CCL-2 levels, while MIP-1alpha, TNF-alpha and IL-10 levels remained unchanged. XTT assays confirmed that in our model IAV infection did not cause significant cell death. Interestingly, IAV infection decreased HAEC potassium currents, which could be counteracted by TREK-1 activation and cell hyperpolarization. Finally, TREK-1 activationmediated cell hyperpolarization inhibited TLR4- and TNFSF13-mediated downstream signaling in IAV-infected HAEC, whereas NFkB, RIG1, TLR3, and TLR7 signaling was not affected. Conclusions: TREK-1 potassium channel activation may represent a novel approach to protect against IAV-induced acute lung injury.

Role of NOX4 in Modulating Alveolar Type II (AT2) Epithelial Cell Phenotype and Mitochondrial Dynamics in Hyperoxic Acute Lung Injury

Introduction: Management of acute respiratory distress including COVID-19 pneumonia involves O2 supplementation, which is lifesaving, but causes severe hyperoxic acute lung injury (HALI). AT2 cells are the most affected cell type in hyperoxia (HO). NADPH oxidase (NOX) is a major source of reactive oxygen species (ROS) in HO. NOX4, the only functionally active NOX present in mitochondria, and primarily produces H2O2 as well as mtROS has been shown to be involved in several human pathologies. Not much is known about NOX4-induced mitochondrial injury in HALI. The current study aims to determine the role of AT2 epithelial cell NOX4 in HALI and the impact of HO on the modulation of mtROS and mitochondrial dynamics in HALI. Methods: Nox4-/-Spc-Cre animals were generated using tamoxifen induction and the knockdown was validated. The Nox4- /-Spc-Cre knockout (KO) and wild type (WT) mice were exposed to room air (NO) or 95% O2 (HO) for 66h to study the structural and functional changes in the lung. Transmission Electron Microscopy (TEM) was used to study the HO-induced changes in mitochondria. Isolated primary AT2 and/ mouse lung epithelial (MLE) cell line was investigated for mtROS, mt dynamics and apoptosis. Mitochondrial injury was assessed in Nox4 WT and Nox4 silenced cells. Results: C57BL/6J WT animals subjected to HO for 66h showed increased expression of NOX4, determining the role of NOX4 in HALI. The H&E staining demonstrated significant HALI in Nox4 WT animals exposed to HO compared to Nox4 KO as determined by increased infiltration of neutrophils, alveolar wall thickening and presence of proteinaceous debris in the alveolar space. Further, increased BAL cell count and protein levels, increased AT2 cell death and elevation of the proinflammatory cytokine IL- 6 and the chemokine KC was seen in WT animals compared to Nox4 KO. Analysis of lung tissues by TEM showed mitochondrial swelling, cristae damage and mitophagy in AT2 cells due to HO. Changes in mt injury markers were also observed. HO-induced NOX4 increase in primary AT2/ MLE-12 cells resulted in increased mtROS production and apoptosis, which was reduced with Nox4 siRNA silencing. Conclusion: This study suggests that the HO induced NOX4 expression in mouse lung, and deletion of Nox4 gene in AT2 cells reduced mtROS production and apoptosis and protected the lungs from severe hyperoxic lung injury. These results suggest NOX4 as a potential target for the treatment of HALI.

Compared to FiO2s >0.60, Few Preclinical Animal Studies Have Examined the Effects of Therapeutic FiO2s ≤ 0.60 in Models of Lung Infection or Noninfectious Injury: Preliminary Results of a Planned Systematic Review and Meta-Analysis

Rationale: While inspired fractional inspired oxygen concentrations (FiO2s) > 0.60 are avoided clinically when possible due in large part to animal study findings, FiO2s ≤ 0.60 have generally been thought relatively safe in hypoxemic patients. However, increasing attention is now being focused on the effects of conservative versus liberal therapeutic oxygen protocols in critically ill patients, especially in light of the prolonged courses of oxygen therapy SARS-CoV-2 patients are receiving. Notably, in the development of a lethal ß-coronavirus pneumonia model in mice that produces lung injury and progressive reductions in oxygen saturations like SARS-CoV-2, we found that atmospheric FiO2s as low as 0.30 reduced survival compared to room air. This finding prompted us to systematically examine the literature for the experience with FiO2s ≤0.60 but >0.21 in animal models of lung infection and non-infectious injury. Preliminary results from this review are presented here. Methods: In collaboration with a Biomedical Librarian, we performed a systematic literature search of Pubmed, EMBASE, and the Web of Science for relevant citations of published studies through September 30, 2021, using individualized search strategies for each database. Published studies that investigated animals challenged with a lung infection or other injury, and that compared outcomes, including survival, measures of organ injury or other changes, in animals administered therapeutic oxygen levels (FiO2 ≤0.60 but >0.21) versus ones administered room air (FiO2=0.21) were selected for further review. Results: After preliminary title and review of 12,446 retrieved reports and then removal of 2,049 duplicates, 51 s were found that described studies specifically examining an FiO2 ≤0.60 but >0.21 in a preclinical animal model with or without an infectious or noninfectious challenge. Based on findings, animals were challenged with bacteria in 14 studies, lipopolysaccharide in 2, acid aspiration in 2, mechanical ventilation in 1, while 12 each examined the effects of oxygen alone or oxygen with another pharmacologic agent. No study examined FiO2s ≤0.60 with viral challenge. By contrast, we found 520 s specifically describing investigations of FiO2s >0.60 and 258 describing the use of “hyperoxic” oxygen administration in similar types of models. Conclusions: A large preclinical literature identified the adverse effects of FiO2s ≥0.60 and hyperoxia and informed clinical practice. While similar preclinical studies examining FiO2s ≤0.60 are limited, they may be just as informative and should be encouraged in light of ongoing questions regarding the benefits and risks of conservative versus liberal therapeutic oxygen protocols.

Potential effect of amniotic fluid-derived stem cells on hyperoxia-induced pulmonary alveolar injury.

BACKGROUND: With the widespread of Coronavirus Disease 2019 pandemic, in spite of the newly emerging vaccines, mutated strains remain a great obstacle to supportive and preventive measures. Coronavirus 19 survivors continue to face great danger of contacting the disease again. As long as no specific treatment has yet to be approved, a great percentage of patients experience real complications, including among others, lung fibrosis. High oxygen inhalation especially for prolonged periods is per se destructive to the lungs. Nevertheless, oxygen remains the first line support for such patients. In the present study we aimed at investigating the role of amniotic fluid-mesenchymal stem cells in preventing versus treating the hyperoxia-induced lung fibrosis in rats. METHODS: The study was conducted on adult albino rats; 5 pregnant female rats were used as amniotic fluid donors, and 64 male rats were randomly divided into two groups: Control group; where 10 rats were kept in normal atmospheric air then sacrificed after 2 months, and hyperoxia-induced lung fibrosis group, where 54 rats were exposed to hyperoxia (100% oxygen for 6 h/day) in air-tight glass chambers for 1 month, then randomly divided into the following 5 subgroups: Hyperoxia group, cell-free media-treated group, stem cells-prophylactic group, stem cells-treated group and untreated group. Isolation, culture and proliferation of stem cells were done till passage 3. Pulmonary function tests, histological examination of lung tissue under light and electron microscopes, biochemical assessment of oxidative stress, IL-6 and Rho-A levels, and statistical analysis of data were performed. F-test (ANOVA) was used for normally distributed quantitative variables, to compare between more than two groups, and Post Hoc test (Tukey) for pairwise comparisons. RESULTS: Labelled amniotic fluid-mesenchymal stem cells homed to lung tissue. Stem cells administration in the stem cells-prophylactic group succeeded to maintain pulmonary functions near the normal values with no significant difference between their values and those of the control group. Moreover, histological examination of lung tissues showed that stem cells-prophylactic group were completely protected while stem cells-treated group still showed various degrees of tissue injury, namely; thickened interalveolar septa, atelectasis and interstitial pneumonia. Biochemical studies after stem cells injection also showed decreased levels of RhoA and IL-6 in the prophylactic group and to a lesser extent in the treated group, in addition to increased total antioxidant capacity and decreased malondialdehyde in the stem cells-injected groups. CONCLUSIONS: Amniotic fluid-mesenchymal stem cells showed promising protective and therapeutic results against hyperoxia-induced lung fibrosis as evaluated physiologically, histologically and biochemically.

Thioredoxin Prevents Loss of UCP2 in Hyperoxia via MKK4-p38 MAPK-PGC1α Signaling and Limits Oxygen Toxicity.

Administration of high concentrations of oxygen (hyperoxia) is one of few available options to treat acute hypoxemia-related respiratory failure, as seen in the current coronavirus disease (COVID-19) pandemic. Although hyperoxia can cause acute lung injury through increased production of superoxide anion (O2•-), the choice of high-concentration oxygen administration has become a necessity in critical care. The objective of this study was to test the hypothesis that UCP2 (uncoupling protein 2) has a major function of reducing O2•- generation in the lung in ambient air or in hyperoxia. Lung epithelial cells and wild-type; UCP2-/-; or transgenic, hTrx overexpression-bearing mice (Trx-Tg) were exposed to hyperoxia and O2•- generation was measured by using electron paramagnetic resonance, and lung injury was measured by using histopathologic analysis. UCP2 expression was analyzed by using RT-PCR analysis, Western blotting analysis, and RNA interference. The signal transduction pathways leading to loss of UCP2 expression were analyzed by using IP, phosphoprotein analysis, and specific inhibitors. UCP2 mRNA and protein expression were acutely decreased in hyperoxia, and these decreases were associated with a significant increase in O2•- production in the lung. Treatment of cells with rhTrx (recombinant human thioredoxin) or exposure of Trx-Tg mice prevented the loss of UCP2 protein and decreased O2•- generation in the lung. Trx is also required to maintain UCP2 expression in normoxia. Loss of UCP2 in UCP2-/- mice accentuated lung injury in hyperoxia. Trx activates the MKK4-p38MAPK (p38 mitogen-activated protein kinase)-PGC1α (PPARγ [peroxisome proliferator-activated receptor γ] coactivator 1α) pathway, leading to rescue of UCP2 and decreased O2•- generation in hyperoxia. Loss of UCP2 in hyperoxia is a major mechanism of O2•- production in the lung in hyperoxia. rhTrx can protect against lung injury in hyperoxia due to rescue of the loss of UCP2.

Oxygen: Friend or foe in the COVID-19 battle.

Hypoxia and hypoxemia are two different entities. Correcting hypoxemia without hypoxia tends to have disastrous effects and delays lung healing. In this study, we share a case of an elderly man with moderate COVID-19 who never received any form of supplemental oxygen as compared to other patients with similar presentation.

Role of SatO2, PaO2/FiO2 Ratio and PaO2 to Predict Adverse Outcome in COVID-19: A Retrospective, Cohort Study.

COVID-19 respiratory failure is a life-threatening condition. Oxygenation targets were evaluated in a non-ICU setting. In this retrospective, observational study, we enrolled all patients admitted to the University Hospital of Genoa, Italy, between 1 February and 31 May 2020 with an RT-PCR positive for SARS-CoV-2. PaO2, PaO2/FiO2 and SatO2% were collected and analyzed at time 0 and in case of admission, patients who required or not C-PAP (groups A and B) were categorized. Each measurement was correlated to adverse outcome. A total of 483 patients were enrolled, and 369 were admitted to hospital. Of these, 153 required C-PAP and 266 had an adverse outcome. Patients with PaO2 <60 and >100 had a higher rate of adverse outcome at time 0, in groups A and B (OR 2.52, 3.45, 2.01, respectively). About the PaO2/FiO2 ratio, the OR for < 300 was 3.10 at time 0, 4.01 in group A and 4.79 in group B. Similar odds were found for < 200 in any groups and < 100 except for group B (OR 11.57). SatO2 < 94% showed OR 1.34, 3.52 and 19.12 at time 0, in groups A and B, respectively. PaO2 < 60 and >100, SatO2 < 94% and PaO2/FiO2 ratio < 300 showed at least two- to three-fold correlation to adverse outcome. This may provide simple but clear targets for clinicians facing COVID-19 respiratory failure in a non ICU-setting.

A General Overview on the Hyperbaric Oxygen Therapy: Applications, Mechanisms and Translational Opportunities.

Hyperbaric oxygen therapy (HBOT) consists of using of pure oxygen at increased pressure (in general, 2-3 atmospheres) leading to augmented oxygen levels in the blood (Hyperoxemia) and tissue (Hyperoxia). The increased pressure and oxygen bioavailability might be related to a plethora of applications, particularly in hypoxic regions, also exerting antimicrobial, immunomodulatory and angiogenic properties, among others. In this review, we will discuss in detail the physiological relevance of oxygen and the therapeutical basis of HBOT, collecting current indications and underlying mechanisms. Furthermore, potential areas of research will also be examined, including inflammatory and systemic maladies, COVID-19 and cancer. Finally, the adverse effects and contraindications associated with this therapy and future directions of research will be considered. Overall, we encourage further research in this field to extend the possible uses of this procedure. The inclusion of HBOT in future clinical research could be an additional support in the clinical management of multiple pathologies.

Oxygen in Metabolic Dysfunction and Its Therapeutic Relevance.

Significance: In recent years, a number of studies have shown altered oxygen partial pressure at a tissue level in metabolic disorders, and some researchers have considered oxygen to be a (macro) nutrient. Oxygen availability may be compromised in obesity and several other metabolism-related pathological conditions, including sleep apnea-hypopnea syndrome, the metabolic syndrome (which is a set of conditions), type 2 diabetes, cardiovascular disease, and cancer. Recent Advances: Strategies designed to reduce adiposity and its accompanying disorders have been mainly centered on nutritional interventions and physical activity programs. However, novel therapies are needed since these approaches have not been sufficient to counteract the worldwide increasing rates of metabolic disorders. In this regard, intermittent hypoxia training and hyperoxia could be potential treatments through oxygen-related adaptations. Moreover, living at a high altitude may have a protective effect against the development of abnormal metabolic conditions. In addition, oxygen delivery systems may be of therapeutic value for supplying the tissue-specific oxygen requirements. Critical Issues: Precise in vivo methods to measure oxygenation are vital to disentangle some of the controversies related to this research area. Further, it is evident that there is a growing need for novel in vitro models to study the potential pathways involved in metabolic dysfunction to find appropriate therapeutic targets. Future Directions: Based on the existing evidence, it is suggested that oxygen availability has a key role in obesity and its related comorbidities. Oxygen should be considered in relation to potential therapeutic strategies in the treatment and prevention of metabolic disorders. Antioxid. Redox Signal. 35, 642-687.

Systemic Oxygen Utilization in Severe COVID-19 Respiratory Failure: A Case Series.

BACKGROUND: Management of hypoxemia in patients with severe COVID-19 respiratory failure is based on the guideline recommendations for specific SpO2 targets. However, limited data exist on systemic O2 utilization. The objective of this study was to examine systemic O2 utilization in a case series of patients with this disease. PATIENTS AND METHODS: Between March 24, and April 9, 2020, 8 patients intubated for severe COVID-19 respiratory failure had near-simultaneous drawing of arterial blood gas (ABG), central venous blood gas (cVBG), and central venous oxygen saturation (ScvO2) at a mean of 6.1 days into hospitalization. Three patients were managed with indirect cardiac output (CO) monitoring by FloTrac sensor and Vigileo monitor (Edwards Lifesciences, Irvine, CA). The oxygen extraction index (OEI; SaO2-ScvO2/SaO2) and oxygen extraction fraction (OEF; CaO2-CvO2/CaO2 ≥ 100) were calculated. Values for hyperoxia (ScvO2 ≥ 90%), normoxia (ScvO2 71-89%), and hypoxia (ScvO2 ≤ 70%) were based on the literature. Mean values were calculated. RESULTS: The mean partial pressure of oxygen (PaO2) was 102 with a mean fraction of inspired O2 (FiO2) of 44%. One patient was hyperoxic with a reduced OEI (17%). Five patients were normoxic, but 2 had a reduced OEF (mean 15.9%). Two patients were hypoxic but had increased systemic O2 utilization based on OEF or OEI. CONCLUSION: In select patients with severe COVID-19 respiratory failure, O2 delivery (DO2) was found to exceed O2 utilization. SpO2 targets based on systemic O2 utilization may help in reducing oxygen toxicity, especially in the absence of anaerobic metabolism. Further data are needed on the prevalence of systemic O2 utilization in COVID-19. HOW TO CITE THIS ARTICLE: Garg RK, Kimbrough T, Lodhi W, DaSilva I. Systemic Oxygen Utilization in Severe COVID-19 Respiratory Failure: A Case Series. Indian J Crit Care Med 2021;25(2):215-218.

Hyperoxia and modulation of pulmonary vascular and immune responses in COVID-19.

Oxygen is the most commonly used therapy in hospitalized patients with COVID-19. In those patients who develop worsening pneumonia and acute respiratory distress syndrome (ARDS), high concentrations of oxygen may need to be administered for prolonged time periods, often together with mechanical ventilation. Hyperoxia, although lifesaving and essential for maintaining adequate oxygenation in the short term, may have adverse long-term consequences upon lung parenchymal structure and function. How hyperoxia per se impacts lung disease in COVID-19 has remained largely unexplored. Numbers of experimental studies have previously established that hyperoxia is associated with deleterious outcomes inclusive of perturbations in immunologic responses, abnormal metabolic function, and alterations in hemodynamics and alveolar barrier function. Such changes may ultimately progress into clinically evident lung injury and adverse remodeling and result in parenchymal fibrosis when exposure is prolonged. Given that significant exposure to hyperoxia in patients with severe COVID-19 may be unavoidable to preserve life, these sequelae of hyperoxia, superimposed on the cytopathic effects of SARS-CoV-2 virus, may well impact pathogenesis of COVID-19-induced ARDS.

Tracing the path of inhaled nitric oxide: Biological consequences of protein nitrosylation.

Nitric oxide (NO) is a comprehensive regulator of vascular and airway tone. Endogenous NO produced by nitric oxide synthases regulates multiple signaling cascades, including activation of soluble guanylate cyclase to generate cGMP, relaxing smooth muscle cells. Inhaled NO is an established therapy for pulmonary hypertension in neonates, and has been recently proposed for the treatment of hypoxic respiratory failure and acute respiratory distress syndrome due to COVID-19. In this review, we summarize the effects of endogenous and exogenous NO on protein S-nitrosylation, which is the selective and reversible covalent attachment of a nitrogen monoxide group to the thiol side chain of cysteine. This posttranslational modification targets specific cysteines based on the acid/base sequence of surrounding residues, with significant impacts on protein interactions and function. S-nitrosothiol (SNO) formation is tightly compartmentalized and enzymatically controlled, but also propagated by nonenzymatic transnitrosylation of downstream protein targets. Redox-based nitrosylation and denitrosylation pathways dynamically regulate the equilibrium of SNO-proteins. We review the physiological roles of SNO proteins, including nitrosohemoglobin and autoregulation of blood flow through hypoxic vasodilation, and pathological effects of nitrosylation including inhibition of critical vasodilator enzymes; and discuss the intersection of NO source and dose with redox environment, in determining the effects of protein nitrosylation.

The Positive Allosteric Modulation of alpha7-Nicotinic Cholinergic Receptors by GAT107 Increases Bacterial Lung Clearance in Hyperoxic Mice by Decreasing Oxidative Stress in Macrophages.

Supplemental oxygen therapy with supraphysiological concentrations of oxygen (hyperoxia; >21% O2) is a life-saving intervention for patients experiencing respiratory distress. However, prolonged exposure to hyperoxia can compromise bacterial clearance processes, due to oxidative stress-mediated impairment of macrophages, contributing to the increased susceptibility to pulmonary infections. This study reports that the activation of the α7 nicotinic acetylcholine receptor (α7nAChR) with the delete allosteric agonistic-positive allosteric modulator, GAT107, decreases the bacterial burden in mouse lungs by improving hyperoxia-induced lung redox imbalance. The incubation of RAW 264.7 cells with GAT107 (3.3 µM) rescues hyperoxia-compromised phagocytic functions in cultured macrophages, RAW 264.7 cells, and primary bone marrow-derived macrophages. Similarly, GAT107 (3.3 µM) also attenuated oxidative stress in hyperoxia-exposed macrophages, which prevents oxidation and hyper-polymerization of phagosome filamentous actin (F-actin) from oxidation. Furthermore, GAT107 (3.3 µM) increases the (1) activity of superoxide dismutase 1; (2) activation of Nrf2 and (3) the expression of heme oxygenase-1 (HO-1) in macrophages exposed to hyperoxia. Overall, these data suggest that the novel α7nAChR compound, GAT107, could be used to improve host defense functions in patients, such as those with COVID-19, who are exposed to prolonged periods of hyperoxia.