Reduced Oxygen Delivery Research Articles

Association between oxygen delivery and digital ulcers in systemic sclerosis.

Tissue hypoxia due to microvasculopathy is the main cause of digital ulcers (DUs) in systemic sclerosis (SSc). Reduced oxygen delivery (DO2) to the tissues may also contribute to the development of DU. This study was conducted to investigate the association between DO2 and DUs in patients with SSc. In all, 111 patients and 30 healthy controls were enrolled. DO2 was calculated by using the formula; DO2=Cardiac output×arterial oxygen saturation (SpO2)×serum haemoglobin level×1.39×10. Both right index finger SpO2 measurements (index-SpO2) and highest value of SpO2 (maximum SpO2) obtained among the fingers of the subjects were used for the calculations and DO2 results were adjusted both for weight and body surface area (BSA). Mean DO2 was lower in SSc patients as compared to controls in all 4 different calculations but the difference was only statistically significant when using index-SpO2 and adjusting for BSA (498mL/min/m2 vs 549mL/min/m2, p=0.03). There was a strong positive correlation between cardiac output and DO2 calculated by using the index-SpO2 (r=0.903; p<0.001). Of the SSc patients, 46 (41.4%) had DUs within the last 12months. Patients with DUs had higher mean mRSS, lover mean FVC and more frequently diffuse disease, interstitial lung disease, anti-SCL70 antibody positivity (p<0.05 for all). No difference was observed in DO2 among DU positive or DU negative groups by any calculation (p>0.05 for all). DO2 in SSc patients seems to be lower than healthy controls. However, DO2 is similar between the patients with and without DUs. Our results suggest that the contribution of DO2 is negligible to the development of DU and support the major role of microvasculopathy in SSc patients with DUs.

Differential Expression of NME4 in Trophoblast Stem-Like Cells and Peripheral Blood Mononuclear Cells of Normal Pregnancy and Preeclampsia.

Preeclampsia (PE) is known to arise from insufficient trophoblast invasion as uterine spiral arteries lack remodeling. A significant reduction in placental perfusion induces an ischemic placental microenvironment due to reduced oxygen delivery to the placenta and fetus, leading to oxidative stress. Mitochondria are involved in the regulation of cellular metabolism and the production of reactive oxygen species (ROS). NME/NM23 nuceloside diphosphate kinase 4 (NME4) gene is known to have the ability to supply nucleotide triphosphate and deoxynucleotide triphosphate for replication and transcription of mitochondria. Our study aimed to investigate changes in NME4 expression in PE using trophoblast stem-like cells (TSLCs) from induced pluripotent stem cells (iPSCs) as a model of early pregnancy and peripheral blood mononuclear cells (PBMNCs) as a model of late preterm pregnancy. Transcriptome analysis using TSLCs was performed to identify the candidate gene associated with the possible pathophysiology of PE. Then, the expression of NME4 associated with mitochondrial function, p53 associated with cell death, and thioredoxin (TRX) linked to ROS were investigated through qRT-PCR, western blotting and deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick end labelling (TUNEL) assay. In patients with PE, NME4 was significantly downregulated in TSLCs but upregulated in PBMNCs. p53 was shown to be upregulated in TSLCs and PBMNCs of PE. In addition, western blot analysis confirmed that TRX expression had the tendency to increase in TSLCs of PE. Similarly, TUNEL analysis confirmed that the dead cells were higher in PE than in normal pregnancy. Our study showed that the expression of the NME4 differed between models of early and late preterm pregnancy of PE, and suggests that this expression pattern may be a potential biomarker for early diagnosis of PE.

Clinical Pediatric Exercise Laboratories, Reactive Balance, Sleep, and Muscle Stimulation Considerations

Clinical Pediatric Exercise Laboratories, Reactive Balance, Sleep, and Muscle Stimulation Considerations

No Code-The Role of Sodium Bicarbonate and Naloxone in Neonatal Resuscitation.

Resuscitations in neonates and infants present caregivers with challenging decisions in a highly stressful environment. Consideration of the pathophysiology of cardiac arrest and respiratory failure prior to an emergency allows for thoughtful utilization of pharmacotherapy. It is vital to remember that establishment of an airway and delivery of breaths and chest compressions should be prioritized. Epinephrine is first-line pharmacotherapy for severe bradycardia or cardiac arrest unresponsive to the provision of respiratory support and chest compressions. Sodium bicarbonate may be considered based on the intrinsic links between cardiac arrest, respiratory failure, and mixed acidosis. However, experimental and clinical data suggest that sodium bicarbonate worsens myocardial performance by several mechanisms (decreased intramyocardial pH, reduced oxygen delivery to tissues, reduced coronary perfusion pressure). Additionally, rapid administration of this hyperosmolar therapy may contribute to intracranial hemorrhage. With no clear benefit and multiple risks, sodium bicarbonate has been excluded from neonatal resuscitation algorithms. Opioids may produce respiratory depression in neonates, whether given to the mother prior to delivery or in neonatal intensive care; therefore, naloxone may be considered to restore respiratory drive. However, 50 years of neonatal utilization has not produced clinical studies documenting efficacy and safety. On the contrary, clinical studies fail to detect clear benefit and numerous concerning adverse reactions have been reported, including acute withdrawal, cardiorespiratory decompensation, and death. For these reasons, naloxone has also been removed from neonatal resuscitation algorithms. Clear understanding of pathophysiology, pharmacology, and clinical data support the use of multiple pharmacotherapies in neonatal resuscitation, including epinephrine, normal saline, intravenous glucose, adenosine, and calcium gluconate as reviewed in a previous column. The same pathways inform confident exclusion of sodium bicarbonate and naloxone.

Different Dimensions of the Effects of SARS-CoV-2 in Causing Fluctuations in the Blood Pressure of Patients

In late 2019, SARS-CoV-2 was transmitted from animal to human in China. Subsequently, the virus spread rapidly throughout the world by human-to-human transmission and caused high mortality the people with underlying diseases, especially hypertension. This virus binds to its receptor, angiotensin-converting enzyme-2 (ACE2), via the S protein. ACE2 has a negative regulatory function in the renin-angiotensin system (RAS) and degrades angiotensin 2 (Ang II) as a vasoconstrictor which causes blood pressure regulation. It also converts Ang II to Ang1-7, which has anti-inflammatory and anti-oxidative effects. SARS-CoV-2 infection in patients with hypertension reduces ACE2 levels due to virus binding, which decreases Ang II degradation. Consequently, the complications associated with hypertension are raised, and blood pumping from the lungs into the left atrium lowers. On the other hand, the final product, Ang1-7, is reduced, and its related anti-inflammatory activity is also eliminated. The virus multiplies and damages lung cells, causing inflammation and edema of the lung tissue through the function of immune cells and cytokines, which eventually leads to lung damage, reduced oxygen delivery, and death. Careful care of patients with hypertension can prevent their infection and reduce their death with appropriate oxygen therapy and possibly using exogenous ACE2 supplements.

FREQUENCY OF MODERATE TO SEVERE BIRTH ASPHYXIA OF NEWBORNS AND ITS RISK FACTORS AT TWO MAJOR HOSPITALS OF KOHAT

Asphyxia is defined as lack of oxygen (hypoxia) due to failure of initiation of breathing. A condition during the perinatal period that severely reduces oxygen delivery and leads to acidosis. A lack of oxygen or an excess of carbon dioxide caused by the interruption in breathing, is the result of the failure of the gas exchange organ. Asphyxia continues to be a major cause of morbidity and mortality in the neonatal period (WHO).

REFRACTORY HYPOXEMIA: A CASE OF DAPSONE-INDUCED METHEMOGLOBINEMIA IN A PATIENT WITH COVID-19

REFRACTORY HYPOXEMIA: A CASE OF DAPSONE-INDUCED METHEMOGLOBINEMIA IN A PATIENT WITH COVID-19

Single Leg Cycling Offsets Reduced Muscle Oxygenation in Hypoxic Environments.

The intensity of large muscle mass exercise declines at altitude due to reduced oxygen delivery to active muscles. The purpose of this investigation was to determine if the greater limb blood flow during single-leg cycling prevents the reduction in tissue oxygenation observed during traditional double-leg cycling in hypoxic conditions. Ten healthy individuals performed bouts of double and single-leg cycling (4, four-minute stages at 50–80% of their peak oxygen consumption) in hypoxic (15% inspired O2) and normoxic conditions. Heart rate, mean arterial pressure, femoral blood flow, lactate, oxygenated hemoglobin, total hemoglobin, and tissue saturation index in the vastus lateralis were recorded during cycling tests. Femoral blood flow (2846 ± 912 mL/min) and oxygenated hemoglobin (−2.98 ± 3.56 au) during single-leg cycling in hypoxia were greater than double-leg cycling in hypoxia (2429 ± 835 mL/min and −6.78 ± 3.22 au respectively, p ≤ 0.01). In addition, tissue saturation index was also reduced in the double-leg hypoxic condition (60.2 ± 3.1%) compared to double-leg normoxic (66.0 ± 2.4%, p = 0.008) and single-leg hypoxic (63.3 ± 3.2, p < 0.001) conditions. These data indicate that while at altitude, use of reduced muscle mass exercise can help offset the reduction in tissue oxygenation observed during larger muscle mass activities allowing athletes to exercise at greater limb/muscle specific intensities.

An unusual case of methemoglobinemia resulting from self-administration of nitrobenzene in a psychiatric patient

Nitrobenzene, when consumed in large enough doses, can cause methemoglobinemia. By reducing oxygen unloading and oxygen binding, methemoglobinemia reduces oxygen delivery. This is a case of 55-year-old man who is a known case of psychiatric disorder was brought to the emergency room with an alleged history of deliberate consumption of nitrobenzene liquid approximately 10 mL in the morning of the day at his residence. He also instilled 2 drops in the right ear and was taken to a private hospital where the initial management with gastric lavage, multidose activated charcoal and methylene blue was given. He was then referred to the government tertiary care setting for further management. Prompt intravenous methylene blue treatment increases PaO2 in patients with methemoglobinemia.

Multi‐Omics Integration and the Development of Gestational High Altitude Induced Pulmonary Arterial Hypertension

High altitude (&gt; 2500 meters) during pregnancy reduces oxygen delivery to the fetus (i.e., gestational hypoxia), causing abnormal fetal lung development. The pulmonary arteries become thicker and less functional, increasing the risk of pulmonary hypertension, which is a multiorgan disease that promotes right heart failure and under five‐years mortality rate. Our previous work showed endoplasmic reticulum stress and metabolomic alterations in fetal sheep pulmonary arteries indicative of an unregulated inflammatory response after gestational hypoxia. To understand the relationships between inflammation, vascular remodeling, and pulmonary arterial hypertension development, we examined the omic links between the pulmonary arteries and plasma exosomes in fetal sheep exposed to high altitude (3801 meters) for the majority of the pregnancy (110+ days out of 138‐141 days of pregnancy). Specifically, metabolomics and proteomic analyses from the pulmonary arteries and transcriptomic analysis of plasma exosomes were integrated from fetal sheep to understand the mechanisms driving this multiorgan disease. Sixteen miRNAs and 75 proteins were differentially expressed between normoxic and hypoxic samples. Gestational hypoxia resulted in significant changes in 90 metabolites in fetal pulmonary arteries. These results show exosomal microRNA are linked with pulmonary artery proteins and metabolites important to cell membrane composition which might explain their role in the facilitation of changes in vascular remodeling, inflammation, and cell signaling. Top canonical pathways noted in omics data integration were acute phase response signaling, atherosclerosis signaling, FXR/RXR activation, intrinsic prothrombin activation pathway, and LXR/RXR activation. This multi‐omics study illustrates the intricacy of complex adaptations that occur in the fetal sheep lung in response to gestational hypoxia.

Weddell seals (Leptonychotes weddellii) respond less to inflammatory stimuli to evade ischemic‐reperfusion injury

During diving, Weddell seals (Leptonychotes weddellii) experience repeated hypoxemia. To mediate hypoxic tissue damage, Weddell seals employ vasoconstriction favoring vital organs (e.g. brain, lung, adrenals) resulting in reduced oxygen delivery to visceral and peripheral tissues. Weddell seals therefore experience periods of local ischemia associated with vasoconstriction followed by reoxygenation and return of perfusion at the surface. Ischemia‐reperfusion injury (IRI) is the expected result from reduced blood flow and localized hypoxia, followed by reoxygenation and reperfusion. A typical human response to IRI induces inflammation. We studied the inflammatory response of Weddell seals to determine whether its downregulation could be a mechanism by which seals avoid hypoxic and IRI injury. Weddell seal white blood cells (n=12) demonstrate a reduced immune reaction (mean ± stdev 247± 200 fold induction of IL‐6 from baseline) compared to human monocytes (n=6 replicates, THP‐1 cells 3091 ± 1126 fold IL‐6 induction, t‐test p&lt;0.0001) when exposed to an inflammatory stimulus in vitro (10 ng/mL lipopolysaccharide). To evaluate species differences in gene pathways associated with the immune response, we conducted RNA‐seq and identified distinct transcriptomic profiles between species. We next evaluated the inflammatory response of Weddell seal primary cells (monocytes and pulmonary endothelial cells) resulting from hypoxia and reoxygenation. By simulating this natural stressor, we aim to discover whether the response of immune cells is an important component of molecular protection against IRI inflammatory sequelae in diving seals.

Hepatic artery flow, inspired oxygen, and hemoglobin determine liver tissue saturation measured with visible diffuse reflectance spectroscopy (vis‐DRS) in an in vivo swine model

Prompt diagnosis of vascular compromise following pediatric liver transplantation and restoration of oxygen delivery to the liver improves organ survival. vis-DRS allows for real-time measurement of liver tissue saturation. The current study used vis-DRS to determine changes in liver saturation during clinically relevant conditions of reduced oxygen delivery. In an in vivo swine model (n=15), we determined liver tissue saturation (St O2 ) during stepwise reduction in hepatic artery flow, different inspiratory oxygen fraction (FiO2 ), and increasing hemodilution. A custom vis-DRS probe was placed directly on the organ. Liver tissue saturation decreased significantly with a decrease in hepatic artery flow. A reduction in hepatic artery flow to 25% of baseline reduced the St O2 by 15.3±1.4% at FiO2 0.3 (mean±SE, p<.0013), and by 8.3±1.9% at FiO2 1.0 (p=.0013). After hemodilution to 7-8g/dl, St O2 was reduced by 31.8%±2.7%, p<.001 (FiO2 0.3) and 26.6±2.7%, p<.001 (FiO2 : 1.0) respectively. Portal venous saturation during low hepatic artery flow was consistently higher at FiO2 1.0. The gradient between portal venous saturation and liver tissue saturation was consistently greater at lower hemoglobin levels (7.0±1.6% per g/dl hemoglobin, p<.001). Vis-DRS showed prompt changes in liver tissue saturation with decreases in hepatic artery blood flow. At hepatic artery flows below 50% of baseline, liver saturation depended on FiO2 and hemoglobin concentration suggesting that during hepatic artery occlusion, packed red blood cell transfusion and increased FiO2 may be useful measures to reduce hypoxic damage until surgical revascularization.

Clinical Update on Vasopressors and Titration Strategies.

Clinical Update on Vasopressors and Titration Strategies.

Pre-hospital continuous positive airway pressure after blast lung injury and hypovolaemic shock: a modelling study

BackgroundIn non-traumatic respiratory failure, pre-hospital application of CPAP reduces the need for intubation. Primary blast lung injury (PBLI) accompanied by haemorrhagic shock is common after mass casualty incidents. We hypothesised that pre-hospital CPAP is also beneficial after PBLI accompanied by haemorrhagic shock. MethodsWe performed a computer-based simulation of the cardiopulmonary response to PBLI followed by haemorrhage, calibrated from published controlled porcine experiments exploring blast injury and haemorrhagic shock. The effect of different CPAP levels was simulated in three in silico patients who had sustained mild, moderate, or severe PBLI (10%, 25%, 50% contusion of the total lung) plus haemorrhagic shock. The primary outcome was arterial partial pressure of oxygen (Pao2) at the end of each simulation. ResultsIn mild blast lung injury, 5 cm H2O ambient-air CPAP increased Pao2 from 10.6 to 12.6 kPa. Higher CPAP did not further improve Pao2. In moderate blast lung injury, 10 cm H2O CPAP produced a larger increase in Pao2 (from 8.5 to 11.1 kPa), but 15 cm H2O CPAP produced no further benefit. In severe blast lung injury, 5 cm H2O CPAP inceased Pao2 from 4.06 to 8.39 kPa. Further increasing CPAP to 10–15 cm H2O reduced Pao2 (7.99 and 7.90 kPa, respectively) as a result of haemodynamic impairment resulting from increased intrathoracic pressures. ConclusionsOur modelling study suggests that ambient air 5 cm H2O CPAP may benefit casualties suffering from blast lung injury, even with severe haemorrhagic shock. However, higher CPAP levels beyond 10 cm H2O after severe lung injury reduced oxygen delivery as a result of haemodynamic impairment.

Can Erythropoietin Reduce Hypoxemic Neurological Damages in Neonates With Congenital Heart Defects?

Congenital heart defects (CHD), the most common cause of birth defects with increasing birth prevalence, affect nearly 1% of live births worldwide. Cyanotic CHD are characterized by hypoxemia, with subsequent reduced oxygen delivery to the brain, especially critical during brain development, beginning in the fetus and continuing through the neonatal period. Therefore, neonates with CHD carry a high risk for neurological comorbidities, even more frequently when there are associated underlying genetic disorders. We review the currently available knowledge on potential prevention strategies to reduce brain damage induced by hypoxemia during fetal development and immediately after birth, and the role of erythropoietin (EPO) as a potential adjunctive treatment. Maternal hyper-oxygenation had been studied as a potential therapeutic to improve fetal oxygenation. Despite demonstrating some effectiveness, maternal hyper-oxygenation has proven to be impractical for extensive clinical application, thus prompting the investigation of specific pathways for pharmacological intervention. Among those, the role of antioxidant pathways and Hypoxia Inducible Factors (HIF) have been studied for their involvement in the protective response to hypoxic injury. One of the proteins induced by HIF, EPO, has properties of being anti-apoptotic, antioxidant, and protective for neurons, astrocytes, and oligodendrocytes. In human trials, EPO administration in neonates with hypoxic ischemic encephalopathy (HIE) significantly reduced the neurological hypoxemic damages in several reported studies. Currently, it is unknown if the mechanisms of pathophysiology of cyanotic CHD are like HIE. Neonates with cyanotic CHD are exposed to both chronic hypoxemia and episodes of acute ischemia-reperfusion injury when undergo cardiopulmonary bypass surgery requiring aortic cross-clamp and general anesthesia. Our review supports future trials to evaluate the potential efficiency of EPO in reducing the hypoxemic neurologic damages in neonates with CHD. Furthermore, it suggests the need to identify early biomarkers of hypoxia-induced neurological damage, which must be sensitive to the neuroprotective effects of EPO.

Characteristics of clinical signs, laboratory and instrumental examinations in various mechanisms of development of type 2 myocardial infarction

Aim. To identify different pathogenetic variants of myocardial infarction type 2 (MI-2).&#x0D; Material and methods. Reviewed 4168 cases of MI admitted in multidisciplinary hospital for 10 years. 353 patients met the criteria for MI-2 without signs of coronary atherothrombosis (CA). In the study group, the features of clinical and laboratory-instrumental manifestations were evaluated.&#x0D; Results. Cases of IM-2 were subdivided into 4 clinical-pathogenic variants (CPV): 1-CPV developed due an increasing in myocardial oxygen demand; 2-CPV, arising from a decrease in the supply of oxygen; 3-CPV associated with local coronary circulation disorder; 4-CPV developed due to the combined oxygen-energy imbalance. In 72 (20.4%) cases, 1-CPV was detected, caused by a hypertensive crisis and/or tachyarrhythmias; 2-CPV observed in 73 (20.68%) patients with hypotension, anemia, microvascular dysfunction, respiratory failure; 3-CPV caused by spasm and embolism of CA was detected in 47 (13.31%) cases; in 161 (45.61%) patients, IM-2 is associated with increased myocardial oxygen demand with reduced oxygen delivery. The gender and risk factors in groups are comparable. The average age of 1-CPV- and 3-CPV-patients was less and amounted to 65.7 and 56.5 versus 70.2 and 73.8 years in the 2-CPV and 4-CPV. Typical clinical and laboratory-instrumental signs of MI were common for patients with 1-CPV and 3-CPV, while 2-CPV and 4-CPV more often had chronic severe pathology, multivessel coronary disorder, and the clinical presentation and ischemic signs were less common.&#x0D; Conclusion. Clinical manifestations and results of examination of patients with MI-2 depend on the mechanism of its development.

Blood volume versus deoxygenated NIRS signal: computational analysis of the effects muscle O2 delivery and blood volume on the NIRS signals.

Near-infrared spectroscopy (NIRS) signals quantify the oxygenated (ΔHbMbO2) and deoxygenated (ΔHHbMb) heme group concentrations. ΔHHbMb has been preferred to ΔHbMbO2 in evaluating skeletal muscle oxygen extraction because it is assumed to be less sensitive to blood volume (BV) changes, but uncertainties exist on this assumption. To analyze this assumption, a computational model of oxygen transport and metabolism is used to quantify the effect of O2 delivery and BV changes on the NIRS signals from a canine model of muscle oxidative metabolism (Sun Y, Ferguson BS, Rogatzki MJ, McDonald JR, Gladden LB. Med Sci Sports Exerc 48: 2013-2020, 2016). The computational analysis accounts for microvascular (ΔHbO2, ΔHHb) and extravascular (ΔMbO2, ΔHMb) oxygenated and deoxygenated forms. Simulations predicted muscle oxygen uptake and NIRS signal changes well for blood flows ranging from resting to contracting muscle. Additional NIRS signal simulations were obtained in the absence or presence of BV changes corresponding to a heme groups concentration changes (ΔHbMb = 0-48 µM). Under normal delivery (Q = 1.0 L·kg-1·min-1) in contracting muscle, capillary oxygen saturation (So2) was 62% with capillary ΔHbO2 and ΔHHb of ± 41 µΜ for ΔHbMb = 0. An increase of BV (ΔHbMb = 24 µΜ) caused a ΔHbO2 decrease (16µΜ) almost twice as much as the increase observed for ΔHHb (9 µΜ). When So2 increased to more than 80%, only ΔHbO2 was significantly affected by BV changes. The analysis indicates that microvascular So2 is a key factor in determining the sensitivity of ΔHbMbO2 and deoxygenated ΔHHbMb to BV changes. Contrary to a common assumption, the ΔHHbMb is affected by BV changes in normal contracting muscle and even more in the presence of impaired O2 delivery.NEW & NOTEWORTHY Deoxygenated is preferred to the oxygenated near-infrared spectroscopy signal in evaluating skeletal muscle oxygen extraction because it is assumed to be insensitive to blood volume changes. The quantitative analysis proposed in this study indicates that even in absence of skin blood flow effects, both NIRS signals in presence of either normal or reduced oxygen delivery are affected by blood volume changes. These changes should be considered to properly quantify muscle oxygen extraction by NIRS methods.

Effect of goal-directed fluid management guided by non-invasive device on incidence of postoperative complications in neurosurgery

Abstract Introduction: Goal-directed hemodynamic therapy aims to reduce the incidence of postoperative complications in patients undergoing surgical procedures. Optimal preload is mandatory to achieve adequate cardiac output and oxygen supply to organs and tissues. Neurosurgical patients are at risk of inadequate preload, decreased blood flow and reduced oxygen delivery, all of which can lead to organ dysfunction. Current knowledge regarding the effect of fluid management on patient-orientated outcomes in neurosurgery is limited. Therefore, this study aims to compare the safety and feasibility of goal-directed therapy with standard management in patients undergoing neurosurgical procedures. Methods and analysis: Patients undergoing neurosurgical operation will be randomised into two groups. Therapy in the first group of patients will be guided by standard perioperative monitoring. In the second group, perioperative therapy will be guided using non-invasive hemodynamic monitoring in addition to standard monitoring. Administration of fluids and vasoactive drugs will depend on the assessment of stroke volume variation and cardiac index. The safety of goal-directed hemodynamic therapy protocol will be assessed by comparing incidences of adverse events between groups.

Gestational Hypoxia and Blood-Brain Barrier Permeability: Early Origins of Cerebrovascular Dysfunction Induced by Epigenetic Mechanisms

Fetal chronic hypoxia leads to intrauterine growth restriction (IUGR), which is likely to reduce oxygen delivery to the brain and induce long-term neurological impairments. These indicate a modulatory role for oxygen in cerebrovascular development. During intrauterine hypoxia, the fetal circulation suffers marked adaptations in the fetal cardiac output to maintain oxygen and nutrient delivery to vital organs, known as the “brain-sparing phenotype.” This is a well-characterized response; however, little is known about the postnatal course and outcomes of this fetal cerebrovascular adaptation. In addition, several neurodevelopmental disorders have their origins during gestation. Still, few studies have focused on how intrauterine fetal hypoxia modulates the normal brain development of the blood-brain barrier (BBB) in the IUGR neonate. The BBB is a cellular structure formed by the neurovascular unit (NVU) and is organized by a monolayer of endothelial and mural cells. The BBB regulates the entry of plasma cells and molecules from the systemic circulation to the brain. A highly selective permeability system achieves this through integral membrane proteins in brain endothelial cells. BBB breakdown and dysfunction in cerebrovascular diseases lead to leakage of blood components into the brain parenchyma, contributing to neurological deficits. The fetal brain circulation is particularly susceptible in IUGR and is proposed to be one of the main pathological processes deriving BBB disruption. In the last decade, several epigenetic mechanisms activated by IU hypoxia have been proposed to regulate the postnatal BBB permeability. However, few mechanistic studies about this topic are available, and little evidence shows controversy. Therefore, in this mini-review, we analyze the BBB permeability-associated epigenetic mechanisms in the brain exposed to chronic intrauterine hypoxia.

Veno-venous extracorporeal blood phototherapy increases the rate of carbon monoxide (CO) elimination in CO-poisoned pigs.

Carbon monoxide (CO) inhalation is the leading cause of poison-related deaths in the United States. CO binds to hemoglobin (Hb), displaces oxygen, and reduces oxygen delivery to tissues. The optimal treatment for CO poisoning in patients with normal lung function is the administration of hyperbaric oxygen (HBO). However, hyperbaric chambers are only available in medical centers with specialized equipment, resulting in delayed therapy. Visible light dissociates CO from Hb with minimal effect on oxygen binding. In a previous study, we combined a membrane oxygenator with phototherapy at 623 nm to produce a "mini" photo-ECMO (extracorporeal membrane oxygenation) device, which improved CO elimination and survival in CO-poisoned rats. The objective of this study was to develop a larger photo-ECMO device ("maxi" photo-ECMO) and to test its ability to remove CO from a porcine model of CO poisoning. The "maxi" photo-ECMO device and the photo-ECMO system (six maxi photo-ECMO devices assembled in parallel), were tested in an in vitro circuit of CO poisoning. To assess the ability of the photo-ECMO device and the photo-ECMO system to remove CO from CO-poisoned blood in vitro, the half-life of COHb (COHb-t1/2 ), as well as the percent COHb reduction in a single blood pass through the device, were assessed. In the in vivo studies, we assessed the COHb-t1/2 in a CO-poisoned pig under three conditions: (1) While the pig breathed 100% oxygen through the endotracheal tube; (2) while the pig was connected to the photo-ECMO system with no light exposure; and (3) while the pig was connected to the photo-ECMO system, which was exposed to red light. The photo-ECMO device was able to fully oxygenate the blood after a single pass through the device. Compared to ventilation with 100% oxygen alone, illumination with red light together with 100% oxygen was twice as efficient in removing CO from blood. Changes in gas flow rates did not alter CO elimination in one pass through the device. Increases in irradiance up to 214 mW/cm2 were associated with an increased rate of CO elimination. The photo-ECMO device was effective over a range of blood flow rates and with higher blood flow rates, more CO was eliminated. A photo-ECMO system composed of six photo-ECMO devices removed CO faster from CO-poisoned blood than a single photo-ECMO device. In a CO-poisoned pig, the photo-ECMO system increased the rate of CO elimination without significantly increasing the animal's body temperature or causing hemodynamic instability. In this study, we developed a photo-ECMO system and demonstrated its ability to remove CO from CO-poisoned 45-kg pigs. Technical modifications of the photo-ECMO system, including the development of a compact, portable device, will permit treatment of patients with CO poisoning at the scene of their poisoning, during transit to a local emergency room, and in hospitals that lack HBO facilities.