Episodes Of Intermittent Hypoxia Research Articles

Chronic intermittent hypoxia facilitates the development of angiotensin II-induced abdominal aortic aneurysm in male mice.

Obstructive sleep apnea (OSA), characterized by episodes of intermittent hypoxia (IH), is highly prevalent in patients with abdominal aortic aneurysm (AAA). However, whether IH serves as an independent risk factor for AAA development remains to be investigated. Here, we determined the effects of chronic (6 mo) IH on angiotensin (Ang II)-induced AAA development in C57BL/6J male mice and investigated the underlying mechanisms of IH in cultured vascular smooth muscle cells (SMCs). IH increased the susceptibility of mice to develop AAA in response to Ang II infusion by facilitating the augmentation of the abdominal aorta's diameter as assessed by transabdominal ultrasound imaging. Importantly, IH with Ang II augmented aortic elastin degradation and the expression of matrix metalloproteinases (MMPs), mainly MMP8, MMP12, and a disintegrin and metalloproteinase-17 (ADAM17) as measured by histology and immunohistochemistry. Mechanistically, IH increased the activities of MMP2, MMP8, MMP9, MMP12, and ADAM17, while reducing the expression of the MMP regulator reversion-inducing cysteine-rich protein with Kazal motifs (RECK) in cultured SMCs. Aortic samples from human AAA were associated with decreased RECK and increased expression of ADAM17 and MMPs. These data suggest that IH facilitates AAA development when additional stressors are superimposed and that this occurs in association with an increased presence of aortic MMPs and ADAM17, potentially due to IH-induced modulation of RECK expression. These findings support a plausible synergistic link between OSA and AAA and provide a better understanding of the molecular mechanisms underlying the pathogenesis of AAA.NEW & NOTEWORTHY IH facilitates Ang II-induced abdominal aortic diameter expansion and AAA development in C57BL/6J male mice. IH upregulates the expression of specific MMPs such as MMP8, MMP12, and ADAM17. IH directly suppresses RECK expression and increases MMPs activity in SMCs. Human AAA tissues exhibit a downregulation of RECK and an upregulation of ADAM17 and MMPs.

P082 Neural aperiodic activity as a novel biomarker of sleepiness in patients with obstructive sleep apnoea

Abstract Background Obstructive sleep apnoea (OSA) is characterised by repetitive collapse of the upper airway causing intermittent episodes of hypoxia and apnoeas during sleep. Excessive daytime sleepiness (EDS) is the cardinal symptom of OSA and presents in between 40.5 to 58% of patients. Currently, the diagnosis of OSA requires demonstration of an elevated apnoea hypopnea index (AHI) on a polysomnogram (PSG). Higher AHI scores denote increased OSA disease severity. The correlation between objective AHI scores and subjective sleepiness reporting tools such as the Epworth Sleepiness Scale (ESS) is less clear. Electroencephalogram (EEG) readings form an important component of PSG testing. Traditionally, the periodic oscillatory waves captured on EEG are examined to accurately identify stages of sleep. EEG aperiodic activity is a measure of neural excitation/inhibition ratios and has emerged as a novel objective measure of sleepiness. Methods Intended data collection from 500 patients who have undergone ambulatory PSG testing at the Royal Adelaide Hospital between January 1st 2021 and December 31st 2022 as part of their routine care. Data collection will include patient demographics, cardiorespiratory comorbidities, medications, body mass index (BMI), Epworth Sleepiness Scale (ESS) and PSG EEG data including sleep parameters [Total sleep time (TST), stage of sleep, periodic limb movement limb index (PLMI), AHI scores]. Progress to date Research proposal is currently under review by the CALHN HREC. Intended outcome and impact In this study we will assess the utility of aperiodic neural activity as a predictor of sleepiness in patients with elevated AHI and ESS scores.

Significance of Intermittent Hypoxic Episodes in Premature Infants Prior to Discharge.

Objective The aim of this study was to determine the rate and severity of intermittent hypoxic episodes in premature infants who underwent overnight pulse oximetry prior to discharge. Methods Preterm infants with a birth weight of 1500 grams or lessand who underwent overnight pulse oximetry prior to discharge were included. Maternal and neonatal demographic data and complications of prematurity were recorded. All infants underwent overnight pulse oximetry prior to discharge and the McGill score was used to categorize the degree of desaturations (categories 1-4; normal, mildly, moderately, and severely abnormal). Results Fifty infants underwent the overnight pulse oximetry The McGill score showed that 2% had no hypoxia, 50% had mild hypoxia, 20% had moderate hypoxia, and 28% had severe hypoxia. The frequency of desaturations (62.5%) was found more in infants with a birth weight of 1000 grams or less. The results showed that the O2 requirement at discharge was significant (p = 0.0341), and increased values of O2 at discharge were associated with more severe hypoxia. As a result of these findings, 40% of infants were discharged home on oxygen and 26% were discharged on caffeine. Fifty-two percent of infants were initially diagnosed to have stages 1 & 2 retinopathy of prematurity (ROP), 14% had stage 3, and 2% had stage 4 ROP. Eight percent of infants required surgical intervention for ROP. Conclusions Clinically inapparent significant episodes ofintermittent hypoxia (IH) are frequent in preterm infants in the early postnatal age, and they may persist post-discharge. Knowledge of the association between IH and morbidity among all neonatal intensive care unit (NICU) caregivers would be of great benefit. Indications for screening preterm infants at risk of severe IH should be reconsidered.

Effects of Gestational Intermittent Hypoxia on Placental Morphology and Fetal Development in a Murine Model of Sleep Apnea.

Obstructive sleep apnea (OSA) during pregnancy is characterized by episodes of intermittent hypoxia (IH) during sleep, resulting in adverse health outcomes for mother and offspring. Despite a prevalence of 8-20% in pregnant women, this disorder is often underdiagnosed.We have developed a murine model of gestational OSA to study IH effects on pregnant mothers, placentas, fetuses, and offspring. One group of pregnant rats was exposed to IH during the last 2weeks of gestation (GIH). One day before the delivery date, a cesarean section was performed. Other group of pregnant rats was allowed to give birth at term to study offspring's evolution.Preliminary results showed no significant weight differences in mothers and fetuses. However, the weight of GIH male offspring was significantly lower than the controls at 14days (p<0.01). The morphological study of the placentas showed an increase in fetal capillary branching, expansion of maternal blood spaces, and number of cells of the external trophectoderm in the tissues from GIH-exposed mothers. Additionally, the placentas from the experimental males were enlarged (p<0.05). Further studies are needed to follow the long-term evolution of these changes to relate the histological findings of the placentas with functional development of the offspring in adulthood.

Circadian molecular clock disruption in chronic pulmonary diseases.

The circadian clock is the biochemical oscillator with a near 24-h period that is responsible for generating the circadian rhythms in peripheral organs including the lung. Mounting evidence suggests that circadian clock disruption during chronic lung diseases plays an essential role in augmented oxidative stress, inflammatory response, metabolic imbalances, hypoxia/hyperoxia, mucus secretion, dysregulated autophagy, and alters pulmonary function. Here, we review circadian clock disruption and discuss candidate clock genes that are altered at the transcriptional or translational level in chronic pulmonary diseases. This review aims to provide the current knowledge and understanding of the circadian molecular clock disruption in chronic pulmonary diseases which will further advance the development of novel clock-based therapeutics in the future.

A New Berlin Questionnaire Simplified by Machine Learning Techniques in a Population of Italian Healthcare Workers to Highlight the Suspicion of Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) syndrome is a condition characterized by the presence of repeated complete or partial collapse of the upper airways during sleep associated with episodes of intermittent hypoxia, leading to fragmentation of sleep, sympathetic nervous system activation, and oxidative stress. To date, one of the major aims of research is to find out a simplified non-invasive screening system for this still underdiagnosed disease. The Berlin questionnaire (BQ) is the most widely used questionnaire for OSA and is a beneficial screening tool devised to select subjects with a high likelihood of having OSA. We administered the original ten-question Berlin questionnaire, enriched with a set of questions purposely prepared by our team and completing the socio-demographic, clinical, and anamnestic picture, to a sample of Italian professional nurses in order to investigate the possible impact of OSA disease on healthcare systems. According to the Berlin questionnaire, respondents were categorized as high-risk and low-risk of having OSA. For both risk groups, baseline characteristics, work information, clinical factors, and symptoms were assessed. Anthropometric data, work information, health status, and symptoms were significantly different between OSA high-risk and low-risk groups. Through supervised feature selection and Machine Learning, we also reduced the original BQ to a very limited set of items which seem capable of reproducing the outcome of the full BQ: this reduced group of questions may be useful to determine the risk of sleep apnea in screening cases where questionnaire compilation time must be kept as short as possible.

Does closed-loop automated oxygen control reduce the duration of mechanical ventilation? A randomised controlled trial in ventilated preterm infants

BackgroundMany preterm infants require supplemental oxygen in the newborn period but experience frequent fluctuations of their oxygen saturation levels. Intermittent episodes of hypoxia or hyperoxia increase the risk of complications. Compliance with achievement of oxygen saturation targets is variable, and the need for frequent adjustments of the inspired oxygen concentration increases workload.Closed-loop automated oxygen control systems (CLAC) improve achievement of oxygen saturation targets and reduce both episodes of hypoxia and hyperoxia and the number of manual adjustments. This study investigates whether CLAC compared with manual oxygen control reduces the duration of mechanical ventilation in preterm infants born at less than 31 weeks of gestation.MethodsThis randomised controlled trial performed at a single tertiary neonatal unit is recruiting 70 infants born at less than 31 weeks of gestational age and within 48 h of initiation of mechanical ventilation. Infants are randomised to CLAC or manual oxygen control from recruitment until successful extubation. The primary outcome is the duration of mechanical ventilation, and secondary outcomes are the percentage of time spent within target oxygen saturation ranges, the time spent in hypoxia or hyperoxia, the number of manual adjustments required, the number of days on oxygen, the incidence of bronchopulmonary dysplasia and the length and cost of neonatal unit stay. The study is performed following informed parental consent and was approved by the Yorkshire and the Humber-Sheffield Research Ethics Committee (protocol version 1.1, 13 July 2021).DiscussionThis trial will investigate the effect of CLAC on the duration of mechanical ventilation, which is an important clinical outcome as prolonged mechanical ventilation is associated with important adverse outcomes, such as bronchopulmonary dysplasia.Trial registrationClinicalTrials.Gov NCT05030337. Registered on 17 August 2021

Renal biomarkers of acute kidney injury in response to increasing intermittent hypoxia episodes in the neonatal rat

BackgroundWe tested the hypotheses that: 1) early exposure to increasing episodes of clinically relevant intermittent hypoxia (IH) is detrimental to the developing kidneys; and 2) there is a critical number of daily IH episodes which will result in irreparable renal damage that may involve angiotensin (Ang) II and endothelin (ET)-1.MethodsAt birth (P0), neonatal rat pups were exposed to brief IH episodes from the first day of life (P0) to P7 or from P0-P14. Pups were either euthanized immediately or placed in room air (RA) until P21. RA littermates served as controls. Kidneys were harvested at P7, P14, and P21 for histopathology; angiotensin converting enzyme (ACE), ACE-2, ET-1, big ET-1, and malondialdehyde (MDA) levels; immunoreactivity of ACE, ACE-2, ET-1, ET-2, ET receptors (ETAR, ETBR), and hypoxia inducible factor (HIF)1α; and apoptosis (TUNEL stain).ResultsHistopathology showed increased renal damage with 8–12 IH episodes/day, and was associated with Ang II, ACE, HIF1α, and apoptosis. ACE-2 was not expressed at P7, and minimally increased at P14. However, a robust ACE-2 response was seen during recovery with maximum levels noted in the groups recovering from 8 IH episodes/day. ET-1, big ET-1, ETAR, ETBR, and MDA increased with increasing levels of neonatal IH.ConclusionsChronic neonatal IH causes severe damage to the developing kidney with associated elevations in vasoconstrictors, suggesting hypertension, particularly with 8 neonatal IH episodes. ACE-2 is not activated in early postnatal life, and this may contribute to IH-induced vasoconstriction. Therapeutic targeting of ACE and ET-1 may help decrease the risk for kidney injury in the developing neonate to prevent and/or treat neonatal acute kidney injury and/or chronic kidney disease.

Comparison of coenzyme Q10 or fish oil for prevention of intermittent hypoxia-induced oxidative injury in neonatal rat lungs

BackgroundNeonatal intermittent hypoxia (IH) results in oxidative distress in preterm infants with immature antioxidant systems, contributing to lung injury. Coenzyme Q10 (CoQ10) and fish oil protect against oxidative injury. We tested the hypothesis that CoQ10 is more effective than fish oil for prevention of IH-induced lung injury in neonatal rats.MethodsNewborn rats were exposed to two clinically relevant IH paradigms at birth (P0): (1) 50% O2 with brief hypoxia (12% O2); or (2) room air (RA) with brief hypoxia (12% O2), until P14 during which they were supplemented with daily oral CoQ10, fish oil, or olive oil from P0 to P14. Pups were studied at P14 or placed in RA until P21 with no further treatment. Lungs were assessed for histopathology and morphometry; biomarkers of oxidative stress and lipid peroxidation; and antioxidants.ResultsOf the two neonatal IH paradigms 21%/12% O2 IH resulted in the most severe outcomes, evidenced by histopathology and morphometry. CoQ10 was effective for preserving lung architecture and reduction of IH-induced oxidative stress biomarkers. In contrast, fish oil resulted in significant adverse outcomes including oversimplified alveoli, hemorrhage, reduced secondary crest formation and thickened septae. This was associated with elevated oxidants and antioxidants activities.ConclusionsData suggest that higher FiO2 may be needed between IH episodes to curtail the damaging effects of IH, and to provide the lungs with necessary respite. The negative outcomes with fish oil supplementation suggest oxidative stress-induced lipid peroxidation.

Intermittent hypoxia changes the interaction of the kinin-VEGF system and impairs myocardial angiogenesis in the hypertrophic heart.

Intermittent hypoxia (IH) is a feature of obstructive sleep apnea (OSA), a condition highly associated with hypertension‐related cardiovascular diseases. Repeated episodes of IH contribute to imbalance of angiogenic growth factors in the hypertrophic heart, which is key in the progression of cardiovascular complications. In particular, the interaction between vascular endothelial growth factor (VEGF) and the kallikrein‐kinin system (KKS) is essential for promoting angiogenesis. However, researchers have yet to investigate experimental models of IH that reproduce OSA, myocardial angiogenesis, and expression of KKS components. We examined temporal changes in cardiac angiogenesis in a mouse IH model. Adult male C57BI/6 J mice were implanted with Matrigel plugs and subjected to IH for 1–5 weeks with subsequent weekly histological evaluation of vascularization. Expression of VEGF and KKS components was also evaluated. After 3 weeks, in vivo myocardial angiogenesis and capillary density were decreased, accompanied by a late increase of VEGF and its type 2 receptor. Furthermore, IH increased left ventricular myocardium expression of the B2 bradykinin receptor, while reducing mRNA levels of B1 receptor. These results suggest that in IH, an unexpected response of the VEGF and KKS systems could explain the reduced capillary density and impaired angiogenesis in the hypoxic heart, with potential implications in hypertrophic heart malfunction.

Randomized Longitudinal Study Comparing Three Nasal Respiratory Support Modes to Prevent Intermittent Hypoxia in Very Preterm Infants.

Nasal continuous positive airway pressure (NCPAP) devices using variable (vf-) and continuous (cf-) flow or synchronized nasal intermittent positive pressure ventilation (s-NIPPV) are used to prevent or treat intermittent hypoxia (IH) in preterm infants. Results concerning which is most effective vary. We aimed to investigate the effect of s-NIPPV and vf-NCPAP compared to cf-NCPAP on the rate of IH episodes. Preterm infants with a gestational age of 24.9–29.7 weeks presenting with IH while being treated with cf-NCPAP were monitored for eight hours, then randomized to eight hours of treatment with vf-NCPAP or s-NIPPV. Data from 16 infants were analyzed. Due to an unexpectedly low sample size, the results were only reported descriptively. No relevant changes in the rate of IH events were detected between cf- vs. vf-NCPAP or between cf-NCPAP vs. s-NIPPV. Although limited by its small sample size, s-NIPPV, vf- and cf-NCPAP seemed to be similarly effective in the treatment of IH in these infants.

Abstract 270: Patients With Acute Ischemic Stroke and Associated Diagnosis of Obstructive Sleep Apnea Have Lower In-hospital Mortality

Background: Obstructive sleep apnea (OSA) is present in almost 60% of patients with cerebrovascular disease and it is an independent predictor of ischemic stroke. Yet, the impact of OSA on outcomes of ischemic stroke is unclear. Some, small cohort studies indicate increased short-term mortality, whereas larger studies, with more complex logistic regression models, show decreased in-hospital mortality. Lower mortality could be attributed to chronic intermittent episodes of hypoxia affecting the remodeling of cerebral collateral circulation. We thought to investigate outcomes in a large unselected population of patients presenting with acute ischemic stroke. Methods: In a retrospective cohort study, using the 2014 Nationwide Inpatient Sample (NIS), we analyzed adult patients with acute ischemic stroke and OSA. We performed univariate analysis of age, sex, race, hospital location, hospital teaching status, insurance type, hospital bed size, Charlson Comorbidity Index and other relevant comorbidities and we included variables with p&lt;0.2 in the multivariate logistic regression model. Results: A total of 95282 patients with acute ischemic stroke were identified. Patients with the associated diagnosis of OSA (5%) had a mean age of 66+/_0.2, vs 71+/_0.1, p&lt;0.001 and a higher percentage of them were male (63% vs 48%, p&lt;0.001). Patients with OSA were more likely to have hypertension (88% vs 83%, p&lt;0.001), heart failure (24% vs 14%, p&lt;0.001), chronic kidney disease (20% vs 14%, p&lt;0.001) ESRD (3% vs 2%, p&lt;0.001) and diabetes mellites (40% vs 30%, p&lt;0.001). Patients with associated diagnosis of OSA had higher incidence of ventricular fibrillation and ventricular tachycardia (OR=1.27, 95%CI=1.02-1.58, p=0.27) with no difference in incidence of cardiac arrest (OR=1.14, 95%CI=0.78-1.66, p=0.50) and lower in-hospital mortality (OR=0.68, 95%CI =0.57-0.82, p&lt;0.001). They were less likely to have hemiplegia (OR= 0.83, 95% CI=0.74-0.95, p=0.004) and less likely to receive a blood product transfusion (OR =0.71, 95%CI =0.54-0.93, p&lt;0.014). There was no difference in utilization of percutaneous endoscopic gastrostomy (OR=0.90, 95%CI=75-1.07, p=0.23), incidence of shock (OR=1.13, 95% CI =0.66-1.90, p=0.66) and utilization of mechanical ventilation (OR=0.96, 95%CI =0.82-1.11, p=0.55) as well as in length of stay (Coef. =-0.039, 95% CI=-0.23—0.16, p=0.70) and total costs of hospitalization (Coef. =180.73, 95% CI= -1925-2287, p=0.87). Conclusion: Patients with OSA and ischemic stroke have a higher number of cardiovascular comorbidities. After adjustment with a complex multivariate regression model in a large population of patients, they have lower in-hospital mortality and lower incidence of hemiplegia. We also uncovered underdiagnosing of obstructive sleep apnea in National Inpatient Sample registry, which is a limitation of the study.

Intermittent hypoxia in preterm infants: Measurement using the desaturation index.

The aims of this study were to: (i) Determine in preterm infants at neonatal discharge the prevalence of intermittent hypoxia (IH), as measured by the oxygen desaturation index (DSI) recorded by pulse oximetry and (ii) Determine the change in values for very preterm infants at 1-month post discharge. Preterm infants were recruited from the Wellington regional neonatal intensive care unit (NICU) and 24-h pulse oximetry recordings performed immediately before discharge. Infants born <32 weeks gestational age (GA) had repeat oximetry 1-month post discharge. Oxygenation measures included the 3% and 4% desaturation (DSI 3%, DSI 4%) indices. At discharge from the neonatal unit the median and interquartile range (IQR) for DSI 4% was 51 (31-74) events per hour with normal mean SpO2 (median of 97.9% [97.2-98.8 IQR]). Episodes of IH 1 month post discharge decreased with improvements of between 42% and 57% seen for the three DSI measures. Infants <32 weeks GA had higher median DSI 3 and 4% values at discharge but differences when compared with late preterm infants were not significant. Preterm infants have frequent episodes of IH as measured by the 3% and 4% DSI when deemed otherwise ready for discharge home. Further research in a larger cohort of very preterm infants and also in term infants is needed to determine the significance of this finding.

Reduced Peripheral Blood Mononuclear Cell ROCK1 and ROCK2 Levels in Obstructive Sleep Apnea Syndrome

Background/Aim: Obstructive sleep apnea syndrome (OSAS) is associated with intermittent episodes of hypoxia, endothelial dysfunction and associated cardiovascular problems. Our aim was to investigate whether OSAS-related hypoxia alters the expression of rho-associated protein kinase (ROCK), a marker of chronic hypoxia and endothelial dysfunction. Materials and Methods: ROCK1 and ROCK2 levels were measured by immunoblotting in peripheral blood mononuclear cells (PBMC) of 47 OSAS patients and 17 healthy controls. Results: OSAS patients showed significantly lower PBMC ROCK1 and ROCK2 levels than healthy controls in the morning, but not in the evening. ROCK1/2 levels were correlated with blood triglyceride, visceral adiposity index, minimum oxygen saturation, C-reactive protein concentration, lymphocyte levels and sleep efficiency. Conclusion: Intermittent hypoxia induced by OSAS does not permanently alter ROCK protein expression levels. OSAS appears to be associated with endothelial dysfunction through inflammation and lipid metabolism pathways.

Reduced Peripheral Blood Mononuclear Cell ROCK1 and ROCK2 Levels in Obstructive Sleep Apnea Syndrome.

Obstructive sleep apnea syndrome (OSAS) is associated with intermittent episodes of hypoxia, endothelial dysfunction and associated cardiovascular problems. Our aim was to investigate whether OSAS-related hypoxia alters the expression of rho-associated protein kinase (ROCK), a marker of chronic hypoxia and endothelial dysfunction. ROCK1 and ROCK2 levels were measured by immunoblotting in peripheral blood mononuclear cells (PBMC) of 47 OSAS patients and 17 healthy controls. OSAS patients showed significantly lower PBMC ROCK1 and ROCK2 levels than healthy controls in the morning, but not in the evening. ROCK1/2 levels were correlated with blood triglyceride, visceral adiposity index, minimum oxygen saturation, C-reactive protein concentration, lymphocyte levels and sleep efficiency. Intermittent hypoxia induced by OSAS does not permanently alter ROCK protein expression levels. OSAS appears to be associated with endothelial dysfunction through inflammation and lipid metabolism pathways.

Intermittent hypoxia alters dose dependent caffeine effects on renal prostanoids and receptors in neonatal rats

Caffeine, one of the most commonly prescribed drugs in preterm neonates, is given in standard or suprapharmacologic doses. Although known as a diuretic, its effects in the neonatal kidneys are not well studied. We tested the hypothesis that neonatal intermittent hypoxia (IH) and high caffeine doses (HCD) alter renal regulators of vasomotor tone and water balance. Newborn rats were randomized to room air, hyperoxia, or IH and treated with standard or high caffeine doses; or placebo saline. Renal prostanoids; histopathology; and cyclooxygenase (COX), prostanoid receptor, and aquaporin (AQP) immunoreactivity were determined. HCD in IH caused severe pathological changes in the glomeruli and proximal tubules, consistent with acute kidney injury. This was associated with reductions in anthropometric growth, PGI2, and IP, DP, and AQP-4 immunoreactivity, well as a robust increase in COX-2, suggesting that the use of HCD should be avoided in preterm infants who experience frequent IH episodes.

Chronic Intermittent Hypoxia Causes Lipid Peroxidation and Altered Phase 1 Drug Metabolizing Enzymes in the Neonatal Rat Liver

Critically ill preterm neonates requiring oxygen therapy often experience frequent apneas with intermittent hypoxia (IH). IH-induced oxidative stress causes lipid peroxidation, which targets the liver and contributes to toxic drug reactions. We tested the hypothesis that incremental IH episodes induce oxidative damage in the neonatal liver and alter the expression of genes that regulate drug metabolism. Newborn rats were exposed to increasing IH episodes (12% O2) during hyperoxia (50% O2), or placed in room air (RA) until postnatal day 21 (P21) for recovery from IH (IHR). RA littermates served as controls, and pups exposed to 50% O2 served as hyperoxia controls. Hepatic histopathology, biomarkers of oxidative stress and oxidative DNA damage, antioxidants, and expression of genes that regulate drug metabolism were assessed. Oxidative stress and DNA damage, evidenced by 8-isoprostaglandin F2α (8-isoPGF2α) and 8-hydroxy-2'-deoxyguanosine (8-OH-dG), respectively, increased as a function of IH episodes, and was associated with decreased superoxide dismutase (SOD) and increased catalase activities. Pathological changes including cellular swelling, steatosis, necrosis, and focal sinusoid congestion were seen in IH, but not in IHR. Similarly, IH was associated with upregulation of several genes involved in DNA repair, which were downregulated during IHR. Of the genes involved in drug metabolism, aldehyde dehydrogenases (involved in lipid peroxidation) and cytochrome P450 (CYP) genes of the 2C family (involved in oxidative stress) were robustly upregulated both in IH and in IHR. Hepatic oxidative stress and lipid peroxidation occurring in response to chronic IH have implications for preterm infants, and may explain, in part, the pharmacokinetic variations and drug toxicities in this vulnerable population.

Neuromodulation of Limb Proprioceptive Afferents Decreases Apnea of Prematurity and Accompanying Intermittent Hypoxia and Bradycardia.

BackgroundApnea of Prematurity (AOP) is common, affecting the majority of infants born at <34 weeks gestational age. Apnea and periodic breathing are accompanied by intermittent hypoxia (IH). Animal and human studies demonstrate that IH exposure contributes to multiple pathologies, including retinopathy of prematurity (ROP), injury to sympathetic ganglia regulating cardiovascular action, impaired pancreatic islet cell and bone development, cerebellar injury, and neurodevelopmental disabilities. Current standard of care for AOP/IH includes prone positioning, positive pressure ventilation, and methylxanthine therapy; these interventions are inadequate, and not optimal for early development.ObjectiveThe objective is to support breathing in premature infants by using a simple, non-invasive vibratory device placed over limb proprioceptor fibers, an intervention using the principle that limb movements trigger reflexive facilitation of breathing.MethodsPremature infants (23–34 wks gestational age), with clinical evidence of AOP/IH episodes were enrolled 1 week after birth. Caffeine treatment was not a reason for exclusion. Small vibration devices were placed on one hand and one foot and activated in 6 hour ON/OFF sequences for a total of 24 hours. Heart rate, respiratory rate, oxygen saturation (SpO2), and breathing pauses were continuously collected.ResultsFewer respiratory pauses occurred during vibration periods, relative to baseline (p<0.005). Significantly fewer SpO2 declines occurred with vibration (p<0.05), relative to control periods. Significantly fewer bradycardic events occurred during vibration periods, relative to no vibration periods (p<0.05).ConclusionsIn premature neonates, limb proprioceptive stimulation, simulating limb movement, reduces breathing pauses and IH episodes, and lowers the number of bradycardic events that accompany aberrant breathing episodes. This low-cost neuromodulatory procedure has the potential to provide a non-invasive intervention to reduce apnea, bradycardia and intermittent hypoxia in premature neonates.Trial RegistrationClinicalTrials.gov NCT02641249

Could the thromboxane A2 pathway be a therapeutic target for the treatment of obstructive sleep apnea-induced atherosclerosis?

Obstructive sleep apnea (OSA) is characterized by recurrent nocturnal episodes of intermittent hypoxia. This disease is associated with premature atherosclerosis and consequently with increased cardiovascular morbidity and mortality. Atherosclerosis is a chronic inflammatory disease characterized by the activation of some components of the cyclooxygenase pathway. In particular, OSA is associated with activation of the thromboxane A2 (TXA2)-pathway, in which obesity seems to be a major confounding factor. Moreover, TXA2-pathway activation is related to the vascular remodeling associated with OSA. In view of the modest effect of the conventional treatment of OSA by continuous positive airway pressure on the cardiovascular risk in obese OSA patients, the identification of new therapeutic targets to treat OSA-induced atherosclerosis seems essential. As disruption of the TXA2-pathway has been suggested to be of potential interest to prevent atherosclerosis progression, we have reviewed the recent findings on the intricate interaction between the TXA2-pathway, chronic intermittent hypoxia and atherosclerosis and suggest promising therapeutic strategies to treat OSA-related atherogenesis, including pharmacological and/or nutritional approaches.

Intermittent hypoxia in childhood: the harmful consequences versus potential benefits of therapeutic uses.

Intermittent hypoxia (IH) often occurs in early infancy in both preterm and term infants and especially at 36–44 weeks postmenstrual age. These episodes of IH could result from sleep-disordered breathing or may be temporally unrelated to apnea or bradycardia events. There are numerous reports indicating adverse effects of IH on development, behavior, academic achievement, and cognition in children with sleep apnea syndrome. It remains uncertain about the exact causative relationship between the neurocognitive and behavioral morbidities and IH and/or its associated sleep fragmentation. On the other hand, well-controlled and moderate IH conditioning/training has been used in sick children for treating their various forms of bronchial asthma, allergic dermatoses, autoimmune thyroiditis, cerebral palsy, and obesity. This review article provides an updated and impartial analysis on the currently available evidence in supporting either side of the seemingly contradictory scenarios. We wish to stimulate a comprehensive understanding of such a complex physiological phenomenon as intermittent hypoxia, which may be accompanied by other confounding factors (e.g., hypercapnia, polycythemia), in order to prevent or reduce its harmful consequences, while maximizing its potential utility as an effective therapeutic tool in pediatric patients.