Anaesthesia associates' clinical activity, case mix, supervision and involvement in peri-operative cardiac arrest: analysis from the 7th National Audit Project.

BACKGROUND: We analysed the clinical practice of anaesthesia associates in the UK, as reported to the 7th National Audit Project of the Royal College of Anaesthetists, and compared these with medically qualified anaesthetists. METHODS: We included data from our baseline survey, activity survey and case registry as with other reports from the project. RESULTS: Among 197 departments of anaesthesia, 52 (26%) employed anaesthesia associates. Of 10,009 responding anaesthesia care providers, 71 (< 1%) were anaesthesia associates, of whom 33 (47%) reporting working nights or weekends (compared with 97% of medically qualified anaesthetists in training and > 90% of consultants). Anaesthesia associates reported less training and confidence in managing peri-operative cardiac arrest and its aftermath compared with medically qualified anaesthetists. Anaesthesia associates were less directly involved in the management and the aftermath of peri-operative cardiac arrest than medically qualified anaesthetists, and the psychological impacts on professional and personal life appeared to be less. Among 24,172 cases, anaesthesia associates attended 432 (2%) and were the senior anaesthesia care provider in 63 (< 1%), with indirect supervision in 27 (43%). Anaesthesia associates worked predominantly in a small number of surgical specialties during weekdays and working daytime hours. Complication rates were low in cases managed by anaesthesia associates, likely reflecting case mix. However, activity and registry case mix data show anaesthesia associates do manage high-risk cases (patients who are older, comorbid, obese and frail) with the potential for serious complications. Registry cases included higher risk cases with respect to the clinical setting and patient factors. CONCLUSION: Anaesthesia associates work in enhanced roles, relative to the scope of practice at qualification agreed by organisations. Recent changes mean the Royal College of Anaesthetists and Association of Anaesthetists do not currently support an enhanced scope of practice.

Advanced life support interventions during intra-operative cardiac arrest among adults as reported to the 7th National Audit Project of the Royal College of Anaesthetists.

BACKGROUND: Few existing resuscitation guidelines include specific reference to intra-operative cardiac arrest, but its optimal treatment is likely to require some adaptation of standard protocols. METHODS: We analysed data from the 7th National Audit Project of the Royal College of Anaesthetists to determine the incidence and outcome from intra-operative cardiac arrest and to summarise the advanced life support interventions reported as being used by anaesthetists. RESULTS: In the baseline survey, > 50% of anaesthetists responded that they would start chest compressions when the non-invasive systolic pressure was < 40-50 mmHg. Of the 881 registry patients, 548 were adult patients (aged > 18 years) having non-obstetric procedures under the care of an anaesthetist, and who had arrested during anaesthesia (from induction to emergence). Sustained return of spontaneous circulation was achieved in 425 (78%) patients and 338 (62%) were alive at the time of reporting. In the 365 patients with pulseless electrical activity or bradycardia, adrenaline was given as a 1 mg bolus in 237 (65%). A precordial thump was used in 14 (3%) patients, and although this was associated with return of spontaneous circulation at the next rhythm check in almost three-quarters of patients, in only one of these was the initial rhythm shockable. Calcium (gluconate or chloride) and 8.4% sodium bicarbonate were given to 51 (9%) and 25 (5%) patients, but there were specific indications for these treatments in less than half of the patients. A thrombolytic drug was given to 5 (1%) patients, and extracorporeal cardiopulmonary resuscitation was used in 9 (2%) of which eight occurred during cardiac procedures. CONCLUSIONS: The specific characteristics of intra-operative cardiac arrest imply that its optimal treatment requires modifications to standard advanced life support guidelines.

Combined Statin and Glucocorticoid Therapy for the Safer Treatment of Preterm Birth.

BACKGROUND: Prematurity is strongly associated with poor respiratory function in the neonate. Rescue therapies include treatment with glucocorticoids due to their anti-inflammatory and maturational effects on the developing lung. However, glucocorticoid treatment in the infant can increase the risk of long-term cardiovascular complications including hypertension, cardiac, and endothelial dysfunction. Accumulating evidence implicates a molecular link between glucocorticoid excess and depletion of nitric oxide (NO) bioavailability as a mechanism underlying the detrimental effects of postnatal steroids on the heart and circulation. Therefore, combined glucocorticoid and statin therapy, by increasing NO bioavailability, may protect the developing cardiovascular system while maintaining beneficial effects on the lung. METHODS: We investigated combined glucocorticoid and statin therapy using an established rodent model of prematurity and combined experiments of cardiovascular function in vivo, with those in isolated organs as well as measurements at the cellular and molecular levels. RESULTS: We show that neonatal glucocorticoid treatment increases the risk of later cardiovascular dysfunction in the offspring. Underlying mechanisms include decreased circulating NO bioavailability, sympathetic hyper-reactivity, and NO-dependent endothelial dysfunction. Combined neonatal glucocorticoid and statin therapy protects the developing cardiovascular system by normalizing NO and sympathetic signaling, without affecting pulmonary maturational or anti-inflammatory effects of glucocorticoids. CONCLUSIONS: Therefore, combined glucocorticoid and statin therapy may be safer than glucocorticoids alone for the treatment of preterm birth.

Molecular regulation of lung maturation in near-term fetal sheep by maternal daily vitamin C treatment in late gestation.

BACKGROUND: In the fetus, the appropriate balance of prooxidants and antioxidants is essential to negate the detrimental effects of oxidative stress on lung maturation. Antioxidants improve respiratory function in postnatal life and adulthood. However, the outcomes and biological mechanisms of antioxidant action in the fetal lung are unknown. METHODS: We investigated the effect of maternal daily vitamin C treatment (200 mg/kg, intravenously) for a month in late gestation (105-138 days gestation, term ~145 days) on molecular regulation of fetal lung maturation in sheep. Expression of genes and proteins regulating lung development was quantified in fetal lung tissue. The number of surfactant-producing cells was determined by immunohistochemistry. RESULTS: Maternal vitamin C treatment increased fetal lung gene expression of the antioxidant enzyme SOD-1, hypoxia signaling genes (HIF-2α, HIF-3α, ADM, and EGLN-3), genes regulating sodium movement (SCNN1-A, SCNN1-B, ATP1-A1, and ATP1-B1), surfactant maturation (SFTP-B and ABCA3), and airway remodeling (ELN). There was no effect of maternal vitamin C treatment on the expression of protein markers evaluated or on the number of surfactant protein-producing cells in fetal lung tissue. CONCLUSIONS: Maternal vitamin C treatment in the last third of pregnancy in sheep acts at the molecular level to increase the expression of genes that are important for fetal lung maturation in a healthy pregnancy. IMPACT: Maternal daily vitamin C treatment for a month in late gestation in sheep increases the expression of gene-regulating pathways that are essential for normal fetal lung development. Following late gestation vitamin C exposure in a healthy pregnancy, an increase in lung gene but not protein expression may act as a mechanism to aid in the preparation for exposure to the air-breathing environment after birth. In the future, the availability/development of compounds with greater antioxidant properties than vitamin C or more specific targets at the site of oxidative stress in vivo may translate clinically to improve respiratory outcomes in complicated pregnancies at birth.

Maternal antioxidant treatment protects adult offspring against memory loss and hippocampal atrophy in a rodent model of developmental hypoxia.

Chronic fetal hypoxia is one of the most common outcomes in complicated pregnancy in humans. Despite this, its effects on the long-term health of the brain in offspring are largely unknown. Here, we investigated in rats whether hypoxic pregnancy affects brain structure and function in the adult offspring and explored underlying mechanisms with maternal antioxidant intervention. Pregnant rats were randomly chosen for normoxic or hypoxic (13% oxygen) pregnancy with or without maternal supplementation with vitamin C in their drinking water. In one cohort, the placenta and fetal tissues were collected at the end of gestation. In another, dams were allowed to deliver naturally, and offspring were reared under normoxic conditions until 4 months of age (young adult). Between 3.5 and 4 months, the behavior, cognition and brains of the adult offspring were studied. We demonstrated that prenatal hypoxia reduced neuronal number, as well as vascular and synaptic density, in the hippocampus, significantly impairing memory function in the adult offspring. These adverse effects of prenatal hypoxia were independent of the hypoxic pregnancy inducing fetal growth restriction or elevations in maternal or fetal plasma glucocorticoid levels. Maternal vitamin C supplementation during hypoxic pregnancy protected against oxidative stress in the placenta and prevented the adverse effects of prenatal hypoxia on hippocampal atrophy and memory loss in the adult offspring. Therefore, these data provide a link between prenatal hypoxia, placental oxidative stress, and offspring brain health in later life, providing insight into mechanism and identifying a therapeutic strategy.

Altered Cardiovascular Defense to Hypotensive Stress in the Chronically Hypoxic Fetus.

The hypoxic fetus is at greater risk of cardiovascular demise during a challenge, but the reasons behind this are unknown. Clinically, progress has been hampered by the inability to study the human fetus non-invasively for long period of gestation. Using experimental animals, there has also been an inability to induce gestational hypoxia while recording fetal cardiovascular function as the hypoxic pregnancy is occurring. We use novel technology in sheep pregnancy that combines induction of controlled chronic hypoxia with simultaneous, wireless recording of blood pressure and blood flow signals from the fetus. Here, we investigated the cardiovascular defense of the hypoxic fetus to superimposed acute hypotension. Pregnant ewes carrying singleton fetuses surgically prepared with catheters and flow probes were randomly exposed to normoxia or chronic hypoxia from 121±1 days of gestation (term ≈145 days). After 10 days of exposure, fetuses were subjected to acute hypotension via fetal nitroprusside intravenous infusion. Underlying in vivo mechanisms were explored by (1) analyzing fetal cardiac and peripheral vasomotor baroreflex function; (2) measuring the fetal plasma catecholamines; and (3) establishing fetal femoral vasoconstrictor responses to the α1-adrenergic agonist phenylephrine. Relative to controls, chronically hypoxic fetal sheep had reversed cardiac and impaired vasomotor baroreflex function, despite similar noradrenaline and greater adrenaline increments in plasma during hypotension. Chronic hypoxia markedly diminished the fetal vasopressor responses to phenylephrine. Therefore, we show that the chronically hypoxic fetus displays markedly different cardiovascular responses to acute hypotension, providing in vivo evidence of mechanisms linking its greater susceptibility to superimposed stress.

Intervention against hypertension in the next generation programmed by developmental hypoxia.

Evidence derived from human clinical studies and experimental animal models shows a causal relationship between adverse pregnancy and increased cardiovascular disease in the adult offspring. However, translational studies isolating mechanisms to design intervention are lacking. Sheep and humans share similar precocial developmental milestones in cardiovascular anatomy and physiology. We tested the hypothesis in sheep that maternal treatment with antioxidants protects against fetal growth restriction and programmed hypertension in adulthood in gestation complicated by chronic fetal hypoxia, the most common adverse consequence in human pregnancy. Using bespoke isobaric chambers, chronically catheterized sheep carrying singletons underwent normoxia or hypoxia (10% oxygen [O2]) ± vitamin C treatment (maternal 200 mg.kg-1 IV daily) for the last third of gestation. In one cohort, the maternal arterial blood gas status, the value at which 50% of the maternal hemoglobin is saturated with oxygen (P50), nitric oxide (NO) bioavailability, oxidative stress, and antioxidant capacity were determined. In another, naturally delivered offspring were raised under normoxia until early adulthood (9 months). Lambs were chronically instrumented and cardiovascular function tested in vivo. Following euthanasia, femoral arterial segments were isolated and endothelial function determined by wire myography. Hypoxic pregnancy induced fetal growth restriction and fetal oxidative stress. At adulthood, it programmed hypertension by enhancing vasoconstrictor reactivity and impairing NO-independent endothelial function. Maternal vitamin C in hypoxic pregnancy improved transplacental oxygenation and enhanced fetal antioxidant capacity while increasing NO bioavailability, offsetting constrictor hyper-reactivity and replenishing endothelial function in the adult offspring. These discoveries provide novel insight into mechanisms and interventions against fetal growth restriction and adult-onset programmed hypertension in an animal model of complicated pregnancy in a species of similar temporal developmental milestones to humans.

Maternal Allopurinol Prevents Cardiac Dysfunction in Adult Male Offspring Programmed by Chronic Hypoxia During Pregnancy.

Integrating functional and molecular levels, we investigated the effects of maternal treatment with a xanthine oxidase inhibitor on the programming of cardiac dysfunction in adult offspring using an established rat model of hypoxic pregnancy. Female Wistar rats were divided into normoxic or hypoxic (13% O2) pregnancy±maternal allopurinol treatment (30 mg kg-1 d-1). At 4 months, hearts were isolated from 1 male per litter per outcome variable to determine cardiac function and responses to ischemia-reperfusion in a Langendorff preparation. Sympathetic dominance, perfusate CK (creatine kinase) and LDH (lactate dehydrogenase) and the cardiac protein expression of the ß1-adrenergic receptor, the M2 Ach receptor (muscarinic type-2 acetylcholine receptor), and the SERCA2a (sarcoplasmic reticulum Ca2+ ATPase 2a) were determined. Relative to controls, offspring from hypoxic pregnancy showed elevated left ventricular end diastolic pressure (+34.7%), enhanced contractility (dP/dtmax, +41.6%), reduced coronary flow rate (-21%) and an impaired recovery to ischemia-reperfusion (left ventricular diastolic pressure, area under the curve recovery -19.1%; all P<0.05). Increased sympathetic reactivity (heart rate, +755.5%; left ventricular diastolic pressure, +418.9%) contributed to the enhanced myocardial contractility ( P<0.05). Perfusate CK (+431%) and LDH (+251.3%) and the cardiac expression of SERCA2a (+71.4%) were also elevated ( P<0.05), further linking molecular markers of cardiac stress and injury to dysfunction. Maternal allopurinol restored all functional and molecular indices of cardiac pathology. The data support a link between xanthine oxidase-derived oxidative stress in hypoxic pregnancy and cardiac dysfunction in the adult offspring, providing a target for early intervention in the developmental programming of heart disease.

Maternal chronic hypoxia increases expression of genes regulating lung liquid movement and surfactant maturation in male fetuses in late gestation.

KEY POINTS: Chronic fetal hypoxaemia is a common pregnancy complication associated with intrauterine growth restriction that may influence respiratory outcome at birth. We investigated the effect of maternal chronic hypoxia for a month in late gestation on signalling pathways regulating fetal lung maturation and the transition to air-breathing at birth using isobaric hypoxic chambers without alterations to maternal food intake. Maternal chronic hypoxia in late gestation increases fetal lung expression of genes regulating hypoxia signalling, lung liquid reabsorption and surfactant maturation, which may be an adaptive response in preparation for the successful transition to air-breathing at birth. In contrast to other models of chronic fetal hypoxaemia, late gestation onset fetal hypoxaemia promotes molecular regulation of fetal lung maturation. This suggests a differential effect of timing and duration of fetal chronic hypoxaemia on fetal lung maturation, which supports the heterogeneity observed in respiratory outcomes in newborns following exposure to chronic hypoxaemia in utero. ABSTRACT: Chronic fetal hypoxaemia is a common pregnancy complication that may arise from maternal, placental and/or fetal factors. Respiratory outcome of the infant at birth likely depends on the duration, timing and severity of the hypoxaemic insult. We have isolated the effect of maternal chronic hypoxia (MCH) for a month in late gestation on fetal lung development. Pregnant ewes were exposed to normoxia (21% O2 ) or hypoxia (10% O2 ) from 105 to 138 days of gestation (term ∼145 days). At 138 days, gene expression in fetal lung tissue was determined by quantitative RT-PCR. Cortisol concentrations were determined in fetal plasma and lung tissue. Numerical density of surfactant protein positive cells was determined by immunohistochemistry. MCH reduced maternal PaO2 (106 ± 2.9 vs. 47 ± 2.8 mmHg) and fetal body weight (4.0 ± 0.4 vs. 3.2 ± 0.9 kg). MCH increased fetal lung expression of the anti-oxidant marker CAT and decreased expression of the pro-oxidant marker NOX-4. MCH increased expression of genes regulating hypoxia signalling and feedback (HIF-3α, KDM3A, SLC2A1, EGLN-3). There was no effect of MCH on fetal plasma/lung tissue cortisol concentrations, nor genes regulating glucocorticoid signalling (HSD11B-1, HSD11B-2, NR3C1, NR3C2). MCH increased expression of genes regulating sodium (SCNN1-B, ATP1-A1, ATP1-B1) and water (AQP-4) movement in the fetal lung. MCH promoted surfactant maturation (SFTP-B, SFTP-D, ABCA3) at the molecular level, but did not alter the numerical density of surfactant positive cells in lung tissue. MCH in late gestation promotes molecular maturation of the fetal lung, which may be an adaptive response in preparation for the successful transition to air-breathing at birth.

Efficient multi-scale 3D CNN with fully connected CRF for accurate brain lesion segmentation.

We propose a dual pathway, 11-layers deep, three-dimensional Convolutional Neural Network for the challenging task of brain lesion segmentation. The devised architecture is the result of an in-depth analysis of the limitations of current networks proposed for similar applications. To overcome the computational burden of processing 3D medical scans, we have devised an efficient and effective dense training scheme which joins the processing of adjacent image patches into one pass through the network while automatically adapting to the inherent class imbalance present in the data. Further, we analyze the development of deeper, thus more discriminative 3D CNNs. In order to incorporate both local and larger contextual information, we employ a dual pathway architecture that processes the input images at multiple scales simultaneously. For post-processing of the network's soft segmentation, we use a 3D fully connected Conditional Random Field which effectively removes false positives. Our pipeline is extensively evaluated on three challenging tasks of lesion segmentation in multi-channel MRI patient data with traumatic brain injuries, brain tumours, and ischemic stroke. We improve on the state-of-the-art for all three applications, with top ranking performance on the public benchmarks BRATS 2015 and ISLES 2015. Our method is computationally efficient, which allows its adoption in a variety of research and clinical settings. The source code of our implementation is made publicly available.

Impaired Nitric Oxide Mediated Vasodilation In The Peripheral Circulation In The R6/2 Mouse Model Of Huntington's Disease.

Recent evidence shows that the Huntington's disease (HD) extends beyond the nervous system to other sites, including the cardiovascular system. Further, the cardiovascular pathology pre-dates neurological decline, however the mechanisms involved remain unclear. We investigated in the R6/2 mouse model of HD nitric oxide (NO) dependent and independent endothelial mechanisms. Femoral artery reactivity was determined by wire myography in wild type (WT) and R6/2 mice at 12 and 16 weeks of adulthood. WT mice showed increased endothelial relaxation between 12 and 16 weeks (Rmax: 72 ± 7% vs. 97 ± 13%, P < 0.05). In contrast, R6/2 mice showed enhanced endothelial relaxation already by 12 weeks (Rmax at 12w: 72 ± 7% vs. 94 ± 5%, WT vs. R6/2, P < 0.05) that declined by 16 weeks compared with WT mice (Rmax at 16w: 97 ± 13% vs. 68 ± 7%, WT vs. R6/2, P < 0.05). In WT mice, the increase in femoral relaxation between 12 and 16 weeks was due to enhanced NO dependent mechanisms. By 16 weeks of adult age, the R6/2 mouse developed overt endothelial dysfunction due to an inability to increase NO dependent vasodilation. The data add to the growing literature of non-neural manifestations of HD and implicate NO depletion as a key mechanism underlying the HD pathophysiology in the peripheral vasculature.

Divergence of mechanistic pathways mediating cardiovascular aging and developmental programming of cardiovascular disease.

Aging and developmental programming are both associated with oxidative stress and endothelial dysfunction, suggesting common mechanistic origins. However, their interrelationship has been little explored. In a rodent model of programmed cardiovascular dysfunction we determined endothelial function and vascular telomere length in young (4 mo) and aged (15 mo) adult offspring of normoxic or hypoxic pregnancy with or without maternal antioxidant treatment. We show loss of endothelial function [maximal arterial relaxation to acetylcholine (71 ± 3 vs. 55 ± 3%) and increased vascular short telomere abundance (4.2-1.3 kb) 43.0 ± 1.5 vs. 55.1 ± 3.8%) in aged vs. young offspring of normoxic pregnancy (P < 0.05). Hypoxic pregnancy in young offspring accelerated endothelial dysfunction (maximal arterial relaxation to acetylcholine: 42 ± 1%, P < 0.05) but this was dissociated from increased vascular short telomere length abundance. Maternal allopurinol rescued maximal arterial relaxation to acetylcholine in aged offspring of normoxic or hypoxic pregnancy but not in young offspring of hypoxic pregnancy. Aged offspring of hypoxic allopurinol pregnancy compared with aged offspring of untreated hypoxic pregnancy had lower levels of short telomeres (vascular short telomere length abundance 35.1 ± 2.5 vs. 48.2 ± 2.6%) and of plasma proinflammatory chemokine (24.6 ± 2.8 vs. 36.8 ± 5.5 pg/ml, P < 0.05). These data provide evidence for divergence of mechanistic pathways mediating cardiovascular aging and developmental programming of cardiovascular disease, and aging being decelerated by antioxidants even prior to birth.-Allison, B. J., Kaandorp, J. J., Kane, A. D., Camm, E. J., Lusby, C., Cross, C. M., Nevin-Dolan, R., Thakor, A. S., Derks, J. B., Tarry-Adkins, J. L., Ozanne, S. E., Giussani, D. A. Divergence of mechanistic pathways mediating cardiovascular aging and developmental programming of cardiovascular disease.

Recognition and management of sepsis by junior doctors.

There is growing evidence that outcomes in sepsis are improved by early recognition and treatment. In this study, we assessed junior doctors' ability to recognise and manage sepsis. We also explored junior doctors' perceptions regarding barriers to delivering timely sepsis care. From 46 respondents, only 4% were able to list the systemic inflammatory response syndrome (SIRS) criteria, 50% could define sepsis and 46% could list the Sepsis Six. Following further teaching on sepsis, 35% could list the SIRS criteria, 87% correctly defined sepsis, and 91% could state the Sepsis Six. Junior doctors perceived time pressure when on call to be the greatest barrier in treating sepsis, and their own knowledge to be the least important barrier. Our data suggest that knowledge of sepsis among junior doctors is poor and that there is a lack of insight into this competency gap.

Induction of controlled hypoxic pregnancy in large mammalian species.

Progress in the study of pregnancy complicated by chronic hypoxia in large mammals has been held back by the inability to measure long-term significant reductions in fetal oxygenation at values similar to those measured in human pregnancy complicated by fetal growth restriction. Here, we introduce a technique for physiological research able to maintain chronically instrumented maternal and fetal sheep for prolonged periods of gestation under significant and controlled isolated chronic hypoxia beyond levels that can be achieved by habitable high altitude. This model of chronic hypoxia permits measurement of materno-fetal blood gases as the challenge is actually occurring. Chronic hypoxia of this magnitude and duration using this model recapitulates the significant asymmetric growth restriction, the pronounced cardiomyopathy, and the loss of endothelial function measured in offspring of high-risk pregnancy in humans, opening a new window of therapeutic research.

The burden of sepsis in the Emergency Department: an observational snapshot.

The primary aim of our study was to establish what proportion of patients in the Emergency Department (ED) fulfill the criteria for sepsis. All adult patients presenting to ED in two 1-week periods, 6 months apart, were included. Notes were reviewed retrospectively to identify which patients fulfilled the criteria for sepsis and severe sepsis. The proportion of patients with sepsis was 4.3% (95% confidence interval 3.3-5.2%) and the proportion with severe sepsis was 2.2% (95% confidence interval 1.5-2.8%). In conclusion our results suggest that sepsis is more common than previously reported and this represents a significant burden on ED.

Heart disease link to fetal hypoxia and oxidative stress.

The quality of the intrauterine environment interacts with our genetic makeup to shape the risk of developing disease in later life. Fetal chronic hypoxia is a common complication of pregnancy. This chapter reviews how fetal chronic hypoxia programmes cardiac and endothelial dysfunction in the offspring in adult life and discusses the mechanisms via which this may occur. Using an integrative approach in large and small animal models at the in vivo, isolated organ, cellular and molecular levels, our programmes of work have raised the hypothesis that oxidative stress in the fetal heart and vasculature underlies the mechanism via which prenatal hypoxia programmes cardiovascular dysfunction in later life. Developmental hypoxia independent of changes in maternal nutrition promotes fetal growth restriction and induces changes in the cardiovascular, metabolic and endocrine systems of the adult offspring, which are normally associated with disease states during ageing. Treatment with antioxidants of animal pregnancies complicated with reduced oxygen delivery to the fetus prevents the alterations in fetal growth, and the cardiovascular, metabolic and endocrine dysfunction in the fetal and adult offspring. The work reviewed offers both insight into mechanisms and possible therapeutic targets for clinical intervention against the early origin of cardiometabolic disease in pregnancy complicated by fetal chronic hypoxia.

Xanthine oxidase and the fetal cardiovascular defence to hypoxia in late gestation ovine pregnancy.

Hypoxia is a common challenge to the fetus, promoting a physiological defence to redistribute blood flow towards the brain and away from peripheral circulations. During acute hypoxia, reactive oxygen species (ROS) interact with nitric oxide (NO) to provide an oxidant tone. This contributes to the mechanisms redistributing the fetal cardiac output, although the source of ROS is unknown. Here, we investigated whether ROS derived from xanthine oxidase (XO) contribute to the fetal peripheral vasoconstrictor response to hypoxia via interaction with NO-dependent mechanisms. Pregnant ewes and their fetuses were surgically prepared for long-term recording at 118 days of gestation (term approximately 145 days). After 5 days of recovery, mothers were infused i.v. for 30 min with either vehicle (n = 11), low dose (30 mg kg(-1), n = 5) or high dose (150 mg kg(-1), n = 9) allopurinol, or high dose allopurinol with fetal NO blockade (n = 6). Following allopurinol treatment, fetal hypoxia was induced by reducing maternal inspired O2 such that fetal basal P aO 2 decreased approximately by 50% for 30 min. Allopurinol inhibited the increase in fetal plasma uric acid and suppressed the fetal femoral vasoconstrictor, glycaemic and lactate acidaemic responses during hypoxia (all P < 0.05), effects that were restored to control levels with fetal NO blockade. The data provide evidence for the activation of fetal XO in vivo during hypoxia and for XO-derived ROS in contributing to the fetal peripheral vasoconstriction, part of the fetal defence to hypoxia. The data are of significance to the understanding of the physiological control of the fetal cardiovascular system during hypoxic stress. The findings are also of clinical relevance in the context of obstetric trials in which allopurinol is being administered to pregnant women when the fetus shows signs of hypoxic distress.

Statins prevent adverse effects of postnatal glucocorticoid therapy on the developing brain in rats.

BACKGROUND: Postnatal glucocorticoid therapy in the treatment of chronic lung disease benefits lung function, however it adversely affects brain development. We hypothesized that combined postnatal glucocorticoid and statin therapy diminishes adverse effects of glucocorticoids on the developing brain. METHODS: On postnatal days (P) 1-3, one male pup per litter received i.p. injections of saline control (C), n = 13) or dexamethasone (0.5, 0.3, 0.1 µg/g; D, n = 13), ± pravastatin (10 mg/kg i.p.; CP, n = 12; DP, n = 15). Statins or saline continued from P4-6. At P21, brains were perfusion fixed for histological and stereological analyses. RESULTS: Relative to controls, dexamethasone reduced total (837 ± 23 vs. 723 ± 37), cortical (378 ± 12 vs. 329 ± 15), and deep gray matter (329 ± 12 vs. 284 ± 15) volume (mm(3)), cortical neuronal number (23 ± 1 vs. 19 ± 1 × 10(6)), and hippocampal neuronal soma volume (CA1: 1,206 ± 32 vs. 999 ± 32; dentate gyrus: 679 ± 28 vs. 542 ± 24 µm(3); all P < 0.05). Dexamethasone increased the glial fibrillary acidic protein-positive astrocyte density in the white matter (96 ± 2 vs. 110 ± 4/0.1 mm(2)); P < 0.05. These effects no longer occurred in brains from pups treated with combined dexamethasone and pravastatin. Pravastatin alone had no effect on these variables. CONCLUSION: Concomitant dexamethasone with statins in premature infants may be safer for the developing brain than dexamethasone alone in the treatment of chronic lung disease.

Vitamin C prevents intrauterine programming of in vivo cardiovascular dysfunction in the rat.

BACKGROUND: Fetal hypoxia is common and in vitro evidence supports its role in the programming of adult cardiovascular dysfunction through the generation of oxidative stress. Whether fetal chronic hypoxia programmes alterations in cardiovascular control in vivo, and if these alterations can be prevented by antioxidant treatment, is unknown. This study investigated the effects of prenatal fetal hypoxia, with and without maternal supplementation with vitamin C, on basal and stimulated cardiovascular function in vivo in the adult offspring at 4 months of age in the rat. METHODS AND RESULTS: From days 6 to 20 of pregnancy, Wistar rats were subjected to Normoxia, Hypoxia (13% O2), Hypoxia+Vitamin C (5mg/ml in drinking water) or Normoxia+Vitamin C. At 4 months, male offspring were instrumented under urethane anaesthesia. Basal mean arterial blood pressure, heart rate and heart rate variability (HRV) were assessed, and stimulated baroreflex curves were generated with phenylephrine and sodium nitroprusside. Chronic fetal hypoxia increased the LF/HF HRV ratio and baroreflex gain, effects prevented by vitamin C administration during pregnancy. CONCLUSIONS: Chronic intrauterine hypoxia programmes cardiovascular dysfunction in vivo in adult rat offspring; effects ameliorated by maternal treatment with vitamin C. The data support a role for fetal chronic hypoxia programming cardiovascular dysfunction in the adult rat offspring in vivo through the generation of oxidative stress in utero.

Maternal-to-fetal allopurinol transfer and xanthine oxidase suppression in the late gestation pregnant rat.

Fetal brain hypoxic injury remains a concern in high-risk delivery. There is significant clinical interest in agents that may diminish neuronal damage during birth asphyxia, such as in allopurinol, an inhibitor of the prooxidant enzyme xanthine oxidase. Here, we established in a rodent model the capacity of allopurinol to be taken up by the mother, cross the placenta, rise to therapeutic levels, and suppress xanthine oxidase activity in the fetus. On day 20 of pregnancy, Wistar dams were given 30 or 100 mg kg(-1) allopurinol orally. Maternal and fetal plasma allopurinol and oxypurinol concentrations were measured, and xanthine oxidase activity in the placenta and maternal and fetal tissues determined. There were significant strong positive correlations between maternal and fetal plasma allopurinol (r = 0.97, P < 0.05) and oxypurinol (r = 0.88, P < 0.05) levels. Under baseline conditions, maternal heart (2.18 ± 0.62 mU mg(-1)), maternal liver (0.29 ± 0.08 mU mg(-1)), placenta (1.36 ± 0.42 mU mg(-1)), fetal heart (1.64 ± 0.59 mU mg(-1)), and fetal liver (0.14 ± 0.08 mU mg(-1)) samples all showed significant xanthine oxidase activity. This activity was suppressed in all tissues 2 h after allopurinol administration and remained suppressed 24 h later (P < 0.05), despite allopurinol and oxypurinol levels returning toward baseline. The data establish a mammalian model of xanthine oxidase inhibition in the mother, placenta, and fetus, allowing investigation of the role of xanthine oxidase-derived reactive oxygen species in the maternal, placental, and fetal physiology during healthy and complicated pregnancy.